Comparing everolimus‐based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from 6 months after heart transplantation: The randomized MANDELA study

In the 12‐month, open‐label MANDELA study, patients were randomized at month 6 after heart transplantation to (1) convert to calcineurin inhibitor (CNI)‐free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI‐free, n = 71), or to (2) continue reduced‐exposure CNI, with EVR and steroids (EVR/redCNI, n = 74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI‐free patients at randomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 posttransplant postrandomization) with superiority of the CNI‐free group vs EVR/redCNI: mean 64.1 mL/min/1.73 m² vs 52.9 mL/min/1.73 m²; difference + 11.3 mL/min/1.73 m² (P < .001). By month 18, estimated GFR had increased by ≥ 10 mL/min/1.73 m² in 31.8% and 55.2% of EVR/redCNI and CNI‐free patients, respectively, and by ≥ 25 mL/min/1.73 m² in 4.5% and 20.9%. Rates of biopsy‐proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI vs the CNI‐free regimen (P = .015); 6 of 15 episodes in CNI‐free patients occurred with EVR concentration < 5 ng/mL. Rates of adverse events and associated discontinuations were comparable. EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One‐year renal function can be improved by early conversion to EVR‐based CNI‐free therapy but requires close EVR monitoring. Clinical trials registry: ClinicalTrials.gov NCT00862979.     

Belatacept treatment for two yr after liver transplantation is not associated with operational tolerance

Belatacept was recently evaluated in liver transplantation (LT) in a phase II multicenter trial, which was terminated prematurely. Patients were more than two yr post‐LT at the time. As high rates of spontaneous tolerance after LT have been reported and as belatacept has marked immunomodulatory effects, we decided to maintain the belatacept patients enrolled at our center (n = 4) on MMF monotherapy. All belatacept patients on MMF monotherapy developed graft dysfunction consistent with acute rejection after a mean period of 10.3 (7–14) wk. Patients were therefore switched to triple therapy with CNI, MMF, and corticosteroids. Graft dysfunction resolved within 1–3 wk after switch. At the time of belatacept discontinuation, mean eGFR was 105.1 mL/min/1.73 m² (92.1–118.9) in belatacept patients compared to 58 mL/min/1.73 m² (36.1–98.2) in controls (p = 0.022). One yr after the switch to CNI therapy, eGFR had declined by 27.4 mL (19.2–39.3; p = 0.008). Thus, LT patients treated with belatacept show superior kidney function that declines upon institution of CNIs. MMF monotherapy following withdrawal of belatacept is associated with a high incidence of graft dysfunction. Belatacept has no obvious immunomodulatory effects in LT recipients that would be sufficient to allow drug withdrawal with a high rate of success.     

Conversion to Mycophenolate Mofetil From Azathioprine Shows Significant Positive Effect on Graft Function in Long-Term Past–Kidney Transplantation Stable-State Patients

Objectives

A number of reports have shown that the efficacy of mycophenolate mofetil (MMF) is superior to that of azathioprine (AZP) for long-term kidney allograft survival. We conducted a retrospective single-center study to evaluate renal function more than 2 years after conversion from AZP to MMF in kidney transplant recipients several years after transplantation.

Methods

AZP was converted to MMF in 51 recipients at 17.0 ± 0.8 years after kidney transplantation who were followed up for more than 2 years after conversion. Estimated glomerular filtration rate (eGFR) was determined using the Formula of the Japanese Society of Nephrology.

Results

The eGFR was significantly greater at 1 year before conversion (41.72 ± 1.91 mL/min/1.73 m²) as compared with the day of conversion (39.04 ± 1.82 mL/min/1.73 m²; P < .05). After conversion, eGFR plateaued to 39.30 ± 2.01 mL/min/1.73 m² at 1 year and 38.24 ± 2.42 mL/min/1.73 m² at 2 years after conversion. The average eGFR slopes were −2.96 ± 0.36 mL/min/1.73 m² per year for AZP and 1.22 ± 0.10 mL/min/1.73 m² per year for MMF (P < .0001). Cyclosporine (CSA) was reduced from 176 ± 9.3 to 165 ± 9.8 mg/d (P = .0394) after the switch, whereas the CSA trough level was increased from 77.3 ± 6.6 to 118 ± 9.8 ng/mL (P = .0017). Furthermore, the daily dose of tacrolimus (TAC) was decreased from 3.5 ± 0.3 to 3.1 ± 0.3 mg/d (P = .0083).

Conclusions

Our findings demonstrated the safety of conversion from AZP to MMF even in the patients who underwent renal transplantation several years prior. In addition, these short-term results indicated the improvement in allograft function following conversion.     

Quantifying lead time bias when estimating patient survival in preemptive living kidney donor transplantation

Preemptive kidney transplantation is the preferred initial renal replacement therapy, by avoiding dialysis and reportedly maximizing patient survival. Lead time bias may account for some or all of the observed survival advantage, but the impact of this has not been quantified. Using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included adult recipients of living donor kidney transplants during 1998‐2017. Patients were transplanted preemptively (n = 1435) or after receiving up to 6 months of dialysis (n = 712). We created a matched cohort using propensity scores, and accounted for lead time (dialysis and estimated predialysis) using left‐truncated Cox models with the primary outcome of patient survival. The median eGFR at transplantation was 6.9 mL/min per 1.73 m² in the non‐pre‐emptive, and 9.6 mL/min per 1.73 m² in the preemptive group. In the matched cohort (n = 1398), preemptive transplantation was not associated with a survival advantage hazard ratio (HR) for preemptive vs non‐pre‐emptive 1.12 (95% confidence interval [CI] 0.79‐1.61). Accounting for lead time moved the point estimates toward a survival disadvantage for preemptive transplantation (eg, HR assuming 4 mL/min per 1.73 m²/year eGFR decline, 1.21 [0.85, 1.73]), but in all cases the 95% CIs crossed 1. The optimal timing of preemptive living donor kidney transplantation requires further study.     

Renal Transplantation in Obese Patients: Experience in an Argentine Center

Possible complications of renal transplants in obese patients have raised concerns among nephrologists. We describe the outcomes of 110 renal transplant patients according to body mass index (BMI). Recipient BMI was calculated by using height and weight at time of transplantation and categorized according to World Health Organization guidelines. The patients' BMI values were as follows: underweight, n = 8 (7.27%); normal weight, n = 55 (50%); overweight, n = 30 (27.27%); and obese, n = 17 (15.45%). Mean age was significantly different among groups: underweight, 27.62 ± 7.57 years; normal weight, 44.98 ± 15.55 years; overweight, 50.53 ± 13.90 years; and obese, 52.11 ± 10.41 years (P < .05). Donor age and mean time of dialysis treatment were comparable in all groups. Underweight patients had a significantly larger proportion of living donors than those with higher BMIs. Calculated glomerular filtration rate (using the Modification of Diet in Renal Disease equation) were significantly different among the groups at 30, 60, and 90 days' posttransplantation. At 180 days, however, it was comparable: underweight, 62.96 ± 40.77 mL/min/1.73 m²; normal weight, 53.55 ± 26.23 mL/min/1.73 m²; overweight, 47.52 ± 16.37 mL/min/1.73 m²; and obese, 46.19 ± 17.56 mL/min/1.73 m² (P = .34). Incidence of delayed graft function was as follows: underweight, 0%; normal weight, 30.4%; overweight, 53.3%; and obese, 64.1% (P < .05). The incidence of surgical complications, incidence of rejection within the first 6 months' posttransplantation, and graft and patient survival rates over 6 months did not differ among the groups. Because transplantation in obese patients may be associated with higher risks and costs, the evaluation of each center experience is imperative. Longer term assessments are warranted, but our short-term results show that outcomes in overweight or obese renal transplant patients are comparable to those in patients with lower BMI.     

Chronic renal outcome after living donor liver transplantation

Chronic kidney disease (CKD) is one of the common complications after deceased donor liver transplantation. Although the worldwide pressing shortage in deceased donors has directed attention to living donor liver transplantation (LDLT), LDLT cohort data focusing on chronic renal dysfunction is limited. A total of 280 adult LDLT recipients (median 49 yr, 156 men) at the University of Tokyo hospital between 1996 and 2006 were reviewed. A total of 224 pre‐transplant liver failure patients (80.0%) showed an estimated glomerular filtration rate (eGFR) of more than 60 mL/min/1.73 m². However, during follow‐up at a mean of 1222 d after transplantation, eGFR declined to 60 mL/min/1.73 m² and 30 mL/min/1.73 m² in 150 (53.2%) and 21 (7.5%), respectively, and four patients (1.4%) required maintenance renal replacement therapy. Multivariate Cox proportional hazard model regression analysis revealed that recipient age (HR, 3.42 per 10‐yr increment; p < 0.001) and pre‐transplant eGFR (HR, 0.85 per 10‐mL/min/1.73 m² increment; p = 0.04) were associated independently with a post‐transplant decrease in eGFR to less than 30 mL/min/1.73 m². We conclude that higher age and lower pre‐transplant eGFR of an LDLT recipient indicate a high likelihood of subsequent development of advanced CKD. Preventive or therapeutic intervention should be optimized for these high‐risk patients.     

Belatacept‐based immunosuppression: A calcineurin inhibitor‐sparing regimen in heart transplant recipients

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m² were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among “late” patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow‐up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.     

Independent risk factors and natural history of renal dysfunction in liver transplant recipients

Renal dysfunction is common after liver transplantation. However, there are only limited data on the predictors and natural history of renal dysfunction after liver transplantation. In this study, we determined independent predictors and the natural history of renal dysfunction in 172 consecutive liver transplant recipients. Survival and time to development of permanent renal dysfunction (renal dysfunction defined as a sustained decrease in estimated glomerular filtration rate (GFR) of > 30 mL/min/1.73 m² from baseline for at least 6 months, severe renal failure defined as absolute GFR <30 mL/min/1.73 m² for at least 6 months) were determined using the Kaplan-Meier method. Cox regression analysis was used to test the independent effect of a given set of variables on time to development of such an event. Nine percent of patients required immediate dialysis, 35% developed permanent renal dysfunction, and 7% developed severe renal failure. The rate of decline in renal dysfunction was maximal, 6.5 mL/min/1.73 m² /mo, at 1 month after liver transplantation. Pre-existing diabetes mellitus, major surgical infection, and waiting time on the transplant list were independent risk factors for immediate dialysis. Presence of serum creatinine > 1.2 mg/dL at any time before liver transplantation and a baseline GFR <70 mL/min/1.73 m² were independent predictors of permanent renal dysfunction. Diabetes mellitus, coronary artery disease, and primary graft nonfunction predicted the development of severe renal failure. GFR stabilized around 9 months, and presence of decreased GFR > 30mL/min/1.73 m² from baseline at 9 months predicted development of permanent renal dysfunction. An absolute GFR of <30mL/min/1.73 m² occurring as early as 3 months after liver transplantation predicted severe renal failure. Severe renal failure was associated with a significantly lower survival by Cox regression analysis. We have identified risk factors and the natural history of permanent renal dysfunction and severe liver failure in liver transplant recipients. These observations may be useful in the development of nonnephrotoxic immunosuppressive regimens for high-risk liver transplant recipients. (Liver Transpl 2003;9:741-747.)     

Efficacy and Safety of Early Cyclosporine Conversion to Sirolimus with Continued MMF—Four‐Year Results of the Postconcept Study

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent‐to‐treat population (ITT): 62.6 mL/min/1.73 m² versus 57.1 mL/min/1.73 m² (p = 0.013) and in the on‐treatment population (OT): 67.5 mL/min/1.73 m² versus 57.4 mL/min/1.73 m² (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new‐onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.     

Long‐term evolution,secular trends,and risk factors of renal dysfunction following cardiac transplantation

Recent reports suggest that individuals who underwent heart transplantation in the last decade have improved post‐transplant kidney function. The objectives of this retrospective study were to describe the incidence and to identify fixed and time‐dependent predictors of renal dysfunction in cardiac recipients transplanted over a 25‐year period (1983–2008). To illustrate temporal trends, patients (n = 306) were divided into five groups based on year of transplantation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at year 1. Secondary endpoints were time to moderate (eGFR <60 ml/min/1.73 m²) and severe renal dysfunction (eGFR <30 ml/min/1.73 m²). Risk factor analyses relied on multivariable regression models. Kidney function was mildly impaired before transplant (median eGFR=61.0 ml/min/1.73 m²), improved at discharge (eGFR=72.3 ml/min/1.73 m²; P < 0.001), decreased considerably in the first year (eGFR = 54.7 ml/min/1.73 m²; P < 0.001), and deteriorated less rapidly thereafter. At year 1, 2004–2008 recipients exhibited a higher eGFR compared with all other patients (P < 0.001). Factors independently associated with eGFR at year 1 and with moderate and severe renal dysfunction included age, gender, pretransplant eGFR, blood pressure, glycemia, and use of prednisone (P < 0.05). In summary, kidney function worsens constantly up to two decades after cardiac transplantation, with the greatest decline occurring in the first year. Corticosteroid minimization and treatment of modifiable risk factors (hypertension, diabetes) may minimize renal deterioration.     

N-Terminal Pro–B-Type Natriuretic Peptide (NT-proBNP) Assessment in the First Year After Renal Transplantation and Its Relationship With Graft Function and Left Ventricular Hypertrophy

Background

NT-proBNP is a natriuretic neurohormone released mainly from ventricular cardiomyocytes in conditions of volumetric or pressure overload; it is suitable for use as a marker of left ventricular hypertrophy (LVH), a common disorder in renal transplant recipients. The study objective here was to assess NT-proBNP levels in the 1st year after renal transplantation (RT) and its relationship with graft function and LVH.

Methods

Sixty patients (age, 49 ± 16.9 y; male, 58%) were subjected to prospective 1-year follow-up. Basic blood tests and NT-proBNP level measurements were performed twice (in the early period and at 1 year after transplantation). Cardiac echography was performed in 40 patients. LVH was diagnosed when left ventricular mass index was >95 g/m² in women and >115 g/m² in men. Statistical analyses were performed with the use of the R Package.

Results

At 1 year after RT, the NT-proBNP level decreased >2-fold compared with the early period (median 171 pg/mL [interquartile range (IQR), 104.5–283] vs 368 pg/mL[IQR, 170–629]; P = .00008). In the early post-transplantation period, NT-proBNP correlated with the patient's age, body mass index, estimated glomerular filtration rate (eGFR), and left ventricular end-diastolic dimension, and at 1 year after transplantation its correlation with the eGFR range (patients with eGFR ≥60 mL min⁻¹ 1.73 m⁻² had significantly lower NT-proBNP levels than those with eGFR <60 mL min⁻¹ 1.73 m⁻²), with age,and with ejection fraction was found. Patients with LVH had higher NT-proBNP levels than those without LVH in the early period (median 511 pg/mL [IQR, 190–736] vs 380 pg/mL [IQR, 217–511]; P = .09), and at 1 year (median 269 pg/mL [IQR, 155–474] vs 133 pg/mL [IQR, 99–134]; P = .057). At NT-proBNP >480 pg/mL in the early period and >280 pg/mL at 1 year, LVH occurred with a 68% probability (P = .05 and P = .03, respectively).

Conclusions

During the 1st year after RT, NT-proBNP levels decrease ≥2-fold and are primarily related to eGFR. NT-proBNP measurements are useful in identifying patients with LVH.     

Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

This randomized, comparative, multinational phase 3b/4 study of patients 1–8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40–90 mL/min/1.73m² were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent‐to‐treat analysis showed the 1‐year adjusted mean change from baseline in creatinine clearance (Cockcroft‐Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. ?1.4 mL/min/1.73 m², respectively; p = 0.004). By on‐therapy analysis, values were +4.7 and –2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment‐emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.     

A randomized trial of everolimus‐based quadruple therapy vs standard triple therapy early after lung transplantation

Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus‐based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open‐label, 12‐month multicenter trial was conducted at 8 German sites. Patients 3‐18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3‐5 ng/mL) with reduced CNI (tacrolimus 3‐5 ng/mL or cyclosporine 25‐75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy‐proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.     

Prevalence Rate of Proteinuria and Metabolic Acidosis Among Kidney Transplant Recipients in a Tertiary Teaching Hospital and Its Relationship to Dietary Intake

BackgroundProteinuria and metabolic acidosis adversely affect long term renal allograft outcome and are highly prevalent in reported studies. The role of dietary intake in influencing proteinuria and metabolic acidosis remained uncertain. This study aims to determine the prevalence rate of proteinuria and metabolic acidosis among kidney transplant recipients (KTRs) and to study their relationship with dietary intake.MethodsWe performed a cross-sectional study on KTRs with functioning renal allograft and at least 3 months post transplant. Dietary protein, salt, and dietary acid load were estimated using 24-hour urine collection. Demographic characteristics, concomitant medications, medical history, and laboratory results were obtained from electronic medical records.ResultsA total of 204 KTRs were recruited with median age of 48 years (interquartile range [IQR], 18 years); male to female ratio was 61:39. A total of 79.9% (n = 163) were living related kidney transplants. The median duration after transplant was 71 months (IQR, 131 months), and median eGFR was 65 mL/min/1.73 m² (IQR, 25 mL/min/1.73 m²). The prevalence rates of proteinuria (defined as ≥ 0.5 g/d) and metabolic acidosis (defined as at least 2 readings of serum bicarbonate ≤ 22 mmol/L in the past 6 months) were 17.7 % and 6.2%, respectively. High dietary protein of > 1.2 g/kg ideal body weight (adjusted odds ratio, 3.13; 95% CI, 1.35-7.28; P = .008) was significantly associated with proteinuria. Dietary protein, salt, and acid load did not correlate with chronic metabolic acidosis.ConclusionsThe prevalence rate of proteinuria is consistent with published literature, but metabolic acidosis rate is extremely low in our cohort. High protein intake (> 1.2 g/kg ideal body weight) is a risk factor of proteinuria and may have negative impact on KTR outcome.     

Correlations with six‐month protocol biopsy findings in pediatric transplant recipients on low‐ and regular‐dose CNI regimens

Protocol biopsies (PB) are seldom performed after pediatric kidney transplantation (KTx), and factors influencing PB results have not previously been investigated. We performed PB in 79 children six months after KTx and evaluated the results using Banff 2007 criteria. Complications such as bleeding or infections were not detected. The influence of different variables on PB results was evaluated by covariance analysis. Children treated with a low‐dose calcineurin inhibitor (CNI) together with an mTOR inhibitor exhibited decreased subclinical rejection (0% vs. 19%, p = 0.001) and decreased interstitial fibrosis and tubular atrophy (IF/TA) (15% vs. 42%, p = 0.013) compared with patients treated with a conventional regimen consisting of normal‐dose CNI and mycophenolate mofetil. Children with IF/TA had a lower GFR four wk after Tx (83 ± 22 vs. 62 ± 20 mL/min/1.73 m², p = 0.001). Cold ischemia time, living‐related donors, pre‐emptive KTx, and donor age did not influence PB results. Treatment with low‐dose CNI and mTOR inhibitor and high GFR directly after Tx are the main factors associated with less inflammation and fibrosis in PB and might therefore lead to better long‐term graft function.     

Cyclosporine versus everolimus: effects on the glomerulus

Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two‐yr protocol biopsies. In a single‐center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light‐ and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above‐described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m²). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light‐ or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL‐treated patients. In conclusion, long‐term treatment with everolimus leaves the GBM and podocytes unaffected.     

Renal transplantation in the elderly: South Indian experience

In developing countries, renal transplantation is offered to young end-stage renal disease (ESRD) patients, while the older ones face limitations due to higher mortality risk. We retrospectively analyzed 225 patients who underwent renal transplantation from living donors, aged 40–60 years (Group A) and >60 years (Group B), focusing on their survival outcome. Group A (n = 181) had mean creatinine (mg/dL) 1.41 ± 0.84, 1.30 ± 0.65 and 1.40 ± 0.60 and mean eGFR (mL/min/1.73 m²) of 65.32 ± 23.03, 69.14 ± 32.65 and 59.21 ± 22.79 at 0, 3 and 6 months post-transplantation. Death-censored graft survival was 93.1% in first year followed by 91.2% in subsequent 4 years. Patient survival was 92.5% in first year, 90.7% in the next 2 years, and 89.2% in 4th year. Highest cumulative graft survival was 86.7% in the first year with 83.4%, 82.7% and 82.4% during the subsequent 3 years. Group B (n = 44) had mean creatinine (mg/dL) of 1.46 ± 1.02, 1.29 ± 0.23 and 1.2 ± 0.29 with a mean eGFR (mL/min/1.73 m²) of 67.90 ± 23.48, 67.02 ± 12.76 and 75.23 ± 15.19 at 0, 3 and 6 months. Highest death-censored graft survival was 97.4% in the first year with 94.7% in next 3 years. Patient survival was 88.1% throughout 4 years post-transplantation. Cumulative graft survival was 84.1% during 4 years. Biopsy-proven acute rejection rate was 28.7% in group A and 15.9% in group B (P = 0.058). There was higher mortality rate in group B with death mainly due to infections and cardiovascular complication. Cardiovascular risk assessment, pre-transplant cancer screening and judicious use of immunosuppressive agents should help minimize adverse events, balanced with an inherently reduced risk of acute rejection, hence the graft survival advantage and is the way forward to maximize patient and renal allograft survival in elderly patients.     

Long-term renal function in living kidney donors with simple renal cysts: A retrospective cohort study

Simple (Bosniak I) renal cysts are considered acceptable in living kidney donor selection in terms of cancer risk. However, they tend to increase in number and size over time and might compromise renal function in donors. To clarify their implications for long-term renal function, we characterized the prevalence of renal cysts in 454 individuals who donated at our center from 2000 to 2007. We estimated the association between the presence of cysts in the kidney remaining after nephrectomy (ie, retained cysts) and postdonation eGFR trajectory using mixed-effects linear regression. Donors with retained cysts (N = 86) were older (P < .001) and had slightly lower predonation eGFR (median 94 vs 98 mL/min/1.73 m², P < .01) than those without cysts. Over a median 7.8 years, donors with retained cysts had lower baseline eGFR (_−8.7 −5.6 _−2.3 mL/min/1.73 m², P < .01) but similar yearly change in eGFR (_−0.4 0.02 _0.4 mL/min/1.73 m², P = .2) compared to those without retained cysts. Adjusting for predonation characteristics, there was no difference in baseline eGFR (P = .6) or yearly change in eGFR (P > .9). There continued to be no evidence of an association when we considered retained cyst(s) ≥10 mm or multiple retained cysts (all P > .05). These findings reaffirm current practices of accepting candidates with simple renal cysts for donor nephrectomy.     

Rate,Factors, and Outcome of Delayed Graft Function After Kidney Transplantation of Deceased Donors

BackgroundDelayed graft function (DGF) is a frequent complication after kidney transplantation affecting long-term outcome.Patients and methodsA total of 525 consecutive recipients (age 54.2 ± 13.4 years, 33% female) of kidneys from deceased donors transplanted between 2005 and 2012 were retrospectively examined. DGF was defined as the need of dialysis within the first week after transplantation.ResultsDGF developed in 21.1% (n = 111). Factors associated with DGF (P ≤ .035, respectively) were recipient body mass index, C-reactive protein of the recipient, residual diuresis, cold ischemia time, donor age, and diuresis in the first hour after transplantation. Median duration of DGF was 16 (2-66) days. Patients after DGF had a significantly lower GFR compared with recipients without DGF either after 3 (32.9 ± 16.5 vs 46.3 ± 18.4 mL/min/1.73 m²) or after 12 months (38.9 ± 19.3 vs 48.6 ± 20.4 mL/min/1.73 m², P < .001, resp.). During DGF, 12.4% developed BANFF II and 18.0% BANFF I rejection, 20.2% had signs of transplant glomerulitis (first biopsy), and 16.2% (n = 18) remained on dialysis.ConclusionDGF affects 1 out of 5 kidney transplants from deceased donors. Minimizing modifiable risk factors, in particular immunologic risk, may ameliorate the incidence and outcome of DGF. The outcome of DGF depends mainly on the diagnosis of any rejection and worsens upon detection of transplant glomerulitis and pronounced interstitial fibrosis and tubular atrophy (IFTA).     

Long-Term Glomerular Filtration Rate in Liver Allograft Recipients According to the Type of Calcineurin Inhibitors

The calcineurin inhibitors (CNI) cyclosporine micro emulsion (CyA-ME) and tacrolimus (Tac) both display renal and vascular toxicities. We undertook a single-center retrospective study among 149 surviving liver transplant recipients. The primary outcome was kidney function over 10 years posttransplant, evaluating the glomerular filtration rate (GFR) by the abbreviated Modification of Diet in Renal Disease formula with subsequent Kidney Disease Outcomes Quality Initiative staging. The secondary outcomes included correlations between CNI trough levels (C₀), GFR, and items of cardiovascular toxicity. At 1 and 5 years, the mean GFRs were 74.2 and 76.9 mL/min/1.73 m² under Tac versus 62.8 and 66.0 mL/min/1.73 m² under CyA-ME (P < .001). The mean value in favor of Tac was + 10 mL/min/1.73 m². Distribution of GFR stages showed more Tac patients at stage 1 or 2 and more at stage 4 or 5 under CyA-ME. There was no significant correlation between CNI-C₀ and GFR. Switches between CNI or to mycophenolate mofetil did not show any significant GFR improvement. Patients under CyA-ME displayed significantly higher blood pressures with 3 requiring dialysis versus none under Tac. In conclusion, we observed that liver transplant patients under Tac maintained significantly better renal function with less progression to dialysis as compared with CyA-ME, indicating a lower renal and vascular (lower BP) toxicity.