Deirdre Sawinski

Successful Treatment of Hepatitis C in Renal Transplant Recipients With Direct-Acting Antiviral Agents.

The direct‐acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end‐stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon‐free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy‐proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon‐based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment‐related side effects.

Trial of Transplantation of HCV-Infected Kidneys into Uninfected Recipients

An open-label pilot trial involving 10 patients shows that hepatitis C virus genotype 1–infected kidneys transplanted into HCV-negative recipients, followed by direct-acting antiviral therapy, can result in excellent allograft function with cure of HCV infection.

Risk of End‐Stage Renal Disease Among Liver Transplant Recipients With Pretransplant Renal Dysfunction

Guidelines recommend restricting simultaneous liver–kidney (SLK) transplant to candidates with prolonged dialysis or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 for 90 days. However, few studies exist to support the latter recommendation. Using Scientific Registry of Transplant Recipients and Medicare dialysis data, we assembled a cohort of 4997 liver transplant recipients from February 27, 2002–January 1, 2008. Serial eGFRs were calculated from serum creatinines submitted with MELD reports. We categorized recipients by eGFR patterns in the 90 days pretransplant: Group 1 (eGFR always >30), Group 2 (eGFR fluctuated), Group 3 (eGFR always <30) and Group 4 (short‐term dialysis). For Group 2, we characterized fluctuations in renal function using time‐weighted mean eGFR. Among liver‐alone recipients in Group 3, the rate of end‐stage renal disease (ESRD) by 3 years was 31%, versus <10% for other groups (p < 0.001). In multivariable Cox regression, eGFR Group, diabetes (HR 2.65, p < 0.001) and black race (HR 1.83, p = 0.02) were associated with ESRD. Among liver‐alone recipients in Group 2, only diabetics with time‐weighted mean eGFR <30 had a substantial ESRD risk (25.6%). In summary, among liver transplant candidates not on prolonged dialysis, SLK should be considered for those whose eGFR is always <30 and diabetic candidates whose weighted mean eGFR is <30 for 90 days.

BK virus infection: an update on diagnosis and treatment

BK virus, first isolated in 1971, is a significant risk factor for renal transplant dysfunction and allograft loss. Unfortunately, treatment options for BK virus infection are limited, and there is no effective prophylaxis. Although overimmunosuppression remains the primary risk factor for BK infection after transplantation, male gender, older recipient age, prior rejection episodes, degree of human leukocyte antigen mismatching, prolonged cold ischemia time, BK serostatus and ureteral stent placement have all been implicated as risk factors. Routine screening for BK has been shown to be effective in preventing allograft loss in patients with BK viruria or viremia. Reduction of immunosuppression remains the mainstay of BK nephropathy treatment and is the best studied intervention. Laboratory-based methods such as ELISPOT assays have provided new insights into the immune response to BK and may help guide therapy in the future. In this review, we will discuss the epidemiology of BK virus infection, screening strategies, treatment options and future research directions.

Persistent BK Viremia Does Not Increase Intermediate-Term Graft Loss but Is Associated with De Novo Donor-Specific Antibodies

There are limited data regarding intermediate-term outcomes in patients with persistent BK viremia. Other viral infections have been implicated in the development of allosensitization through heterologous immunity, but the relationship between BK viremia and donor-specific antibodies (DSAs) is unexplored. In 2008, we initiated routine post-transplant BK viremia and DSA screening at our center; 785 kidney or kidney-pancreas transplant recipients were included in our study. Of these recipients, 132 (17%) recipients developed BK viremia during the study period. The median duration of BK viremia was 140 days (interquartile range=40-393 days), and persistent BK viremia was defined as lasting ≥140 days. Kaplan-Meier curves were generated to assess differences in patient and allograft survival on the basis of BK viremia status; survival was modeled using Cox proportional hazard regression. After a median follow-up of 3 years, there was no significant difference in terms of patient (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.28 to 2.49) or allograft survival (HR, 0.80; 95% CI, 0.37 to 1.73) between patients with and without BK viremia, which was confirmed in a time-varying analysis. In our logistic regression model, persistent BK viremia was strongly associated with the development of class II (HR, 2.55; 95% CI, 1.30 to 4.98) but not class I (HR, 1.13; 95% CI, 0.46 to 2.77) DSAs. These data suggest that persistent BK viremia does not negatively affect intermediate-term patient or allograft survival but is associated with increased risk for de novo DSA, although the exact mechanism is unclear.

Superior outcomes in HIV-positive kidney transplant patients compared with HCV-infected or HIV/HCV-coinfected recipients.

The prerequisite for an “undetectable” HIV viral load has restricted access to transplantation for HIV-infected kidney recipients. However, HCV-infected recipients, due the historic limitations of HCV therapy in patients with renal disease, are commonly viremic at transplant and have universal access. In order to compare the effect of HIV, HCV and HIV/HCV co-infection on kidney transplant patient and allograft outcomes, we performed a retrospective study of kidney recipients transplanted from January 1996 through December 2013. In multivariable analysis, patient (hazard ratio 0.90, 95% confidence interval 0.66–1.24) and allograft survival (0.60, 40–0.88) in 492 HIV patients did not differ significantly from the 117,791 patient uninfected reference group. This was superior to outcomes in both the 5605 patient HCV group for death (1.44, 1.33–1.56) and graft loss (1.43, 1.31–1.56) as well as the 147 patient HIV/HCV co-infected group for death (2.26, 1.45–3.52) and graft loss (2.59, 1.60–4.19). HIV infection did not adversely affect recipient or allograft survival and was associated with superior outcomes compared to both HCV infection and HIV/HCV co-infection in this population. Thus, pre-transplant viral eradication and/ or immediate post-transplant eradication should be studied as potential strategies to improve post-transplant outcomes in HCV-infected kidney recipients.

Clinical InvestigationSuperior outcomes in HIV–positive kidney transplant patients compared with HCV–infected or HIV/HCV–coinfected recipients

The prerequisite for an “undetectable” HIV viral load has restricted access to transplantation for HIV-infected kidney recipients. However, HCV-infected recipients, due the historic limitations of HCV therapy in patients with renal disease, are commonly viremic at transplant and have universal access. In order to compare the effect of HIV, HCV and HIV/HCV co-infection on kidney transplant patient and allograft outcomes, we performed a retrospective study of kidney recipients transplanted from January 1996 through December 2013. In multivariable analysis, patient (hazard ratio 0.90, 95% confidence interval 0.66–1.24) and allograft survival (0.60, 40–0.88) in 492 HIV patients did not differ significantly from the 117,791 patient uninfected reference group. This was superior to outcomes in both the 5605 patient HCV group for death (1.44, 1.33–1.56) and graft loss (1.43, 1.31–1.56) as well as the 147 patient HIV/HCV co-infected group for death (2.26, 1.45–3.52) and graft loss (2.59, 1.60–4.19). HIV infection did not adversely affect recipient or allograft survival and was associated with superior outcomes compared to both HCV infection and HIV/HCV co-infection in this population. Thus, pre-transplant viral eradication and/ or immediate post-transplant eradication should be studied as potential strategies to improve post-transplant outcomes in HCV-infected kidney recipients.

Novel Hepatitis C Treatment and the Impact on Kidney Transplantation.

With a worldwide prevalence of 6% to 40% among patients with end-stage renal disease, hepatitis C virus (HCV) infection is a significant cause of comorbidity in kidney transplant candidates and recipients alike. Hepatitis C infection negatively impacts patient and allograft outcomes, predisposes to progressive liver disease and increases the risks of glomerular disease as well as new onset diabetes after transplantation. Treatment options until now have revolved around interferon, limited in efficacy, restricted to pretransplant administration because of concerns related to allograft dysfunction and immune stimulation, and fraught with high rates of intolerance. Direct-acting antivirals therapies are now emerging, providing the opportunity to effectively cure chronic HCV infection and to reduce the burden of hepatic and extrahepatic complications of HCV that are observed in kidney recipients, thereby offering hope of improved patient outcomes. Against a description of the major outcomes and risks that HCV+ kidney candidates and recipients encounter, and a summary of the pertinent studies of interferon-based therapies in this population, this review discusses the potential role for emerging direct-acting antivirals, proposing treatment algorithms that should be considered in the management of these complex patients. Conundrums relating to the new treatment, including the potential impact on the utilization of kidneys from HCV-infected donors, are presented.

Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis.

Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta‐analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate‐ to high‐strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard‐dose regimens; moderate‐strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate‐ to high‐strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine‐based strategies and low‐risk populations. Additional research is needed with tacrolimus‐based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient‐centered outcomes.

Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis

We compared the effectiveness of lower‐dose (LD) (450 mg/day for 6 months) to standard‐dose (SD) (900 mg/day for 6 months) valganciclovir (VGCV) prophylaxis for prevention of cytomegalovirus (CMV) infection and disease in high‐risk CMV donor‐positive/recipient‐negative (D+/R−) kidney recipients.