Robert T. Neff

Nephrotoxicity Associated with Intravenous Colistin (Colistimethate Sodium) Treatment at a Tertiary Care Medical Center

The incidence of acute renal failure, defined by the risk, injury, or failure criteria of the RIFLE criteria (risk, injury, failure, loss, and end-stage kidney disease), in 66 patients who received colistimethate sodium was 45%, and 21% of patients stopped therapy because of nephrotoxicity. The RIFLE criteria should be used in the future to allow for comparison of nephrotoxicity among studies.

Progressive Multifocal Leukoencephalopathy and Use of Mycophenolate Mofetil After Kidney Transplantation

Mycophenolate mofetil (MMF) use may be associated with progressive multifocal leukoencephalopathy (PML). We conducted a retrospective cohort study of 32,757 renal transplant recipients using the United States Renal Data System kidney transplant files for the incidence, prognosis, and clinical features associated with PML occurring after kidney transplant. Subjects were transplanted from January 1, 2000 to July 31, 2004 and followed through December 31, 2004. The incidence density of PML in MMF users was 14.4 cases/100,000 person-years at risk versus 0 for non-MMF users (P=0.11) by log rank test. Factors significantly associated with PML were BK virus infection (22.2% vs. 1.1%), pretransplant transfusion (75% vs. 34%), panel reactive antibody more than 20% (56% vs. 14%), and use of antirejection medications in the first year (33% vs. 9.2%), all P less than 0.05. PML is rare in the renal transplant population. There was no significant association between PML and MMF, but MMF use in this cohort is too high to accurately assess an association.

Analysis of USRDS: Incidence and Risk Factors for Pneumocystis jiroveci Pneumonia

Background. To investigate the effect of modern immunosuppression on the incidence, risk factors, morbidity, and mortality of Pneumocystis pneumonia (PCP) in recipients of kidney transplants. Methods. We conducted a retrospective cohort study of 32,757 Medicare primary transplant recipients in the United States Renal Data System from January 1, 2000 through July 31, 2004. PCP infection was defined by Medicare claims using International Classification of Disease, 9th Revision codes. The incidence of PCP infections, graft loss, and death were measured. Results. There were a total of 142 cases (cumulative incidence 0.4%) of PCP after kidney transplantation during the study period. By using multivariate analysis with Cox regression, expanded criteria donor, donation after cardiac death, and earlier year of transplant were associated with development of PCP disease. Induction immunosuppression and acute rejections were not associated with risk for PCP infections. However, based on adjusted hazard ratio (AHR), maintenance immunosuppression regimens containing the combination of tacrolimus and sirolimus (AHR 3.60, confidence interval [CI] 2.03–6.39), Neoral and mycophenolate mofetil (AHR 2.09, CI 1.31–3.31), and sirolimus and mycophenolate mofetil (AHR 2.77, CI 1.40–5.47), were associated with development of PCP. As a time dependent variable, PCP was associated with an increased risk of both graft loss and death. Conclusion. PCP infections are rare in the modern era of prophylaxis; however, these infections are a serious risk factor for graft loss and patient death, in particular, in patients who are on sirolimus as part of the immunosuppressive regimen. The median time to development of PCP after transplant was 0.80±0.95 years, suggesting a longer period of PCP prophylaxis.

Incidence, Predictors and Outcomes of Transplant Renal Artery Stenosis after Kidney Transplantation: Analysis of USRDS

Objective: We analyzed the United States Renal Data System registry to study the risks, predictors, and outcomes of transplant renal artery stenosis (TRAS) in contemporary practice. Methods: The study sampled comprised adults with Medicare primary insurance who received kidney transplants in 2000–2005. We examined associations of recipient, donor and transplant factors with time-to-TRAS by the Kaplan-Meier method and multivariate Cox regression. Survival analysis methods were employed to estimate graft survival after TRAS, and to model TRAS as a time-dependent outcome predictor. Kaplan-Meier analysis was used to estimate time to allograft loss in patients who did or did not have an angioplasty procedure for TRAS. Results: There were 823 cases of TRAS among 41,867 transplant patients, with an incidence rate of 8.3 (95% CI 7.8–8.9) cases per 1,000 patient-years. Mean time to diagnosis of TRAS was 0.83 ± 0.81 years after transplant. Factors associated with TRAS were older recipient and donor age, extended criteria donors, induction immunosuppression, delayed graft function, and ischemic heart disease. There was no association of TRAS with deceased donors, prolonged cold ischemia time, acute rejection or cytomegalovirus status. TRAS was associated with increased risk of graft loss (including death; adjusted hazard ratio 2.84, 95% CI 1.70–4.72). Among the 823 patients with TRAS, 145 (17.6%) underwent angioplasty. Graft survival after TRAS was not significantly different in patients treated with angioplasty compared to those without angioplasty. Conclusions: TRAS is an important complication that predicts adverse patient and graft outcomes. Treatment strategies for TRAS warrant prospective investigation in clinical trials.

Association of Incident Gout and Mortality in Dialysis Patients

Previous studies have shown that gout is associated with an increased risk for cardiovascular mortality in the general population, but this has not been well studied in patients with ESRD. In this study, the incidence of gout and its association with mortality was evaluated in 259,209 patients in the United States Renal Data System. Overall, the incidence of gout in the first year of dialysis was 5% and in the first 5 yr was 15.4%. Independent risk factors for gout in adjusted analyses included black race, older age, female gender, hypertension, ischemic heart disease, congestive heart failure, and alcohol use. Factors associated with a lower risk for gout included a history of diabetes, smoking, and peripheral vascular disease. Time-dependent Cox regression analysis suggested that an episode of gout was independently associated with a 1.5-fold increase in mortality risk (adjusted hazard ratio 1.49; 95% confidence interval 1.43 to 1.55). The mechanisms underlying this association require further study.

Retransplantation After BK Virus Nephropathy in Prior Kidney Transplant: An OPTN Database Analysis

BK virus (BKV) has emerged as a major complication of kidney transplantation. Since June 30, 2004, the OPTN in the USA collects BKV as a primary or secondary cause of graft loss and also if treatment for BK virus (TBKV) is administered. In this study, we determined characteristics of those recipients of repeat kidney transplants from the OPTN database, where either (a) a graft loss occurred between June 30, 2004 and December 31, 2008 and database recorded prior TBKV in that allograft or (b) a graft loss between June 30, 2004 and December 31, 2008 was attributed primarily or secondarily due to BKV. In the study time period, 823 graft losses have occurred where TBKV or graft failure attributable to BKV was reported in prior transplant; of these, 126 have received a retransplant as of June 5, 2009. Induction and maintenance immunosuppression usage mirrored current trends. As of June 5, 2009, 118/126 grafts are still functioning, one graft failure attributed to BKV. TBKV was reported in 17.5% of the retransplants. In the retransplants performed through December 31, 2007, 1‐year acute rejection rate was 7%, 1‐year and 3‐year Kaplan–Meier graft survival rates and median GFR were 98.5%, 93.6%, 65.5 and 68.4 mL/min, respectively. Retransplantation after BKV appears to be associated with good results.

Incidence, predictors, and associated outcomes of prostatism after kidney transplantation.

BACKGROUND AND OBJECTIVES Renal transplantation is increasingly performed in elderly patients, and the incidence of benign prostatic hyperplasia (BPH) increases with age. Anuric males on dialysis may have occult BPH and not develop obstructive symptoms until urine flow is restored after transplantation. If left untreated, BPH poses a risk for numerous complications, including acute urinary retention (AUR), recurrent urinary tract infections (UTI), and renal failure. The authors hypothesized that incident BPH after renal transplantation would adversely affect allograft survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Medicare claims for BPH, AUR, UTI, and prostate resection procedures (transurethral resection of the prostate; TURP) were assessed in a retrospective cohort of 23,622 adult male Medicare primary renal transplant recipients in the United States Renal Data System database who received transplants from 1 January 2000 to 31 July 2005 and followed through 31 December 2005. RESULTS The 3-yr incidence of BPH post-transplant was 9.7%. The incidences of AUR, UTI, and TURP after BPH diagnosis (up to 3 yr posttransplant) were 10.3%, 6.5%, and 7.3% respectively, and each was significantly associated with BPH. Cox regression analysis showed that recipient age per year, later year of transplant, and dialysis vintage were associated with incident BPH. Using Cox nonproportional hazards regression, BPH was significantly associated with renal allograft loss (including death). CONCLUSIONS BPH is common in males after renal transplant and is independently associated with AUR, UTI, and graft loss. It is unknown whether treatment of BPH, either medical or surgical, attenuates these risks.

Incidence, predictors and associated outcomes of rhabdomyolysis after kidney transplantation

BACKGROUND There are several case reports of rhabdomyolysis (RM) in renal transplant recipients, but the actual incidence of this complication is not known. Most of the reported cases have been attributed to drug-drug interactions with calcineurin inhibitors, with the majority of interactions reported between cyclosporine and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). Pharmacokinetic studies have demonstrated that cyclosporine increases statin drug levels, presumably via competitive inhibition of cytochrome P450 3A4. METHODS In a retrospective cohort of 20 366 adult Medicare primary renal transplant recipients in the USRDS database transplanted from 1 January 2003 to 31 July 2005 and followed through 31 December 2005, we assessed Medicare claims for RM and dyslipidaemia (HPL), which was used as a surrogate for statin use. RESULTS The incidence rate of RM post-transplant for the study period was 1.4 (95% CI 1.1-1.8) per 1000 person-years. By Cox regression analysis, cyclosporine (versus tacrolimus) use [AHR 2.36 (95% CI 1.23-4.35); P = 0.006] and black race [AHR 2.33 (95% CI 1.30-4.17); P = 0.005] were associated with RM. By Cox non-proportional hazards regression, RM was associated with graft loss (including death) [AHR 2.84 (95% CI 1.70-4.72); P < 0.001]. CONCLUSIONS RM is a rare complication after renal transplantation and is significantly associated with allograft loss (including death). RM is significantly more likely to occur with cyclosporine (versus tacrolimus)-based immunosuppression and possibly in persons of black race. Increased surveillance for RM is warranted in these at-risk patients.

Trends in renal transplantation in patients with human immunodeficiency virus infection: an analysis of the United States renal data system.

Background. We examined the United States Renal Data System registry to analyze trends in renal transplantation in patients with human immunodeficiency virus (HIV) infection. Methods. A retrospective cohort study was performed using the United States Renal Data System, analyzing patients receiving renal transplants from January 1, 1995, to September 29, 2006. Factors independently associated with transplantation in HIV-infected patients with end-stage renal disease were identified. Results. There was a significant increase in renal transplant recipients who were HIV seropositive who received renal transplants from 2001 to 2006 (n=208, 0.26%) versus 1995 to 2000 era (n=43, 0.06%, P<0.001). Before 2001, only 18 states performed renal transplants in HIV-infected patients, whereas most states transplanted HIV-infected patients in the second era. There were more African American recipients with HIV infection from 2001 to 2006 compared with the earlier cohort (n=118 vs. 8, P<0.001). Patients with HIV infection were more likely to have received induction therapy (n=121 vs. 37, P<0.001) and tacrolimus maintenance suppression (n=105 vs. 13, P<0.001) in the latter era. There were also more deceased donor transplants from 2001 to 2006 (n=143 vs. 25, P<0.001). In logistic regression analysis, when adjusted for multiple factors including recipient and donor age, race, gender, and donor type, patients with HIV infection were more likely to have been transplanted after 2001 (adjusted odds ratio, 2.21; 95% confidence interval=1.49–3.28). In analysis adjusted for multiple factors including hepatitis C virus coinfection, HIV infection was not significantly associated with all-cause graft loss. Conclusions. There has been a dramatic increase in the number of transplants among HIV-infected patients. These findings suggest improved access to transplant wait listing and better management of immunosuppression, especially among African American patients.

Influence of Race on Kidney Transplantation in the Department of Defense Healthcare System

Background: We report the influence of race on transplant outcomes in the Department of Defense (DOD) system. Methods: Retrospective cohort analysis of all kidney transplants performed at WRAMC from 1996 to 2005. Kaplan-Meier analysis was used to assess for differences in graft survival, and Cox regression was used to calculate adjusted hazard ratios for graft loss. For our analyses, we used the cutoff of 6 years (year 2000) when we introduced thymoglobulin induction; maintenance immunosuppression consisted of mycophenolate mofetil and tacrolimus, and rapid steroid taper (completed withdrawal at 6 weeks) was used for all patients. Results: There were 220 transplants (91 Blacks, 107 Caucasians and 22 Asians). Because the curve for graft survival for Blacks over time violated the proportional hazards assumption (at 6 years post-transplant), analysis was segregated into two segments. Through 6 years of follow-up, graft survival was 77% for Blacks and 81% for non-Blacks (p = 0.74 by log rank). Through 9 potential years of follow-up, graft survival for Blacks was 56% and 78% for Whites (p = 0.005). In Cox regression analysis, Black race, compared with non-Black race, was not significantly associated with graft loss at 6 years, but was significantly associated with graft loss occurring after 6 years. Conclusions: In the DOD health system, no significant differences were seen in graft survival among recipients of different races at 6 years. Black recipients who received a kidney transplant before the year 2000 showed decreased graft survival compared to non-Blacks. This was consistent with change in immunosuppressive regimen in our institution with the introduction of thymoglobulin induction and maintenance therapy with tacrolimus, mycophenolate mofetil and withdrawal of prednisone at 6 weeks.