Bio

Clinical Focus


  • Nephrology
  • hypertension
  • chronic kidney disease

Academic Appointments


Professional Education


  • Fellowship:Stanford University - CAPS (2009) CA
  • Board Certification: Nephrology, American Board of Internal Medicine (2009)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2006)
  • Residency:UCSF-Graduate Medical Education (2006) CA
  • Internship:UCSF-Internal Medicine (2004) CA
  • Medical Education:University of Michigan Health System (2003) MI

Research & Scholarship

Current Research and Scholarly Interests


As a board-certified nephrologist, I see first-hand the pervasiveness of cardiovascular disease in patients with chronic kidney disease (CKD). As a trained epidemiologist and clinical researcher, I also see the lack of evidence available to guide treatment decision-making in CKD. Motivated by these evidence gaps, my research seeks to clarify questions about cardiovascular care in patients with CKD. My research specifically focuses on issues such as blood pressure control, coronary revascularization, and the comparative effectiveness of cardioprotective medications in patients with CKD, with the long-term goal of improving outcomes in these high-risk patients.

Publications

Journal Articles


  • 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

  • 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

  • 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

  • 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 Web of Science ID 000317270600002

    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 ?-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of ?-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 ?-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 ?-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). ?-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).?-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

  • 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, ?-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 ?-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), ?-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

  • 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

  • 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 Web of Science ID 000293729400016

    View details for PubMedID 21835294

  • 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 Web of Science ID 000294083300019

    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), ?-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, ?-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 ?-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

  • 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 Web of Science ID 000286179500005

    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 Web of Science ID 000284401800006

    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 Web of Science ID 000283174100021

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

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