Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Genetic diversity of Pneumocystis jirovecii from a cluster of cases of pneumonia in renal transplant patients: Cross-sectional study.

Pneumocystis jirovecii can cause severe potentially life-threatening pneumonia (PCP) in kidney transplant patients. Prophylaxis of patients against PCP in this setting is usually performed during 6 months after transplantation. The aim of this study is to describe the molecular epidemiology of a cluster of PCP in renal transplant recipients in Brazil. Renal transplant patients who developed PCP between May and December 2011 had their formalin-fixed paraffin-embedded (FFPE) lung biopsy samples analysed. Pneumocystis jirovecii 23S mitochondrial large subunit of ribosomal RNA (23S mtLSU-rRNA), 26S rRNA, and dihydropteroate synthase (DHPS) genes were amplified by polymerase chain reaction (PCR), sequenced, and analysed for genetic variation. During the study period, 17 patients developed PCP (only four infections were documented within the first year after transplantation) and six (35.3%) died. Thirty FFPE samples from 11 patients, including one external control HIV-infected patient, had fungal DNA successfully extracted for further amplification and sequencing for all three genes. A total of five genotypes were identified among the 10 infected patients. Of note, four patients were infected by more than one genotype and seven patients were infected by the same genotype. DNA extracted from FFPE samples can be used for genotyping; this approach allowed us to demonstrate that multiple P. jirovecii strains were responsible for this cluster, and one genotype was found infecting seven patients. The knowledge of the causative agents of PCP may help to develop new initiatives for control and prevention of PCP among patients undergoing renal transplant and improve routine PCP prophylaxis.

Sepsis-like histoplasmosis in a kidney transplant patient.

Histoplasmosis is a fungus infection that mainly affects immunosuppressed patients. The authors present a case of a kidney transplant recipient who developed sepsis-like histoplasmosis, na atypical but severe manifestation of the disease. The fungus was found in blood and in a skin biopsy, and the treatment with liposomal amphotericin resulted in hepatotoxicity.

Sepsis-like histoplasmosis in a kidney transplant patient / Histoplasmose disseminada em uma paciente transplantada renal

Abstract Histoplasmosis is a fungus infection that mainly affects immunosuppressed patients. The authors present a case of a kidney transplant recipient who developed sepsis-like histoplasmosis, na atypical but severe manifestation of the disease. The fungus was found in blood and in a skin biopsy, and the treatment with liposomal amphotericin resulted in hepatotoxicity.

Resumo Histoplasmose é uma infecção fúngica que afeta principalmente pacientes imunossuprimidos. Os autores apresentam um caso de uma receptora de transplante de rim que desenvolveu histoplasmose disseminada, uma manifestação atípica, mas grave da doença. O fungo foi encontrado no sangue e na biópsia cutânea, e o tratamento com anfotericina lipossomal resultou em hepatotoxicidade.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial.

BACKGROUND: 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN: Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS: 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION: LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS: Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS: 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS: Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS: Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPT's improved bioavailability and absorption.

Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation.

BACKGROUND: Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. METHODS: A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3-8 or 6-12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab ± corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. RESULTS: Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (-2.2%, 13.0%), 26.9% (-7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3-8 and 6-12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (-2.1, 5.5 mL/min/1.73 m(2)), 49.4 (-4.8, 2.7 mL/min/1.73 m(2)), and 50.5 mL/min/1.73 m(2), respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P = 0.03 vs. MPA), 30.6% (P = 0.007 vs. MPA), and 20.5% of patients receiving everolimus 3-8 and 6-12 ng/mL and MPA, respectively. CONCLUSIONS: Everolimus trough concentrations targeted to 3-8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

How delayed graft function impacts exposure to mycophenolic acid in patients after renal transplantation.

INTRODUCTION: Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome. METHODS: Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC0₋12. Free MPA AUC values were available for a subgroup of patients (n = 269). RESULTS: The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections. CONCLUSION: Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.

Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial.

BACKGROUND: Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant. METHODS: Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation. RESULTS: Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively). CONCLUSIONS: There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.

Time-dependent changes in cyclosporine exposure: implications for achieving target concentrations.

This study analyzed early changes in trough blood cyclosporine concentrations and cyclosporine exposures after kidney transplantation. Seventy-two patients who received cyclosporine-based immunosuppressive therapy were intensively monitored (C0) during the first 6 months after transplantation. Full pharmacokinetic studies were performed at day 4, and months 2, 3, and 6 after transplantation. Mean steady-state, dose-adjusted trough cyclosporine blood concentrations increased from 1.1+/-0.60 (day 7) to 2.0+/-1.20 ng/ml per mg (day 30, P<0.01). Steady-state, dose-adjusted cyclosporine exposure parameters (C0, Cmax, AUC, Cavg, and C12) were significantly lower at day 4 than at months 2, 3, and 6 after transplantation ( P<0.01). Initial cyclosporine doses produced target concentrations in only 30% of the patients at day 3. C2 was the single concentration that showed high and consistent correlation with serial AUC measurements ( r(2)>/=0.76). The incidence of biopsy-proven acute rejection was 20.5% and was not associated with ethnicity, HLA mismatch, adjunctive therapy, or blood trough cyclosporine concentrations below 200 ng/ml at day 3. Significant time-dependent increases in steady-state cyclosporine exposure occur during the first month after kidney transplantation. Due to the low relative bioavailability early after surgery, higher doses and more frequent cyclosporine dose adjustments are necessary to produce target exposures early after transplantation.