Dialysis Modality, Transplant Characteristics, and Incident Atrial Fibrillation After Kidney Transplant: An Observational Study Using USRDS Data.

Rationale & Objective: Atrial fibrillation is the most common arrhythmia and is increasing in prevalence. The prevalence of atrial fibrillation is high among patients receiving dialysis, affecting ∼21.3% of the patients receiving hemodialysis and 15.5% of those receiving peritoneal dialysis. The association of previous dialysis modality with incident atrial fibrillation in patients after receiving their first kidney transplant has not been studied. Study Design: We used the United States Renal Data System to retrospectively identify adult, Medicare-insured patients who received their first kidney transplant between January 1, 2005, and September 30, 2012 and who had not previously been diagnosed with atrial fibrillation. Setting & Participants: The study included 43,621 patients who were aged 18 years older when receiving a first kidney transplant between January 1, 2005, and September 30, 2012 and whose primary payer was Medicare (parts A and B) at the time of transplantation and the 6 months preceding it. Exposure: Dialysis modality used before transplant. Outcome: Time to incidence of atrial fibrillation up to 3 years posttransplant. Analytical Approach: Multivariable Cox regression was used to estimate HRs. Results: Of 43,621 patients, 84.9% received hemodialysis and 15.1% received peritoneal dialysis before transplant. The mean ± SD age was 51 ± 13.6 years; 60.8% were male, 55.6% White, and 35.8% Black race. The mean dialysis vintage was 4.3 ± 2.8 years. Newly diagnosed atrial fibrillation after kidney transplant occurred in 286 patients (during 15,363 person-years) who had received peritoneal dialysis and in 2,315 patients (during 83,536 person-years) who had received hemodialysis. After multivariable adjustment, atrial fibrillation was 20% (95% CI, 4%-38%) more likely in those who had been receiving hemodialysis versus peritoneal dialysis, regardless of whether death was considered a competing risk or a censoring event. Each year of pretransplant dialysis vintage increased the risk of posttransplant atrial fibrillation by 6% (95% CI, 3%-9%). Limitations: Residual confounding; data from billing claims does not specify the duration of atrial fibrillation or whether it is valvular. Conclusions: Pretransplant hemodialysis, as compared with peritoneal dialysis, was associated with higher risk of newly diagnosed atrial fibrillation after a first kidney transplant. Plain-Language Summary: New-onset atrial fibrillation (AF) occurs in 7% of kidney transplant recipients in the first 3 years posttransplantation. We conducted this study to determine whether pretransplant dialysis modality was associated with posttransplant AF. We identified 43,621 patients; 84.9% used hemodialysis and 15.1% used peritoneal dialysis pretransplant. Multivariable Cox regression was used to estimate hazard ratios. We found that patients receiving hemodialysis pretransplant were at 20% increased risk of developing posttransplant AF as compared with patients receiving peritoneal dialysis. As our understanding of transplant-specific risk factors for AF increases, we may be able to better risk-stratify transplant patients and develop monitoring and management strategies that can improve outcomes.

Kidney Stone Events after Kidney Transplant in the United States.

BACKGROUND: Kidney stone disease is common and can lead to complications such as AKI, urinary tract obstruction, and urosepsis. In kidney transplant recipients, complications from kidney stone events can also lead to rejection and allograft failure. There is limited information on the incidence of kidney stone events in transplant recipients. METHODS: We identified 83,535 patients from the United States Renal Data System who received their first kidney transplant between January 1, 2007, and December 31, 2018. We examined the incidence of kidney stone events and identified risk factors associated with a kidney stone event in the first 3 years after transplantation. RESULTS: We found 1436 patients (1.7%) who were diagnosed with a kidney stone in the 3 years after kidney transplant. The unadjusted incidence rate for a kidney stone event was 7.8 per 1000 person-years. The median time from transplant to a kidney stone diagnosis was 0.61 (25%-75% range 0.19-1.46) years. Patients with a history of kidney stones were at greatest risk of a kidney stone event after transplant (hazard ratio [HR], 4.65; 95% confidence interval [CI], 3.82 to 5.65). Other notable risk factors included a diagnosis of gout (HR, 1.53; 95% CI, 1.31 to 1.80), hypertension (HR, 1.29; 95% CI, 1.00 to 1.66), and a dialysis of vintage of ≥9 years (HR, 1.48; 95% CI, 1.18 to 1.86; ref vintage ≤2.5 years). CONCLUSIONS: Approximately 2% of kidney transplant recipients were diagnosed with a kidney stone in the 3 years after kidney transplant. Risk factors of a kidney stone event include a history of kidney stones and longer dialysis vintage.

Parathyroidectomy and Cinacalcet Use in Medicare-Insured Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Posttransplant hyperparathyroidism is common, and treatment practices are poorly characterized. The goal of this study was to examine the incidence, associations, and outcomes of posttransplant parathyroidectomy and calcimimetic use in a cohort of Medicare-insured US kidney transplant recipients. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: We used the US Renal Data System to extract demographic, clinical, and prescription data from Medicare Parts A, B, and D-insured patients who received their first kidney transplant in 2007-2013. We excluded patients with pretransplant parathyroidectomy. PREDICTORS: Calendar year of transplantation and pretransplant patient characteristics. OUTCOME: (1) Incidence of and secular trends in parathyroidectomy and cinacalcet use in the 3 years after transplant; (2) 90-day outcomes after posttransplant parathyroidectomy and cinacalcet initiation. ANALYTICAL APPROACH: Temporal trends and pretransplant correlates of parathyroidectomy and cinacalcet use were assessed using proportional hazards models and multivariable Poisson regression, respectively. RESULTS: The inclusion criteria were met by 30,127 patients, of whom 10,707 used cinacalcet before transplant, 551 underwent posttransplant parathyroidectomy, and 5,413 filled≥1 prescription for cinacalcet. The rate of posttransplant parathyroidectomy was stable over time. By contrast, cinacalcet use increased during the period studied. Long dialysis vintage and pretransplant cinacalcet use were strongly associated with posttransplant parathyroidectomy and cinacalcet use. Roughly 1 in 4 patients were hospitalized within 90 days of posttransplant parathyroidectomy, with hypocalcemia-related diagnoses being the most common complication. Parathyroidectomy (vs cinacalcet initiation) was not associated with an increase in acute kidney injury. LIMITATIONS: We lacked access to laboratory data to help assess the severity of secondary/tertiary hyperparathyroidism. The cohort was limited to Medicare beneficiaries. CONCLUSIONS: Almost one-fifth of our study cohort was treated with parathyroidectomy and/or cinacalcet. Further studies are needed to establish the optimal treatment for posttransplant hyperparathyroidism.

SARS-CoV-2 Neutralizing Monoclonal Antibodies for the Treatment of COVID-19 in Kidney Transplant Recipients.

Background: Morbidity and mortality associated with coronavirus disease 2019 (COVID-19) infection in kidney transplant recipients are high and early outpatient interventions to prevent progression to severe disease are needed. SARS-CoV-2 neutralizing mAbs, including bamlanivimab and casirivimab-imdevimab, received emergency use authorization in the United States in November 2020 for treatment of mild to moderate COVID-19 disease. Methods: We performed a retrospective analysis of 27 kidney transplant recipients diagnosed with COVID-19 between July 2020 and February 2021 who were treated with bamlanivimab or casirivimab-imdevimab and immunosuppression reduction. We additionally identified 13 kidney transplant recipients with COVID-19 who had mild to moderate disease at presentation, who did not receive mAbs, and had SARS-CoV-2 serology testing available. Results: There were no deaths or graft failures in either group. Both infusions were well tolerated. Four of the 27 patients treated with mAbs required hospitalization due to COVID-19. Four of 13 patients who did not receive mAbs required hospitalization due to COVID-19. Patients who received mAbs demonstrated measurable anti-SARS-CoV-2 IgG with angiotensin-converting enzyme 2 (ACE2) receptor blocking activity at the highest level detectable at 90 days postinfusion, whereas ACE2 blocking activity acquired from natural immunity in the mAb-untreated group was weak. Conclusions: Bamlanivimab and casirivimab-imdevimab combined with immunosuppression reduction were well tolerated and associated with favorable clinical outcomes in kidney transplant recipients diagnosed with mild to moderate COVID-19.

The Association of Pre-Kidney Transplant Dialysis Modality with de novo Posttransplant Heart Failure.

BACKGROUND: Heart failure (HF) after kidney transplantation is a significant but understudied problem. Pretransplant dialysis modality could influence incident HF risk through differing cardiac stressors. However, whether pretransplant dialysis modality is associated with the development of posttransplant HF is unknown. METHODS: We used the US Renal Data System to assemble a cohort of 27,701 patients who underwent their first kidney transplant in the USA between the years 2005 and 2012 and who had Medicare fee-for-service coverage for >6 months preceding their transplant date. Patients with any HF diagnosis prior to transplant were excluded. Detailed baseline patient characteristics and comorbidities were abstracted. The outcome of interest was de novo posttransplant HF. Pretransplant dialysis modality was defined as the dialysis modality used at the time of transplant. We conducted time-to-event analyses using Cox regression. Death was treated as a competing risk in the study's primary analysis. Graft failure was included as a time-varying covariate. RESULTS: Among eligible patients, 81% were treated with hemodialysis prior to transplant, and hemodialysis patients were more likely to be male, had a shorter dialysis vintage, and had more diabetes and vascular disease diagnoses. When adjusted for all available demographic and clinical data, pretransplant treatment with hemodialysis (vs. peritoneal dialysis) was associated with a 19% increased risk in de novo posttransplant HF, with sub-distribution HR 1.19 (95% CI: 1.09-1.29). CONCLUSIONS: Our results suggest that choice of pretransplant dialysis modality may impact the development of posttransplant HF.

Progression of proliferative glomerulonephritis with monoclonal IgG deposits in pediatric patients.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain-restricted immunoglobulin and is rarely reported in children. METHODS: We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. RESULTS: Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. CONCLUSIONS: Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. Graphical abstract.

Influence of immunosuppression on seroconversion against SARS-CoV-2 in two kidney transplant recipients.

Solid organ transplant recipients are at risk for infectious complications due to chronic immunosuppression. The outbreak of coronavirus disease 2019 (COVID-19) in the United States has raised growing concerns for the transplant patient population. We seek to add to the current limited literature on COVID-19 in transplant recipients by describing the clinical course of two kidney transplant recipients with SARS-CoV-2 infection monitored by both RT-PCR and serology. Through careful adjustment of their immunosuppression regimen, both patients had excellent recovery with intact graft function and development of anti-SARS-CoV-2 antibodies.

Trends in the Medical Complexity and Outcomes of Medicare-insured Patients Undergoing Kidney Transplant in the Years 1998-2014.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association Between Type of Vascular Access Used in Hemodialysis Patients and Subsequent Kidney Transplant Outcomes.

RATIONALE & OBJECTIVE: Vascular access type (arteriovenous fistula [AVF] vs arteriovenous graft [AVG] vs central venous catheter [CVC]) associates with clinical outcomes in patients with end-stage kidney disease undergoing hemodialysis. Whether a similar association exists with outcomes after kidney transplantation is unknown. We hypothesized that AVGs would associate with worse outcomes, perhaps owing to persistent subclinical inflammation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Using US registry data merged with electronic health records of a large dialysis organization (2006-2011), we selected patients receiving a first-ever kidney transplant after undergoing more than 30 days of hemodialysis. EXPOSURE: Hemodialysis access used during the patient's last pretransplantation hemodialysis session. OUTCOMES: Patients were followed up from kidney transplantation for all-cause mortality, kidney allograft loss from any cause, and allograft loss not from death. ANALYTICAL APPROACH: Time-to-event analysis including Kaplan-Meier plots and Cox proportional hazards regression estimated cause-specific HRs and 95% CIs. RESULTS: Among 9,291 patients who underwent kidney transplantation between 2006 and 2011, a total of 65.3% used an AVF, 20.4% used an AVG, and 14.3% used a CVC for hemodialysis before transplantation. Multivariable regression models adjusted for demographic variables, comorbid conditions, transplant characteristics, and laboratory parameters identified no independent associations between vascular access type and all-cause mortality (HRAVG, 1.13 [95% CI, 0.97-1.33]; HRCVC, 1.00 [95% CI, 0.83-1.21]). Similarly, AVG and CVC use were not independently associated with all-cause allograft loss compared with AVF use (HRAVG, 1.13 [95% CI, 1.00-1.28]; HRCVC, 1.12 [95% CI, 0.96-1.29]). CVC use was associated with 30% higher risk for allograft loss from causes other than death compared with AVF use (HRCVC, 1.30 [95% CI, 1.06-1.57]), but AVGs were not (HRAVG, 1.17 [95% CI, 0.98-1.39]). LIMITATIONS: Nonrandomized exposure leading to potential residual confounding. CONCLUSIONS: No association was found for AVG use before kidney transplantation with mortality, all-cause allograft loss, and allograft loss from all causes other than death, compared with AVF use. The association of CVC use with allograft loss from causes other than death requires further investigation.

Proton Pump Inhibitors, Histamine-2 Receptor Antagonists, and Hip Fracture Risk among Patients on Hemodialysis.

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.

De Novo Heart Failure After Kidney Transplantation: Trends in Incidence and Outcomes.

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 a diagnosis 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.

Statin use and hip fractures in U.S. kidney transplant recipients.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: Statin use was not associated with hip fracture risk in first-time kidney transplant recipients.

Drug-Eluting Stents Versus Bare Metal Stents for Percutaneous Coronary Intervention in Kidney Transplant Recipients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In this retrospective study of US kidney transplant recipients undergoing PCI, DES was associated with better clinical outcomes beyond 2 years of follow-up.

Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients.

BACKGROUND: 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. STUDY DESIGN: A case-control study. SETTING & PARTICIPANTS: 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. PREDICTOR: PPI use. OUTCOMES: First hip fracture. RESULTS: 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. LIMITATIONS: Potential residual confounding through either incorrectly ascertained or unavailable confounders; cohort limited to Medicare beneficiaries receiving low-income subsidy. CONCLUSIONS: In summary, PPI use was associated with hip fracture risk in the US kidney transplant population.

Kidney Transplantation Outcomes across GN Subtypes in the United States.

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.

Prolyl hydroxylase-1 regulates hepatocyte apoptosis in an NF-κB-dependent manner.

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-κB). Reduced PHD1 activity is linked to decreased apoptosis. Here, we investigated the underlying mechanism(s) in hepatocytes. Basal NF-κB activity was elevated in PHD1(-/-) hepatocytes compared to wild type controls. ChIP-seq analysis confirmed enhanced binding of NF-κB to chromatin in regions proximal to the promoters of genes involved in the regulation of apoptosis. Inhibition of NF-κB (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-κB-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.

Glomerular Function and Structure in Living Donors: Lessons from Single Nephron Studies.

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.

Outcomes After Warfarin Initiation in a Cohort of Hemodialysis Patients With Newly Diagnosed Atrial Fibrillation.

BACKGROUND: 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. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: 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. PREDICTOR: Warfarin therapy initiation, identified by a filled prescription within 30 days of the AF event. OUTCOMES: Death, ischemic stroke, hemorrhagic stroke, severe gastrointestinal bleeding, and composite outcomes. MEASUREMENTS: HRs estimated by applying Cox regression to an inverse probability of treatment and censoring-weighted cohort. RESULTS: 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). LIMITATIONS: Short observation period, limited number of nonfatal events, limited generalizability of results to more affluent patients. CONCLUSIONS: 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.