Bio

Clinical Focus


  • Nephrology
  • Kidney Transplant

Academic Appointments


Professional Education


  • Fellowship: Stanford University Nephrology Fellowship (2014) CA
  • Board Certification: Royal College of Physicians of Ireland, Nephrology (2012)
  • Fellowship: Stanford University Transplant Nephrology Fellowship (2012) CA
  • Residency: Royal College of Physicians in Ireland (2012) Ireland
  • Residency: Mater Misericordiae (2004) Ireland
  • Internship: St Vincent's University Hospital (2002) Ireland
  • Medical Education: University College Dublin (2001) Ireland
  • Fellowship, Stanford University, California, Nephrology (2015)
  • PhD, University College Dublin, Ireland (2013)
  • CCST, Royal College of Physicians in Ireland, Nephrology and Internal Medicine (2012)
  • Fellowship, Stanford University, California, Transplant Nephrology (2012)
  • Basic Medical Training, Royal College of Physicians in Ireland (2004)
  • MB BCh BAO, University College Dublin, Ireland (2001)

Publications

All Publications


  • Trends in the Medical Complexity and Outcomes of Medicare-insured Patients Undergoing Kidney Transplant in the Years 1998-2014 TRANSPLANTATION Lenihan, C. R., Liu, S., Montez-Rath, M. E., Winkelmayer, W. C. 2019; 103 (11): 2413?22

    Abstract

    Graft and patient survival following kidney transplant are improving. However, the drivers of this trend are unclear. To gain further insight, we set out to examine concurrent changes in pretransplant patient complexity, posttransplant survival, and cause-specific hospitalization.We identified 101?332 Medicare-insured patients who underwent their first kidney transplant in the United States between the years 1998 and 2014. We analyzed secular trends in (1) posttransplant patient and graft survival and (2) posttransplant hospitalization for cardiovascular disease, infection, and cancer using Cox models with year of kidney transplant as the primary exposure of interest.Age, dialysis vintage, body mass index, and the prevalence of a number of baseline medical comorbidities increased during the study period. Despite these adverse changes in case mix, patient survival improved: the unadjusted and multivariable-adjusted hazard ratios (HRs) for death in 2014 (versus 1998) were 0.61 (confidence interval [CI], 0.52-0.73) and 0.46 (CI, 0.39-0.55), respectively. For graft failure excluding death with a functioning graft, the unadjusted and multivariable adjusted subdistribution HRs in 2014 versus 1998 were 0.4 (CI, 0.25-0.55) and 0.45 (CI, 0.3-0.6), respectively. There was a marked decrease in hospitalizations for cardiovascular disease following transplant between 1998 and 2011, subdistribution HR 0.51 (CI, 0.43-0.6). Hospitalization for infection remained unchanged, while cancer hospitalization increased modestly.Medicare-insured patients undergoing kidney transplant became increasingly medically complex between 1998 and 2014. Despite this, both patient and graft survival improved during this period. A marked decrease in serious cardiovascular events likely contributed to this positive trend.

    View details for DOI 10.1097/TP.0000000000002670

    View details for Web of Science ID 000509347800046

    View details for PubMedID 30801531

  • THE RISK OF DE NOVO ANTI-HLA ANTIBODY FORMATION ASSOCIATED WITH SEASONAL INFLUENZA VACCINATION IN HEMODIALYSIS-TREATED PATIENTS ON THE KIDNEY TRANSPLANT WAITING LIST Liu, H., Chen, G., Lin, L., Tyan, D. B., Lenihan, C. ELSEVIER SCIENCE INC. 2019: 177?78
  • ADRENAL INSUFFICIENCY AFTER BILATERAL NEPHRECTOMY FOR POLYCYSTIC KIDNEY DISEASE Bolanos, C. G., Lenihan, C. R. W B SAUNDERS CO-ELSEVIER INC. 2019: 658?59
  • Combined Deceased Donor Parathyroid and Kidney Transplantation - An Underutilized Approach for ESRD Patients with Permanent Hypoparathyroidism Lee, L., Pan, J., Vasa, P., Berry, G., Lenihan, C., Busque, S. WILEY. 2019: 56
  • Proton Pump Inhibitors, Histamine-2 Receptor Antagonists, and Hip Fracture Risk among Patients on Hemodialysis. Clinical journal of the American Society of Nephrology : CJASN Vangala, C., Niu, J., Lenihan, C. R., Mitch, W. E., Navaneethan, S. D., Winkelmayer, W. C. 2018; 13 (10): 1534?41

    Abstract

    BACKGROUND AND OBJECTIVES: An association between proton pump inhibitor (PPI) use and hip fracture risk has been described in the general population, where the primary causative hypothesis focuses on impaired gastrointestinal calcium absorption. The impact of acid suppressor use on hip fracture risk in a high-risk subset, patients with ESKD requiring hemodialysis, is unknown and could help further distinguish the reason for higher susceptibility among PPI users.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using the US Renal Data System, we identified all hip fracture events recorded between 2009 and 2014 among patients dependent on hemodialysis. Eligible cases were matched on index date with ten controls. We identified PPI and histamine-2 receptor antagonist use from Medicare Part D claims covering 3 years before the index date and stratified according to proportion of days covered by filled prescriptions. Using logistic regression with multiple imputation for missing data, we estimated unadjusted and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs).RESULTS: We studied 4551 cases and 45,510 controls. Patients were older, more likely to be female and white, and had shorter dialysis vintage; fewer were obese. A larger proportion of patients had any prior PPI (70% versus 63%) or histamine-2 receptor antagonist (25% versus 23%) use. Use of PPI was associated with higher risk of hip fracture (adjusted OR, 1.19; 95% CI, 1.11 to 1.28). This association remained within subgroups of low, moderate, and high PPI use, yielding adjusted ORs of 1.16 (95% CI, 1.06 to 1.27), 1.21 (95% CI, 1.11 to 1.31), and 1.19 (95% CI, 1.08 to 1.31), respectively.CONCLUSIONS: Among patients with ESKD on hemodialysis, PPIs and not histamine-2 receptor antagonists were associated with hip fracture events.

    View details for PubMedID 30262672

  • De Novo Heart Failure After Kidney Transplantation: Trends in Incidence and Outcomes. American journal of kidney diseases : the official journal of the National Kidney Foundation Lenihan, C. R., Liu, S., Deswal, A., Montez-Rath, M. E., Winkelmayer, W. C. 2018

    Abstract

    BACKGROUND: Heart failure is an important cause of morbidity and mortality following kidney transplantation. Some studies in the general population have shown that the incidence of heart failure has decreased during the past 20 years. However, it is not currently known whether such a trend exists in the kidney transplantation population.STUDY DESIGN: Retrospective observational cohort study.SETTING & PARTICIPANTS: Adult patients included in the US Renal Data System who underwent their first kidney transplantation in the United States between 1998 and 2010 with at least 6 months of continuous Medicare parts A and B coverage before transplantation and no prior evidence for adiagnosis of heart failure before kidney transplantation.PREDICTORS: Calendar year of transplantation and calendar year of posttransplantation heart failure diagnosis.OUTCOMES: De novo posttransplantation heart failure defined using International Classification of Diseases, Ninth Revision diagnosis codes and mortality following de novo posttransplantation heart failure diagnosis. Secular trends in de novo post-kidney transplantation heart failure were examined using Cox proportional hazards analysis.RESULTS: Within a study cohort of 48,771 patients, 7,269 developed de novo heart failure within 3 years of kidney transplantation, with a median time to heart failure of 0.76 years. The adjusted HR for heart failure with death as competing risk comparing patients who underwent transplantation in 2010 with those who underwent transplantation in 1998 was 0.69 (95% CI, 0.60-0.79). No temporal trend in mortality following a diagnosis of post-kidney transplantation heart failure was observed.LIMITATIONS: Potential residual confounding from either incorrectly ascertained or unavailable confounders. The cohort was limited to Medicare beneficiaries.CONCLUSIONS: Adjusted for demographic and clinical characteristics, the risk for developing de novo post-kidney transplantation heart failure has declined significantly between 1998 and 2010, with no apparent change in subsequent mortality.

    View details for DOI 10.1053/j.ajkd.2018.01.041

    View details for PubMedID 29605378

  • Statin use and hip fractures in US kidney transplant recipients BMC NEPHROLOGY Vangala, C., Lenihan, C. R., Montez-Rath, M. E., Nair, S. S., Navaneethan, S. D., Ramanathan, V., Winkelmayer, W. C. 2017; 18

    Abstract

    Basic and translational research supports beneficial effects of statins on bone metabolism. Clinical studies suggest that statin use may reduce the risk of hip fractures in the general population. Whether statin use is associated with hip fracture risk in kidney transplant recipients, a particularly high-risk group for this outcome, is unknown.From the U.S. Renal Data System (2007-2011), we identified all hip fracture events recorded in Medicare billing claims of first-time kidney transplant recipients. We then matched all cases to an unlimited number of controls on age (±3 years), sex, race (black vs. non-black), and time since transplant. Cases and controls were required to have >1 year of Medicare Parts A?+?B?+?D coverage and be without a recorded history of hip fracture. We ascertained any statin use in the previous year and defined adherent statin use as those who had filled prescriptions for statins to cover >80% of days in that year (proportion of days covered, PDC). We ascertained several potential confounders (demographics, comorbidities, BMI, transplant-related factors) and applied conditional logistic regression with multiple imputation for missing data to estimate odds ratios (OR) and 95% confidence intervals (CI).We identified 231 hip fracture cases (mean age 51.8 years; 53% female; 11.3% black; 6.9 years from transplant, and 9.9 years from ESRD) and 15,575 matched controls. Any prior statin use was present in 64.1% of cases and 60.3% of controls with 37.2% of cases and 33.9% of controls being found adherent. Unadjusted conditional logistic regression showed an OR of 1.17 (0.89-1.54) for any statin use, and a fully-adjusted OR of 0.89 (0.67-1.19). Compared with statin non-users, the adjusted OR for patients with lesser adherence (PDC ?80%) and those with greater adherence (PDC >80%) were 0.93 (0.66-1.31) and 0.87 (0.63-1.20), respectively.Statin use was not associated with hip fracture risk in first-time kidney transplant recipients.

    View details for DOI 10.1186/s12882-017-0559-9

    View details for Web of Science ID 000400586100004

    View details for PubMedID 28460645

  • Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients AMERICAN JOURNAL OF KIDNEY DISEASES Lenihan, C. R., Nair, S. S., Vangala, C., Ramanathan, V., Montez-Rath, M. E., Winkelmayer, W. C. 2017; 69 (5): 595-601
  • 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

    Abstract

    The comparative effectiveness of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus bare metal stents (BMS) has not been studied in the kidney transplant population.Using the US Renal Data System, we identified 3245 kidney transplant patients who underwent PCI between April 2003 and December 2010; 2400 and 845 patients received DES and BMS, respectively. We used propensity score matching and inverse probability of treatment weighting to create DES- and BMS-treated groups whose observed baseline characteristics were well-balanced. The associations between stent type and the outcomes of (1) death; (2) death or myocardial infarction (MI); (3) death, MI, or repeat revascularization (RR); and (4) hospitalized bleeding were compared using Cox proportional hazards regression.Drug-eluting stent use increased during the study period, mirroring the trend described in the general population. In the propensity score-matched cohort, no significant association among DES (vs BMS) use and outcomes was observed at 1 and 2 years of follow-up. However, at 3 years, DES was associated with 20% (95% confidence interval [CI], 4-33%) lower risk of death, 15% (95% CI, 1-27%) lower risk of death or MI, and 14% (95% CI, 2-24%) lower risk of death, MI, or repeat revascularization. There were no significant differences in rates of hospitalized bleeding at any time point. Results were similar in the inverse probability of treatment weighting analysis.In this retrospective study of US kidney transplant recipients undergoing PCI, DES was associated with better clinical outcomes beyond 2 years of follow-up.

    View details for DOI 10.1097/TP.0000000000001446

    View details for PubMedID 27517730

  • 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
  • Kidney Transplantation Outcomes across GN Subtypes in the United States JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY O'Shaughnessy, M. M., Liu, S., Montez-Rath, M. E., Lenihan, C. R., Lafayette, R. A., Winkelmayer, W. C. 2017; 28 (2): 632-644

    Abstract

    Differences in kidney transplantation outcomes across GN subtypes have rarely been studied. From the US Renal Data System, we identified all adult (?18 years) first kidney transplant recipients (1996-2011) with ESRD attributed to one of six GN subtypes or two comparator kidney diseases. We computed hazard ratios (HRs) for death, all-cause allograft failure, and allograft failure excluding death as a cause (competing risks framework) using Cox proportional hazards regression. Among the 32,131 patients with GN studied, patients with IgA nephropathy (IgAN) had the lowest mortality rates and patients with IgAN or vasculitis had the lowest allograft failure rates. After adjusting for patient- and transplant-related factors, compared with IgAN (referent), FSGS, membranous nephropathy, membranoproliferative GN, lupus nephritis, and vasculitis associated with HRs (95% confidence intervals) for death of 1.57 (1.43 to 1.72), 1.52 (1.34 to 1.72), 1.76 (1.55 to 2.01), 1.82 (1.63 to 2.02), and 1.56 (1.34 to 1.81), respectively, and with HRs for allograft failure excluding death as a cause of 1.20 (1.12 to 1.28), 1.27 (1.14 to 1.41), 1.50 (1.36 to 1.66), 1.11 (1.02 to 1.20), and 0.94 (0.81 to 1.09), respectively. Considering external comparator groups, and comparing with IgAN, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy associated with higher HRs for mortality [1.22 (1.12 to 1.34) and 2.57 (2.35 to 2.82), respectively], but ADPKD associated with a lower HR for allograft failure excluding death as a cause [0.85 (0.79 to 0.91)]. Reasons for differential outcomes by GN subtype and cause of ESRD should be examined in future research.

    View details for DOI 10.1681/ASN.2016020126

    View details for Web of Science ID 000393017600025

    View details for PubMedID 27432742

  • Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients. American journal of kidney diseases Lenihan, C. R., Nair, S. S., Vangala, C., Ramanathan, V., Montez-Rath, M. E., Winkelmayer, W. C. 2016

    Abstract

    Posttransplantation bone disease is a significant problem, with few well-evidenced therapeutic options. Proton pump inhibitors (PPIs) are associated with hip fracture in the general population and are widely prescribed for kidney transplant recipients.A case-control study.From the US Renal Data System, we identified from diagnoses and procedures 231 kidney transplant recipients with a first hip fracture. Cases were matched at the hip fracture index date with 15,575 controls on age, sex, race, and transplantation year.PPI use.First hip fracture.In the year prior to the index date, a PPI was prescribed to 65.4% of cases and 57.4% of controls. Additionally, in 34.6% of cases and 28.9% of controls, a PPI was prescribed for >80% of the year preceding the index date (higher PPI users). Unadjusted ORs of hip fracture associated with any and higher PPI use were 1.55 (95% CI, 1.18-2.05) and 1.65 (95% CI, 1.2-2.27), respectively. When adjusted for baseline demographic, clinical, and pharmacologic covariables, any and higher PPI use remained associated with hip fracture, with ORs of 1.39 (95% CI, 1.04-1.84) and 1.41 (95% CI, 1.02-1.95), respectively.Potential residual confounding through either incorrectly ascertained or unavailable confounders; cohort limited to Medicare beneficiaries receiving low-income subsidy.In summary, PPI use was associated with hip fracture risk in the US kidney transplant population.

    View details for DOI 10.1053/j.ajkd.2016.09.019

    View details for PubMedID 27866965

  • The Dawning of a New Day in CKD Anemia Care? Journal of the American Society of Nephrology Lenihan, C. R., Winkelmayer, W. C. 2016; 27 (4): 968-970

    View details for DOI 10.1681/ASN.2015091009

    View details for PubMedID 26494832

    View details for PubMedCentralID PMC4814199

  • Glomerular Function and Structure in Living Donors: Lessons from Single Nephron Studies. Current transplantation reports Lenihan, C. R., Myers, B. D., Tan, J. C. 2016; 3: 24-32

    Abstract

    One third of the kidney transplants performed in the USA come from living kidney donors. The long-term outcome of healthy individuals who donate kidneys is mostly excellent, although recent studies have suggested that living donation is associated with a small absolute increase in the risk of end stage renal failure. Much of our understanding about the progression of kidney disease comes from experimental models of nephron loss. For this reason, living kidney donation has long been of great interest to renal physiologists. This review will summarize the determinants of glomerular filtration and the physiology that underlies post-donation hyperfiltration. We describe the 'remnant kidney' model of kidney disease and the reasons why such progressive kidney disease very rarely ensues in healthy humans following uninephrectomy. We also review some of the methods used to determine glomerular number and size and outline their associations.

    View details for PubMedID 27004159

  • Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-?B-dependent manner. Biochemical and biophysical research communications Fitzpatrick, S. F., Fábián, Z., Schaible, B., Lenihan, C. R., Schwarzl, T., Rodriguez, J., Zheng, X., Li, Z., Tambuwala, M. M., Higgins, D. G., O'Meara, Y., Slattery, C., Manresa, M. C., Fraisl, P., Bruning, U., Baes, M., Carmeliet, P., Doherty, G., von Kriegsheim, A., Cummins, E. P., Taylor, C. T. 2016; 474 (3): 579?86

    Abstract

    Hepatocyte death is an important contributing factor in a number of diseases of the liver. PHD1 confers hypoxic sensitivity upon transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-?B). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-?B activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-?B to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-?B (but not knock-out of HIF-1 or HIF-2) reversed the anti-apoptotic effects of pharmacologic hydroxylase inhibition. We hypothesize that PHD1 inhibition leads to altered expression of NF-?B-dependent genes resulting in reduced apoptosis. This study provides new information relating to the possible mechanism of therapeutic action of hydroxylase inhibitors that has been reported in pre-clinical models of intestinal and hepatic disease.

    View details for DOI 10.1016/j.bbrc.2016.04.085

    View details for PubMedID 27130823

  • 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

  • The Association of Predonation Hypertension with Glomerular Function and Number in Older Living Kidney Donors JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lenihan, C. R., Busque, S., Derby, G., Blouch, K., Myers, B. D., Tan, J. C. 2015; 26 (6): 1261-1267

    Abstract

    The effect of preexisting hypertension on living donor nephron number has not been established. In this study, we determined the association between preexisting donor hypertension and glomerular number and volume and assessed the effect of predonation hypertension on postdonation BP, adaptive hyperfiltration, and compensatory glomerular hypertrophy. We enrolled 51 living donors to undergo physiologic, morphometric, and radiologic evaluations before and after kidney donation. To estimate the number of functioning glomeruli (NFG), we divided the whole-kidney ultrafiltration coefficient (Kf) by the single-nephron ultrafiltration coefficient (SNKf). Ten donors were hypertensive before donation. We found that, in donors ages >50 years old, preexisting hypertension was associated with a reduction in NFG. In a comparison of 10 age- and sex-matched hypertensive and normotensive donors, we observed more marked glomerulopenia in hypertensive donors (NFG per kidney, 359,499±128,929 versus 558,239±205,152; P=0.02). Glomerulopenia was associated with a nonsignificant reduction in GFR in the hypertensive group (89±12 versus 95±16 ml/min per 1.73 m(2)). We observed no difference in the corresponding magnitude of postdonation BP, hyperfiltration capacity, or compensatory renocortical hypertrophy between hypertensive and normotensive donors. Nevertheless, we propose that the greater magnitude of glomerulopenia in living kidney donors with preexisting hypertension justifies the need for long-term follow-up studies.

    View details for DOI 10.1681/ASN.2014030304

    View details for Web of Science ID 000355386100007

    View details for PubMedID 25525178

    View details for PubMedCentralID PMC4446872

  • Longitudinal study of living kidney donor glomerular dynamics after nephrectomy JOURNAL OF CLINICAL INVESTIGATION Lenihan, C. R., Busque, S., Derby, G., Blouch, K., Myers, B. D., Tan, J. C. 2015; 125 (3): 1311-1318

    Abstract

    Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors.We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects.Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria.Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation.Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology.

    View details for DOI 10.1172/JCI78885

    View details for Web of Science ID 000350616500041

    View details for PubMedID 25689253

  • 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

  • Comparison of longer-term outcomes after kidney transplantation between Hispanic and non-Hispanic whites in the United States. American journal of transplantation Arce, C. M., Lenihan, C. R., Montez-Rath, M. E., Winkelmayer, W. C. 2015; 15 (2): 499-507

    Abstract

    Little is known about the longer-term kidney transplant outcomes in the rapidly growing Hispanic population. Using the United States Renal Data System, we identified 105?250 Caucasian patients who received a first kidney transplant between January 1, 1996 and December 31, 2010. We tested for differences between Hispanic and non-Hispanic patients in the outcomes of (1) mortality, (2) all-cause graft failure, and (3) graft failure excluding death with a functioning graft. We used Cox regression to estimate (with 95% confidence intervals) multivariable-adjusted cause-specific hazard ratios (aHRCS ) for mortality and all-cause graft failure and subdistribution hazard ratios (aHRSD ) accounting for death as a competing risk for graft failure excluding death with a functioning graft. Both mortality [aHRCS ?=?0.69 (0.65-0.73)] and all-cause graft failure [aHRCS ?=?0.79 (0.75-0.83)] were lower in Hispanics. The association between Hispanic ethnicity and graft failure excluding death was modified by age (p?

    View details for DOI 10.1111/ajt.13043

    View details for PubMedID 25556854

  • Glomerular Effects of Age and APOL1. Journal of the American Society of Nephrology : JASN Meyer, T. W., Lenihan, C. R. 2015

    View details for PubMedID 26038527

  • The Consequences of Chronic Kidney Disease Mislabeling in Living Kidney Donors MAYO CLINIC PROCEEDINGS Lenihan, C. R., Tan, J. C. 2014; 89 (8): 1126-1129

    Abstract

    Despite numerous studies that substantiate its long-term safety, barriers to kidney donation persist. These include issues of insurability after donation and its consequent financial and emotional burdens. We present 2 cases in which mislabeling of kidney donors as having chronic kidney disease shortly after kidney donation adversely affected their insurability. A concerted effort should be made to affect public policy such that insurability and the psychosocial well-being of living donors are protected.

    View details for DOI 10.1016/j.mayocp.2014.04.002

    View details for Web of Science ID 000341411200015

    View details for PubMedCentralID PMC5096430

  • Temporal trends in the incidence, treatment and outcomes of hip fracture after first kidney transplantation in the United States. American journal of transplantation Sukumaran Nair, S., Lenihan, C. R., Montez-Rath, M. E., Lowenberg, D. W., Chertow, G. M., Winkelmayer, W. C. 2014; 14 (4): 943-951

    Abstract

    It is currently unknown whether any secular trends exist in the incidence and outcomes of hip fracture in kidney transplant recipients (KTR). We identified first-time KTR (1997-2010) who had >1 year of Medicare coverage and no recorded history of hip fracture. New hip fractures were identified from corresponding diagnosis and surgical procedure codes. Outcomes studied included time to hip fracture, type of surgery received and 30-day mortality. Of 69?740 KTR transplanted in 1997-2010, 597 experienced a hip fracture event during 155?341 person-years of follow-up for an incidence rate of 3.8 per 1000 person-years. While unadjusted hip fracture incidence did not change, strong confounding by case mix was present. Using year of transplantation as a continuous variable, the hazard ratio (HR) for hip fracture in 2010 compared with 1997, adjusted for demographic, dialysis, comorbid and most transplant-related factors, was 0.56 (95% confidence interval [CI]: 0.41-0.77). Adjusting for baseline immunosuppression modestly attenuated the HR (0.68; 95% CI: 0.47-0.99). The 30-day mortality was 2.2 (95% CI: 1.3-3.7) per 100 events. In summary, hip fractures remain an important complication after kidney transplantation. Since 1997, case-mix adjusted posttransplant hip fracture rates have declined substantially. Changes in immunosuppressive therapy appear to be partly responsible for these favorable findings.

    View details for DOI 10.1111/ajt.12652

    View details for PubMedID 24712332

  • A new clinical prediction tool for 5-year kidney transplant outcome. American journal of kidney diseases Lenihan, C. R., Lockridge, J. B., Tan, J. C. 2014; 63 (4): 549-551

    View details for DOI 10.1053/j.ajkd.2014.01.004

    View details for PubMedID 24670483

    View details for PubMedCentralID PMC4088343

  • The consequences of chronic kidney disease mislabeling in living kidney donors. Mayo Clinic proceedings Lenihan, C. R., Tan, J. C. 2014; 89 (8): 1126?29

    Abstract

    Despite numerous studies that substantiate its long-term safety, barriers to kidney donation persist. These include issues of insurability after donation and its consequent financial and emotional burdens. We present 2 cases in which mislabeling of kidney donors as having chronic kidney disease shortly after kidney donation adversely affected their insurability. A concerted effort should be made to affect public policy such that insurability and the psychosocial well-being of living donors are protected.

    View details for PubMedID 24867395

  • Differences in Access to Kidney Transplantation between Hispanic and Non-Hispanic Whites by Geographic Location in the United States CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Arce, C. M., Goldstein, B. A., Mitani, A. A., Lenihan, C. R., Winkelmayer, W. C. 2013; 8 (12): 2149-2157

    Abstract

    Hispanic patients undergoing chronic dialysis are less likely to receive a kidney transplant compared with non-Hispanic whites. This study sought to elucidate disparities in the path to receipt of a deceased donor transplant between Hispanic and non-Hispanic whites.Using the US Renal Data System, 417,801 Caucasians who initiated dialysis between January 1, 1995 and December 31, 2007 with follow-up through 2008 were identified. This study investigated time from first dialysis to first kidney transplantation, time from first dialysis to waitlisting, and time from waitlisting to kidney transplantation. Multivariable Cox regression estimated cause-specific hazard ratios (HRCS) and subdistribution (competing risk) hazard ratios (HRSD) for Hispanics versus non-Hispanic whites.Hispanics experienced lower adjusted rates of deceased donor kidney transplantation than non-Hispanic whites (HRCS, 0.77; 95% confidence interval [95% CI], 0.75 to 0.80) measured from dialysis initiation. No meaningful differences were found in time from dialysis initiation to placement on the transplant waitlist. Once waitlisted, Hispanics had lower adjusted rates of deceased donor kidney transplantation (HRCS, 0.66; 95% CI, 0.64 to 0.68), and the association attenuated once accounting for competing risks (HRSD, 0.79; 95% CI, 0.77 to 0.81). Additionally controlling for blood type and organ procurement organization further reduced the disparity (HRSD, 0.99; 95% CI, 0.96 to 1.02).After accounting for geographic location and controlling for competing risks (e.g., Hispanic survival advantage), the disparity in access to deceased donor transplantation was markedly attenuated among Hispanics compared with non-Hispanic whites. To overcome the geographic disparities that Hispanics encounter in the path to transplantation, organ allocation policy revisions are needed to improve donor organ equity.

    View details for DOI 10.2215/CJN.01560213

    View details for Web of Science ID 000327951100017

    View details for PubMedID 24115195

    View details for PubMedCentralID PMC3848391

  • Acute transplant glomerulopathy with monocyte rich infiltrate. Transplant immunology Lenihan, C. R., Tan, J. C., Kambham, N. 2013; 29 (1-4): 114-117

    Abstract

    Acute transplant glomerulopathy refers to alloimmune mediated endothelial injury and glomerular inflammation that typically occurs early post-kidney transplantation. We report a case of a 48-year old woman with end stage renal disease from lupus nephritis who developed an unexplained rise in serum creatinine 2months after renal transplant. As immunosuppression, she received alemtuzumab induction followed by a tacrolimus, mycophenolate mofetil and prednisone maintenance regimen. Her biopsy revealed severe glomerular endothelial injury associated with monocyte/macrophage-rich infiltrate in addition to mild acute tubulointerstitial cellular rejection. We briefly discuss acute transplant glomerulitis, its pathology and association with chronic/overt transplant glomerulopathy, C4d negative antibody-mediated rejection and the significance of monocytes in rejection. We also postulate that alemtuzumab induction may have contributed to the unusual pattern of monocyte-rich transplant glomerulitis.

    View details for DOI 10.1016/j.trim.2013.09.004

    View details for PubMedID 24056179

  • 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

  • High-potency statins and acute kidney injury-associated hospitalizations. American journal of kidney diseases Lenihan, C. R., Lafayette, R. A. 2013; 62 (5): 877-879

    View details for DOI 10.1053/j.ajkd.2013.07.006

    View details for PubMedID 23972947

    View details for PubMedCentralID PMC4090769

  • Outcomes after kidney transplantation of patients previously diagnosed with atrial fibrillation. American journal of transplantation Lenihan, C. R., Montez-Rath, M. E., Scandling, J. D., Turakhia, M. P., Winkelmayer, W. C. 2013; 13 (6): 1566-1575

    Abstract

    Little is known about the prevalence and outcomes of patients with atrial fibrillation/flutter (AF) who receive a kidney transplant. We identified all patients who had >1 year of uninterrupted Medicare A+B coverage before receiving their first kidney transplant (1997-2009). The presence of pretransplant AF was ascertained from diagnosis codes in Medicare physician claims. We studied the posttransplant outcomes of death, all-cause graft failure, death-censored graft failure and stroke using multivariable Cox regression. Of 62 706 eligible first kidney transplant recipients studied, 3794 (6.4%) were diagnosed with AF prior to kidney transplant. Over a mean follow up of 4.9 years, 40.6% of AF patients and 24.9% without AF died. All-cause and death-censored graft failure were 46.8% and 16.5%, respectively, in the AF group and 36.4% and 19.5%, respectively, in those without AF. Ischemic stroke occurred in 2.8% of patients with and 1.6% of patients without AF. In patients with AF, multivariable-adjusted hazard ratios (95% confidence intervals) for death, graft failure, death-censored graft failure and ischemic stroke were 1.46 (1.38-1.54), 1.41 (1.34-1.48), 1.26 (1.15-1.37) and 1.36 (1.10-1.68), respectively. Pre-existing AF is associated with poor posttransplant outcomes. Special attention should be paid to AF in pretransplant evaluation, counseling and risk stratification of kidney transplant candidates.

    View details for DOI 10.1111/ajt.12197

    View details for PubMedID 23721555

  • The impact of hypoxia on cell death pathways BIOCHEMICAL SOCIETY TRANSACTIONS Lenihan, C. R., Taylor, C. T. 2013; 41: 657-663

    Abstract

    Hypoxia is a frequently encountered feature of the cellular microenvironment in a number of pathophysiological processes in which programmed cell death (apoptosis) affects disease progression including, but not limited to, cancer, chronic inflammation, myocardial infarction, stroke and ischaemic acute kidney injury. In these diseases, the presence of hypoxia can significantly affect the rate of cell death and thus may make a significant contribution to disease progression. In the present review, we discuss the complex relationship that exists between the presence of hypoxia and the regulation of cell death pathways.

    View details for DOI 10.1042/BST20120345

    View details for Web of Science ID 000316560900034

    View details for PubMedID 23514172

  • Comorbidities and Kidney Transplant Evaluation in the Elderly AMERICAN JOURNAL OF NEPHROLOGY Lenihan, C. R., Hurley, M. P., Tan, J. C. 2013; 38 (3): 204-211

    Abstract

    The elderly are the fastest growing subpopulation with end-stage renal disease. The goal of our study was to define characteristics of elderly patients who were considered ineligible for transplantation compared to those who were listed.984 patients were referred for evaluation during a 2-year period. Records of patients ?65 years of age (n = 123) were reviewed. Patients who were listed versus not listed were characterized. Factors associated with waitlisting were determined using standard statistical tools.Half of elderly transplant candidates were accepted for listing compared to 75.4% of those aged <65 years. In multivariable logistic regression, older age (OR 1.29 per year ?65, 95% CI 1.14-1.45), coronary artery disease (OR 8.57, 95% CI 2.41-30.53), and poor mobility (OR 13.97, 95% CI 4.76-41.00) were independently associated with denial of listing. The receiver operating characteristic curve showed good discrimination for denial of listing (area under the receiver operating characteristic curve of 0.88).Elderly candidates carry a heavy burden of comorbidities and over half of those evaluated are deemed unsuitable for waitlisting. Better delineation of characteristics associated with suitability for transplant candidacy in the elderly is warranted to facilitate appropriate referrals by physicians and management of expectations in potential candidates.

    View details for DOI 10.1159/000354483

    View details for Web of Science ID 000325242000004

    View details for PubMedID 23988670

  • Trends in Acute Kidney Injury, Associated Use of Dialysis, and Mortality After Cardiac Surgery, 1999 to 2008 ANNALS OF THORACIC SURGERY Lenihan, C. R., Montez-Rath, M. E., Mangano, C. T., Chertow, G. M., Winkelmayer, W. C. 2013; 95 (1): 20-28

    Abstract

    The development of acute kidney injury (AKI) after cardiac surgery is associated with significant mortality, morbidity, and cost. The last decade has seen major changes in the complexity of cardiac surgical candidates and in the number and type of cardiac surgical procedures being performed.Using data from the Nationwide Inpatient Sample, we determined the annual rates of AKI, AKI requiring dialysis (AKI-D), and inpatient mortality after cardiac surgery in the United States in the years 1999 through 2008.Inpatient mortality with AKI and AKI-D decreased from 27.9% and 45.9%, respectively, in 1999 to 12.8% and 35.3%, respectively, in 2008. Compared with 1999, the odds of AKI and AKI-D in 2008, adjusted for demographic and clinical factors, were 3.30 (95% confidence interval [CI]: 2.89 to 3.77) and 2.23 (95% CI: 1.78 to 2.80), respectively. Corresponding adjusted odds of death associated with AKI and AKI-D were 0.31 (95% CI: 0.26 to 0.36) and 0.47 (95% CI: 0.34 to 0.65.) Taken together, the attributable risks for death after cardiac surgery associated with AKI and AKI-D increased from 30% and 5%, respectively, in 1999 to 47% and 14%, respectively, in 2008.In sum, despite improvements in individual patient outcomes over the decade 1999 to 2008, the population contribution of AKI and AKI-D to inpatient mortality after surgery increased over the same period.

    View details for DOI 10.1016/j.athoracsur.2012.05.131

    View details for Web of Science ID 000313343700013

  • Trends in acute kidney injury, associated use of dialysis, and mortality after cardiac surgery, 1999 to 2008. Annals of thoracic surgery Lenihan, C. R., Montez-Rath, M. E., Mora Mangano, C. T., Chertow, G. M., Winkelmayer, W. C. 2013; 95 (1): 20-28

    Abstract

    The development of acute kidney injury (AKI) after cardiac surgery is associated with significant mortality, morbidity, and cost. The last decade has seen major changes in the complexity of cardiac surgical candidates and in the number and type of cardiac surgical procedures being performed.Using data from the Nationwide Inpatient Sample, we determined the annual rates of AKI, AKI requiring dialysis (AKI-D), and inpatient mortality after cardiac surgery in the United States in the years 1999 through 2008.Inpatient mortality with AKI and AKI-D decreased from 27.9% and 45.9%, respectively, in 1999 to 12.8% and 35.3%, respectively, in 2008. Compared with 1999, the odds of AKI and AKI-D in 2008, adjusted for demographic and clinical factors, were 3.30 (95% confidence interval [CI]: 2.89 to 3.77) and 2.23 (95% CI: 1.78 to 2.80), respectively. Corresponding adjusted odds of death associated with AKI and AKI-D were 0.31 (95% CI: 0.26 to 0.36) and 0.47 (95% CI: 0.34 to 0.65.) Taken together, the attributable risks for death after cardiac surgery associated with AKI and AKI-D increased from 30% and 5%, respectively, in 1999 to 47% and 14%, respectively, in 2008.In sum, despite improvements in individual patient outcomes over the decade 1999 to 2008, the population contribution of AKI and AKI-D to inpatient mortality after surgery increased over the same period.

    View details for DOI 10.1016/j.athoracsur.2012.05.131

    View details for PubMedID 23272825

  • Hypercapnia Induces Cleavage and Nuclear Localization of RelB Protein, Giving Insight into CO2 Sensing and Signaling JOURNAL OF BIOLOGICAL CHEMISTRY Oliver, K. M., Lenihan, C. R., Bruning, U., Cheong, A., Laffey, J. G., McLoughlin, P., Taylor, C. T., Cummins, E. P. 2012; 287 (17): 14004-14011

    Abstract

    Carbon dioxide (CO(2)) is increasingly being appreciated as an intracellular signaling molecule that affects inflammatory and immune responses. Elevated arterial CO(2) (hypercapnia) is encountered in a range of clinical conditions, including chronic obstructive pulmonary disease, and as a consequence of therapeutic ventilation in acute respiratory distress syndrome. In patients suffering from this syndrome, therapeutic hypoventilation strategy designed to reduce mechanical damage to the lungs is accompanied by systemic hypercapnia and associated acidosis, which are associated with improved patient outcome. However, the molecular mechanisms underlying the beneficial effects of hypercapnia and the relative contribution of elevated CO(2) or associated acidosis to this response remain poorly understood. Recently, a role for the non-canonical NF-?B pathway has been postulated to be important in signaling the cellular transcriptional response to CO(2). In this study, we demonstrate that in cells exposed to elevated CO(2), the NF-?B family member RelB was cleaved to a lower molecular weight form and translocated to the nucleus in both mouse embryonic fibroblasts and human pulmonary epithelial cells (A549). Furthermore, elevated nuclear RelB was observed in vivo and correlated with hypercapnia-induced protection against LPS-induced lung injury. Hypercapnia-induced RelB processing was sensitive to proteasomal inhibition by MG-132 but was independent of the activity of glycogen synthase kinase 3? or MALT-1, both of which have been previously shown to mediate RelB processing. Taken together, these data demonstrate that RelB is a CO(2)-sensitive NF-?B family member that may contribute to the beneficial effects of hypercapnia in inflammatory diseases of the lung.

    View details for DOI 10.1074/jbc.M112.347971

    View details for Web of Science ID 000303996300055

    View details for PubMedID 22396550

  • An Intact Canonical NF-kappa B Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia JOURNAL OF IMMUNOLOGY Fitzpatrick, S. F., Tambuwala, M. M., Bruning, U., Schaible, B., Scholz, C. C., Byrne, A., O'Connor, A., Gallagher, W. M., Lenihan, C. R., Garvey, J. F., Howell, K., Fallon, P. G., Cummins, E. P., Taylor, C. T. 2011; 186 (2): 1091-1096

    Abstract

    Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-?B. Recent studies have revealed a high degree of interdependence between HIF and NF-?B signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-?B to demonstrate that hypoxia activates NF-?B in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-?B, we confirm a unidirectional dependence of hypoxic HIF-1? accumulation upon an intact canonical NF-?B pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-?B dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-?B pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1? and the p65 subunit of NF-?B directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-?B signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

    View details for DOI 10.4049/jimmunol.1002256

    View details for Web of Science ID 000285917700048

    View details for PubMedID 21149600

  • Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function GASTROENTEROLOGY Tambuwala, M. M., Cummins, E. P., Lenihan, C. R., Kiss, J., Stauch, M., Scholz, C. C., Fraisl, P., Lasitschka, F., Mollenhauer, M., Saunders, S. P., Maxwell, P. H., Carmeliet, P., Fallon, P. G., Schneider, M., Taylor, C. T. 2010; 139 (6): 2093-2101

    Abstract

    Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved.The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)-induced colitis was examined in mice.PHD1(-/-), but not PHD2(+/-) or PHD3(-/-), mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1(-/-) mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice.These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.

    View details for DOI 10.1053/j.gastro.2010.06.068

    View details for Web of Science ID 000284843600047

    View details for PubMedID 20600011

  • NF-kappa B Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells JOURNAL OF IMMUNOLOGY Cummins, E. P., Oliver, K. M., Lenihan, C. R., Fitzpatrick, S. F., Bruning, U., Scholz, C. C., Slattery, C., Leonard, M. O., McLoughlin, P., Taylor, C. T. 2010; 185 (7): 4439-4445

    Abstract

    Molecular O(2) and CO(2) are the primary substrate and product of aerobic metabolism, respectively. Levels of these physiologic gases in the cell microenvironment vary dramatically both in health and in diseases, such as chronic inflammation, ischemia, and cancer, in which metabolism is significantly altered. The identification of the hypoxia-inducible factor led to the discovery of an ancient and direct link between tissue O(2) and gene transcription. In this study, we demonstrate that mammalian cells (mouse embryonic fibroblasts and others) also sense changes in local CO(2) levels, leading to altered gene expression via the NF-?B pathway. IKK?, a central regulatory component of NF-?B, rapidly and reversibly translocates to the nucleus in response to elevated CO(2). This response is independent of hypoxia-inducible factor hydroxylases, extracellular and intracellular pH, and pathways that mediate acute CO(2)-sensing in nematodes and flies and leads to attenuation of bacterial LPS-induced gene expression. These results suggest the existence of a molecular CO(2) sensor in mammalian cells that is linked to the regulation of genes involved in innate immunity and inflammation.

    View details for DOI 10.4049/jimmunol.1000701

    View details for Web of Science ID 000282059500072

    View details for PubMedID 20817876

  • MDRD-estimated GFR at one year post-renal transplant is a predictor of long-term graft function RENAL FAILURE Lenihan, C. R., O'Kelly, P., Mohan, P., Little, D., Walshe, J. J., Kieran, N. E., Conlon, P. J. 2008; 30 (4): 345-352

    Abstract

    Renal transplantation is the optimal mode of renal replacement. Improvements in graft survival and acute rejection rates have made these outcomes less useful for prognostication and as end-points in clinical trials; accurate surrogate markers of long-term graft outcome are therefore increasingly important. This study examines the relationship between both serum creatinine (SCr(1 yr)) and MDRD estimated glomerular filtration rate measured at one year (eGFR(MDRD)(1 yr)) as predictors of graft survival. Data on 1,110 patients who received a renal transplant between 1989 and 2005 were extracted from the Irish Renal Transplant Registry. The study group was divided into quartiles of patient numbers according to SCr(1 yr) and eGFR(MDRD)(1 yr). Kaplan-Meier estimates of the primary end-point graft survival were constructed for each quartile. Additionally, a Cox Regression restricted cubic spline model was performed for both eGFR(MDRD)(1 yr) and SCr(1 yr). Both overall graft outcome and outcome censored for death with a functioning graft (CDWFG) were used as endpoints. Cox regression analysis was performed along with tests for the proportionality assumption to compare the predictive value of eGFR(MDRD)(1 yr)and SCr(1 yr). Both eGFR(MDRD)(1yr) and SCr(1 yr) were independently associated with long-term renal transplant survival. eGFR(MDRD)(1 yr) and SCr(1 yr) had similarly strong associations with long-term outcome when the quartile variables were compared using the Bayesian Information Criterion method. The Cox regression restricted cubic spline modeling demonstrated that an eGFR(MDRD)(1 yr) value < 27 mLs/min/1.73 m(2) and a SCr(1 yr) value > 229 micromol/L were associated with poor graft survival.

    View details for DOI 10.1080/08860220801947686

    View details for Web of Science ID 000256352500001

    View details for PubMedID 18569905

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