Tara I. Chang

All Publications

• Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney international Cheung, A. K., Chang, T. I., Cushman, W. C., Furth, S. L., Hou, F. F., Ix, J. H., Knoll, G. A., Muntner, P., Pecoits-Filho, R., Sarnak, M. J., Tobe, S. W., Tomson, C. R., Lytvyn, L., Craig, J. C., Tunnicliffe, D. J., Howell, M., Tonelli, M., Cheung, M., Earley, A., Mann, J. F. 2021; 99 (3): 559–69

  Abstract

  The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mmHg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

  View details for DOI 10.1016/j.kint.2020.10.026

  View details for PubMedID 33637203

• Potential implications of the 2021 KDIGO blood pressure guideline for adults with chronic kidney disease in the United States. Kidney international Foti, K. E., Wang, D., Chang, A. R., Selvin, E., Sarnak, M. J., Chang, T. I., Muntner, P., Coresh, J. 2021; 99 (3): 686–95

  Abstract

  The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease (CKD) recommends a target systolic blood pressure under 120 mmHg based on standardized office blood pressure measurement. Here, we examined the potential implications of this new guideline for blood pressure lowering with antihypertensive medication among adults in the United States with CKD compared to the 2012 KDIGO guideline (target blood pressure 130/80 mmHg or under with albuminuria or 140/90 mmHg or under without albuminuria) and the 2017 American College of Cardiology/American Heart Association (target blood pressure under 130/80 mmHg) guideline. Additionally, we determined implications of the 2021 KDIGO guideline for angiotensin converting enzyme inhibitor (ACEi) or angiotensin II-receptor blocker (ARB) use for those with albuminuria (recommended at systolic blood pressure of 120 mmHg or over) compared to the 2012 KDIGO guideline (recommended at blood pressures over 130/80 mmHg). Data were analyzed from 1,699 adults with CKD (estimated glomerular filtration rate 15-59 ml/min/1.73m2 or a urinary albumin-to-creatinine ratio of 30 mg/g or more) in the 2015-2018 National Health and Nutrition Examination Survey and averaged up to three standardized blood pressure measurements. Among adults with CKD, 69.5% were eligible for blood pressure lowering according to the 2021 KDIGO guideline, compared with 49.8% as per 2012 KDIGO or 55.6% as per 2017 American College of Cardiology/American Heart Association guidelines. Among those with albuminuria, 78.2% were eligible for ACEi/ARB use by the 2021 KDIGO guideline compared with 71.0% by the 2012 KDIGO guideline. However, only 39.1% were taking an ACEi/ARB. Thus, our findings highlight opportunities to improve blood pressure management and reduce cardiovascular risk among adults in the United States with CKD.

  View details for DOI 10.1016/j.kint.2020.12.019

  View details for PubMedID 33637204

• Kidney Case Conference Series: How We Manage Hypertension in a Patient with a Recent Stroke. Clinical journal of the American Society of Nephrology : CJASN Chang, T. I., Bhalla, V. 2020

  View details for DOI 10.2215/CJN.00030120

  View details for PubMedID 32393466

• Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference KIDNEY INTERNATIONAL Cheung, A. K., Chang, T., Cushman, W. C., Furth, S. L., Ix, J. H., Pecoits-Filho, R., Perkovic, V., Sarnak, M. J., Tobe, S. W., Tomson, C. R., Cheung, M., Wheeler, D. C., Winkelmayer, W. C., Mann, J. E., Bakris, G. L., Damasceno, A., Dwyer, J. P., Fried, L. F., Haynes, R., Hirawa, N., Holdaas, H., Ibrahim, H. N., Ingelfinger, J. R., Iseki, K., Khwaja, A., Kimmel, P. L., Kovesdy, C. P., Ku, E., Lerma, E., Luft, F. C., Lv, J., McFadden, C. B., Muntner, P., Myers, M. G., Navaneethan, S. D., Parati, G., Peixoto, A. J., Prasad, R., Rahman, M., Rocco, M., Saad Rodrigues, C., Roger, S. D., Stergiou, G. S., Tomlinson, L. A., Tonelli, M., Toto, R. D., Tsukamoto, Y., Walker, R., Wang, A., Wang, J., Warady, B. A., Whelton, P. K., Williamson, J. D. 2019; 95 (5): 1027–36

  View details for DOI 10.1016/j.kint.2018.12.025

  View details for Web of Science ID 000465213400009

• KDOQI US Commentary on the 2017 ACC/AHA Hypertension Guideline. American journal of kidney diseases : the official journal of the National Kidney Foundation Kramer, H. J., Townsend, R. R., Griffin, K., Flynn, J. T., Weiner, D. E., Rocco, M. V., Choi, M. J., Weir, M. R., Chang, T. I., Agarwal, R., Beddhu, S. 2019; 73 (4): 437–58

  Abstract

  Hypertension is a modifiable risk factor for cardiovascular morbidity and mortality and reduction of elevated blood pressure (BP) remains an important intervention for slowing kidney disease progression. Over the past decade, the most appropriate BP target for initiation and titration of BP-lowering medications has been an area of intense research and debate within the clinical community. In 2017, the American College of Cardiology and the American Heart Association (ACC/AHA) in conjunction with several other professional societies released new hypertension guidelines based on data from a systematic review of clinical trials and observational data. While many of the recommendations in the ACC/AHA hypertension guideline are relevant to nephrology practice, BP targets and management strategies for patients receiving dialysis are not discussed. This Kidney Disease Outcomes Quality Initiative (KDOQI) commentary focuses largely on recommendations from the ACC/AHA hypertension guidelines that are pertinent to individuals at risk of chronic kidney disease or with non-dialysis-dependent chronic kidney disease. This KDOQI commentary also includes a brief discussion of the consensus statement regarding hypertension diagnosis and management for adults receiving maintenance dialysis published by the European Renal and Cardiovascular Medicine Working Group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension. Overall, we support the vast majority of the ACC/AHA recommendations and highlight select areas in which best diagnosis and treatment options remain controversial.

  View details for DOI 10.1053/j.ajkd.2019.01.007

  View details for PubMedID 30905361

• Ultrafiltration rate and incident atrial fibrillation among older individuals initiating hemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Flythe, J. E., Liu, S., Montez-Rath, M. E., Winkelmayer, W. C., Chang, T. I. 2021

  Abstract

  BACKGROUND: Higher ultrafiltration (UF) rates are associated with numerous adverse cardiovascular outcomes among individuals receiving maintenance hemodialysis. We undertook this study to investigate the association of UF rate and incident atrial fibrillation in a large, nationally representative US cohort of incident, older hemodialysis patients.METHODS: We used the US Renal Data System linked to the records of a large dialysis provider to identify individuals ≥67years of age initiating hemodialysis between January 2006 and December 2011. We applied an extended Cox model as a function of a time-varying exposure to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of delivered UF rate and incident atrial fibrillation.RESULTS: Among the 15414 individuals included in the study, 3177 developed atrial fibrillation. In fully adjusted models, a UF rate >13mL/h/kg (versus ≤13mL/h/kg) was associated with a higher hazard of incident atrial fibrillation [adjusted HR 1.19 (95% CI 1.07-1.30)]. Analyses using lower UF rate thresholds (≤10 versus >10mL/h/kg and ≤8 versus >8mL/h/kg, separately) yielded similar results. Analyses specifying the UF rate as a cubic spline (per 1mL/h/kg) confirmed an approximately linear dose-response relationship between the UF rate and the risk of incident atrial fibrillation: risk began at UF rates of ~6mL/h/kg and the magnitude of this risk flattened, but remained elevated, at rates ≥9mL/h/kg.CONCLUSION: In this observational study of older individuals initiating hemodialysis, higher UF rates were associated with higher incidences of atrial fibrillation.

  View details for DOI 10.1093/ndt/gfaa332

  View details for PubMedID 33561218

• Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. The Lancet. Respiratory medicine Cohen, J. B., Hanff, T. C., William, P., Sweitzer, N., Rosado-Santander, N. R., Medina, C., Rodriguez-Mori, J. E., Renna, N., Chang, T. I., Corrales-Medina, V., Andrade-Villanueva, J. F., Barbagelata, A., Cristodulo-Cortez, R., Diaz-Cucho, O. A., Spaak, J., Alfonso, C. E., Valdivia-Vega, R., Villavicencio-Carranza, M., Ayala-Garcia, R. J., Castro-Callirgos, C. A., Gonzalez-Hernandez, L. A., Bernales-Salas, E. F., Coacalla-Guerra, J. C., Salinas-Herrera, C. D., Nicolosi, L., Basconcel, M., Byrd, J. B., Sharkoski, T., Bendezu-Huasasquiche, L. E., Chittams, J., Edmonston, D. L., Vasquez, C. R., Chirinos, J. A. 2021

  Abstract

  BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19.METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009.FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; beta-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (chi2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups.INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19.FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

  View details for DOI 10.1016/S2213-2600(20)30558-0

  View details for PubMedID 33422263

• Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights from the CREDENCE Trial. Circulation Ye, N., Jardine, M. J., Oshima, M., Hockham, C., Heerspink, H. J., Agarwal, R., Bakris, G., Schutte, A. E., Arnott, C., Chang, T. I., Górriz, J. L., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Levin, A., Mahaffey, K. W., Neal, B., Pollock, C., Wheeler, D. C., Di Tanna, G. L., Cheng, H., Perkovic, V., Neuen, B. L. 2021

  Abstract

  Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown. Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo. Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4,401 participants of whom 3,361 (76.4%) had baseline systolic BP ≥130 mmHg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50mmHg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 0.70, 95% CI 0.59-0.82) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥0.35), as were effects on other key kidney, cardiovascular and safety outcomes. Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT02065791.

  View details for DOI 10.1161/CIRCULATIONAHA.120.048740

  View details for PubMedID 33554616

• Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial. American heart journal Sarraju, A., Li, J., Cannon, C. P., Chang, T. I., Agarwal, R., Bakris, G., Charytan, D. M., de Zeeuw, D., Greene, T., Heerspink, H. J., Levin, A., Neal, B., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Perkovic, V., Jardine, M., Mahaffey, K. W. 2020

  Abstract

  We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P<0.001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >0.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

  View details for DOI 10.1016/j.ahj.2020.12.008

  View details for PubMedID 33358942

• Intradialytic Hypotension and Newly Recognized Peripheral Artery Disease in Patients Receiving Hemodialysis. American journal of kidney diseases : the official journal of the National Kidney Foundation Seong, E. Y., Liu, S., Song, S. H., Leeper, N. J., Winkelmayer, W. C., Montez-Rath, M. E., Chang, T. I. 2020

  Abstract

  RATIONALE & OBJECTIVE: Intradialytic hypotension (IDH) may decrease systemic circulation to the legs, exacerbating symptoms of peripheral artery disease (PAD). We sought to evaluate the relationship between IDH and newly recognized lower extremity PAD among hemodialysis patients STUDY DESIGN: Retrospective cohort study.SETTING & PARTICIPANTS: Linking the data from USRDS to the electronic health records of a large dialysis provider, we identified adults patients (≥18 years) with Medicare Parts A and B who initiated dialysis (2006-2011) without previously recognized PAD.EXPOSURE: Time-varying proportion of hemodialysis sessions with IDH defined as nadir intradialytic systolic blood pressure <90 mmHg. We categorized the proportion of sessions with IDH within serial 30-day intervals as 0%, >0-<15%, 15-<30%, and ≥30%.OUTCOME: Newly recognized PAD, ascertained using PAD diagnosis codes and procedure codes for amputation or revascularization, in serial 30-day intervals subsequent to each 30-day exposure interval.ANALYTIC APPROACH: To account for the competing risks of death and kidney transplantation, we estimated unadjusted and adjusted sub-distribution hazard ratios using the Kaplan-Meier multiple imputation method in combination with the extended Cox model to account for IDH as a time-varying exposure.RESULTS: Among 45,591 patients, those with more frequent baseline IDH had a higher prevalence of cardiovascular diseases. During 61,725 person-years of follow-up, 7,886 patients had newly recognized PAD. We found a graded, direct association of IDH with newly recognized PAD. For example, having IDH in ≥30% of dialysis sessions during a given 30-day interval (versus 0%) was associated with a 24% higher hazard of having newly recognized PAD (95% CI, 17% to 32%) in the subsequent 30 days.LIMITATIONS: Unmeasured confounding; ascertainment of PAD from claims CONCLUSIONS: Patients receiving hemodialysis who had more frequent IDH had higher rates of newly recognized PAD. Patients with frequent IDH may warrant careful examination for PAD.

  View details for DOI 10.1053/j.ajkd.2020.10.012

  View details for PubMedID 33316351

• Factors Associated With Failure to Achieve the Intensive Blood Pressure Target in the Systolic Blood Pressure Intervention Trial (SPRINT). Hypertension (Dallas, Tex. : 1979) Wang, K. M., Stedman, M. R., Chertow, G. M., Chang, T. I. 2020: HYPERTENSIONAHA12016155

  Abstract

  SPRINT (Systolic Blood Pressure Intervention Trial) found that randomization of nondiabetic participants at high cardiovascular risk to an intensive (systolic blood pressure [SBP] <120 mm Hg) versus standard (SBP <140 mm Hg) target resulted in 25% risk reduction in the first cardiovascular composite event (ie, cardiovascular death or nonfatal myocardial infarction, stroke, or hospitalization for heart failure) and a 27% risk reduction in all-cause mortality. In this post hoc analysis, we sought to determine the factors associated with failure to achieve the SBP target in 4678 SPRINT participants randomized to the intensive treatment group. Using a generalized estimating equation model, we assessed variables associated with failure to achieve the intensive SBP target as a repeated outcome collected during serial follow-up visits, including the occurrence of serious adverse events. In the multivariable model adjusted for baseline demographic, clinical, and laboratory variables, older age, higher SBP, underlying chronic kidney disease, higher number of antihypertensives, and moderate cognitive impairment at screening were associated with failure to achieve the intensive SBP target. Occurrence of a serious adverse event during the trial was associated with 20% higher odds of failure to achieve the SBP target. Participants of Hispanic ethnicity had 47% lower odds of failure to achieve the intensive SBP target relative to non-Hispanic Whites. Understanding barriers to achieving intensive SBP targets should allow clinicians to optimize management of hypertension in patients at high risk for cardiovascular disease.

  View details for DOI 10.1161/HYPERTENSIONAHA.120.16155

  View details for PubMedID 33131314

• Independent predictors of heart failure in patients with type 2 diabetes and chronic kidney disease: modeling from the CREDENCE trial Mahaffey, K. W., Li, J., Chang, T., Sarraju, A., Agarwal, R., Charytan, D. M., Greene, T., Heerspink, H. L., Levin, A., Neal, B., Pollock, C., Yavin, Y., Jardine, M., Perkovic, Cannon, G. P. OXFORD UNIV PRESS. 2020: 1175

  View details for Web of Science ID 000606106301178

• The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial de Zeeuw, D., Arnott, C., Li, J., Cannon, C. P., Neuen, B. L., Heerspink, H. L., Neal, B., Charytan, D. M., Bakris, G., Chang, T., Rosenthal, N., Zinman, B., Perkovic, V., Jardine, M. J., Mahaffey, K. W. SPRINGER. 2020: S61–S62

  View details for Web of Science ID 000565776600123

• Does really central venous pressure affect the risk of diuretic-associated acute kidney injury after cardiac surgery? American heart journal McCoy, I., Montez-Rath, M., Chertow, G., Chang, T. 2020; 226: 252

  View details for DOI 10.1016/j.ahj.2020.04.002

  View details for PubMedID 32811639

• Outcomes Among Patients With Left Ventricular Assist Devices Receiving Maintenance Outpatient Hemodialysis: A Case Series. American journal of kidney diseases : the official journal of the National Kidney Foundation Franz, D. D., Hussein, W. F., Abra, G., Diskin, C. D., Duggal, V., Teuteberg, J. J., Chang, T. I., Schiller, B. 2020

  Abstract

  RATIONALE & OBJECTIVE: The incidence of left ventricular assist device (LVAD) implantation as destination therapy for heart failure is increasing and kidney failure requiring maintenance hemodialysis is a common complication. As little is known about the safety or efficacy of outpatient hemodialysis among patients with LVADs, this study sought to describe their clinical course.STUDY DESIGN: Case series of patients with a LVAD undergoing maintenance outpatient hemodialysis whose clinical data were obtained from an electronic medical record.SETTING & PARTICIPANTS: Adults who received an LVAD, survived to hospital discharge, and were subsequently treated with maintenance hemodialysis by a non-profit dialysis provider between 2011 and 2019.RESULTS: Eleven patients were included. Six had a known prior history of chronic kidney disease. Patients underwent outpatient hemodialysis for a mean duration of 165.2 days (range 31-542) during which they were treated with 544 total dialysis sessions. Six of these sessions were stopped early due to dialysis-related adverse events (1.1%). Over 80% of follow-up time was spent out of hospital, however, 54.5% of patients were rehospitalized within one month of starting outpatient hemodialysis. The most common reason for hospitalization was infection (32.1%), followed by hypervolemia (14.3%), and cerebrovascular accident (CVA) or transient ischemic attack (TIA) (10.7%). Four patients recovered kidney function, one underwent combined heart and kidney transplantation, two continued treatment, two died, and two were lost to follow-up.LIMITATIONS: Retrospective design, small number of cases, and lack of complete follow-up data.CONCLUSIONS: Approximately half of the patients with complete follow-up either recovered kidney function or underwent combined heart and kidney transplantation. This case series demonstrates that outpatient hemodialysis centers, in partnership with LVAD treatment teams, can successfully provide hemodialysis to patients on LVAD support.

  View details for DOI 10.1053/j.ajkd.2020.04.018

  View details for PubMedID 32711070

• A Call for a New Paradigm for Diabetes Care in the Era of Sodium-Glucose Cotransporter2 Inhibitors (SGLT2i). Cardiology and therapy Kim, S. H., Chang, T. I., Mahaffey, K. W. 2020

  Abstract

  In 2013, canagliflozin was the first sodium-glucose cotransporter2 inhibitor (SGLT2i) approved by the US Food and Drug Administration for the treatment of type2 diabetes (T2DM). Today, there are four SGLT2i approved for T2DM, and some SGLT2i have been approved for indications beyond glucose control. For example, SGLT2i reduce major adverse clinical events (MACE) including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (canagliflozin); cardiovascular death (empagliflozin, dapagliflozin); diabetic kidney disease progression (canagliflozin); and heart failure hospitalization (canagliflozin, dapagliflozin). However, despite the potential benefits of SGLT2i in reducing adverse clinical events, providers underprescribe SGLT2i for eligible patients. Thus, we propose the CKD-PCP framework which allows multiple providers to utilize the benefits of SGLT2i. CKD-PCP has dual meaning: it applies to providers who most often care for patients with T2DM (Cardiologists, Kidney specialists, Diabetologists, and Primary Care Physicians) and it refers to the benefits of SGLT2i (treatment of Cardiovascular disease, Kidney disease, Diabetes, and reduction of blood Pressure, Calories, and Plasma volume). This article is based on previously conducted studies and the authors disclosetheir roles in relevant trialsin the Acknowledgements.

  View details for DOI 10.1007/s40119-020-00190-7

  View details for PubMedID 32661684

• Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference KIDNEY INTERNATIONAL Flythe, J. E., Chang, T. I., Gallagher, M. P., Lindley, E., Madero, M., Sarafidis, P. A., Unruh, M. L., Wang, A., Weiner, D. E., Cheung, M., Jadoul, M., Winkelmayer, W. C., Polkinghorne, K. R. 2020; 97 (5): 861–76

  View details for Web of Science ID 000530724500012

• CANAGLIFLOZIN (CANA) REDUCES CARDIOVASCULAR (CV) AND RENAL EVENTS INDEPENDENT OF BASELINE HEART FAILURE (HF): A CREDENCE SECONDARY ANALYSIS Sarraju, A., Li, J., Cannon, C. P., Chang, T. I., Agarwal, R., Bakris, G. L., Charytan, D. M., de Zeeuw, D., Greene, T., Heerspink, H. L., Levin, A., Neal, B., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Perkovic, V., Jardine, M., Mahaffey, K. W. ELSEVIER SCIENCE INC. 2020: 1018

  View details for Web of Science ID 000522979101006

• Outcomes after left ventricular assist device implantation in patients with acute kidney injury JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Silver, S. A., Long, J., Zheng, Y., Goldstone, A. B., Franz, D., Chang, T. I., Chertow, G. M. 2020; 159 (2): 477-+

  View details for DOI 10.1016/j.jtcvs.2019.03.064

  View details for Web of Science ID 000507380200052

• Effect of Intensive Blood Pressure Lowering on the Risk of Atrial Fibrillation. Hypertension (Dallas, Tex. : 1979) Soliman, E. Z., Rahman, A. F., Zhang, Z. M., Rodriguez, C. J., Chang, T. I., Bates, J. T., Ghazi, L., Blackshear, J. L., Chonchol, M., Fine, L. J., Ambrosius, W. T., Lewis, C. E. 2020: HYPERTENSIONAHA12014766

  Abstract

  It remains uncertain whether intensive control of blood pressure (BP) results in a lower risk of atrial fibrillation (AF) in patients with hypertension. Using data from SPRINT (Systolic Blood Pressure Intervention Trial), which enrolled participants with hypertension at increased risk of cardiovascular disease, we examined whether intensive BP lowering (target systolic BP [SBP] <120 mm Hg), compared with standard BP lowering (target SBP<140 mm Hg), results in a lower risk of AF. This analysis included 8022 participants (4003 randomized to the intensive arm and 4019 to standard BP arm) who were free of AF at the time of enrollment and with available baseline and follow-up electrocardiographic data. AF was ascertained from standard 12-lead electrocardiograms recorded at biannual study examinations and an exit visit. During up to 5.2 years of follow-up and a total of 28 322 person-years, 206 incident AF cases occurred; 88 in the intensive BP-lowering arm and 118 in the standard BP-lowering arm. Intensive BP lowering was associated with a 26% lower risk of developing new AF (hazard ratio, 0.74 [95% CI, 0.56-0.98]; P=0.037). This effect was consistent among prespecified subgroups of SPRINT participants stratified by age, sex, race, SBP tertiles, prior cardiovascular disease, and prior chronic kidney disease when interactions between treatment effect and these subgroups were assessed using Hommel adjusted P values. In conclusion, intensive treatment to a target of SBP <120 mm Hg in patients with hypertension at high risk of cardiovascular disease has the potential to reduce the risk of AF. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

  View details for DOI 10.1161/HYPERTENSIONAHA.120.14766

  View details for PubMedID 32362229

• Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol. Journal of clinical hypertension (Greenwich, Conn.) Cohen, J. B., Hanff, T. C., Corrales-Medina, V., William, P., Renna, N., Rosado-Santander, N. R., Rodriguez-Mori, J. E., Spaak, J., Andrade-Villanueva, J., Chang, T. I., Barbagelata, A., Alfonso, C. E., Bernales-Salas, E., Coacalla, J., Castro-Callirgos, C. A., Tupayachi-Venero, K. E., Medina, C., Valdivia, R., Villavicencio, M., Vasquez, C. R., Harhay, M. O., Chittams, J., Sharkoski, T., Byrd, J. B., Edmonston, D. L., Sweitzer, N., Chirinos, J. A. 2020

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.

  View details for DOI 10.1111/jch.14011

  View details for PubMedID 32937008

• Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international Flythe, J. E., Chang, T. I., Gallagher, M. P., Lindley, E., Madero, M., Sarafidis, P. A., Unruh, M. L., Wang, A. Y., Weiner, D. E., Cheung, M., Jadoul, M., Winkelmayer, W. C., Polkinghorne, K. R. 2020

  Abstract

  Blood pressure (BP) and volume control are critical components of dialysis care and have substantial impacts on patient symptoms, quality of life, and cardiovascular complications. Yet, developing consensus best practices for BP and volume control have been challenging, given the absence of objective measures of extracellular volume status and the lack of high-quality evidence for many therapeutic interventions. In February of 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference titled Blood Pressure and Volume Management in Dialysis to assess the current state of knowledge related to BP and volume management and identify opportunities to improve clinical and patient-reported outcomes among individuals receiving maintenance dialysis. Four major topics were addressed: BP measurement, BP targets, and pharmacologic management of suboptimal BP; dialysis prescriptions as they relate to BP and volume; extracellular volume assessment and management with a focus on technology-based solutions; and volume-related patient symptoms and experiences. The overarching theme resulting from presentations and discussions was that managing BP and volume in dialysis involves weighing multiple clinical factors and risk considerations as well as patient lifestyle and preferences, all within a narrow therapeutic window for avoiding acute or chronic volume-related complications. Striking this challenging balance requires individualizing the dialysis prescription by incorporating comorbid health conditions, treatment hemodynamic patterns, clinical judgment, and patient preferences into decision-making, all within local resource constraints.

  View details for DOI 10.1016/j.kint.2020.01.046

  View details for PubMedID 32278617

• Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international Marwick, T. H., Amann, K., Bangalore, S., Cavalcante, J. L., Charytan, D. M., Craig, J. C., Gill, J. S., Hlatky, M. A., Jardine, A. G., Landmesser, U., Newby, L. K., Herzog, C. A., Cheung, M., Wheeler, D. C., Winkelmayer, W. C., Sarnak, M. J., Conference Participants, Banerjee, D., Briguori, C., Chang, T. I., Chen, C., deFilippi, C. R., Ding, X., Ferro, C. J., Gill, J., Gossl, M., Isbel, N. M., Ishii, H., Jardine, M. J., Kalra, P. A., Laufer, G., Lentine, K. L., Lobdell, K. W., Lok, C. E., London, G. M., Malyszko, J., Mark, P. B., Marwan, M., Nie, Y., Parfrey, P. S., Pecoits-Filho, R., Pilmore, H., Qunibi, W. Y., Raggi, P., Rattazzi, M., Rossignol, P., Ruturi, J., Sabanayagam, C., Shanahan, C. M., Shroff, G. R., Shroff, R., Webster, A. C., Weiner, D. E., Winther, S., Wiseman, A. C., Yip, A., Zarbock, A. 2019; 96 (4): 836–49

  Abstract

  Chronic kidney disease (CKD) is a major risk factor for valvular heart disease (VHD). Mitral annular and aortic valve calcifications are highly prevalent in CKD patients and commonly lead to valvular stenosis and regurgitation, as well as complications including conduction system abnormalities and endocarditis. VHD, especially mitral regurgitation and aortic stenosis, is associated with significantly reduced survival among CKD patients. Knowledge related to VHD in the general population is not always applicable to CKD patients because the pathophysiology may be different, and CKD patients have a high prevalence of comorbid conditions and elevated risk for periprocedural complications and mortality. This Kidney Disease: Improving Global Outcomes (KDIGO) review of CKD and VHD seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of VHD in CKD by summarizing knowledge gaps, areas of controversy, and priorities for research.

  View details for DOI 10.1016/j.kint.2019.06.025

  View details for PubMedID 31543156

• Effect of Intensive and Standard Clinic-Based Hypertension Management on the Concordance Between Clinic and Ambulatory Blood Pressure and Blood Pressure Variability in SPRINT. Journal of the American Heart Association Ghazi, L., Pajewski, N. M., Rifkin, D. E., Bates, J. T., Chang, T. I., Cushman, W. C., Glasser, S. P., Haley, W. E., Johnson, K. C., Kostis, W. J., Papademetriou, V., Rahman, M., Simmons, D. L., Taylor, A., Whelton, P. K., Wright, J. T., Bhatt, U. Y., Drawz, P. E. 2019; 8 (14): e011706

  Abstract

  Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit-to-visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27-month follow-up visit and obtained a second reading in 203 participants 293±84days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland-Altman plots of -21 to 34mmHg in the intensive-treatment group and -26 to 32mmHg in the standard-treatment group. Overall, there was poor agreement between clinic visit-to-visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (-27 to 21mmHg) and the standard group (-23 to 20mmHg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

  View details for DOI 10.1161/JAHA.118.011706

  View details for PubMedID 31307270

• Association of Total Medication Burden With Intensive and Standard Blood Pressure Control and Clinical Outcomes: A Secondary Analysis of SPRINT. Hypertension (Dallas, Tex. : 1979) Derington, C. G., Gums, T. H., Bress, A. P., Herrick, J. S., Greene, T. H., Moran, A. E., Weintraub, W. S., Kronish, I. M., Morisky, D. E., Trinkley, K. E., Saseen, J. J., Reynolds, K., Bates, J. T., Berlowitz, D. R., Chang, T. I., Chonchol, M., Cushman, W. C., Foy, C. G., Herring, C. T., Katz, L. A., Krousel-Wood, M., Pajewski, N. M., Tamariz, L., King, J. B., SPRINT Research Group 2019: HYPERTENSIONAHA11912907

  Abstract

  Total medication burden (antihypertensive and nonantihypertensive medications) may be associated with poor systolic blood pressure (SBP) control. We investigated the association of baseline medication burden and clinical outcomes and whether the effect of the SBP intervention varied according to baseline medication burden in SPRINT (Systolic Blood Pressure Intervention Trial). Participants were randomized to intensive or standard SBP goal (below 120 or 140 mm Hg, respectively); n=3769 participants with high baseline medication burden (≥5 medications) and n=5592 with low burden (<5 medications). Primary outcome: differences in SBP. Secondary outcomes: 8-item Morisky Medication Adherence Scale and modified Treatment Satisfaction Questionnaire for Medications measured at baseline and 12 months and incident cardiovascular disease events and serious adverse events throughout the trial. Participants in the intensive group with high versus low medication burden were less likely to achieve their SBP goal at 12 months (risk ratio, 0.91; 95% CI, 0.85-0.97) but not in the standard group (risk ratio, 0.98; 95% CI, 0.93-1.03; Pinteraction<0.001). High medication burden was associated with increased cardiovascular disease events (hazard ratio, 1.39; 95% CI, 1.14-1.70) and serious adverse events (hazard ratio, 1.34; 95% CI, 1.24-1.45), but the effect of intensive versus standard treatment did not vary between medication burden groups ( Pinteraction>0.5). Medication burden had minimal association with adherence or satisfaction. High baseline medication burden was associated with worse intensive SBP control and higher rates of cardiovascular disease events and serious adverse events. The relative benefits and risks of intensive SBP goals were similar regardless of medication burden. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01206062.

  View details for DOI 10.1161/HYPERTENSIONAHA.119.12907

  View details for PubMedID 31256717

• Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy NEW ENGLAND JOURNAL OF MEDICINE Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019; 380 (24): 2295–2306

  View details for DOI 10.1056/NEJMoa1811744

  View details for Web of Science ID 000471299100008

• Comparison of routine and automated office blood pressure measurement. Blood pressure monitoring Cheng, R. Z., Bhalla, V., Chang, T. I. 2019

  Abstract

  OBJECTIVES: From April to October 2018, we implemented a blood pressure measurement quality improvement project at our Hypertension Center. We aimed to compare blood pressure measured using routine, non-standardized office blood pressure and Systolic Blood Pressure Intervention Trial-like automated office blood pressure protocols.METHODS: In 202 consecutive patients, we measured blood pressure using routine clinic methods and an automated office blood pressure protocol (5min of rest followed by three blood pressure measurements at 1-min intervals).RESULTS: The mean routine blood pressure was 145.6/76.4 mmHg and the mean automated office blood pressure was 135.3/70.1 mmHg. The mean paired difference in blood pressure was 10.3/6.3 mmHg, and Bland-Altman plots demonstrated wide limits of agreement. Using the systolic blood pressure goal of 130 mmHg, 26.9% of the patients not at goal by routine blood pressure were at goal by automated office blood pressure.CONCLUSIONS: Misclassifications of patient blood pressure control status and the wide variability between routine blood pressure and automated office blood pressure support the wider clinical implementation of automated office blood pressure to improve standardization, minimize incorrect blood pressure measurement and avoid over-treatment.

  View details for DOI 10.1097/MBP.0000000000000392

  View details for PubMedID 31116155

• Predialysis Nephrology Care and Incident Atrial Fibrillation in Older Patients WithESKD Initiating Dialysis. Kidney international reports Anumudu, S., Airy, M., Erickson, K. F., Navaneethan, S. D., Chang, T. I., Winkelmayer, W. C., Niu, J. 2019; 4 (5): 679–87

  Abstract

  Background: Atrial fibrillation (AF) is common in patients with end-stage kidney disease (ESKD) on dialysis. Whether pre-ESKD nephrology care associates with AF is uncertain.Methods: We conducted a retrospective cohort study of older US patients (≥67 years) with Medicare A&B who initiated dialysis (1996-2013) without a prior diagnosis of AF. Patients were categorized by the duration and number of predialysis nephrology outpatient visits. Patients were followed for 1 year for a new diagnosis of AF. We used multivariable Cox proportional hazards regression while accounting for the competing risks of kidney transplantation and death.Results: We identified 316,067 patients with ESKD initiating dialysis between 1996 and 2013 who had no prior AF diagnosis. In this cohort, 66.9% had any pre-ESKD outpatient nephrology care, with the first outpatient nephrology visit before dialysis initiation occurring at≤6 months in 17.9%, 7 to 12 months in 9.4%, and >12 months in 39.6%. Outpatient pre-ESKD nephrology care for≤6, 7 to 12, and >12 months versus none yielded adjusted cause-specific hazard ratios (HRs) of 0.87 (95% CI: 0.84-0.89), 0.83 (95% CI: 0.81-0.86), and 0.85 (95% CI: 0.83-0.87) for incident AF, respectively. Further, having 1 to 4 pre-ESKD outpatient nephrology visits, 5 to 9 visits, and≥10 visits versus none yielded adjusted cause-specific HRs of 0.89 (95% CI: 0.86-0.91), 0.86 (95% CI: 0.83-0.88), and 0.81 (95% CI: 0.79-0.83), respectively.Conclusions: Having any predialysis nephrology care before initiation of dialysis was associated with slightly lower adjusted rates of incident AF over the first year of dialysis. The optimal timing and intensity of nephrology care to reduce the incidence of AF and other adverse health events requires further study.

  View details for PubMedID 31080923

• Blood pressure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international Cheung, A. K., Chang, T. I., Cushman, W. C., Furth, S. L., Ix, J. H., Pecoits-Filho, R., Perkovic, V., Sarnak, M. J., Tobe, S. W., Tomson, C. R., Cheung, M., Wheeler, D. C., Winkelmayer, W. C., Mann, J. F., Conference Participants, Bakris, G. L., Damasceno, A., Dwyer, J. P., Fried, L. F., Haynes, R., Hirawa, N., Holdaas, H., Ibrahim, H. N., Ingelfinger, J. R., Iseki, K., Khwaja, A., Kimmel, P. L., Kovesdy, C. P., Ku, E., Lerma, E. V., Luft, F. C., Lv, J., McFadden, C. B., Muntner, P., Myers, M. G., Navaneethan, S. D., Parati, G., Peixoto, A. J., Prasad, R., Rahman, M., Rocco, M. V., Rodrigues, C. I., Roger, S. D., Stergiou, G. S., Tomlinson, L. A., Tonelli, M., Toto, R. D., Tsukamoto, Y., Walker, R., Wang, A. Y., Wang, J., Warady, B. A., Whelton, P. K., Williamson, J. D. 2019; 95 (5): 1027–36

  Abstract

  In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.

  View details for PubMedID 31010478

• Predialysis Nephrology Care and Incident Atrial Fibrillation in Older Patients With ESKD Initiating Dialysis KIDNEY INTERNATIONAL REPORTS Anumudu, S., Airy, M., Erickson, K. F., Navaneethan, S. D., Chang, T., Winkelmayer, W. C., Niu, J. 2019; 4 (5): 679–87

  View details for DOI 10.1016/j.ekir.2019.02.007

  View details for Web of Science ID 000466813000009

• Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies A Scientific Statement From the American Heart Association CIRCULATION Rangaswami, J., Bhalla, V., Blair, J. A., Chang, T., Costa, S., Lentine, K. L., Lerma, E., Mezue, K., Molitch, M., Mullens, W., Ronco, C., Tang, W., McCullough, P. A., Amer Heart Assoc Council Kidney Ca, Council Clinical Cardiology 2019; 139 (16): E840–E878

  Abstract

  Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.

  View details for DOI 10.1161/CIR.0000000000000664

  View details for Web of Science ID 000469321500001

  View details for PubMedID 30852913

• Response by Itoga et al to Letter Regarding Article, "Association of Blood Pressure Measurements With Peripheral Arterial Disease Events" CIRCULATION Itoga, N. K., Tawfik, D. S., Leeper, N. J., Chang, T. I. 2019; 139 (15): 1855–56

  View details for DOI 10.1161/CIRCULATIONAHA.119.039293

  View details for Web of Science ID 000469320700013

• Response by Itoga et al to Letter Regarding Article, "Association of Blood Pressure Measurements With Peripheral Arterial Disease Events". Circulation Itoga, N. K., Tawfik, D. S., Leeper, N. J., Chang, T. I. 2019; 139 (15): 1855–56

  View details for PubMedID 30958720

• Outcomes after left ventricular assist device implantation in patients with acute kidney injury. The Journal of thoracic and cardiovascular surgery Silver, S. A., Long, J., Zheng, Y., Goldstone, A. B., Franz, D., Chang, T. I., Chertow, G. M. 2019

  Abstract

  OBJECTIVE: The study objective was to compare outcomes for patients with and without acute kidney injury during hospitalizations when left ventricular assist devices are implanted.METHODS: By using the National Inpatient Sample from 2008 to 2013, we identified patients with an International Classification of Diseases, Ninth Revision procedure code for left ventricular assist device implantation (37.66). We ascertained the presence of acute kidney injury and acute kidney injury requiring dialysis using validated International Classification of Diseases, Ninth Revision codes. We used logistic regression to examine the association of nondialysis-requiring acute kidney injury and acute kidney injury requiring dialysis with mortality, procedural complications, and discharge destination.RESULTS: We identified 8362 patients who underwent left ventricular assist device implantation, of whom 3760 (45.0%) experienced nondialysis-requiring acute kidney injury and 426 (5.1%) experienced acute kidney injury requiring dialysis. In-hospital mortality was 3.9% for patients without acute kidney injury, 12.2% for patients with nondialysis-requiring acute kidney injury, and 47.4% for patients with acute kidney injury requiring dialysis. Patients with nondialysis-requiring acute kidney injury and acute kidney injury requiring dialysis had higher adjusted odds of mortality (3.24, 95% confidence interval [CI], 2.04-5.13 and 20.8, 95% CI, 9.7-44.2), major bleeding (1.38, 95% CI, 1.08-1.77 and 2.44, 95% CI, 1.47-4.04), sepsis (2.69, 95% CI, 1.93-3.75 and 5.75, 95% CI, 3.46-9.56), and discharge to a nursing facility (2.15, 95% CI, 1.51-3.07 and 5.89, 95% CI, 2.67-12.99).CONCLUSIONS: More than 1 in 10 patients with acute kidney injury and approximately 1 in 2 patients with acute kidney injury requiring dialysis died during their hospitalization, with only 30% of patients with acute kidney injury requiring dialysis discharged to home. This information is necessary to support shared decision-making for patients with advanced heart failure and acute kidney injury.

  View details for PubMedID 31053433

• Long-Term Changes in Kidney Function after Left Ventricular Assist Device Implant: An Analysis of the STS Intermacs Database Franz, D. D., Stedman, M. R., Myers, S. L., Naftel, D. C., Silver, S. A., Banerjee, D., Chang, T. I. ELSEVIER SCIENCE INC. 2019: S89–S90

  View details for DOI 10.1016/j.healun.2019.01.206

  View details for Web of Science ID 000461365100196

• Timing of blood pressure medications and intradialytic hypotension. Seminars in dialysis Wang, K. M., Sirich, T. L., Chang, T. I. 2019

  Abstract

  Intradialytic hypotension (IDH) is a prevalent yet serious complication of hemodialysis, associated with decreased quality of life, inadequate dialysis, vascular access thrombosis, global hypoperfusion, and increased cardiovascular and all-cause mortality. Current guidelines recommend antihypertensive medications be given at night and held the morning of dialysis for affected patients. Despite little evidence to support this recommendation, more than half of patients on dialysis may employ some form of this method. In this article, we will review the available evidence and clinical considerations regarding timing of blood pressure medications and occurrence of IDH, and conclude that witholding BP medications before hemodialysis should not be a routine practice.

  View details for DOI 10.1111/sdi.12777

  View details for PubMedID 30836447

• Central venous pressure and the risk of diuretic-associated acute kidney injury in patients after cardiac surgery. American heart journal McCoy, I. E., Montez-Rath, M. E., Chertow, G. M., Chang, T. I. 2019; 221: 67–73

  Abstract

  When prescribing diuretics in the postcardiac surgical intensive care unit (ICU), clinicians may use central venous pressure (CVP) to assess volume status and the risk of acute kidney injury (AKI). In this study, we examined how the risk of diuretic-associated AKI varied with CVP in patients undergoing cardiac surgery.We used the Medical Information Mart for Intensive Care database to study adults admitted to the postcardiac surgical ICU at an urban, academic medical center between 2001 and 2012. We examined the odds of AKI per 1-mm Hg increase in CVP among patients receiving intravenous loop diuretics using multivariable adjusted logistic regression. We examined the risk of AKI among patients with diuretic use (vs nonuse) across tertiles of CVP using inverse probability treatment weighting.Among 4,164 patients receiving intravenous loop diuretics, the adjusted odds of subsequent AKI were 1.11 (95% CI 1.08-1.13) times higher per mm Hg increase in mean CVP. This association was log-linear across the entire range of CVPs observed. In the analysis of diuretic use (n = 5,396), the adjusted risk ratio for AKI with diuretic use (vs nonuse) was 1.33 (95% CI 1.21-1.47) and did not materially differ across tertile of CVP.Higher rather than lower CVP is an independent marker of AKI risk. The risk of AKI associated with diuretic use may not be influenced by CVP. Novel methods of assessing volume status and AKI risk are needed to guide patient selection for diuretic therapy.

  View details for DOI 10.1016/j.ahj.2019.12.013

  View details for PubMedID 31931418

• Effect of Intensive and Standard Clinic-Based Hypertension Management on the Concordance Between Clinic and Ambulatory Blood Pressure and Blood Pressure Variability: Systolic Blood Pressure Intervention Trial (SPRINT) Ghazi, L., Pajewski, N. M., Rifkin, D. E., Bates, J. T., Chang, T. I., Cushman, W. C., Glasser, S. P., Haley, W. E., Johnson, K. C., Kostis, W. J., Papademetriou, V., Pinion, M., Rahman, M., Simmons, D. L., Taylor, A., Whelton, P. K., Wright, J. T., Drawz, P. E. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for DOI 10.1161/circ.139.suppl_1.P171

  View details for Web of Science ID 000478079000120

• Estimated effects of early diuretic use in critical illness. Critical care explorations McCoy, I. E., Montez-Rath, M. E., Chertow, G. M., Chang, T. I. 2019; 1 (7)

  Abstract

  To estimate the effects of diuretic use during the first 24 hours of an intensive care unit stay on in-hospital mortality and other clinical outcomes including acute kidney injury and duration of mechanical ventilation.Retrospective cohort study.Urban, academic medical center.Adult patients admitted to medical or cardiac ICUs between 2001 and 2012, excluding those on maintenance dialysis or with ICU length of stay < 24 hours.None.We included 13,589 patients: 2,606 with and 10,983 without early diuretic use (loop diuretic exposure during the first 24 hours of an ICU stay). Propensity score matching generated 2523 pairs with well-balanced baseline characteristics. Early diuretic use was unassociated with in-hospital mortality (risk ratio 1.01, 99.5% confidence interval 0.83-1.22). We found no evidence of associations with ICU or hospital length of stay, or duration or provision of mechanical ventilation. Early diuretic use was associated with higher rates of subsequent acute kidney injury (risk ratio 1.41, 99.5% confidence interval 1.25 to 1.59) and electrolyte abnormalities. Results were not materially different in subgroups of patients with heart failure, chronic kidney disease, or acute lung injury.Early diuretic use in critical illness was unassociated with in-hospital mortality, ICU or hospital length of stay, or duration of mechanical ventilation, but risks of acute kidney injury and electrolyte abnormalities were higher.

  View details for DOI 10.1097/CCE.0000000000000021

  View details for PubMedID 31440746

  View details for PubMedCentralID PMC6705600

• Sodium Excretion and Cardiovascular Outcomes in African American Patients With CKD: Findings From the African American Study of Kidney Disease and Hypertension. Kidney medicine Pearson, K., Anderson, C. A., Jimenez, S., Montez-Rath, M. E., Chang, T. I. 2019; 2 (1): 80–82

  View details for DOI 10.1016/j.xkme.2019.10.008

  View details for PubMedID 32734229

  View details for PubMedCentralID PMC7380340

• Canagliflozin review - safety and efficacy profile in patients with T2DM DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Jakher, H., Chang, T. I., Tan, M., Mahaffey, K. W. 2019; 12: 209–15

  View details for DOI 10.2147/DMSO.S184437

  View details for Web of Science ID 000457974300001

• Canagliflozin review - safety and efficacy profile in patients with T2DM. Diabetes, metabolic syndrome and obesity : targets and therapy Jakher, H., Chang, T. I., Tan, M., Mahaffey, K. W. 2019; 12: 209–15

  Abstract

  Canagliflozin is a sodium glucose-cotransporter (SGLT) receptor inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). This article reviews the mechanism of action of SGLT-2 receptor inhibitors and the efficacy of canagliflozin as an antidiabetic agent, its cardiovascular and renal benefits, and safety profile. During the development of canagliflozin, Phase II trials showed an improvement in cardiac and renal biomarkers such as blood pressure, body weight, and albuminuria. The large CANVAS program showed that canagliflozin reduced the composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The CANVAS program also showed a possible benefit of canagliflozin on a renal composite of sustained 40% reduction in estimated glomerular filtration rate, the need for renal replacement therapy, or death from renal causes. The safety profile of canagliflozin has been well characterized, and known side effects such as mycotic genital infections were confirmed in CANVAS. However, an increased risk of amputations was observed in CANVAS that requires further study. Overall, canagliflozin is an effective antidiabetic medication with cardiovascular and likely renal benefits, and with a generally well-tolerated safety profile. Results from the CREDENCE trial will further evaluate the safety and potential renal benefits of canagliflozin in patients with established diabetic nephropathy.

  View details for PubMedID 30787627

• Patterns of diuretic use in the intensive care unit. PloS one McCoy, I. E., Chertow, G. M., Chang, T. I. 2019; 14 (5): e0217911

  Abstract

  To inform future outcomes research on diuretics, we sought to describe modern patterns of diuretic use in the intensive care unit (ICU), including diuretic type, combination, and dosing. We also investigated two possible quality improvement targets: furosemide dosing in renal impairment and inclusion of an initial bolus with continuous furosemide infusions.In this descriptive study, we retrospectively studied 46,037 adult ICU admissions from a publicly available database of patients in an urban, academic medical center.Diuretics were employed in nearly half (49%, 22,569/46,037) of ICU admissions. Mechanical ventilation, a history of heart failure, and admission to the post-cardiac surgery unit were associated with a higher frequency of diuretic use. Combination use of different diuretic classes was uncommon. Patients with severely impaired kidney function were less likely to receive diuretics. Furosemide was by far the most common diuretic given and the initial intravenous dose was only 20 mg in more than half of ICU admissions. Among patients treated with a continuous infusion, 30% did not receive a bolus on the day of infusion initiation.Patterns of diuretic use varied by patient-specific factors and by ICU type. Diuretic dosing strategies may be suboptimal.

  View details for DOI 10.1371/journal.pone.0217911

  View details for PubMedID 31150512

• Blood Pressure and Incident Atrial Fibrillation in Older Patients Initiating Hemodialysis. Clinical journal of the American Society of Nephrology : CJASN Chang, T. I., Liu, S., Airy, M., Niu, J., Turakhia, M. P., Flythe, J. E., Montez-Rath, M. E., Winkelmayer, W. C. 2019

  Abstract

  We examined the association of predialysis systolic and diastolic BP and intradialytic hypotension with incident atrial fibrillation in older patients initiating hemodialysis.We used the US Renal Data System linked to the records of a large dialysis provider to identify patients aged ≥67 years initiating hemodialysis between January 2006 and October 2011. We examined quarterly average predialysis systolic BP, diastolic BP, and proportion of sessions with intradialytic hypotension (i.e., nadir systolic BP <90 mm Hg). We applied an extended Cox model to compute adjusted hazard ratios (HRs) of each exposure with incident atrial fibrillation.Among 17,003 patients, 3785 developed atrial fibrillation. When comparing predialysis systolic BP to a fixed reference of 140 mm Hg, lower predialysis systolic BP was associated with a higher hazard of atrial fibrillation, whereas higher systolic BP was associated with a lower hazard of atrial fibrillation. When comparing across a range of systolic BP for two hypothetical patients with similar measured covariates, the association varied by mean systolic BP: at systolic BP 190 mm Hg, each 10 mm Hg lower systolic BP was associated with lower atrial fibrillation hazard (HR, 0.94; 95% confidence interval, 0.90 to 1.00), whereas at systolic BP 140 mm Hg, a 10 mm Hg lower systolic BP was associated with a higher atrial fibrillation hazard (HR, 1.12; 95% confidence interval, 1.10 to 1.14). Lower diastolic BP was associated with higher atrial fibrillation hazards. Intradialytic hypotension was weakly associated with atrial fibrillation.In this observational study of older patients initiating hemodialysis, lower predialysis systolic BP and diastolic BP were associated with higher incidence of atrial fibrillation.

  View details for DOI 10.2215/CJN.13511118

  View details for PubMedID 31175104

• Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review. Journal of the American College of Cardiology Sarnak, M. J., Amann, K., Bangalore, S., Cavalcante, J. L., Charytan, D. M., Craig, J. C., Gill, J. S., Hlatky, M. A., Jardine, A. G., Landmesser, U., Newby, L. K., Herzog, C. A., Cheung, M., Wheeler, D. C., Winkelmayer, W. C., Marwick, T. H. 2019; 74 (14): 1823–38

  Abstract

  Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage kidney disease and transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and priorities for research.

  View details for DOI 10.1016/j.jacc.2019.08.1017

  View details for PubMedID 31582143

• Dialysis Modality and Incident Atrial Fibrillation in Older Patients With ESRD. American journal of kidney diseases : the official journal of the National Kidney Foundation Niu, J., Shah, M. K., Perez, J. J., Airy, M., Navaneethan, S. D., Turakhia, M. P., Chang, T. I., Winkelmayer, W. C. 2018

  Abstract

  RATIONALE & OBJECTIVE: Atrial fibrillation (AF) is common in patients with kidney failure treated by maintenance dialysis. Whether the incidence of AF differs between patients receiving hemodialysis and peritoneal dialysis is uncertain.STUDY DESIGN: Retrospective cohort study.SETTING & PARTICIPANTS: Using the US Renal Data System, we identified older patients (≥67 years) with Medicare Parts A and B who initiated dialysis therapy (1996-2011) without a diagnosis of AF during the prior 2 years.EXPOSURE: Dialysis modality at incident end-stage renal disease (ESRD) and maintained for at least 90 days.OUTCOME: Patients were followed up for 36 months or less for a new diagnosis of AF.ANALYTICAL APPROACH: Time-to-event analysis usingmultivariable Cox proportional hazards regression to estimate cause-specific HRs whilecensoring at modality switch, kidney transplantation, or death.RESULTS: Overall, 271,722 older patients were eligible; 17,487 (6.9%) were treated with peritoneal dialysis, and 254,235 (93.1%), with hemodialysis, at the onset of ESRD. During 406,225 person-years of follow-up, 69,705 patients had AF newly diagnosed. Because the proportionality assumption was violated, we introduced an interaction term between time (first 90 days vs thereafter) and modality. The AF incidence during the first 90 days was 187/1,000 person-years on peritoneal dialysis therapy and 372/1,000 person-years on hemodialysis therapy. Patients on peritoneal dialysis therapy had an adjusted 39% (95% CI, 34%-43%) lower incidence of AFthan those on hemodialysis therapy. From day91 onward, AF incidence was 140/1,000 person-years with no major difference between modalities.LIMITATIONS: Residual confounding from unobserved differences between exposure groups; ascertainment of AF from billing claims; study of first modality may not generalize to patients switching modalities; uncertain generalizability to younger patients.CONCLUSIONS: Although patients initiating dialysis therapy using peritoneal dialysis had a lower AF incidence during the first 90 days of ESRD, therewas no major difference in AF incidence thereafter. The value of interventions to reduce the early excess AF risk in patients receiving hemodialysismay warrant further study.

  View details for PubMedID 30449517

• Prognostic relevance of visit-to-visit office blood pressure variability in Systolic Blood Pressure Intervention Trial: Same data, different conclusions? Journal of clinical hypertension (Greenwich, Conn.) Chang, T. I., Reboussin, D. M., Chertow, G. M., Cheung, A. K., Cushman, W. C., Kostis, W. J., Parati, G., Riessen, E., Shapiro, B., Stergiou, G. S., Tsioufis, K., Whelton, P. K., Whittle, J., Wright, J. T., Papademetriou, V. 2018; 20 (11): 1644–45

  View details for PubMedID 30328272

• Risk Stratification and Treatment of Coronary Disease in Chronic Kidney Disease and End-Stage Kidney Disease. Seminars in nephrology Shroff, G. R., Chang, T. I. 2018; 38 (6): 582–99

  Abstract

  Patients with advanced chronic kidney disease have an enormous burden of cardiovascular morbidity and mortality, but, paradoxically, their representation in randomized trials for the evaluation and management of coronary artery disease has been limited. Clinicians therefore are faced with the conundrum of synergizing evidence from observational studies, expert opinion, and extrapolation from the general population to provide care to this complex and clinically distinct patient population. In this review, we address clinical risk stratification of patients with chronic kidney disease and end-stage kidney disease using traditional cardiovascular risk factors, noninvasive functional and structural cardiac imaging, invasive coronary angiography, and cardiovascular biomarkers. We highlight the unique characteristics of this population, including the high competing risk of all-cause mortality relative to the risk of major adverse cardiac events, likely owing to important contributions from nonatherosclerotic mechanisms. We further discuss the management of coronary artery disease in patients with chronic kidney disease and end-stage kidney disease, including evidence pertaining to medical management, coronary revascularization with percutaneous coronary intervention, and coronary artery bypass grafting. Our discussion includes considerations of drug-eluting versus bare metal stents for percutaneous coronary intervention and off-pump versus on-pump coronary artery bypass graft surgery. Finally, we address currently ongoing randomized trials, from which clinicians are optimistic about receiving guidance regarding the best strategies to incorporate into their practice for the evaluation and management of coronary artery disease in this high-risk population.

  View details for PubMedID 30413253

• The Relationship between Intradialytic Hypotension and Hospitalized Mesenteric Ischemia: A Case-Control Study. Clinical journal of the American Society of Nephrology : CJASN Seong, E. Y., Zheng, Y., Winkelmayer, W. C., Montez-Rath, M. E., Chang, T. I. 2018

  Abstract

  BACKGROUND AND OBJECTIVES: Mesenteric ischemia is a rare but devastating condition caused by insufficient blood supply to meet the demands of intestinal metabolism. In patients with ESKD, it can be difficult to diagnose and has a >70% mortality rate. Patients on hemodialysis have a high prevalence of predisposing conditions for mesenteric ischemia, but the contribution of intradialytic hypotension, a potential modifiable risk factor, has not been well described.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from the US Renal Data System to identify 626 patients on hemodialysis with a hospitalized mesenteric ischemia event (cases). We selected 2428 controls in up to a 1:4 ratio matched by age, sex, black race, incident dialysis year, diabetes mellitus, coronary artery disease, and peripheral artery disease. We used six different definitions of intradialytic hypotension on the basis of prior studies, and categorized patients as having had intradialytic hypotension if ≥30% of hemodialysis sessions in the 30 days before the event met the specified definition.RESULTS: The proportion of patients with intradialytic hypotension varied depending on its definition: from 19% to 92% of cases and 11% to 94% of controls. Cases had a higher adjusted odds (1.82; 95% confidence interval, 1.47 to 2.26) of having had intradialytic hypotension in the preceding 30 days than controls when using nadir-based intradialytic hypotension definitions such as nadir systolic BP <90 mm Hg. To examine a potential dose-response association of intradialytic hypotension with hospitalized mesenteric ischemia, we categorized patients by the proportion of hemodialysis sessions having intradialytic hypotension, defined using the Nadir90 definition (0%, 1%-9%, 10%-29%, 30%-49%, and ≥50%), and found a direct association of proportion of intradialytic hypotension with hospitalized mesenteric ischemia (P-trend<0.001).CONCLUSIONS: Patients with hospitalized mesenteric ischemia had significantly higher odds of having had intradialytic hypotension in the preceding 30 days than controls, as defined by nadir-based definitions.

  View details for PubMedID 30237215

• Association of Blood Pressure Measurements with Peripheral Arterial Disease Events: A Reanalysis of the ALLHAT Data. Circulation Itoga, N. K., Tawfik, D. S., Lee, C. K., Maruyama, S., Leeper, N. J., Chang, T. I. 2018

  Abstract

  Background -Current guidelines recommend treating hypertension in patients with peripheral arterial disease (PAD) to reduce the risk of cardiac events and stroke, but the effect of reducing blood pressure on lower extremity PAD events is largely unknown. We investigated the association of blood pressure with lower extremity PAD events using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Methods -ALLHAT investigated the effect of different antihypertensive medication classes (chlorthalidone, amlodipine, lisinopril, or doxazosin) on cardiovascular events. Using these data, the primary outcome in our analysis was time to first lower extremity PAD event, defined as PAD-related hospitalization, procedures, medical treatment, or PAD-related death. Given the availability of longitudinal standardized blood pressure measurements, we analyzed systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) as time-varying categorical variables (reference categories 120-129 mm Hg for SBP, 70-79 mm Hg for DBP, and 45-54 mm Hg for PP) in separate models. We used extended Cox regression with death as a competing risk to calculate the association of each BP component with PAD events, and report the results as sub-distribution hazard ratios (HR) and 95% confidence intervals (CI). Results -The present analysis included 33,357 patients with an average age of 67.4 years, 53.1% men, 59.7% white race, and 36.2% with diabetes mellitus. The median baseline blood pressure was 146/84 mm Hg. Participants were followed for a median of 4.3 (IQR 3.6-5.3) years, during which time 1,489 (4.5%) had a lower extremity PAD event, and 4,148 (12.4%) died. In models adjusted for demographic and clinical characteristics, SBP <120 mm Hg was associated with a 26% (CI 5-52%, P=0.015) higher hazard and SBP≥160 mm Hg was associated with a 21% (CI 0-48%, P=0.050) higher hazard for a PAD event, compared with SBP 120-129 mm Hg. In contrast, lower, but not higher, DBP was associated with higher hazard of PAD events: for DBP <60 mm Hg HR = 1.72 (CI 1.38 - 2.16). PP had a U-shaped association with PAD events. Conclusions -In this re-analysis of data from ALLHAT, we found a higher rate of lower extremity PAD events with higher and lower SBP and PP, and with lower DBP. Given the recent revised blood pressure guidelines advocating lower SBP targets for overall cardiovascular risk reduction, further refinement of optimal blood pressure targets specific to PAD is needed. Clinical Trial Registration -URL: www.clinicaltrials.gov Unique identifier: NCT00000542.

  View details for PubMedID 29930023

• Intensive Blood Pressure Targets and Kidney Disease. Clinical journal of the American Society of Nephrology : CJASN Chang, T. I., Sarnak, M. J. 2018

  View details for PubMedID 29798887

• Antihypertensive medication withholding practices in hemodialysis: A survey study of patients and providers. Hemodialysis international. International Symposium on Home Hemodialysis Haase, S. B., Chang, S., Schiller, B., Chertow, G. M., Chang, T. I. 2018

  View details for DOI 10.1111/hdi.12640

  View details for PubMedID 29436151

• Trends in Rates of Lower Extremity Amputation Among Patients With End-Stage Renal Disease Who Receive Dialysis JAMA Internal Medicine Franz, D., Zheng, Y., Leeper, N. J., Chandra, V., Montez-Rath, M., Chang, T. I. 2018

  View details for DOI 10.1001/jamainternmed.2018.2436

• Trends in Rates of Lower Extremity Amputation Among Patients With End-stage Renal Disease Who Receive Dialysis. JAMA internal medicine Franz, D., Zheng, Y., Leeper, N. J., Chandra, V., Montez-Rath, M., Chang, T. I. 2018

  Abstract

  Patients with end-stage renal disease (ESRD) who receive dialysis are at high risk of lower extremity amputation. Recent studies indicate decreasing rates of lower extremity amputation in non-ESRD populations, but contemporary data for patients with ESRD who receive dialysis are lacking.To assess rates of lower extremity amputation among patients with ESRD who receive dialysis during a recent 15-year period; to analyze whether those rates differed by age, sex, diabetes, or geographic region; and to determine 1-year mortality rates in this population after lower extremity amputation.This retrospective study of 3 700 902 records obtained from a US national registry of patients with ESRD who receive dialysis assessed cross-sectional cohorts for each calendar year from 2000 through 2014. Adult patients with prevalent ESRD treated with hemodialysis or peritoneal dialysis covered by Medicare Part A and B on January 1 of each cohort year were included. Data analysis was conducted from August 2017 to April 2018.Age, sex, diabetes, and hospital referral region.Annual rates per 100 person-years of nontraumatic major (above- or below-knee) and minor (below-ankle) amputations.For each annual cohort, there were fewer women (47.5% in 2000, 46.2% in 2005, 44.9% in 2010, and 44.0% in 2014) than men, more than half the patients were white individuals (58.1% in 2000, 56.9% in 2005, 56.9% in 2010, and 56.7% in 2014), and a small proportion were employed (13.9% in 2000, 15.1% in 2005, 16.1% in 2010, and 16.5% in 2014). The rate of lower extremity amputations for patients with ESRD who receive dialysis decreased by 51.0% from 2000 to 2014, driven primarily by a decrease in the rate of major amputations (5.42 [95% CI, 5.28-5.56] in 2000 vs 2.66 [95% CI, 2.59-2.72] per 100 person-years in 2014). Patients with diabetes had amputation rates more than 5 times as high as patients without diabetes. Patients younger than 65 years had higher adjusted amputation rates than older patients, and men had consistently higher adjusted amputation rates than women. Adjusted 1-year mortality rates after lower extremity amputation for patients with ESRD who receive dialysis decreased from 52.2% (95% CI, 50.9%-53.4%) in 2000 to 43.6% (95% CI, 42.5%-44.8%) in 2013. In general, amputation rates decreased among all regions from 2000 to 2014, but regional variability persisted across time despite adjustment for differences in patient demographics and comorbid conditions.Although rates of lower extremity amputations among US patients with ESRD who receive dialysis decreased by 51% during a recent 15-year period, mortality rates remained high, with nearly half of patients dying within a year after lower extremity amputation. Our results highlight the need for more research on ways to prevent lower extremity amputation in this extremely high-risk population.

  View details for PubMedID 29987332

• Receipt of Nephrology Care and Clinical Outcomes Among Veterans With Advanced CKD AMERICAN JOURNAL OF KIDNEY DISEASES Fung, E., Chang, T. I., Chertow, G. M., Thomas, I., Asch, S. M., Tamura, M. 2017; 70 (5): 705–14

  Abstract

  Clinical practice guidelines recommend referral to nephrology when estimated glomerular filtration rate (eGFR) decreases to <30mL/min/1.73m2; however, evidence for benefits of nephrology care are mixed.Observational cohort using landmark analysis.A national cohort of veterans with advanced chronic kidney disease, defined as an outpatient eGFR≤30mL/min/1.73m2 for January 1, 2010, through December 31, 2010, and a prior eGFR<60mL/min/1.73m2, using administrative and laboratory data from the Department of Veterans Affairs and the US Renal Data System.Receipt and frequency of outpatient nephrology care over 12 months.Survival and progression to end-stage renal disease (ESRD; receipt of dialysis or kidney transplantation) were the primary outcomes. In addition, control of associated clinical parameters over 12 months were intermediate outcomes.Of 39,669 patients included in the cohort, 14,983 (37.8%) received nephrology care. Older age, heart failure, dementia, depression, and rapidly declining kidney function were independently associated with the absence of nephrology care. During a mean follow-up of 2.9 years, 14,719 (37.1%) patients died and 4,310 (10.9%) progressed to ESRD. In models adjusting for demographics, comorbid conditions, and trajectory of kidney function, nephrology care was associated with lower risk for death (HR, 0.88; 95% CI, 0.85-0.91), but higher risk for ESRD (HR, 1.48; 95% CI, 1.38-1.58). Among patients with clinical parameters outside guideline recommendations at cohort entry, a significantly higher adjusted proportion of patients who received nephrology care had improvement in control of hemoglobin, potassium, albumin, calcium, and phosphorus concentrations compared with those who did not receive nephrology care.May not be generalizable to nonveterans.Among patients with advanced chronic kidney disease, nephrology care was associated with lower mortality, but was not associated with lower risk for progression to ESRD.

  View details for PubMedID 28811048

• Hospitalizations and Nursing Facility Stays During the Transition from CKD to ESRD on Dialysis: An Observational Study JOURNAL OF GENERAL INTERNAL MEDICINE Montez-Rath, M. E., Zheng, Y., Tamura, M., Grubbs, V., Winkelmayer, W. C., Chang, T. I. 2017; 32 (11): 1220–27

  Abstract

  There is little information on hospital and nursing facility stays during the transition from pre-dialysis kidney disease to end-stage renal disease treated with dialysis.To examine hospital and nursing facility stays in the years pre- and post-dialysis initiation, and to develop a novel method for visualizing these data.Observational study of patients in the US Renal Data System initiating dialysis from October 2011 to October 2012.Patients aged ≥67 years with Medicare Part A/B coverage for 1 year pre-dialysis initiation.Proportion of patients with ≥1 facility day, and among these, the mean number of days and the mean proportion of time spent in a facility in the first year post-dialysis initiation. We created "heat maps" to represent data visually.Among 28,049 patients, > 60% initiated dialysis in the hospital. Patients with at least 1 facility day spent 37-42 days in a facility in the year pre-dialysis initiation and 59-67 facility days in the year post-dialysis initiation. The duration of facility stay varied by age: patients aged 67-70 years spent 60 (95% CI 57-62) days or 25.8% of the first year post-dialysis initiation in a facility, while patients aged >80 years spent 67 (CI 65-69) days or 36.8% of the first year post-dialysis initiation in a facility. Patterns varied depending on the presence or absence of certain comorbid conditions, with dementia having a particularly large effect: patients with dementia spent approximately 50% of the first year post-dialysis initiation in a facility, regardless of age.Older patients, particularly octogenarians and patients with dementia or other comorbidities, spend a large proportion of time in a facility during the first year after dialysis initiation. Our heat maps provide a novel and concise visual representation of a large amount of quantitative data regarding expected outcomes after initiation of dialysis.

  View details for PubMedID 28808869

  View details for PubMedCentralID PMC5653560

• Visit-to-Visit Office Blood Pressure Variability and Cardiovascular Outcomes in SPRINT (Systolic Blood Pressure Intervention Trial) HYPERTENSION Chang, T. I., Reboussin, D. M., Chertow, G. M., Cheung, A. K., Cushman, W. C., Kostis, W. J., Parati, G., Raj, D., Riessen, E., Shapiro, B., Stergiou, G. S., Townsend, R. R., Tsioufis, K., Whelton, P. K., Whittle, J., Wright, J. T., Papademetriou, V., SPRINT Res Grp 2017; 70 (4): 751-+

  Abstract

  Studies of visit-to-visit office blood pressure (BP) variability (OBPV) as a predictor of cardiovascular events and death in high-risk patients treated to lower BP targets are lacking. We conducted a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial), a well-characterized cohort of participants randomized to intensive (<120 mm Hg) or standard (<140 mm Hg) systolic BP targets. We defined OBPV as the coefficient of variation of the systolic BP using measurements taken during the 3-,6-, 9-, and 12-month study visits. In our cohort of 7879 participants, older age, female sex, black race, current smoking, chronic kidney disease, and coronary disease were independent determinants of higher OBPV. Use of thiazide-type diuretics or dihydropyridine calcium channel blockers was associated with lower OBPV whereas angiotensin-converting enzyme inhibitors or angiotensin receptor blocker use was associated with higher OBPV. There was no difference in OBPV in participants randomized to standard or intensive treatment groups. We found that OBPV had no significant associations with the composite end point of fatal and nonfatal cardiovascular events (n=324 primary end points; adjusted hazard ratio, 1.20; 95% confidence interval, 0.85-1.69, highest versus lowest quintile) nor with heart failure or stroke. The highest quintile of OBPV (versus lowest) was associated with all-cause mortality (adjusted hazard ratio, 1.92; confidence interval, 1.22-3.03) although the association of OBPV overall with all-cause mortality was marginal (P=0.07). Our results suggest that clinicians should continue to focus on office BP control rather than on OBPV unless definitive benefits of reducing OBPV are shown in prospective trials.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.

  View details for PubMedID 28760939

• Effects of Intensive BP Control in CKD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Cheung, A. K., Rahman, M., Reboussin, D. M., Craven, T. E., Greene, T., Kimmel, P. L., Cushman, W. C., Hawfield, A. T., Johnson, K. C., Lewis, C. E., Oparil, S., Rocco, M. V., Sink, K. M., Whelton, P. K., Wright, J. T., Basile, J., Beddhu, S., Bhatt, U., Chang, T. I., Chertow, G. M., Chonchol, M., Freedman, B. I., Haley, W., Ix, J. H., Katz, L. A., Killeen, A. A., Papademetriou, V., Ricardo, A. C., Servilla, K., Wall, B., Wolfgram, D., Yee, J., SPRINT Res Grp 2017; 28 (9): 2812–23

  Abstract

  The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n=1330) or <140 mm Hg (standard group; n=1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m2 per year; P<0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.

  View details for PubMedID 28642330

• Associations of Glycemic Control With Cardiovascular Outcomes Among US Hemodialysis Patients With Diabetes Mellitus. Journal of the American Heart Association Rhee, J. J., Zheng, Y., Montez-Rath, M. E., Chang, T. I., Winkelmayer, W. C. 2017; 6 (6)

  Abstract

  There is a lack of data on the relationship between glycemic control and cardiovascular end points in hemodialysis patients with diabetes mellitus.We included adult Medicare-insured patients with diabetes mellitus who initiated in-center hemodialysis treatment from 2006 to 2008 and survived for >90 days. Quarterly mean time-averaged glycated hemoglobin (HbA1c) values were categorized into <48 mmol/mol (<6.5%) (reference), 48 to <58 mmol/mol (6.5% to <7.5%), 58 to <69 mmol/mol (7.5% to <8.5%), and ≥69 mmol/mol (≥8.5%). Medicare claims were used to identify outcomes of cardiovascular mortality, nonfatal myocardial infarction (MI), fatal or nonfatal MI, stroke, and peripheral arterial disease. We used Cox models as a function of time-varying exposure to estimate multivariable adjusted hazard ratios and 95%CI for the associations between HbA1c and time to study outcomes in a cohort of 16 387 eligible patients. Patients with HbA1c 58 to <69 mmol/mol (7.5% to <8.5%) and ≥69 mmol/mol (≥8.5%) had 16% (CI, 2%, 32%) and 18% (CI, 1%, 37%) higher rates of cardiovascular mortality (P-trend=0.01) and 16% (CI, 1%, 33%) and 15% (CI, 1%, 32%) higher rates of nonfatal MI (P-trend=0.05), respectively, compared with those in the reference group. Patients with HbA1c ≥69 mmol/mol (≥8.5%) had a 20% (CI, 2%, 41%) higher rate of fatal or nonfatal MI (P-trend=0.02), compared with those in the reference group. HbA1c was not associated with stroke, peripheral arterial disease, or all-cause mortality.Higher HbA1c levels were significantly associated with higher rates of cardiovascular mortality and MI but not with stroke, peripheral arterial disease, or all-cause mortality in this large cohort of hemodialysis patients with diabetes mellitus.

  View details for DOI 10.1161/JAHA.117.005581

  View details for PubMedID 28592463

• Safety of Intravenous Iron in Hemodialysis: Longer-term Comparisons of Iron Sucrose Versus Sodium Ferric Gluconate Complex. American journal of kidney diseases Winkelmayer, W. C., Goldstein, B. A., Mitani, A. A., Ding, V. Y., Airy, M., Mandayam, S., Chang, T. I., Brookhart, M. A., Fishbane, S. 2017; 69 (6): 771-779

  Abstract

  Controversy exists about any differences in longer-term safety across different intravenous iron formulations routinely used in hemodialysis (HD) patients. We exploited a natural experiment to compare outcomes of patients initiating HD therapy in facilities that predominantly (in ≥90% of their patients) used iron sucrose versus sodium ferric gluconate complex.Retrospective cohort study of incident HD patients.Using the US Renal Data System, we hard-matched on geographic region and center characteristics HD facilities predominantly using ferric gluconate with similar ones using iron sucrose. Subsequently, incident HD patients were assigned to their facility iron formulation exposure.Facility-level use of iron sucrose versus ferric gluconate.Patients were followed up for mortality from any, cardiovascular, or infectious causes. Medicare-insured patients were followed up for infectious and cardiovascular (stroke or myocardial infarction) hospitalizations and for composite outcomes with the corresponding cause-specific deaths.HRs.We matched 2,015 iron sucrose facilities with 2,015 ferric gluconate facilities, in which 51,603 patients (iron sucrose, 24,911; ferric gluconate, 26,692) subsequently initiated HD therapy. All recorded patient characteristics were balanced between groups. Over 49,989 person-years, 10,381 deaths (3,908 cardiovascular and 1,209 infectious) occurred. Adjusted all-cause (HR, 0.98; 95% CI, 0.93-1.03), cardiovascular (HR, 0.96; 95% CI, 0.89-1.03), and infectious mortality (HR, 0.98; 95% CI, 0.86-1.13) did not differ between iron sucrose and ferric gluconate facilities. Among Medicare beneficiaries, no differences between ferric gluconate and iron sucrose facilities were observed in fatal or nonfatal cardiovascular events (HR, 1.01; 95% CI, 0.93-1.09). The composite infectious end point occurred less frequently in iron sucrose versus ferric gluconate facilities (HR, 0.92; 95% CI, 0.88-0.96).Unobserved selection bias from nonrandom treatment assignment.Patients initiating HD therapy in facilities almost exclusively using iron sucrose versus ferric gluconate had similar longer-term outcomes. However, there was a small decrease in infectious hospitalizations and deaths in patients dialyzing in facilities predominantly using iron sucrose. This difference may be due to residual confounding, random chance, or a causal effect.

  View details for DOI 10.1053/j.ajkd.2016.10.031

  View details for PubMedID 28063734

  View details for PubMedCentralID PMC5441933

• Comparative effectiveness of angiotensin receptor blockers vs. angiotensin-converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis JOURNAL OF NEPHROLOGY Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Leng, L., Chang, T. I., Winkelmayer, W. C. 2017; 30 (2): 281-288

  View details for DOI 10.1007/s40620-016-0340-3

  View details for Web of Science ID 000398460700015

• Drug-Eluting Stents Versus Bare Metal Stents for Percutaneous Coronary Intervention in Kidney Transplant Recipients TRANSPLANTATION Lenihan, C. R., Montez-Rath, M. E., Winkelmayer, W. C., Chang, T. I. 2017; 101 (4): 851-857

  View details for DOI 10.1097/TP.0000000000001446

  View details for Web of Science ID 000398157200042

• Impact of drugs on intradialytic hypotension: Antihypertensives and vasoconstrictors. Seminars in dialysis Chang, T. I. 2017; 30 (6): 532–36

  Abstract

  Intradialytic hypotension (IDH) is a common complication of hemodialysis and is associated with numerous adverse outcomes including cardiovascular events, inadequate dialysis, loss of vascular access, and death. It is estimated that approximately 20%-30% of all dialysis sessions are affected by IDH. In seeking ways to reduce the occurrence of IDH, dialysis providers often turn to pharmacological approaches: withholding antihypertensive medications prior to hemodialysis or administering vasoconstrictor medications. This review will focus on what is known about the relation between antihypertensive medications and IDH, and summarize studies that have examined the efficacy of vasoconstrictor medications on IDH, including midodrine, arginine vasopressin, and droxidopa. However, there is currently scant evidence that any pharmacological approach is particularly effective in reducing IDH. Additional studies of potential treatments for IDH are needed, and should examine not only hemodynamic effects such as changes in nadir blood pressure during dialysis, but also on patient-centered and clinical outcomes such as symptoms of IDH, quality of life, and cardiovascular events.

  View details for PubMedID 28681510

  View details for PubMedCentralID PMC5668164

• Risk profiles for acute health events after incident atrial fibrillation in patients with end-stage renal disease on hemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Airy, M., Chang, T. I., Ding, V. Y., Goldstein, B. A., Bansal, N., Niu, J., Navaneethan, S. D., Turakhia, M. P., Winkelmayer, W. C. 2017

  Abstract

  Little is known about the cardiovascular risks of incident atrial fibrillation/flutter (AF) in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD).We studied older US patients who newly initiated HD for ESRD (2006-11) and who had not previously been diagnosed with AF, stroke, myocardial infarction (MI) or hip fracture. We used Cox regression with AF as a time-varying covariate, adjusted for socio-demographic characteristics and comorbidities to estimate hazard ratios [HRs (95% confidence intervals)] for the events of ischemic stroke, MI and death. Hip fracture served as a negative control outcome.We identified 85 377 older patients (mean age: 76.5 years) who initiated HD; of these, 14.3% were subsequently diagnosed with AF (14.9% thereof as primary diagnosis) and 49.8% died during follow-up. Incident AF was associated with nine times higher adjusted mortality during the first 30 days [9.2 (8.8-9.6)], 5-fold higher mortality between 31 and 90 days [4.6 (4.3-4.8)] and double the mortality beyond 90 days from first AF diagnosis [2.2 (2.1-2.3)]. Incident AF was similarly associated with higher adjusted risk of ischemic stroke: 2.1 (1.6-2.7) during the first 30 days, 2.5 (2.0-3.0) between 31 and 90 days and 1.5 (1.3-1.7) beyond 90 days. Similar findings were obtained for MI. However, the risk of hip fracture was only marginally increased following AF diagnosis [≤30 days: 1.1 (0.7-1.6); 31-90 days: 1.4 (1.0-1.8); >90 days: 1.2 (1.1-1.4)]. All associations were attenuated and the association with hip fracture was null when incident AF was defined by a primary diagnosis code.AF was strongly associated with increased risks of ischemic stroke, MI and death, with risks highest soon after AF diagnosis but extending beyond 90 days.

  View details for PubMedID 29145634

• An experimentum crucis in salt sensitivity. American journal of physiology. Renal physiology Pao, A. C., Chang, T. I. 2017; 312 (1): F190–F191

  View details for PubMedID 27654894

• Orthostatic changes in systolic blood pressure among SPRINT participants at baseline JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Townsend, R. R., Chang, T. I., Cohen, D. L., Cushman, W. C., Evans, G. W., Glasser, S. P., Haley, W. E., Olney, C., Oparil, S., Del Pinto, R., Pisoni, R., Taylor, A. A., Umanath, K., Wright, J. T., Yeboah, J. 2016; 10 (11): 847-856

  Abstract

  Orthostatic changes in systolic blood pressure (SBP) impact cardiovascular outcomes. In this study, we aimed to determine the pattern of orthostatic systolic pressure changes in participants enrolled in the SBP Intervention Trial (SPRINT) at their baseline visit before randomization and sought to understand clinical factors predictive of these changes. Of the 9323 participants enrolled in SPRINT, 8662 had complete data for these analyses. The SBP after 1 minute of standing was subtracted from the mean value of the three preceding seated SBP values. At the baseline visit, medical history, medications, anthropometric measures, and standard laboratory testing were undertaken. The mean age of SPRINT participants was 68 years, two-thirds were male, with 30% black, 11% Hispanic, and 55% Caucasian. The spectrum of SBP changes on standing demonstrated that increases in SBP were as common as declines, and about 5% of participants had an increase, and 5% had a decrease of >20 mm Hg in SBP upon standing. Female sex, taller height, more advanced kidney disease, current smoking, and several drug classes were associated with larger declines in BP upon standing, while black race, higher blood levels of glucose and sodium, and heavier weight were associated with more positive values of the change in BP upon standing. Our cross-sectional results show a significant spectrum of orthostatic SBP changes, reflecting known (eg, age) and less well-known (eg, kidney function) relationships that may be important considerations in determining the optimal target blood pressure in long-term outcomes of older hypertensive patients.

  View details for DOI 10.1016/j.jash.2016.08.005

  View details for Web of Science ID 000388546600004

  View details for PubMedID 27665708

• Balancing the Evidence: How to Reconcile the Results of Observational Studies vs. Randomized Clinical Trials in Dialysis SEMINARS IN DIALYSIS Shen, J. I., Lum, E. L., Chang, T. I. 2016; 29 (5): 342-346

  Abstract

  Because large randomized clinical trials (RCTs) in dialysis have been relatively scarce, evidence-based dialysis care has depended heavily on the results of observational studies. However, when results from RCTs appear to contradict the findings of observational studies, nephrologists are left to wonder which type of study they should believe. In this editorial, we explore the key differences between observational studies and RCTs in the context of such seemingly conflicting studies in dialysis. Confounding is the major limitation of observational studies, whereas low statistical power and problems with external validity are more likely to limit the findings of RCTs. Differences in the specification of the population, exposure, and outcomes can also contribute to different results among RCTs and observational studies. Rigorous methods are required regardless of what type of study is conducted, and readers should not automatically assume that one type of study design is superior to the other. Ultimately, dialysis care requires both well-designed, well-conducted observational studies and RCTs to move the field forward.

  View details for DOI 10.1111/sdi.12518

  View details for Web of Science ID 000388438700003

  View details for PubMedID 27207819

  View details for PubMedCentralID PMC5014621

• Antihypertensive Medication Use in Older Patients Transitioning from Chronic Kidney Disease to End-Stage Renal Disease on Dialysis. Clinical journal of the American Society of Nephrology Chang, T. I., Zheng, Y., Montez-Rath, M. E., Winkelmayer, W. C. 2016; 11 (8): 1401-1412

  Abstract

  The transition from CKD to ESRD can be particularly unstable, with high rates of death and hospitalizations. Few studies have examined medication use during this critical period. We examined patterns of antihypertensive medication use from the four quarters before and eight quarters after incident ESRD treated with maintenance dialysis.We used the US Renal Data System to identify patients aged ≥67 years initiating dialysis for ESRD between January 2008 and December 2010 with Medicare Part D and a low-income subsidy. We ascertained the incidence of AKI and hyperkalemia during each quarter on the basis of having at least 1 payment claim for the condition. We used Poisson regression with robust SEMs to formally test for changes in the trend and level of antihypertensive medication use in a series of intervention analyses.The number of antihypertensive drugs used increased as patients neared ESRD, peaking at an average of 3.4 in the quarter immediately preceding dialysis initiation, then declining to 2.2 medications by 2 years later. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use was stable at approximately 40%, even among patients with coronary disease and systolic heart failure, and did not correlate with AKI or hyperkalemia. Dialysis initiation was associated with a 40% (95% confidence interval, 38% to 43%) lower adjusted level of diuretic use, which continued to decline after ESRD. Three- and four-drug combinations that included a diuretic were most common before ESRD, whereas after ESRD, one- and two-drug β-blocker or calcium-channel blocker-based combinations were most common.The use of antihypertensive medications, particularly angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and diuretics, may be suboptimal during the transition from CKD to ESRD, especially in patients with coronary disease or systolic heart failure. Future studies are needed to identify strategies to increase the appropriate use of antihypertensive medications during this critical transition period.

  View details for DOI 10.2215/CJN.10611015

  View details for PubMedID 27354656

• Comparative effectiveness of angiotensin receptor blockers vs. angiotensin-converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis. Journal of nephrology Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Leng, L., Chang, T. I., Winkelmayer, W. C. 2016: -?

  Abstract

  There is evidence that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) may reduce cardiovascular (CV) risk in patients undergoing peritoneal dialysis (PD), but no studies have compared the effectiveness between these drug classes. In this observational cohort study, we compared the association of ARB vs. ACEI use on CV outcomes in patients initiating PD.We identified from the US Renal Data System all adult patients who initiated PD from 2007 to 2011 and participated in Medicare Part D, a federal prescription drug benefits program, for the first 90 days of dialysis. Patients who filled a prescription for an ACEI or ARB in those 90 days were considered users. We excluded patients who used both ACEI and ARB. We applied Cox proportional hazards regression to an inverse probability of treatment-weighted cohort to estimate the hazard ratios (HR) for the combined outcome of all-cause death, ischemic stroke, or myocardial infarction; all-cause mortality; and CV death.Among 1892 patients using either drug class, 39 % were ARB users. We observed 624 events over 2,898 person-years of follow-up, for a composite event rate of 22 events per 100 person-years. We observed no differences between ARB vs. ACEI users: composite outcome HR 0.94, 95 % confidence interval (CI) 0.79-1.11; all-cause mortality HR 0.92, 95 % CI 0.76-1.10; CV death HR: 1.06, 95 % CI 0.80-1.41.We identified no significant difference in the risks of CV events or death between users of ARBs vs. ACEIs in patients initiating PD, thus supporting their mostly interchangeable use in this population.

  View details for PubMedID 27485007

• The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure HYPERTENSION Kronish, I. M., Lynch, A. I., Oparil, S., Whittle, J., Davis, B. R., Simpson, L. M., Krousel-Wood, M., Cushman, W. C., Chang, T. I., Muntner, P. 2016; 68 (1): 39-?

  View details for DOI 10.1161/HYPERTENSIONAHA.115.06960

  View details for Web of Science ID 000377466200014

• Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and cardiovascular outcomes in patients initiating peritoneal dialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Shen, J. I., Saxena, A. B., Montez-Rath, M. E., Chang, T. I., Winkelmayer, W. C. 2016

  Abstract

  Data on the effectiveness of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in reducing cardiovascular (CV) risk in patients undergoing peritoneal dialysis (PD) are limited. We investigated the association between ACEI/ARB use and CV outcomes in patients initiating PD.In this observational cohort study, we identified from the United States Renal Data System all adult patients who initiated PD from 2007 to 2011 and participated in Medicare Part D, a federal prescription drug benefits program, for the first 90 days of dialysis. Patients who filled a prescription for an ACEI or ARB in those 90 days were considered users. We applied Cox regression to an inverse probability of treatment weighted cohort to estimate the hazard ratios (HRs) for the combined outcome of death, ischemic stroke or myocardial infarction (MI) and each outcome individually.Among 4879 patients, 2063 (42%) used an ACEI/ARB. Patients were followed up for a median of 1.2 years. We recorded 1771 events, for a composite rate of 25 events per 100 person-years. ACEI/ARB use (versus nonuse) was associated with a reduced risk of the composite outcome {HR 0.84 [95% confidence interval (CI) 0.76-0.93]}, all-cause mortality [HR 0.83 (95% CI 0.75-0.92)] and CV death [HR 0.74 (95% CI 0.63-0.87)], but not MI [HR 0.88 (95% CI 0.69-1.12)] or ischemic stroke [HR 1.06 (95% CI 0.79-1.43)]. Results were similar in as-treated analyses. In a subgroup analysis, we did not find any effect modification by residual renal function.ACEI/ARB use is common in patients initiating PD and is associated with a lower risk of fatal CV outcomes.

  View details for PubMedID 27190342

• Drug-Eluting Versus Bare-Metal Stents During PCI in Patients With End-Stage Renal Disease on Dialysis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Chang, T. I., Montez-Rath, M. E., Tsai, T. T., Hlatky, M. A., Winkelmayer, W. C. 2016; 67 (12): 1459-1469

  Abstract

  In patients undergoing percutaneous coronary intervention (PCI), drug-eluting stents (DES) reduce repeat revascularizations compared with bare-metal stents (BMS), but their effects on death and myocardial infarction (MI) are mixed. Few studies have focused on patients with end-stage renal disease.This study compared mortality and cardiovascular morbidity during percutaneous coronary intervention with DES and with BMS in dialysis patients.We identified 36,117 dialysis patients from the USRDS (United States Renal Data System) who had coronary stenting in the United States between April 23, 2003, and December 31, 2010, and examined the association of DES versus BMS with 1-year outcomes: death; death or MI; and death, MI, or repeat revascularization. We also conducted a temporal analysis by dividing the study period into 3 DES eras: Transitional (April 23, 2003, to June 30, 2004); Liberal (July 1, 2004, to December 31, 2006); and Selective (January 1, 2007, to December 31, 2010).One-year event rates were high, with 38 deaths; 55 death or MI events; and 71 death, MI, or repeat revascularization events per 100 person-years. DES, compared with BMS, were associated with a significant 18% lower risk of death; 16% lower risk of death or MI; and 13% lower risk of death, MI, or repeat revascularization. DES use varied, from 56% in the Transitional era to 85% in the Liberal era and 62% in the Selective era. DES outcomes in the Liberal era were significantly better than in the Transitional Era, but not significantly better than in the Selective Era.DES for percutaneous coronary intervention appears to be safe for use in U.S. dialysis patients and is associated with lower rates of death, MI, and repeat revascularization.

  View details for DOI 10.1016/j.jacc.2015.10.104

  View details for Web of Science ID 000372408500011

  View details for PubMedCentralID PMC4808241

• Drug-Eluting Versus Bare-Metal Stents During PCI in Patients With End-Stage Renal Disease on Dialysis. Journal of the American College of Cardiology Chang, T. I., Montez-Rath, M. E., Tsai, T. T., Hlatky, M. A., Winkelmayer, W. C. 2016; 67 (12): 1459-1469

  Abstract

  In patients undergoing percutaneous coronary intervention (PCI), drug-eluting stents (DES) reduce repeat revascularizations compared with bare-metal stents (BMS), but their effects on death and myocardial infarction (MI) are mixed. Few studies have focused on patients with end-stage renal disease.This study compared mortality and cardiovascular morbidity during percutaneous coronary intervention with DES and with BMS in dialysis patients.We identified 36,117 dialysis patients from the USRDS (United States Renal Data System) who had coronary stenting in the United States between April 23, 2003, and December 31, 2010, and examined the association of DES versus BMS with 1-year outcomes: death; death or MI; and death, MI, or repeat revascularization. We also conducted a temporal analysis by dividing the study period into 3 DES eras: Transitional (April 23, 2003, to June 30, 2004); Liberal (July 1, 2004, to December 31, 2006); and Selective (January 1, 2007, to December 31, 2010).One-year event rates were high, with 38 deaths; 55 death or MI events; and 71 death, MI, or repeat revascularization events per 100 person-years. DES, compared with BMS, were associated with a significant 18% lower risk of death; 16% lower risk of death or MI; and 13% lower risk of death, MI, or repeat revascularization. DES use varied, from 56% in the Transitional era to 85% in the Liberal era and 62% in the Selective era. DES outcomes in the Liberal era were significantly better than in the Transitional Era, but not significantly better than in the Selective Era.DES for percutaneous coronary intervention appears to be safe for use in U.S. dialysis patients and is associated with lower rates of death, MI, and repeat revascularization.

  View details for DOI 10.1016/j.jacc.2015.10.104

  View details for PubMedID 27012407

• The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial JOURNAL OF HUMAN HYPERTENSION Chang, T. I., AbdAlla, S., London, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Dehmel, B., Goodman, W. G., Chertow, G. M. 2016; 30 (3): 204-209

  Abstract

  Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

  View details for DOI 10.1038/jhh.2015.56

  View details for PubMedID 26040438

• Patterns and Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial HYPERTENSION Chang, T. I., Evans, G., Cheung, A. K., Cushman, W. C., Diamond, M. J., Dwyer, J. P., Huan, Y., Kitzman, D., Kostis, J. B., Oparil, S., Rastogi, A., Roumie, C. L., Sahay, R., Stafford, R. S., Taylor, A. A., Wright, J. T., Chertow, G. M. 2016; 67 (3): 550-555

  Abstract

  Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness.

  View details for DOI 10.1161/HYPERTENSIONAHA.115.06851

  View details for PubMedID 26865200

• Sleep disordered breathing and cardiovascular risk in older patients initiating dialysis in the United States: a retrospective observational study using medicare data BMC NEPHROLOGY Tuohy, C. V., Montez-Rath, M. E., Turakhia, M., Chang, T. I., Winkelman, J. W., Winkelmayer, W. C. 2016; 17

  Abstract

  Sleep disordered breathing (SDB) such as sleep apnea is associated with cardiovascular disease in the general population. However, little is known about the cardiovascular risks of SDB in patients with end-stage renal disease (ESRD).We identified Medicare fee-for-service beneficiaries aged ≥67 years initiating dialysis between 2004 and 2009. Outcomes of interest included all-cause mortality, incident myocardial infarction, ischemic stroke, and atrial fibrillation. We compared patients with and without diagnosed SDB using Cox proportional hazards regression.Between 2004 and 2009, 184,217 older patients developed ESRD, of whom 15,121 (8.2 %) were previously diagnosed with SDB. Patients diagnosed with SDB were younger, more likely to be male and Caucasian, less Medicaid eligible, had more non-Nephrology clinic visits, higher body mass index, and more comorbidity. In analyses adjusting for demographics and BMI, diagnosed SDB was associated with higher risk of death and atrial fibrillation, but not associated with myocardial infarction or ischemic stroke risk. After further adjustment for all baseline characteristics, diagnosed SDB was associated with slightly lower risks of death (hazard ratio [HR]: 0.93, 95 % confidence interval [CI]: 0.91-0.96), myocardial infarction (HR: 0.92, CI: 0.87-0.98), and ischemic stroke (HR: 0.90, 95 % CI: 0.82-0.98), and not associated with atrial fibrillation (HR: 1.02, CI: 0.98-1.07).In older patients initiating dialysis in the U.S., diagnosed SDB was weakly associated with lower risks of death and important cardiovascular outcomes, thus adding to the list of established risk factors that are paradoxically associated with cardiovascular outcomes in the ESRD population.

  View details for DOI 10.1186/s12882-016-0229-3

  View details for Web of Science ID 000369620700001

  View details for PubMedCentralID PMC4748630

• Visit-to-visit variability of blood pressure and death, end-stage renal disease, and cardiovascular events in patients with chronic kidney disease JOURNAL OF HYPERTENSION Chang, T. I., Tabada, G. H., Yang, J., Tan, T. C., Go, A. S. 2016; 34 (2): 244-252

  View details for DOI 10.1097/HJH.0000000000000779

  View details for Web of Science ID 000369671400014

• Coffee and caffeine consumption and the risk of hypertension in postmenopausal women AMERICAN JOURNAL OF CLINICAL NUTRITION Rhee, J. J., Qin, F., Hedlin, H. K., Chang, T. I., Bird, C. E., Zaslavsky, O., Manson, J. E., Stefanick, M. L., Winkelmayer, W. C. 2016; 103 (1): 210-217

  Abstract

  The associations of coffee and caffeine intakes with the risk of incident hypertension remain controversial.We sought to assess longitudinal relations of caffeinated coffee, decaffeinated coffee, and total caffeine intakes with mean blood pressure and incident hypertension in postmenopausal women in the Women's Health Initiative Observational Study.In a large prospective study, type and amount of coffee and total caffeine intakes were assessed by using self-reported questionnaires. Hypertension status was ascertained by using measured blood pressure and self-reported drug-treated hypertension. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2-3 cups/d, 1 cup/d, and 196 mg/d, respectively. Using multivariable linear regression, we examined the associations of baseline intakes of caffeinated coffee, decaffeinated coffee, and caffeine with measured systolic and diastolic blood pressures at annual visit 3 in 29,985 postmenopausal women who were not hypertensive at baseline. We used Cox proportional hazards models to estimate HRs and their 95% CIs for time to incident hypertension.During 112,935 person-years of follow-up, 5566 cases of incident hypertension were reported. Neither caffeinated coffee nor caffeine intake was associated with mean systolic or diastolic blood pressure, but decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean diastolic blood pressure. Decaffeinated coffee intake was not associated with mean systolic blood pressure. Intakes of caffeinated coffee, decaffeinated coffee, and caffeine were not associated with the risk of incident hypertension (P-trend > 0.05 for all).In summary, these findings suggest that caffeinated coffee, decaffeinated coffee, and caffeine are not risk factors for hypertension in postmenopausal women.

  View details for DOI 10.3945/ajcn.115.120147

  View details for Web of Science ID 000367869500025

  View details for PubMedCentralID PMC4691674

• Coffee and caffeine consumption and the risk of hypertension in postmenopausal women. The American journal of clinical nutrition Rhee, J. J., Qin, F., Hedlin, H. K., Chang, T. I., Bird, C. E., Zaslavsky, O., Manson, J. E., Stefanick, M. L., Winkelmayer, W. C. 2016; 103 (1): 210–17

  Abstract

  The associations of coffee and caffeine intakes with the risk of incident hypertension remain controversial.We sought to assess longitudinal relations of caffeinated coffee, decaffeinated coffee, and total caffeine intakes with mean blood pressure and incident hypertension in postmenopausal women in the Women's Health Initiative Observational Study.In a large prospective study, type and amount of coffee and total caffeine intakes were assessed by using self-reported questionnaires. Hypertension status was ascertained by using measured blood pressure and self-reported drug-treated hypertension. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2-3 cups/d, 1 cup/d, and 196 mg/d, respectively. Using multivariable linear regression, we examined the associations of baseline intakes of caffeinated coffee, decaffeinated coffee, and caffeine with measured systolic and diastolic blood pressures at annual visit 3 in 29,985 postmenopausal women who were not hypertensive at baseline. We used Cox proportional hazards models to estimate HRs and their 95% CIs for time to incident hypertension.During 112,935 person-years of follow-up, 5566 cases of incident hypertension were reported. Neither caffeinated coffee nor caffeine intake was associated with mean systolic or diastolic blood pressure, but decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean diastolic blood pressure. Decaffeinated coffee intake was not associated with mean systolic blood pressure. Intakes of caffeinated coffee, decaffeinated coffee, and caffeine were not associated with the risk of incident hypertension (P-trend > 0.05 for all).In summary, these findings suggest that caffeinated coffee, decaffeinated coffee, and caffeine are not risk factors for hypertension in postmenopausal women.

  View details for PubMedID 26657046

• Sleep disordered breathing and cardiovascular risk in older patients initiating dialysis in the United States: a retrospective observational study using medicare data. BMC nephrology Tuohy, C. V., Montez-Rath, M. E., Turakhia, M., Chang, T. I., Winkelman, J. W., Winkelmayer, W. C. 2016; 17: 16

  Abstract

  Sleep disordered breathing (SDB) such as sleep apnea is associated with cardiovascular disease in the general population. However, little is known about the cardiovascular risks of SDB in patients with end-stage renal disease (ESRD).We identified Medicare fee-for-service beneficiaries aged ≥67 years initiating dialysis between 2004 and 2009. Outcomes of interest included all-cause mortality, incident myocardial infarction, ischemic stroke, and atrial fibrillation. We compared patients with and without diagnosed SDB using Cox proportional hazards regression.Between 2004 and 2009, 184,217 older patients developed ESRD, of whom 15,121 (8.2 %) were previously diagnosed with SDB. Patients diagnosed with SDB were younger, more likely to be male and Caucasian, less Medicaid eligible, had more non-Nephrology clinic visits, higher body mass index, and more comorbidity. In analyses adjusting for demographics and BMI, diagnosed SDB was associated with higher risk of death and atrial fibrillation, but not associated with myocardial infarction or ischemic stroke risk. After further adjustment for all baseline characteristics, diagnosed SDB was associated with slightly lower risks of death (hazard ratio [HR]: 0.93, 95 % confidence interval [CI]: 0.91-0.96), myocardial infarction (HR: 0.92, CI: 0.87-0.98), and ischemic stroke (HR: 0.90, 95 % CI: 0.82-0.98), and not associated with atrial fibrillation (HR: 1.02, CI: 0.98-1.07).In older patients initiating dialysis in the U.S., diagnosed SDB was weakly associated with lower risks of death and important cardiovascular outcomes, thus adding to the list of established risk factors that are paradoxically associated with cardiovascular outcomes in the ESRD population.

  View details for PubMedID 26861778

• The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure: Findings From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Hypertension (Dallas, Tex. : 1979) Kronish, I. M., Lynch, A. I., Oparil, S., Whittle, J., Davis, B. R., Simpson, L. M., Krousel-Wood, M., Cushman, W. C., Chang, T. I., Muntner, P. 2016; 68 (1): 39–45

  Abstract

  Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability (VVV) of blood pressure (BP). We assessed the association between antihypertensive medication adherence and VVV of BP in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of BP was calculated using SD independent of mean, SD, and average real variability across study visits conducted 6 to 28 months after randomization. Participants who reported taking <80% of their antihypertensive medication at ≥1 study visits were categorized as nonadherent. Participants were followed up for cardiovascular events and mortality after the assessment of adherence and VVV of BP. SD independent of mean of BP was higher for nonadherent (n=2912) versus adherent (n=16 878) participants; 11.4±4.9 versus 10.5±4.5 for systolic BP; 6.8±2.8 versus 6.2±2.6 for diastolic BP (each P<0.001). SD independent of mean of BP remained higher among nonadherent than among adherent participants after multivariable adjustment (0.8 [95% confidence interval, 0.7-1.0] higher for systolic BP and 0.4 [95% confidence interval, 0.3-0.5] higher for diastolic BP]. SD and average real variability of systolic BP and diastolic BP were also higher among nonadherent than among adherent participants. Adjustment for nonadherence did not explain the association of VVV of BP with higher fatal coronary heart disease or nonfatal myocardial infarction, stroke, heart failure, or mortality risk. In conclusion, improving medication adherence may lower VVV of BP. However, VVV of BP is associated with cardiovascular outcomes independent of medication adherence.

  View details for PubMedID 27217410

• Medication adherence and visit-to-visit variability of systolic blood pressure in African Americans with chronic kidney disease in the AASK trial JOURNAL OF HUMAN HYPERTENSION Hong, K., Muntner, P., Kronish, I., Shilane, D., Chang, T. I. 2016; 30 (1): 73-78

  Abstract

  Lower adherence to antihypertensive medications may increase visit-to-visit variability of blood pressure (VVV of BP), a risk factor for cardiovascular events and death. We used data from the African American Study of Kidney Disease and Hypertension (AASK) trial to examine whether lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive chronic kidney disease (CKD). Determinants of VVV of BP were also explored. AASK participants (n=988) were categorized by self-report or pill count as having perfect (100%), moderately high (75-99%), moderately low (50-74%) or low (<50%) proportion of study visits with high medication adherence over a 1-year follow-up period. We used multinomial logistic regression to examine determinants of medication adherence, and multivariable-adjusted linear regression to examine the association between medication adherence and systolic VVV of BP, defined as the coefficient of variation or the average real variability (ARV). Participants with lower self-reported adherence were generally younger and had a higher prevalence of comorbid conditions. Compared with perfect adherence, moderately high, moderately low and low adherence was associated with 0.65% (±0.31%), 0.99% (±0.31%) and 1.29% (±0.32%) higher systolic VVV of BP (defined as the coefficient of variation) in fully adjusted models. Results were qualitatively similar when using ARV or when using pill counts as the measure of adherence. Lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive CKD; efforts to improve medication adherence in this population may reduce systolic VVV of BP.

  View details for DOI 10.1038/jhh.2015.26

  View details for Web of Science ID 000367734100013

  View details for PubMedID 25833706

• Comparative outcomes of predominant facility-level use of ferumoxytol versus other intravenous iron formulations in incident hemodialysis patients NEPHROLOGY DIALYSIS TRANSPLANTATION Airy, M., Mandayam, S., Mitani, A. A., Chang, T. I., Ding, V. Y., Brookhart, M. A., Goldstein, B. A., Winkelmayer, W. C. 2015; 30 (12): 2068-2075

  Abstract

  Ferumoxytol was first approved for clinical use in 2009 solely based on data from trial comparisons with oral iron on biochemical anemia efficacy end points. To compare the rates of important patient outcomes (infection, cardiovascular events and death) between facilities predominantly using ferumoxytol versus iron sucrose (IS) or ferric gluconate (FG) in patients with end-stage renal disease (ESRD)-initiating hemodialysis (HD).Using the United States Renal Data System, we identified all HD facilities that switched (almost) all patients from IS/FG to ferumoxytol (July 2009-December 2011). Each switching facility was matched with three facilities that continued IS/FG use. All incident ESRD patients subsequently initiating HD in these centers were studied and assigned their facility exposure. They were followed for all-cause mortality, cardiovascular hospitalization/death or infectious hospitalization/death. Follow-up ended at kidney transplantation, switch to peritoneal dialysis, transfer to another facility, facility switch to another iron formulation and end of database (31 December 2011). Cox proportional hazards regression was then used to estimate adjusted hazard ratios [HR (95% confidence intervals)].In July 2009-December 2011, 278 HD centers switched to ferumoxytol; 265 units (95.3%) were matched with 3 units each that continued to use IS/FG. Subsequently, 14 206 patients initiated HD, 3752 (26.4%) in ferumoxytol and 10 454 (73.6%) in IS/FG centers; their characteristics were very similar. During 6433 person-years, 1929 all-cause, 726 cardiovascular and 191 infectious deaths occurred. Patients in ferumoxytol (versus IS/FG) facilities experienced similar all-cause [0.95 (0.85-1.07)], cardiovascular [0.99 (0.83-1.19)] and infectious mortality [0.88 (0.61-1.25)]. Among 5513 Medicare (Parts A + B) beneficiaries, cardiovascular events [myocardial infarction, stroke and cardiovascular death; 1.05 (0.79-1.39)] and infectious events [hospitalization/death; 0.96 (0.85-1.08)] did not differ between the iron exposure groups.In incident HD patients, ferumoxytol showed similar short- to mid-term safety profiles with regard to cardiovascular, infectious and mortality outcomes compared with the more commonly used intravenous iron formulations IS and FG.

  View details for DOI 10.1093/ndt/gfv305

  View details for Web of Science ID 000368453700020

  View details for PubMedID 26311216

• Outcomes After Warfarin Initiation in a Cohort of Hemodialysis Patients With Newly Diagnosed Atrial Fibrillation. American journal of kidney diseases Shen, J. I., Montez-Rath, M. E., Lenihan, C. R., Turakhia, M. P., Chang, T. I., Winkelmayer, W. C. 2015; 66 (4): 677-688

  Abstract

  Although warfarin is indicated to prevent ischemic strokes in most patients with atrial fibrillation (AF), evidence supporting its use in hemodialysis patients is limited. Our aim was to examine outcomes after warfarin therapy initiation, relative to no warfarin use, following incident AF in a large cohort of hemodialysis patients who had comprehensive prescription drug coverage through Medicare Part D.Retrospective observational cohort study.Patients in the US Renal Data System undergoing maintenance hemodialysis who had AF newly diagnosed in 2007 to 2011, with Medicare Part D coverage, who had no recorded history of warfarin use.Warfarin therapy initiation, identified by a filled prescription within 30 days of the AF event.Death, ischemic stroke, hemorrhagic stroke, severe gastrointestinal bleeding, and composite outcomes.HRs estimated by applying Cox regression to an inverse probability of treatment and censoring-weighted cohort.Of 12,284 patients with newly diagnosed AF, 1,838 (15%) initiated warfarin therapy within 30 days; however, ∼70% discontinued its use within 1 year. In intention-to-treat analyses, warfarin use was marginally associated with a reduced risk of ischemic stroke (HR, 0.68; 95% CI, 0.47-0.99), but not with the other outcomes. In as-treated analyses, warfarin use was associated with reduced mortality (HR, 0.84; 95% CI, 0.73-0.97).Short observation period, limited number of nonfatal events, limited generalizability of results to more affluent patients.In hemodialysis patients with incident AF, warfarin use was marginally associated with reduced risk of ischemic stroke, and there was a signal toward reduced mortality in as-treated analyses. These results support clinical equipoise regarding the use of warfarin in hemodialysis patients and underscore the need for randomized trials to fill this evidence gap.

  View details for DOI 10.1053/j.ajkd.2015.05.019

  View details for PubMedID 26162653

• Classifying individuals based on a densely captured sequence of vital signs: An example using repeated blood pressure measurements during hemodialysis treatment JOURNAL OF BIOMEDICAL INFORMATICS Goldstein, B. A., Chang, T. I., Winkelmayer, W. C. 2015; 57: 219-224

  Abstract

  Electronic Health Records (EHRs) present the opportunity to observe serial measurements on patients. While potentially informative, analyzing these data can be challenging. In this work we present a means to classify individuals based on a series of measurements collected by an EHR. Using patients undergoing hemodialysis, we categorized people based on their intradialytic blood pressure. Our primary criteria were that the classifications were time dependent and independent of other subjects. We fit a curve of intradialytic blood pressure using regression splines and then calculated first and second derivatives to come up with four mutually exclusive classifications at different time points. We show that these classifications relate to near term risk of cardiac events and are moderately stable over a succeeding two-week period. This work has general application for analyzing dense EHR data.

  View details for DOI 10.1016/j.jbi.2015.08.010

  View details for Web of Science ID 000363437500020

  View details for PubMedID 26277118

• Longer-term Outcomes of Darbepoetin Alfa Versus Epoetin Alfa in Patients With ESRD Initiating Hemodialysis: A Quasi-experimental Cohort Study AMERICAN JOURNAL OF KIDNEY DISEASES Winkelmayer, W. C., Chang, T. I., Mitani, A. A., Wilhelm-Leen, E. R., Ding, V., Chertow, G. M., Brookhart, M. A., Goldstein, B. A. 2015; 66 (1): 106-113

  Abstract

  Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking.Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO.Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure.DPO versus EPO.All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.Unadjusted and adjusted HRs from Cox proportional hazards regression models.Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25).Nonrandom treatment assignment, potential residual confounding.In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

  View details for DOI 10.1053/j.ajkd.2015.02.339

  View details for PubMedID 25943715

• Coronary artery bypass graft type and outcomes in maintenance dialysis. journal of cardiovascular surgery Shilane, D., Hlatky, M. A., Winkelmayer, W. C., Chang, T. I. 2015; 56 (3): 463-471

  Abstract

  Aim: Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high burden of coronary disease. Prior studies in non-dialysis patients show better outcomes in coronary artery bypass surgery using the internal mammary artery (IMA) compared with the saphenous vein graft (SVG), but less is known about outcomes in ESRD. We sought to compare the effectiveness of multivessel bypass grafting using IMA versus SVG in patients on maintenance dialysis in the United States. Methods: Cohort study using data from the United States Renal Data System to examine IMA versus SVG in patients on maintenance dialysis undergoing multivessel coronary revascularization. We used Cox proportional hazards regression with multivariable adjustment in the full cohort and in a propensity-score matched cohort. The primary outcome was death from any cause; the secondary outcome was a composite of non-fatal myocardial infarction or death. Results: Overall survival rates were low in this patient population (5-year survival in the matched cohort 25.3%). Use of the IMA compared to SVG was associated with lower risk of death (adjusted hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.84-0.92) and lower risk of the composite outcome (adjusted HR 0.89; CI 0.85-0.93). Results did not materially change in analyses using the propensity-score matched cohort. We found similar results irrespective of patient sex, age, race, or the presence of diabetes, peripheral vascular disease or heart failure. Conclusion: Although overall survival rates were low, IMA was associated with lower risk of mortality and cardiovascular morbidity compared to SVG in patients on dialysis.

  View details for PubMedID 24343371

• Association of Spontaneous Bleeding and Myocardial Infarction With Long-Term Mortality After Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kazi, D. S., Leong, T. K., Chang, T. I., Solomon, M. D., Hlatky, M. A., Go, A. S. 2015; 65 (14): 1411-1420

  Abstract

  Platelet inhibition after percutaneous coronary intervention (PCI) reduces the risk of myocardial infarction (MI) but increases the risk of bleeding. MIs and bleeds during the index hospitalization for PCI are known to negatively affect long-term outcomes. The impact of spontaneous bleeding occurring after discharge on long-term mortality is unknown.This study sought to examine, in a real-world cohort, the association between spontaneous major bleeding or MI after PCI and long-term mortality.We conducted a retrospective cohort study of patients ≥30 years of age who underwent a PCI between 1996 and 2008 in an integrated healthcare delivery system. We used extended Cox regression to examine the associations of spontaneous bleeding and MI with all-cause mortality, after adjustment for time-updated demographics, comorbidities, periprocedural events, and longitudinal medication exposure.Among 32,906 patients who had a PCI and survived the index hospitalization, 530 had bleeds and 991 had MIs between 7 and 365 days post-discharge. There were 4,048 deaths over a mean follow-up of 4.42 years. The crude annual death rate after a spontaneous bleed (9.5%) or MI (7.6%) was higher than among patients who experienced neither event (2.6%). Bleeding was associated with an increased rate of death (adjusted hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.30 to 2.00), similar to that after an MI (HR: 1.91; 95% CI: 1.62 to 2.25). The association of bleeding with death remained significant after additional adjustment for the longitudinal use of antiplatelet agents.Spontaneous bleeding after a PCI was independently associated with higher long-term mortality, and conveyed a risk comparable to that of an MI during follow-up. This tradeoff between efficacy and safety bolsters the argument for personalizing antiplatelet therapy after PCI on the basis of the patient's long-term risk of both thrombotic and bleeding events.

  View details for DOI 10.1016/j.jacc.2015.01.047

  View details for Web of Science ID 000352419100005

  View details for PubMedID 25857906

• Visit-to-Visit Variability of Systolic Blood Pressure and Cardiovascular Disease CURRENT HYPERTENSION REPORTS Hussein, W. F., Chang, T. I. 2015; 17 (4)

  Abstract

  Visit-to-visit variability of blood pressure (VVV of BP) is gaining interest as a prognostic marker for stroke, cardiovascular disease, and all-cause mortality. In this review, we discuss different metrics used to define VVV of BP, explore the potential sources of this phenomenon including patient characteristics and antihypertensive medication classes, and discuss recent evidence of its relation with cardiovascular outcomes. Current evidence relies on secondary analyses of clinical trials or on observational studies, none of which was designed to examine VVV of BP specifically. More research is required to develop standardized definitions of VVV of BP, to confirm the value of VVV as a prognostic indicator, and to ascertain whether efforts to reduce VVV of BP in addition to mean BP will improve outcomes.

  View details for DOI 10.1007/s11906-014-0527-8

  View details for Web of Science ID 000351563900004

  View details for PubMedID 25754319

• Correlates and outcomes of warfarin initiation in kidney transplant recipients newly diagnosed with atrial fibrillation. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Lenihan, C. R., Montez-Rath, M. E., Shen, J. I., Scandling, J. D., Turakhia, M. P., Chang, T. I., Winkelmayer, W. C. 2015; 30 (2): 321-329

  Abstract

  In the kidney transplant population with atrial fibrillation (AF), evidence regarding the effectiveness and safety of warfarin treatment is lacking. We used fee-for-service Medicare claims to identify kidney transplant recipients with newly diagnosed AF from the United States Renal Data System. Warfarin use within 30 days of AF diagnosis was ascertained from Medicare Part D prescription claims (2007-11) or using a validated algorithm (1997-2011). The study end points were (i) the composite of death, stroke or gastrointestinal bleed, (ii) death and (iii) death-censored graft failure. Warfarin user and non-user groups were balanced using inverse probability of treatment weighting and hazard ratios were (HRs) estimated using Cox regression. Among 718 subjects with an indication for anticoagulation, 24% initiated warfarin treatment within 30 days of AF diagnosis. Age was the only independent correlate of warfarin use [odds ratio = 1.02 per year; 95% confidence interval (95% CI) 1.01-1.04]. In the larger cohort of 6492 patients with AF, warfarin use [(23.5%) versus non-use (76.5%)] was associated with small and non-significant reductions in the composite of death, stroke or gastrointestinal bleed (HR = 0.92; 95% CI 0.83-1.02), death (HR = 0.92; 95% CI 0.82-1.02) and death-censored graft failure (HR = 0.90; 95% CI 0.76-1.08). Our study suggests the need for clinical trials of warfarin use in the kidney transplant population with AF.

  View details for DOI 10.1093/ndt/gfu323

  View details for PubMedID 25335507

• Use of novel oral anticoagulants in patients with end-stage renal disease HEMODIALYSIS INTERNATIONAL Winkelmayer, W. C., Herzog, C. A., Montez-Rath, M. E., Chang, T. I., Chertow, G. M. 2015; 19 (1): 150–53

  View details for PubMedID 25495752

• Thienopyridine use after coronary stenting in low income patients enrolled in medicare part D receiving maintenance dialysis. Journal of the American Heart Association Chang, T. I., Montez-Rath, M. E., Shen, J. I., Solomon, M. D., Chertow, G. M., Winkelmayer, W. C. 2014; 3 (5)

  Abstract

  Coronary stenting in patients on dialysis has increased by nearly 50% over the past decade, despite heightened risks of associated stent thrombosis and bleeding relative to the general population. We examined clopidogrel, prasugrel or ticlopidine use after percutaneous coronary intervention (PCI) with stenting in patients on dialysis. We conducted 3-, 6-, and 12-month landmark analyses to test the hypothesis that thienopyridine discontinuation prior to those time points would be associated with higher risks of death, myocardial infarction, or repeat revascularization, and a lower risk of major bleeding episodes compared with continued thienopyridine use.Using the US Renal Data System, we identified 8458 patients on dialysis with Medicare Parts A+B+D undergoing PCI with stenting between July 2007 and December 2010. Ninety-nine percent of all thienopyridine prescriptions were for clopidogrel. At 3 months, 82% of patients who received drug-eluting stents (DES) had evidence of thienopyridine use. These proportions fell to 62% and 40% at 6 and 12 months, respectively. In patients who received a bare-metal stent (BMS), 70%, 34%, and 26% of patients had evidence of thienopyridine use at 3, 6, and 12 months, respectively. In patients who received a DES, there was a suggestion of higher risks of death or myocardial infarction associated with thienopyridine discontinuation in the 3-, 6-, and 12-months landmark analyses, but no higher risk of major bleeding episodes. In patients who received a BMS, there were no differences in death or cardiovascular events, and possibly lower risk of major bleeding with thienopyridine discontinuation in the 3- and 6-month landmark analyses.The majority of patients on dialysis who undergo PCI discontinue thienopyridines before 1 year regardless of stent type. While not definitive, these data suggest that longer-term thienopyridine use may be of benefit to patients on dialysis who undergo PCI with DES.

  View details for DOI 10.1161/JAHA.114.001356

  View details for PubMedID 25336465

• Thienopyridine use after coronary stenting in low income patients enrolled in medicare part D receiving maintenance dialysis. Journal of the American Heart Association Chang, T. I., Montez-Rath, M. E., Shen, J. I., Solomon, M. D., Chertow, G. M., Winkelmayer, W. C. 2014; 3 (5)

  View details for DOI 10.1161/JAHA.114.001356

  View details for PubMedID 25336465

• Acute Kidney Injury After CABG Versus PCI: An Observational Study Using 2 Cohorts. Journal of the American College of Cardiology Chang, T. I., Leong, T. K., Boothroyd, D. B., Hlatky, M. A., Go, A. S. 2014; 64 (10): 985-994

  Abstract

  Acute kidney injury (AKI) is a known complication after coronary revascularization, but few studies have directly compared the incidence of AKI after coronary artery bypass surgery (CABG) or after percutaneous coronary intervention (PCI) in similar patients.The aim of this study was to investigate whether multivessel CABG compared with PCI as an initial revascularization strategy is associated with a higher risk for AKI.A retrospective analysis of patients undergoing first documented coronary revascularization was conducted using 2 complementary cohorts: 1) Kaiser Permanente Northern California, a diverse, integrated health care delivery system; and 2) Medicare beneficiaries, a large, nationally representative older cohort. AKI was defined in the Kaiser Permanente Northern California cohort by an increase in serum creatinine of ≥0.3 mg/dl or ≥150% above baseline and in the Medicare cohort by discharge diagnosis codes and the use of dialysis.The incidence of AKI was 20.4% in the Kaiser Permanente Northern California cohort and 6.2% in the Medicare cohort. The incidence of AKI requiring dialysis was <1%. CABG was associated with a 2- to 3-fold significantly higher adjusted odds for developing AKI compared with PCI in both cohorts.AKI is common after multivessel coronary revascularization and is more likely after CABG than after PCI. The risk for AKI should be considered when choosing a coronary revascularization strategy, and ways to prevent AKI after coronary revascularization are needed.

  View details for DOI 10.1016/j.jacc.2014.04.077

  View details for PubMedID 25190232

• The Association of Gender to Cardiovascular Outcomes After Coronary Artery Revascularization in Patients With End-Stage Renal Disease CLINICAL CARDIOLOGY Krishnaswami, A., Chang, T. I., Jang, J. J., Leong, T. K., Go, A. S. 2014; 37 (9): 546-551

  Abstract

  Inadequate recruitment of women and an exclusion of patients with end-stage renal disease (ESRD) in coronary revascularization trials have led to knowledge gaps of gender-based outcomes.Women have equivalent cardiovascular outcomes when compared to men.We conducted a retrospective observational study utilizing Kaiser Permanente Northern California (KPNC) databases and identified 1015 adults with ESRD who underwent coronary revascularization between 1996 and 2008. We ascertained baseline characteristics, primary (mortality at 5 years) and secondary (myocardial infarction [MI] and repeat revascularization) outcomes from KPNC databases, state death certificates, and Social Security Administration files. A multivariable logistic regression was used to determine the association of gender to the prespecified outcomes.Men and women were similar in age (P = 0.23). The mean number of baseline comorbidities was higher in women (2.7, 95% confidence interval [CI]: 2.5-2.9) compared to men (2.3, 95% CI: 2.1-2.4, P = 0.0002). The risk-adjusted odds ratios (OR) of female gender to death at 5 years (OR: 1.12, 95% CI: 0.83-1.52), MI (OR: 1.19, 95% CI: 0.86-1.64), and repeat revascularization (OR: 1.01, 95% CI: 0.70-1.45) were similar to men. Age modified the effect of gender for the primary outcome death (Pinteraction < 0.048), with a trend toward worse outcomes in younger women and improved outcomes in older women. This effect was noted more in patients who underwent coronary artery bypass grafting.Although the overall relative risk of cardiovascular outcomes after coronary revascularization in ESRD was equivalent between men and women, age had a significant interaction with gender on overall mortality.

  View details for DOI 10.1002/clc.22306

  View details for Web of Science ID 000342236900006

  View details for PubMedCentralID PMC6649527

• Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. Journal of the American College of Cardiology Andersson, C., Shilane, D., Go, A. S., Chang, T. I., Kazi, D., Solomon, M. D., Boothroyd, D. B., Hlatky, M. A. 2014; 64 (3): 247-252

  Abstract

  The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI).The purpose of this study was to assess the association of beta-blockers with outcomes among patients with new-onset CHD.We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (pint) to determine whether the association differed for patients with or without a recent MI.A total of 26,793 patients were included, 19,843 of whom initiated beta-blocker treatment within 7 days of discharge from their initial CHD event. Over an average of 3.7 years of follow-up, 6,968 patients had an MI or died. Use of beta-blockers was associated with an adjusted HR for mortality of 0.90 (95% confidence limits [CL]: 0.84 to 0.96), and an adjusted HR for death or MI of 0.92 (CL: 0.87 to 0.97). The association between beta-blockers and outcomes differed significantly between patients with and without a recent MI (HR for death: 0.85 vs. 1.02, pint = 0.007; and HR for death or MI: 0.87 vs. 1.03, pint = 0.005).Use of beta-blockers among patients with new-onset CHD was associated with a lower risk of cardiac events only among patients with a recent MI.

  View details for DOI 10.1016/j.jacc.2014.04.042

  View details for PubMedID 25034059

• Temporal trends in mortality after coronary artery revascularization in patients with end-stage renal disease. The Permanente journal Krishnaswami, A., Leong, T. K., Hlatky, M. A., Chang, T. I., Go, A. S. 2014; 18 (3): 11-16

  Abstract

  Recent studies that have assessed the comparative effectiveness between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD) that have included analyses of temporal trends in mortality have noted mixed results.We conducted an observational longitudinal cohort study of all adults with ESRD undergoing CABG or PCI within Kaiser Permanente Northern California. The primary predictor, index period of revascularization, was categorized into 3 periods: 1996-1999 (reference), 2000-2003, and 2004-2008, with the primary outcome being 3-year all-cause mortality. A multivariable Cox regression model with the assumption of independent censoring was used to determine the adjusted relative risk of the primary predictor.Among 1015 ESRD patients, 3-year mortality showed no significant change in the 2000-2003 period but was lower during the 2004-2008 period with an adjusted hazard ratio of 0.66 (95% confidence interval: 0.49-0.88; trend test p = 0.01). No change in 30-day mortality was noted. Further adjustment for receipt of medications at baseline and after revascularization did not materially affect risk estimates. No significant interactions were observed between the type of revascularization (CABG or PCI) and the period of the index revascularization.Among a high-risk cohort of patients with ESRD and coronary artery disease within Kaiser Permanente Northern California who were referred for coronary revascularization by either CABG or PCI, the relative risk of mortality in the 2004-2008 period decreased by 34% compared with the 1996-1999 period, with the benefit primarily in the decrease in late mortality.

  View details for DOI 10.7812/TPP/14-003

  View details for PubMedID 25102514

  View details for PubMedCentralID PMC4116259

• Comparative Effectiveness of Clopidogrel in Medically Managed Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology Solomon, M. D., Go, A. S., Shilane, D., Boothroyd, D. B., Leong, T. K., Kazi, D. S., Chang, T. I., Hlatky, M. A. 2014; 63 (21): 2249-2257

  Abstract

  This study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI).Although clinical trials have demonstrated the efficacy of clopidogrel to reduce cardiovascular (CV) morbidity and mortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinical practice is less certain.A retrospective cohort study was conducted of Kaiser Permanente Northern California members without known coronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 and were medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting during the index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the association between clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI using propensity-matched multivariable Cox analyses.We identified 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribed clopidogrel within 7 days of discharge. In 8,562 propensity score-matched patients, clopidogrel users had lower rates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.54 to 0.72) and the composite of death or MI (13.5% vs. 17.4%; p < 0.01; HR: 0.74, CI: 0.66 to 0.84), but not MI alone (6.7% vs. 7.2%; p = 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The association between clopidogrel use and the composite of death or MI was significant only among patients presenting with NSTEMI (HR: 0.67; CI: 0.59 to 0.76; pint < 0.01), not among those presenting with UA (HR: 1.25; CI: 0.94 to 1.67).In a large, community-based cohort of patients who were medically managed after UA/NSTEMI, clopidogrel use was associated with a lower risk of death and MI, particularly among patients with NSTEMI.

  View details for DOI 10.1016/j.jacc.2014.02.586

  View details for PubMedID 24703914

• Lowering Blood Pressure to Lower the Risk of Cardiovascular Events in CKD AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Owens, D. K., Chertow, G. M. 2014; 63 (6): 900–902

  View details for PubMedID 24685064

• Near-Term Prediction of Sudden Cardiac Death in Older Hemodialysis Patients Using Electronic Health Records CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Goldstein, B. A., Chang, T. I., Mitani, A. A., Assimes, T. L., Winkelmayer, W. C. 2014; 9 (1): 82-91

  Abstract

  Sudden cardiac death is the most common cause of death among individuals undergoing hemodialysis. The epidemiology of sudden cardiac death has been well studied, and efforts are shifting to risk assessment. This study aimed to test whether assessment of acute changes during hemodialysis that are captured in electronic health records improved risk assessment.Data were collected from all hemodialysis sessions of patients 66 years and older receiving hemodialysis from a large national dialysis provider between 2004 and 2008. The primary outcome of interest was sudden cardiac death the day of or day after a dialysis session. This study used data from 2004 to 2006 as the training set and data from 2007 to 2008 as the validation set. The machine learning algorithm, Random Forests, was used to derive the prediction model.In 22 million sessions, 898 people between 2004 and 2006 and 826 people between 2007 and 2008 died on the day of or day after a dialysis session that was serving as a training or test data session, respectively. A reasonably strong predictor was derived using just predialysis information (concordance statistic=0.782), which showed modest but significant improvement after inclusion of postdialysis information (concordance statistic=0.799, P<0.001). However, risk prediction decreased the farther out that it was forecasted (up to 1 year), and postdialytic information became less important.Subtle changes in the experience of hemodialysis aid in the assessment of sudden cardiac death and are captured by modern electronic health records. The collected data are better for the assessment of near-term risk as opposed to longer-term risk.

  View details for DOI 10.2215/CJN.03050313

  View details for Web of Science ID 000329364700013

  View details for PubMedID 24178968

• Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis JOURNAL OF HUMAN HYPERTENSION Chang, T. I., Flythe, J. E., Brunelli, S. M., Muntner, P., Greene, T., Cheung, A. K., Chertow, G. M. 2014; 28 (1): 18-24

  Abstract

  Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9±4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.Journal of Human Hypertension advance online publication, 27 June 2013; doi:10.1038/jhh.2013.49.

  View details for DOI 10.1038/jhh.2013.49

  View details for Web of Science ID 000327940600005

• Contemporary Incidence, Predictors, and Outcomes of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions JACC-CARDIOVASCULAR INTERVENTIONS Tsai, T. T., Patel, U. D., Chang, T. I., Kennedy, K. F., Masoudi, F. A., Matheny, M. E., Kosiborod, M., Amin, A. P., Messenger, J. C., Rumsfeld, J. S., Spertus, J. A. 2014; 7 (1): 1-9

  Abstract

  This study sought to examine the contemporary incidence, predictors and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions.Acute kidney injury (AKI) is a serious and potentially preventable complication of percutaneous coronary interventions (PCIs) that is associated with adverse outcomes. The contemporary incidence, predictors, and outcomes of AKI are not well defined, and clarifying these can help identify high-risk patients for proactive prevention.A total of 985,737 consecutive patients underwent PCIs at 1,253 sites participating in the National Cardiovascular Data Registry Cath-PCI registry from June 2009 through June 2011. AKI was defined on the basis of changes in serum creatinine level in the hospital according to the Acute Kidney Injury Network (AKIN) criteria. Using multivariable regression analyses with generalized estimating equations, we identified patient characteristics associated with AKI.Overall, 69,658 (7.1%) patients experienced AKI, with 3,005 (0.3%) requiring new dialysis. On multivariable analyses, the factors most strongly associated with development of AKI included ST-segment elevation myocardial infarction (STEMI) presentation (odds ratio [OR]: 2.60; 95% confidence interval [CI]: 2.53 to 2.67), severe chronic kidney disease (OR: 3.59; 95% CI: 3.47 to 3.71), and cardiogenic shock (OR: 2.92; 95% CI: 2.80 to 3.04). The in-hospital mortality rate was 9.7% for patients with AKI and 34% for those requiring dialysis compared with 0.5% for patients without AKI (p < 0.001). After multivariable adjustment, AKI (OR: 7.8; 95% CI: 7.4 to 8.1, p < 0.001) and dialysis (OR: 21.7; 95% CI: 19.6 to 24.1; p < 0.001) remained independent predictors of in-hospital mortality.Approximately 7% of patients undergoing a PCI experience AKI, which is strongly associated with in-hospital mortality. Defining strategies to minimize the risk of AKI in patients undergoing PCI are needed to improve the safety and outcomes of the procedure.

  View details for DOI 10.1016/j.jcin.2013.06.016

  View details for Web of Science ID 000330953100003

  View details for PubMedCentralID PMC4122507

• Incremental prognostic information from kidney function in patients with new onset coronary heart disease AMERICAN HEART JOURNAL Hlatky, M. A., Shilane, D., Chang, T. I., Boothroyd, D., Go, A. S. 2014; 167 (1): 86-92

  Abstract

  Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain.We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement.Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m(2)). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007).Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.

  View details for DOI 10.1016/j.ahj.2013.10.006

  View details for Web of Science ID 000328458600013

  View details for PubMedID 24332146

• Multivessel coronary revascularization and outcomes in kidney transplant recipients. Transplant international Lenihan, C. R., Montez-Rath, M. E., Winkelmayer, W. C., Chang, T. I. 2013; 26 (11): 1080-1087

  Abstract

  Coronary artery disease is a major cause of morbidity and mortality in the kidney transplant population. We compared the long-term outcomes of coronary artery bypass graft (CABG) surgery with percutaneous coronary intervention (PCI) for multivessel coronary disease in a contemporary cohort of US kidney transplant recipients. From the U.S. Renal Data System, we identified all adult kidney transplant patients with ≥6 months of Medicare A+B undergoing first recorded multivessel coronary revascularization from 1997 to 2009. The associations of CABG versus PCI with death and the composite of death or myocardial infarction (MI) were compared using proportional hazards regression. Of the 2272 patients included in the study, 1594 underwent CABG and 678 underwent PCI. The estimated 5-year survival rate was 55% [95% confidence interval (CI) 53% to 57%] following coronary revascularization, with no significant association between revascularization type and death [adjusted hazard ratio (aHR) = 1.08; CI 0.94-1.23] or the composite of death or MI (aHR = 1.07; CI 0.96-1.18). Separate propensity score-matched analyses yielded similar results. In this analysis of kidney transplant recipients undergoing multivessel coronary revascularization, we found no difference between CABG and PCI in terms of survival or the composite of death and MI.

  View details for DOI 10.1111/tri.12168

  View details for PubMedID 23957580

  View details for PubMedCentralID PMC3816637

• Use and safety of heparin-free maintenance hemodialysis in the USA NEPHROLOGY DIALYSIS TRANSPLANTATION Shen, J. I., Mitani, A. A., Chang, T. I., Winkelmayer, W. C. 2013; 28 (6): 1589-1602

  Abstract

  BACKGROUND: Although heparin is used to anticoagulate the extracorporeal circuit for most patients on maintenance hemodialysis (HD), some patients undergo heparin-free HD. We describe the determinants of heparin-free HD and its association with adverse outcomes using data from a national dialysis provider merged with Medicare claims. METHODS: We identified patients aged ≥67 years with no recent history of warfarin use who initiated maintenance HD from 2007 to 2008. We applied the Cox regression to a propensity score-matched cohort to estimate the hazards of all-cause mortality, bleeding (gastrointestinal hemorrhage, hemorrhagic stroke, other hemorrhage), atherothrombosis (ischemic stroke, myocardial infarction) and venous thromboembolism (VTE) (deep vein thrombosis, pulmonary embolism). RESULTS: Among 12 468 patients, 836 (6.7%) were dialyzed heparin-free. In multivariable-adjusted analyses, a history of gastrointestinal bleeding, hemorrhagic stroke and lower hemoglobin and platelet counts were associated with higher odds of heparin-free HD. Heparin-free HD use also varied as much as 4-fold by facility region. We found no significant association of heparin-free HD with all-cause mortality [hazard ratio (HR) 1.08; 95% confidence interval (CI): 0.94-1.26], bleeding (HR 1.15; 95% CI: 0.83-1.60), atherothrombosis (HR 1.09, 95% CI: 0.90-1.31) or VTE (HR 1.23, 95% CI: 0.93-1.64) compared with HD with heparin. CONCLUSIONS: Patient markers of increased risk of bleeding and facility region associated with heparin-free HD use. Despite the potential benefits of avoiding heparin use, heparin-free HD was not significantly associated with decreased hazards of death, bleeding or thrombosis, suggesting that it may be no safer than HD with heparin.

  View details for DOI 10.1093/ndt/gft067

  View details for Web of Science ID 000321057700040

  View details for PubMedID 23563280

• Association of Intradialytic Blood Pressure Variability With Increased All-Cause and Cardiovascular Mortality in Patients Treated With Long-term Hemodialysis AMERICAN JOURNAL OF KIDNEY DISEASES Flythe, J. E., Inrig, J. K., Shafi, T., Chang, T. I., Cape, K., Dinesh, K., Kunaparaju, S., Brunelli, S. M. 2013; 61 (6): 966-974

  Abstract

  Blood pressure is known to fluctuate widely during hemodialysis; however, little is known about the association between intradialytic blood pressure variability and outcomes.Retrospective observational cohort.A random sample of 6,393 adult, thrice-weekly, in-center, maintenance hemodialysis patients dialyzing at 1,026 dialysis units within a single large dialysis organization.Intradialytic systolic blood pressure (SBP) variability. This was calculated using a mixed linear effects model. Peridialytic SBP phenomena were defined as starting SBP (regression intercept), systematic change in SBP over the course of dialysis (2 regression slopes), and random intradialytic SBP variability (absolute regression residual).All-cause and cardiovascular mortality.SBPs (n = 631,922) measured during hemodialysis treatments (n = 78,961) during the first 30 days in the study. Outcome data were obtained from the dialysis unit electronic medical record and were considered beginning on day 31.High (ie, greater than the median) versus low SBP variability was associated with greater risk of all-cause mortality (adjusted HR, 1.26; 95% CI, 1.08-1.47). The association between high SBP variability and cardiovascular mortality was even more potent (adjusted HR, 1.32; 95% CI, 1.01-1.72). A dose-response trend was observed across quartiles of SBP variability for both all-cause (P = 0.001) and cardiovascular (P = 0.04) mortality.Inclusion of patients from a single large dialysis organization, over-representation of African Americans and patients with diabetes and heart failure, and lack of standardized SBP measurements.Greater intradialytic SBP variability is associated independently with increased all-cause and cardiovascular mortality. Further prospective studies are needed to confirm findings and identify means of reducing SBP variability to facilitate randomized study.

  View details for DOI 10.1053/j.ajkd.2012.12.023

  View details for Web of Science ID 000318999200018

  View details for PubMedID 23474007

• Comparative effectiveness of multivessel coronary bypass surgery and multivessel percutaneous coronary intervention: a cohort study. Annals of internal medicine Hlatky, M. A., Boothroyd, D. B., Baker, L., Kazi, D. S., Solomon, M. D., Chang, T. I., Shilane, D., Go, A. S. 2013; 158 (10): 727-734

  Abstract

  Chinese translationRandomized trials of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) suggest that patient characteristics modify the effect of treatment on mortality.To assess whether clinical characteristics modify the comparative effectiveness of CABG versus PCI in an unselected, general patient population.Observational treatment comparison using propensity score matching and Cox proportional hazards models.United States, 1992 to 2008.Medicare beneficiaries aged 66 years or older.Multivessel CABG or multivessel PCI.The CABG-PCI hazard ratio (HR) for all-cause mortality, with prespecified treatment-by-covariate interaction tests, and the absolute difference in life-years of survival in clinical subgroups after CABG or PCI, both over 5 years of follow-up.Among 105 156 propensity score-matched patients, CABG was associated with lower mortality than PCI (HR, 0.92 [95% CI, 0.90 to 0.95]; P < 0.001). Association of CABG with lower mortality was significantly greater (interaction P ≤ 0.002 for each) among patients with diabetes (HR, 0.88), a history of tobacco use (HR, 0.82), heart failure (HR, 0.84), and peripheral arterial disease (HR, 0.85). The overall predicted difference in survival between CABG and PCI treatment over 5 years was 0.053 life-years (range, -0.017 to 0.579 life-years). Patients with diabetes, heart failure, peripheral arterial disease, or tobacco use had the largest predicted differences in survival after CABG, whereas those with none of these factors had slightly better survival after PCI.Treatments were chosen by patients and physicians rather than being randomly assigned.Multivessel CABG is associated with lower long-term mortality than multivessel PCI in the community setting. This association is substantially modified by patient characteristics, with improvement in survival concentrated among patients with diabetes, tobacco use, heart failure, or peripheral arterial disease.National Heart, Lung, and Blood Institute.

  View details for DOI 10.7326/0003-4819-158-10-201305210-00639

  View details for PubMedID 23609014

• Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease. American heart journal Chang, T. I., Leong, T. K., Kazi, D. S., Lee, H. S., Hlatky, M. A., Go, A. S. 2013; 165 (5): 800-808 e2

  Abstract

  Randomized clinical trials comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) have largely excluded patients with chronic kidney disease (CKD), leading to uncertainty about the optimal coronary revascularization strategy. We sought to test the hypothesis that an initial strategy of CABG would be associated with lower risks of long-term mortality and cardiovascular morbidity compared with PCI for the treatment of multivessel coronary heart disease in the setting of CKD.We created a propensity score-matched cohort of patients aged ≥30 years with no prior dialysis or renal transplant who received multivessel coronary revascularization between 1996 and 2008 within a large integrated health care delivery system in northern California. We used extended Cox regression to examine death from any cause, acute coronary syndrome, and repeat revascularization.Coronary artery bypass grafting was associated with a significantly lower adjusted rate of death than PCI across all strata of estimated glomerular filtration rate (eGFR) (in mL/min per 1.73 m(2)): the adjusted hazard ratio (HR) was 0.81, 95% CI 0.68 to 1.00 for patients with eGFR ≥60; HR 0.73 (CI 0.56-0.95) for eGFR of 45 to 59; and HR 0.87 (CI 0.67-1.14) for eGFR <45. Coronary artery bypass grafting was also associated with significantly lower rates of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with PCI.Among adults with and without CKD, multivessel CABG was associated with lower risks of death and coronary events compared with multivessel PCI.

  View details for DOI 10.1016/j.ahj.2013.02.012

  View details for PubMedID 23622918

• Risk Factors for ESRD in Individuals With Preserved Estimated GFR With and Without Albuminuria: Results From the Kidney Early Evaluation Program (KEEP) AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Li, S., Chen, S., Peralta, C. A., Shlipak, M. G., Fried, L. F., Whaley-Connell, A. T., McCullough, P. A., Tamura, M. K. 2013; 61 (4): S4-S11

  Abstract

  Given the increasing costs and poor outcomes of end-stage renal disease (ESRD), we sought to identify risk factors for ESRD in people with preserved estimated glomerular filtration rate (eGFR), with or without albuminuria, who were at high risk of ESRD.This cohort study included participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) with eGFR ≥ 60 mL/min/1.73 m(2) at baseline stratified by the presence or absence of albuminuria. The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate eGFR. Urine was tested for albuminuria by semiquantitative dipstick. The outcome was the development of treated chronic kidney failure, defined as initiation of maintenance dialysis therapy or kidney transplantation, determined by linkage to the US Renal Data System. We used a Cox model with the Fine-Gray method to assess risk factors for treated chronic kidney failure while accounting for the competing risk of death.During a median follow-up of 4.8 years, 126 of 13,923 participants with albuminuria (16/10,000 patient-years) and 56 of 109,135 participants without albuminuria (1.1/10,000 patient-years) developed treated chronic kidney failure. Diabetes was a strong risk factor for developing treated chronic kidney failure in participants with and without albuminuria (adjusted HRs of 9.3 [95% CI, 5.7-15.3] and 7.8 [95% CI, 4.1-14.8], respectively). Black race, lower eGFR, and higher systolic blood pressure also were associated with higher adjusted risks of developing treated chronic kidney failure.In a diverse high-risk cohort of KEEP participants with preserved eGFR, we showed that diabetes, higher systolic blood pressure, lower eGFR, and black race were risk factors for developing treated chronic kidney failure irrespective of albuminuria status, although the absolute risk of kidney failure in participants without albuminuria was very low. Our findings support testing for kidney disease in high-risk populations, which often have otherwise unrecognized kidney disease.

  View details for DOI 10.1053/j.ajkd.2012.12.016

  View details for PubMedID 23507268

• Effectiveness of beta-Blockers in Heart Failure With Left Ventricular Systolic Dysfunction and Chronic Kidney Disease JOURNAL OF CARDIAC FAILURE Chang, T. I., Yang, J., Freeman, J. V., Hlatky, M. A., Go, A. S. 2013; 19 (3): 176-182

  Abstract

  Establishing medication effectiveness outside of a randomized trial requires careful study design to mitigate selection bias. Previous observational studies of β-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of β-blocker therapy was associated with better outcomes among patients with chronic kidney disease and newly diagnosed heart failure with left ventricular systolic dysfunction.We identified 668 adults in the Kaiser Permanente Northern California system from 2006 to 2008 with chronic kidney disease, incident heart failure, left ventricular systolic dysfunction, and no previous β-blocker use. We defined chronic kidney disease as estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2) or proteinuria, and we excluded patients receiving dialysis. We used extended Cox regression to assess the association of treatment with death and the combined end point of death or heart failure hospitalization. Initiation of β-blocker therapy was associated with a significantly lower crude risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35-0.63), but this association was attenuated and no longer significant after multivariable adjustment (HR 0.75, CI 0.51-1.12). β-Blocker therapy was significantly associated with a lower risk of death or heart failure hospitalization even after adjustment for potential confounders (HR 0.67, CI 0.51-0.88).β-Blocker therapy is associated with lower risk of death or heart failure hospitalization among patients with chronic kidney disease, incident heart failure, and left ventricular systolic dysfunction.

  View details for DOI 10.1016/j.cardfail.2013.01.006

  View details for Web of Science ID 000316529900005

  View details for PubMedID 23482078

• Comparative Effectiveness Research in Heart Failure Therapies Women, Elderly Patients, and Patients with Kidney Disease HEART FAILURE CLINICS Shah, R. U., Chang, T. I., Fonarow, G. C. 2013; 9 (1): 79-?

  View details for DOI 10.1016/j.hfc.2012.09.003

  View details for Web of Science ID 000313137800008

  View details for PubMedID 23168319

• Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis. Journal of human hypertension Chang, T. I., Flythe, J. E., Brunelli, S. M., Muntner, P., Greene, T., Cheung, A. K., Chertow, G. M. 2013

  Abstract

  Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9±4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.Journal of Human Hypertension advance online publication, 27 June 2013; doi:10.1038/jhh.2013.49.

  View details for PubMedID 23803593

• Multivessel Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention in ESRD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Shilane, D., Kazi, D. S., Montez-Rath, M. E., Hlatky, M. A., Winkelmayer, W. C. 2012; 23 (12): 2042-2049

  Abstract

  Thirty to sixty percent of patients with ESRD on dialysis have coronary heart disease, but the optimal strategy for coronary revascularization is unknown. We used data from the United States Renal Data System to define a cohort of 21,981 patients on maintenance dialysis who received initial coronary revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) between 1997 and 2009 and had at least 6 months of prior Medicare coverage as their primary payer. The primary outcome was death from any cause, and the secondary outcome was a composite of death or myocardial infarction. Overall survival rates were consistently poor during the study period, with unadjusted 5-year survival rates of 22%-25% irrespective of revascularization strategy. Using multivariable-adjusted proportional hazards regression, we found that CABG compared with PCI associated with significantly lower risks for both death (HR=0.87, 95% CI=0.84-0.90) and the composite of death or myocardial infarction (HR=0.88, 95% CI=0.86-0.91). Results were similar in analyses using a propensity score-matched cohort. In the absence of data from randomized trials, these results suggest that CABG may be preferred over PCI for multivessel coronary revascularization in appropriately selected patients on maintenance dialysis.

  View details for DOI 10.1681/ASN.2012060554

  View details for Web of Science ID 000311819000017

  View details for PubMedID 23204445

  View details for PubMedCentralID PMC3507369

• Preoperative Statin Use and Postoperative Acute Kidney Injury AMERICAN JOURNAL OF MEDICINE Brunelli, S. M., Waikar, S. S., Bateman, B. T., Chang, T. I., Lii, J., Garg, A. X., Winkelmayer, W. C., Choudhry, N. K. 2012; 125 (12): 1195-?

  Abstract

  Acute kidney injury is a frequent postoperative complication that confers increased mortality, morbidity, and costs. The purpose of this study was to evaluate whether preoperative statin use is associated with a decreased risk of postoperative acute kidney injury.We assembled a retrospective cohort of 98,939 patients who underwent a major open abdominal, cardiac, thoracic, or vascular procedure between 2000 and 2010. Statin users were pair-matched to nonusers on the basis of surgery type, baseline kidney function, days from admission until surgery, and propensity score based on demographics, comorbid conditions, and concomitant medications. Acute kidney injury was defined based on changes in serum creatinine measurements applying Acute Kidney Injury Network and Risk-Injury-Failure staging systems, and on the need for renal replacement therapy. Associations between statin use and acute kidney injury were estimated by conditional logistic regression.Across various acute kidney injury definitions, statin use was consistently associated with a decreased risk: adjusted odds ratios (95% confidence intervals) varied from 0.74 (0.58-0.95) to 0.80 (0.71-0.90). Associations were similar among diabetics and nondiabetics, and across strata of baseline kidney function. The protective association of statins was most pronounced among patients undergoing vascular surgery and least among patients undergoing cardiac surgery.Preoperative statin use is associated with a decreased risk of postoperative acute kidney injury. Future randomized clinical trials are needed to determine causality.

  View details for DOI 10.1016/j.amjmed.2012.06.021

  View details for Web of Science ID 000311217600020

  View details for PubMedID 23062398

• Comparative effectiveness research: what is it and why do we need it in nephrology? NEPHROLOGY DIALYSIS TRANSPLANTATION Chang, T. I., Winkelmayer, W. C. 2012; 27 (6): 2156-2161

  Abstract

  The USA leads other industrialized countries in health care spending but lags behind in terms of health outcomes. There has been growing interest in comparative effectiveness research (CER) as a means to identify best practices to create a more efficient and effective health care system. Two key concepts of CER are that it should (i) compare two or more alternative tests, therapies or procedures and (ii) be conducted in persons, clinical settings and conditions that are representative of the real world. The goal of CER is to provide evidence for clinicians, patients, policy makers and others to make informed decisions that will ultimately improve the overall health of specific subgroups and of the population as a whole. In this narrative review, we first describe the strengths and limitations of various types of studies that constitute CER, including randomized clinical trials, observational studies and systematic reviews, providing examples from the nephrology literature. Because of the concerns regarding confounding in observational CER, we also provide an overview of methods to reduce confounding in these types of studies. Finally, we will discuss why CER pertaining to kidney disease care needs to be a top priority in order to move our field from a largely opinion-based specialty to an evidence-based specialty.

  View details for DOI 10.1093/ndt/gfs154

  View details for Web of Science ID 000304832100008

  View details for PubMedID 22649210

• Use of Secondary Prevention Medications among Adults with Reduced Kidney Function CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Gao, L., Brown, T. M., Safford, M. M., Judd, S. E., McClellan, W. M., Limdi, N. A., Muntner, P., Winkelmayer, W. C. 2012; 7 (4): 604-611

  Abstract

  Persons with kidney disease often have cardiovascular disease, but they are less likely to use recommended medications for secondary prevention. The hypothesis was that participants with reduced estimated GFR have lower use of medications recommended for secondary prevention of cardiovascular events (antiplatelet agents, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, β-blockers, and statins) and lower medication adherence than participants with preserved estimated GFR.In this cross-sectional analysis, we analyzed data from 6913 participants in the Reasons for Geographic and Racial Differences in Stroke study with a history of cardiovascular disease. Medication use was ascertained by an in-home pill bottle review. Medication adherence was assessed using a validated four-item scale.Among participants with a history of cardiovascular disease, 59.8% used antiplatelet agents, 49.9% used angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, 41.6% used β-blockers, and 53.0% used statins. Compared with the referent group (estimated GFR ≥60 ml/min per 1.73 m(2)), participants with estimated GFR <45 ml/min per 1.73 m(2) were more likely to use angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (adjusted prevalence ratio=1.14, 95% confidence interval=1.06-1.23), β-blockers (adjusted prevalence ratio=1.20, 95% confidence interval=1.09-1.32), and statins (adjusted prevalence ratio=1.10, 95% confidence interval=1.01-1.19). Antiplatelet agent use did not differ by estimated GFR category; 30% of participants reported medication nonadherence across all categories of estimated GFR.Among participants with a history of cardiovascular disease, mild to moderate reductions in estimated GFR were associated with similar and even more frequent use of medications for secondary prevention compared with participants with preserved estimated GFR. Overall medication use and adherence were suboptimal.

  View details for DOI 10.2215/CJN.11441111

  View details for Web of Science ID 000302281900013

  View details for PubMedID 22344513

  View details for PubMedCentralID PMC3315345

• Blood Pressure Components and End-stage Renal Disease in Persons With Chronic Kidney Disease The Kidney Early Evaluation Program (KEEP) ARCHIVES OF INTERNAL MEDICINE Peralta, C. A., Norris, K. C., Li, S., Chang, T. I., Tamura, M. K., Jolly, S. E., Bakris, G., McCullough, P. A., Shlipak, M. 2012; 172 (1): 41-47

  Abstract

  Treatment of hypertension is difficult in chronic kidney disease (CKD), and blood pressure goals remain controversial. The association between each blood pressure component and end-stage renal disease (ESRD) risk is less well known.We studied associations of systolic and diastolic blood pressure (SBP and DBP, respectively) and pulse pressure (PP) with ESRD risk among 16,129 Kidney Early Evaluation Program (KEEP) participants with an estimated glomerular filtration rate of 60 mL/min/1.73 m(2) using Cox proportional hazards. We estimated the prevalence and characteristics associated with uncontrolled hypertension (SBP ≥ 150 or DBP ≥ 90 mm Hg).The mean (SD) age of participants was 69 (12) years; 25% were black, 6% were Hispanic, and 43% had diabetes mellitus. Over 2.87 years, there were 320 ESRD events. Higher SBP was associated with higher ESRD risk, starting at SBP of 140 mm Hg or higher. After sex and age adjustment, compared with SBP lower than 130 mm Hg, hazard ratios (HRs) were 1.08 (95% CI, 0.74-1.59) for SBP of 130 to 139 mm Hg, 1.72 (95% CI, 1.21-2.45) for SBP of 140 to 149 mm Hg, and 3.36 (95% CI, 2.51-4.49) for SBP of 150 mm Hg or greater. After full adjustment, HRs for ESRD were 1.27 (95% CI, 0.88-1.83) for SBP of 140 to 149 mm Hg and 1.36 (95% CI, 1.02-1.85) for SBP of 150 mm Hg or higher. Persons with DBP of 90 mm Hg or higher were at higher risk for ESRD compared with persons with DBP of 60 to 74 mm Hg (HR, 1.81; 95% CI, 1.33-2.45). Higher PP was also associated with higher ESRD risk (HR, 1.44 [95% CI, 1.00-2.07] for PP ≥ 80 mm Hg compared with PP < 50 mm Hg). Adjustment for SBP attenuated this association. More than 33% of participants had uncontrolled hypertension (SBP ≥ 150 mm Hg or DBP ≥ 90 mm Hg), mostly due to isolated systolic hypertension (54%).In this large, diverse, community-based sample, we found that high SBP seemed to account for most of the risk of progression to ESRD. This risk started at SBP of 140 mm Hg rather than the currently recommended goal of less than 130 mm Hg, and it was highest among those with SBP of at least 150 mm Hg. Treatment strategies that preferentially lower SBP may be required to improve BP control in CKD.

  View details for Web of Science ID 000298958900008

  View details for PubMedID 22232147

  View details for PubMedCentralID PMC3417125

• Systolic Blood Pressure and Mortality in Patients on Hemodialysis CURRENT HYPERTENSION REPORTS Chang, T. I. 2011; 13 (5): 362-369

  Abstract

  Hypertension is extremely common in patients with end-stage renal disease who are receiving hemodialysis, and cardiovascular disease remains the leading cause of death in these patients. However, optimal blood pressure management strategies in this high-risk population are still controversial. This review first discusses the complex association of systolic blood pressure with clinical outcomes in patients on hemodialysis, with a focus on several recent studies. Next, it updates the reader on issues related to optimal timing and methods of blood pressure measurement, appropriate blood pressure targets, and pharmacologic and nonpharmacologic hypertension treatment strategies for patients on hemodialysis.

  View details for DOI 10.1007/s11906-011-0223-x

  View details for Web of Science ID 000295167300007

  View details for PubMedID 21800233

• Chronic Kidney Disease and Cardiovascular Therapeutics Time to Close the Evidence Gaps JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Chang, T. I., Chertow, G. M. 2011; 58 (11): 1162-1164

  View details for DOI 10.1016/j.jacc.2011.06.010

  View details for Web of Science ID 000294449200013

  View details for PubMedID 21884955

• Angiotensin-converting enzyme inhibitors and cardiovascular outcomes in patients on maintenance hemodialysis AMERICAN HEART JOURNAL Chang, T. I., Shilane, D., Brunelli, S. M., Cheung, A. K., Chertow, G. M., Winkelmayer, W. C. 2011; 162 (2): 324-330

  Abstract

  Persons with end-stage renal disease (ESRD) on hemodialysis carry an exceptionally high burden of cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEIs) are recommended for patients on dialysis, but there are few data regarding their effectiveness in ESRD.We conducted a secondary analysis of results of the HEMO study, a randomized trial of dialysis dose and membrane flux in patients on maintenance hemodialysis. We focused on the nonrandomized exposure of ACEI use, using proportional hazards regression and a propensity score analysis. The primary outcome was all-cause mortality. Secondary outcomes examined in the present analysis were cardiovascular hospitalization, heart failure hospitalization, and the composite outcomes of death or cardiovascular hospitalization and death or heart failure hospitalization.In multivariable-adjusted analyses, there were no significant associations among ACEI use and mortality (hazard ratio 0.97, 95% CI 0.82-1.14), cardiovascular hospitalization, and either composite outcome. Angiotensin-converting enzyme inhibitor use was associated with a higher risk of heart failure hospitalization (hazard ratio 1.41, 95% CI 1.11-1.80). In the propensity score-matched cohort, ACEI use was not significantly associated with any outcomes, including heart failure hospitalization.In a well-characterized cohort of patients on maintenance hemodialysis, ACEI use was not significantly associated with mortality or cardiovascular morbidity. The higher risk of heart failure hospitalization associated with ACEI use may not only reflect residual confounding but also highlights gaps in evidence when applying treatments proven effective in the general population to patients with ESRD. Our results underscore the need for definitive trials in ESRD to inform the treatment of cardiovascular disease.

  View details for DOI 10.1016/j.ahj.2011.05.004

  View details for PubMedID 21835294

• Angiotensin Converting Enzyme Inhibitors in Hemodialysis Chang, T. I., Shilane, D., Brunelli, S. M., Cheung, A. K., Chertow, G. M., Winkelmayer, W. C. WILEY PERIODICALS, INC. 2011: S15–S15

  View details for Web of Science ID 000294946600034

• Intradialytic Hypotension and Vascular Access Thrombosis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Paik, J., Greene, T., Desai, M., Bech, F., Cheung, A. K., Chertow, G. M. 2011; 22 (8): 1526-1533

  Abstract

  Identifying potential modifiable risk factors to reduce the incidence of vascular access thrombosis in hemodialysis could reduce considerable morbidity and health care costs. We analyzed data from a subset of 1426 HEMO study subjects to determine whether more frequent intradialytic hypotension and/or lower predialysis systolic BP were associated with higher rates of vascular access thrombosis. Our primary outcome measure was episodes of vascular access thrombosis occurring within a given 6-month period during HEMO study follow-up. There were 2005 total episodes of vascular access thrombosis during a median 3.1 years of follow-up. The relative rate of thrombosis of native arteriovenous fistulas for the highest quartile of intradialytic hypotension was approximately twice that of the lowest quartile, independent of predialysis systolic BP and other covariates. There was no significant association of intradialytic hypotension with prosthetic arteriovenous graft thrombosis after multivariable adjustment. Higher predialysis systolic BP was associated with a lower rate of fistula and graft thrombosis, independent of intradialytic hypotension and other covariates. In conclusion, more frequent episodes of intradialytic hypotension and lower predialysis systolic BP associate with increased rates of vascular access thrombosis. These results underscore the importance of including vascular access patency in future studies of BP management in hemodialysis.

  View details for DOI 10.1681/ASN.2010101119

  View details for PubMedID 21803971

• Kidney Function and Long-Term Medication Adherence after Myocardial Infarction in the Elderly CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chang, T. I., Desai, M., Solomon, D. H., Winkelmayer, W. C. 2011; 6 (4): 864-869

  Abstract

  The association of kidney function with long-term outpatient medication adherence in the elderly remains understudied.A cohort of 2103 patients over the age of 65 years enrolled in a pharmacy benefits program after hospital discharge for myocardial infarction was studied. Using linear mixed effects models, the association of baseline kidney function with long-term adherence to recommended medications after myocardial infarction was examined, including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), β-blockers, and statins. The primary outcome measure was the percentage of days covered as calculated by pharmacy refill data for 12 serial 3-month intervals (totaling 36 months of follow-up).Overall long-term adherence to ACEIs/ARBs, β-blockers, and statins was poor. The mean percentage of days covered by 36 months was only 50% to 60% for all three medication classes. Patients with baseline kidney dysfunction had significantly lower long-term ACEI/ARB and β-blocker adherence compared with patients with higher baseline kidney function. Long-term statin adherence did not vary by baseline level of kidney function.Long-term medication adherence after myocardial infarction in the elderly is low, especially in patients with kidney dysfunction. Future strategies to improve medication adherence should pay special attention to the elderly with kidney dysfunction because they may be especially vulnerable to its adverse clinical consequences.

  View details for DOI 10.2215/CJN.07290810

  View details for Web of Science ID 000289223600025

  View details for PubMedID 21233459

  View details for PubMedCentralID PMC3069380

• Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study JOURNAL OF HUMAN HYPERTENSION Chang, T. I., Friedman, G. D., Cheung, A. K., Greene, T., Desai, M., Chertow, G. M. 2011; 25 (2): 98-105

  Abstract

  Previous studies of blood pressure and mortality in haemodialysis have yielded mixed results, perhaps due to confounding by comorbid conditions. We hypothesized that after improved accounting for confounding factors, higher systolic blood pressure (SBP) would be associated with higher all-cause mortality. We conducted a secondary analysis of data from the haemodialysis study, a randomized trial in prevalent haemodialysis patients. We used three proportional hazard models to determine the relative hazard at different levels of SBP: (1) Model-BL used baseline SBP; (2) Model-TV used SBP as a time-varying variable; and (3) Model-TV-Lag added a 3-month lag to Model-TV to de-emphasize changes in SBP associated with acute illness. In all the models, pre-dialysis SBP <120 mm Hg was associated with a higher risk of mortality compared with the referent group (140-159 mm Hg); higher pre-dialysis SBP was not associated with higher risk of mortality. In conclusion, we observed a robust association between lower pre-dialysis SBP and higher risk for all-cause and cardiovascular mortality in a well-characterized cohort of prevalent haemodialysis patients. Randomized clinical trials are needed to define optimal blood pressure targets in the haemodialysis population.

  View details for DOI 10.1038/jhh.2010.42

  View details for PubMedID 20410919

• Blood Pressure Control in Type 2 Diabetes Mellitus AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Cheung, A. K., Chertow, G. M. 2010; 56 (6): 1029-1031

  View details for DOI 10.1053/j.ajkd.2010.08.007

  View details for PubMedID 20870328

• Updated comorbidity assessments and outcomes in prevalent hemodialysis patients HEMODIALYSIS INTERNATIONAL Chang, T. I., Paik, J., Greene, T., Miskulin, D. C., Chertow, G. M. 2010; 14 (4): 478-485

  Abstract

  When evaluating clinical characteristics and outcomes in patients on hemodialysis, the prevalence and severity of comorbidity may change over time. Knowing whether updated assessments of comorbidity enhance predictive power will assist the design of future studies. We conducted a secondary data analysis of 1846 prevalent hemodialysis patients from 15 US clinical centers enrolled in the HEMO study. Our primary explanatory variable was the Index of Coexistent Diseases score, which aggregates comorbidities, as a time-constant and time-varying covariate. Our outcomes of interest were all-cause mortality, time to first hospitalization, and total hospitalizations. We used Cox proportional hazards regression. Accounting for an updated comorbidity assessment over time yielded a more robust association with mortality than accounting for baseline comorbidity alone. The variation explained by time-varying comorbidity assessments on time to death was greater than age, baseline serum albumin, diabetes, or any other covariates. There was a less pronounced advantage of updated comorbidity assessments on determining time to hospitalization. Updated assessments of comorbidity significantly strengthen the ability to predict death in patients on hemodialysis. Future studies in dialysis should invest the necessary resources to include repeated assessments of comorbidity.

  View details for DOI 10.1111/j.1542-4758.2010.00468.x

  View details for PubMedID 20955281

• Kidney Disease and Antihypertensive Medication Adherence: The Need for Improved Measurement Tools AMERICAN JOURNAL OF KIDNEY DISEASES Chang, T. I., Winkelmayer, W. C. 2010; 56 (3): 423-426

  View details for DOI 10.1053/j.ajkd.2010.05.006

  View details for Web of Science ID 000281203200002

  View details for PubMedID 20728787

• Kidney Disease, Hospitalized Hypertension, and Cardiovascular Events: Cause or Consequence? CIRCULATION Chertow, G. M., Chang, T. I. 2010; 121 (20): 2160-2161

  View details for DOI 10.1161/CIRCULATIONAHA.110.956904

  View details for Web of Science ID 000278018500002

  View details for PubMedID 20458007

• GFR estimating equations, CKD prevalence and the public health JOURNAL OF INTERNAL MEDICINE Chang, T. I., Chertow, G. M. 2010; 267 (4): 354-356

  View details for DOI 10.1111/j.1365-2796.2009.02172.x

  View details for Web of Science ID 000275518600002

  View details for PubMedID 20433581

• Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects DIABETOLOGIA Chang, T. I., Horal, M., Jain, S. K., Wang, F., Patel, R., Loeken, M. R. 2003; 46 (4): 538-545

  Abstract

  Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy.Maternal diabetes-induced oxidative stress was blocked with alpha-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and alpha-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by alpha-tocopherol and GSH-ethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks.Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress.

  View details for DOI 10.1007/s00125-003-1063-2

  View details for Web of Science ID 000183198600015

  View details for PubMedID 12739027

• Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy DIABETES Fine, E. L., Horal, M., Chang, T. I., Fortin, G., Loeken, M. R. 1999; 48 (12): 2454-2462

  Abstract

  Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.

  View details for Web of Science ID 000083880900025

  View details for PubMedID 10580436

• Genotoxicity and diabetic embryopathy: Impaired expression of developmental control genes as a cause of defective morphogenesis SEMINARS IN REPRODUCTIVE ENDOCRINOLOGY Chang, T. I., Loeken, M. R. 1999; 17 (2): 153-165

  Abstract

  Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.

  View details for Web of Science ID 000083025700006

  View details for PubMedID 10528366