Simin Goral

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.

Reduction of Immunosuppression as Initial Therapy for Posttransplantation Lymphoproliferative Disorder

Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and predictors of response to RI in adult patients with PTLD. Sixty‐seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response—37%, partial response—8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI‐containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome—age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3‐year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low‐risk PTLD and suggest factors that predict response and survival.

Recurrent lupus nephritis in renal transplant recipients revisited: It is not rare

Background. Although recurrent lupus nephritis (RLN) after kidney transplantation is reported to be rare (1%–4%), recent studies suggest a higher incidence. The purpose of this study was to determine the incidence of RLN in a large cohort of renal transplant recipients with systemic lupus erythematosus (SLE). Methods. The records of 54 renal transplant recipients with SLE were reviewed. Thirty-one patients underwent biopsy because of worsening renal function and proteinuria. All biopsy specimens were evaluated by light microscopy, immunofluorescence (IF), and electron microscopy (EM). Results. Among the 50 patients with at least 3 months of follow-up, RLN was present in 15 (52% of patients who underwent biopsy, 30% of total patients): mesangial lupus nephritis (LN) (class II) in eight, focal proliferative LN (class III) in four, and membranous LN (class Vb) in three patients. One patient had graft loss because of RLN (class II) at 10.5 years. The duration of dialysis before transplantation was not different between patients with RLN compared to patients without RLN (P =0.40). Overall patient survival (n=50) was 96% at 1 year and 82% at 5 years, and graft survival was 87% at 1 year and 60% at 5 years. Graft survival was worse in patients who underwent biopsy compared with patients who never underwent biopsy (P <0.01). Conclusions. RLN is more common than previously reported, but in our series, graft loss because of RLN was rare. Aggressive use of allograft biopsies and morphologic evaluation with IF and EM are important factors in the diagnosis of RLN. The impact of new immunosuppressive agents on the incidence of RLN remains to be seen.

Posttransplantation Anemia at 12 Months in Kidney Recipients Treated with Mycophenolate Mofetil: Risk Factors and Implications for Mortality

Although posttransplantation anemia (PTA) is common in the mycophenolate mofetil era, its impact on patient survival is unknown. This retrospective cohort study characterized factors that are associated with PTA 12 mo after transplantation in mycophenolate mofetil-treated kidney recipients and explored whether 12-mo PTA affects outcomes. The records of 626 kidney recipients were examined for presence of anemia (hemoglobin <12 g/dl). Multivariate regression models, fit with covariates that had unadjusted relationships, investigated both risk factors for 12-mo PTA and whether 12-mo PTA contributes to mortality. Anemia prevalence was 72, 40, and 20.3% at 1, 3, and 12 mo, respectively. By multivariate logistic regression, anemia at 3 mo (odds ratio [OR] 10.0; 95% confidence interval [CI] 5.3 to 17.1; P = 0.0001), donor age (OR 1.0; 95% CI 1.1 to 1.3; P = 0.005), and 3-mo creatinine (OR 2.0; 95% CI 1.2 to 3.3; P = 0.044) were associated with 12-mo PTA. The PTA cohort had inferior patient survival (P = 0.02, log rank) and a higher proportion of cardiovascular deaths (6.3 versus 2.2%; P = 0.017) than nonanemic patients. By Cox regression, 12-mo PTA (hazard ratio [HR] 3.0; 95% CI 1.3 to 6.7; P = 0.009), 12-mo creatinine (HR 1.3; 95% CI 1.1 to 1.4; P = 0.008), age at transplantation (HR 1.1; 95% CI 1.1 to 1.2; P = 0.004), and hepatitis C seropositivity (HR 2.8; 95% CI 1.1 to 7.0; P = 0.03) were associated with mortality. There was no interaction between 12-mo PTA and serum creatinine. In conclusion, 12-mo PTA is associated with an increased risk for patient death. The presence of anemia 3 mo after kidney transplantation is a major determinant of 12-mo PTA. PTA in kidney recipients therefore should be defined by its persistence or occurrence beyond the third posttransplantation month.

24-Week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course

Background. Cytomegalovirus (CMV) infection is associated with reduced graft and patient survival among kidney recipients. The highest risk of CMV infection occurs in CMV-naïve recipients of kidneys from seropositive donors (D+/R−). Optimal CMV prophylaxis is not established. This prospective cohort study compared the safety and efficacy of prophylaxis with 12 versus 24 weeks of oral ganciclovir. Methods. We prospectively administered 24 weeks ganciclovir to 31 D+/R− recipients. The control group comprised 39 patients transplanted in the immediately preceding era who received a 12-week course of prophylaxis. All patients received cytolytic therapy within the first month, as well as a tacrolimus-based maintenance regimen. A logistic regression model was fit to examine the relationship between 24 weeks ganciclovir prophylaxis and the odds of developing CMV infection by one year. Results. Groups were matched, though the 12-week cohort had more delayed graft function than their 24-week counterparts (45% vs. 29%, P=0.04). CMV infection occurred in 31% and 7% patients in the 12-week and 24-week groups, respectively (P≤0.01). Mean time to development of CMV infection was 17.5±2.2 weeks in the 12-week, and 22.0±10.0 weeks in the 24-week, groups (P=0.79). Both 24 weeks ganciclovir prophylaxis (O.R. 0.15, 95% C.I. 0.03–0.91, P=0.04) and delayed graft function (O.R. 4.49, 95% C.I. 1.67–36.56, P<0.01) were associated with CMV infection. Conclusions. Oral ganciclovir prophylaxis for 24 weeks is associated with a lower risk of symptomatic CMV disease than a 12-week course in high risk D+/R− kidney recipients.

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.

Screening asymptomatic diabetic patients for coronary artery disease prior to renal transplantation.

Background. Coronary artery disease (CAD) is a significant contributor to excess mortality in renal transplant candidates with diabetes mellitus (DM). Prior studies relating to risk stratification for significant CAD in diabetics are confined to Caucasian type 1 DM patients. Methods. To assess the prevalence of clinically silent CAD and to identify variables that are associated with CAD, we retrospectively analyzed the cardiac catheterization data of 97 asymptomatic type 1 and 2 DM kidney and kidney-pancreas transplant candidates. Results. Thirty-three percent of type 1 and 48% of type 2 DM patients had significant stenosis (≥70%) in 1 or more coronary arteries. On multivariate logistic regression analysis, body mass index (BMI) >25 was significantly associated with CAD (relative risk = 4.8, P = 0.002). The age of the patient (7% increase in risk/year, P = 0.01; or relative risk = 3.0 if age >47 years, P = 0.032) and smoking history (2% increase in risk/pack-year of smoking, P = 0.10) were also associated with CAD. African American patients, who comprised 30% of the sample, had a 71% lower risk compared with Caucasian patients (P = 0.03). Factors that were not significantly associated with CAD included gender, type of diabetes, and whether dialyzed for >6 months prior to catheterization. Conclusions. We conclude that a notable proportion (approximately one-third to one-half) of asymptomatic type 1 and type 2 diabetic renal transplant candidates have significant CAD. Additionally, young African American DM patients with no smoking history and a BMI ≤25 are at reduced risk, and invasive tests may not be necessary in this group.

A pilot protocol of a calcineurin-inhibitor free regimen for kidney transplant recipients of marginal donor kidneys or with delayed graft function

Abstract: Background: The worsening shortage of cadaver donor kidneys has prompted use of expanded or marginal donor kidneys (MDK), i.e. older age or donor history of hypertension or diabetes. MDK may be especially susceptible to calcineurin‐inhibitor (CI) mediated vasoconstriction and nephrotoxicity. Similarly, early use of CI in patients with delayed graft function may prolong ischaemic injury. We developed a CI‐free protocol of antibody induction, sirolimus, mycophenolate mofetil, and prednisone in recipients with MDK or DGF.

Aortic calcification predicts cardiovascular events and all-cause mortality in renal transplantation

BACKGROUND Cardiovascular disease is a leading cause of death among renal transplant recipients. Aortic calcification is associated with increased mortality in dialysis subjects. The significance of aortic calcification among renal transplant recipients is unknown. Our objective was to prospectively examine the association of aortic calcification with cardiovascular events and all-cause mortality among asymptomatic incident renal transplant recipients. METHODS One hundred and twelve renal transplant recipients underwent electron beam computed tomography. Aortic calcification was scored by the Agatston method. The mean follow-up time was 5.1 years. Cardiovascular events (heart failure, coronary artery disease, peripheral arterial disease and stroke) and all-cause mortality were recorded. RESULTS The cohort consisted of 62% Caucasians, 38% African Americans and 62% male gender. The mean age was 49.0 +/- 12.5 years. Thirty-four percent had aortic calcification. During follow-up, 12 cardiovascular events and 10 deaths were recorded. Subjects with aortic calcification had more cardiovascular events compared to those without aortic calcification (23.7 versus 4.1%, P = 0.001). Recipients with aortic calcification had higher mortality compared to those without aortic calcification but it did not reach statistical significance (15.8 versus 5.4%, P = 0.07). The univariate hazard ratio of aortic calcification score in a proportional hazard Cox model to assess event-free survival was 1.15 (1.04-1.27, P = 0.01). Diabetes and aortic calcification score were independently associated with survival. In addition to the predictors above, dialysis vintage was an independent predictor for combined future cardiovascular event and mortality. CONCLUSIONS In conclusion, aortic calcification is prevalent among renal transplant recipients and is predictive of future cardiovascular events. Aortic calcification is easily identified by non-invasive testing, and should be considered when assessing cardiovascular risk in asymptomatic renal transplant recipients.

L-Carnitine Treatment of Anemia

Recombinant human erythropoietin (rHuEPO) and iron supplementation have had a profoundly positive impact on the anemia of patients with chronic kidney disease. However, a significant number of patients remain hyporesponsive to rHuEPO, with hemoglobin values less than target levels. A suboptimal response to rHuEPO is associated with complications that can reduce quality of life and increase morbidity, mortality, and costs. There are a number of other metabolic derangements associated with uremia that can impact on the production and survival of red blood cells. Dialysis-related carnitine disorder is a functional metabolic deficiency, common in chronic dialysis patients, that can have a negative impact on erythrocyte production and survival. This article reviews the role of L-carnitine in the pathogenesis and adjunctive treatment of anemia associated with kidney failure. After a comprehensive database search, primary and secondary reports were analyzed. Laboratory studies examining the influence of carnitine on red blood cell function and clinical trials of L-carnitine in dialysis patients support the use of L-carnitine in the setting of rHuEPO hyporesponsiveness. Consensus groups, including the National Kidney Foundation-Kidney Disease Outcome Quality Initiative (K/DOQI), consider the use of L-carnitine for hyporesponsive rHuEPO-dependent anemia a promising application of this therapy, recommending an empiric trial of L-carnitine in these patients.