Jose O. Medina-Pestana

Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies.

Background. At 1 year, belatacept was associated with similar patient/graft survival, better renal function, and an improved cardiovascular/metabolic risk profile versus cyclosporine A (CsA) in the Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT) studies. Acute rejection was more frequent with belatacept in BENEFIT. Posttransplant lymphoproliferative disorder (PTLD)—specifically central nervous system PTLD—was observed more frequently in belatacept-treated patients. This analysis assesses outcomes from BENEFIT and BENEFIT-EXT after 2 years of treatment. Methods. Patients received a more intensive (MI) or a less intensive (LI) regimen of belatacept or a CsA-based regimen. Results. Four hundred ninety-three of 666 patients (74%) in BENEFIT and 347 of 543 (64%) in BENEFIT-EXT completed 2 years of treatment. The proportion of patients who survived with a functioning graft was similar across groups (BENEFIT: 94% MI, 95% LI, and 91% CsA; BENEFIT-EXT: 83% MI, 84% LI, and 83% CsA). Belatacepts renal benefits were sustained, as evidenced by a 16 to 17 mL/min (BENEFIT) and an 8 to 10 mL/min (BENEFIT-EXT) higher calculated glomerular filtration rate in the belatacept groups versus CsA. There were few new acute rejection episodes in either study between years 1 and 2. Because PTLD risk was highest in Epstein-Barr virus (EBV) (−) patients, an efficacy analysis of EBV (+) patients was performed and was consistent with the overall population results. There were two previously reported cases of PTLD in each study between years 1 and 2 in the belatacept groups. The overall balance of safety and efficacy favored the LI over the MI regimen. Conclusions. At 2 years, belatacept-based regimens sustained better renal function, similar patient/graft survival, and an improved cardiovascular/metabolic risk profile versus CsA; outcomes that were maintained in EBV (+) patients. No new safety signals emerged.

Post-Transplant Anti-HLA Class II Antibodies as Risk Factor for Late Kidney Allograft Failure

The purpose of this study was to prospectively analyze the relationship between the post‐transplant anti‐HLA class I and/or class II panel reactive antibodies and graft failure due to chronic allograft nephropathy (CAN). We studied 512 first kidney recipients transplanted at a single center, with a graft functioning for at least 3 years. A single blood sample was collected from each patient for antibody evaluation. The median posttransplant time after blood collection was 4.4 years and did not differ between patients with (n = 91) or without anti‐HLA antibodies (n = 421). Female gender, pregnancies and blood transfusions were associated with the presence of anti‐HLA class I antibodies. Graft function deterioration was associated with anti‐HLA class II antibodies. Multivariate analysis showed independent association for creatinine levels (RR = 7.5), acute rejection (RR = 2.6), recipient male gender (RR = 3.6) and anti‐HLA class II antibodies (RR = 2.9) and CAN‐associated graft loss. In conclusion, the presence of anti‐HLA class II antibodies conferred a risk for graft loss before a decline in renal function and increased the risk of graft failure in patients who already had a decline in graft function. Thus, anti‐HLA class II antibody monitoring is a useful tool for the management of long‐term kidney recipients.

Living kidney donor follow-up: State-of-the-art and future directions, conference summary and recommendations

In light of continued uncertainty regarding postkidney donation medical, psychosocial and socioeconomic outcomes for traditional living donors and especially for donors meeting more relaxed acceptance criteria, a meeting was held in September 2010 to (1) review limitations of existing data on outcomes of living kidney donors; (2) assess and define the need for long‐term follow‐up of living kidney donors; (3) identify the potential system requirements, infrastructure and costs of long‐term follow‐up for living kidney donor outcomes in the United States and (4) explore practical options for future development and funding of United States living kidney donor data collection, metrics and endpoints. Conference participants included prior kidney donors, physicians, surgeons, medical ethicists, social scientists, donor coordinators, social workers, independent donor advocates and representatives of payer organizations and the federal government. The findings and recommendations generated at this meeting are presented.

O contexto do transplante renal no Brasil e sua disparidade geográfica

The Brazilian National Transplantation System coordinates and regulates perhaps the largest public transplantation program worldwide. Since its implementation in 1997, the number of kidney transplantations increased from 920 (5.8 pmp) in 1998, to 4,630 (24.1 pmp) in 2010. This growth was primarily due to the increased number of effective donors (from 1.8 pmp in 1998 to 9.3 pmp in 2010), with a corresponding increased number of kidneys transplanted from deceased donors (3.8 pmp in 1999 versus 9.9 pmp in 2010).The number of kidney transplantations from living donors has not increased significantly, from 1,065 (6.7 pmp) in 1998 to 1,641 (8.6 pmp) in 2010, either as a consequence of the observed increase in the deceased donor program or perhaps because of strict government regulations allowing only transplantations from related donors. From 2000 to 2009, the mean age of living donors increased from 40 to 45 years, while it increased from 33 to 41 years for deceased donors, of whom roughly 50% die of stroke. There are clear regional disparities in transplantation performance across the national regions. While the state of Sao Paulo is ranked first in organ donation and recovery (22.5 pmp), some states of the Northern region have much poorer performances. These disparities are directly related to different regional population densities, gross domestic product distribution, and number of trained transplantation physicians. The initial evaluation of the centers with robust outcomes indicates no clear differences in graft survival in comparison with centers in the USA and Europe. Ethnicity and time on dialysis, but not the type of immunosuppressive regimen, decisively influence the measured outcomes. Since the implementation of national clinical research regulations in 1996, Brazilian centers have participated in a number of national and international collaborative trials for the development of immunosuppressive regimens. Besides the challenge of reducing the regional disparities related to access to transplantation, further improvements can be obtained by the creation of a national registry of the outcomes of transplanted patients and living donors, and also by the promotion of clinical and experimental studies to better understand the transplantation-related immune response of the Brazilian population.

Bloodstream infection after kidney transplantation: epidemiology, microbiology, associated risk factors, and outcome.

Background. Bloodstream infection (BSI) is associated with both relevant morbidity and mortality rates after kidney transplantation. Methods. From January 1, 2000 to January 31, 2006, all episodes of BSI were retrospectively assessed through the review of medical records in two tertiary teaching Hospitals in Sao Paulo, Brazil, where 3308 transplant procedures were performed during this period. Contaminants and polymicrobial infections were excluded. The main objectives of the study were to describe clinical and microbiologic aspects of BSI, as well as risk factors for both BSI and mortality from these infections in kidney transplant patients. Results. BSI was detected in 185 patients, with onset after a median of 235 days after transplantation; 62% occurred after 6 months. The primary source of infection was the urinary tract in 37.8%. The most prevalent pathogen overall was Escherichia coli (30.3%). Risk factors for early acquired BSI (first 6 months after transplantation) were acute rejection, ureteric stent placement, and receiving an organ from a deceased donor. For late BSI (after 6 months), associated risk factors were acute rejection, Charlson Comorbidity Score more than or equal to 3, and receiving an organ from a deceased donor. Risk factors related to 30-day mortality were Acute Physiology and Chronic Health Evaluation II Score more than or equal to 20, shock, and respiratory failure. Conclusions. BSI is most frequently a consequence of urinary tract infection, with a high prevalence of gram-negative bacilli. Severity of disease was the main determinant of 30-day mortality after BSI, and based on the knowledge of risk factors, some interventions are suggested for reducing the rate of BSI after transplantation.

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r‐ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end‐point was the incidence of first CMV infection/disease in the intention‐to‐treat population at 12 months. Patients treated with r‐ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037–0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13–0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound‐healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced‐dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate (ClinicalTrials.gov NCT01354301).

Risk Factors Associated With Graft Loss and Patient Survival After Kidney Transplantation

OBJECTIVE To evaluate the influence of traditional risk factors on major kidney transplantation outcome. PATIENTS AND METHODS Data from kidney transplantation procedures performed between 2003 and 2006 were retrospectively analyzed for the influence of traditional risk factors on transplantation outcome. Of 2364 transplants, 67% were from living donors, 27% were from donors who met standard criteria, and 6% were from donor who met expanded criteria. Two hundred thirty-nine procedures (10%) were performed in pediatric patients. Immunosuppression was selected on the basis of subgroup population. RESULTS At 1 year posttransplantation, cumulative freedom from a treated acute rejection episode (ARE) was 76.7%, with no difference between black vs nonblack recipients (75.0% vs 73.4%; P = .79). At 2 years, survival for patients (95.3% vs 88.3% vs 82.1%; P < .001) and grafts 92.3% vs 80.3% vs 70.9%; P < .001) was better in recipients of living donor grafts compared with donors who met standard or expanded criteria, respectively. Moreover, graft survival was poorer in black vs nonblack patients (83.6% vs 88.7%; P < .05) because of high mortality (13% vs 7%; P<.001). Risk factors associated with death included cadaveric donor organ (odds ratio [OR], 2.4) and black race (OR, 1.8), and risk factors associated with graft loss included cadaveric donor organ (OR, 2.1), extended-criteria criteria donor organ (OR, 2.0), delayed graft function (OR, 1.8), and any ARE (OR, 3.5). At 6 months posttransplantation, risk factors associated with death included cadaveric donor organ (OR, 2.5) or ARE (OR, 2.4), and risk factors associated with graft loss included cadaveric donor organ (OR, 2.0), extended-criteria donor organ (OR, 2.6), ARE (OR, 9.5), and impaired graft function (creatinine concentration >1.5 mg/dL; OR, 2.1). CONCLUSION Traditional risk factors are still associated with transplantation outcome. Poorer graft survival in black vs nonblack recipients was due to higher mortality rather than graft loss.

Treatment of subcutaneous phaeohyphomycosis and prospective follow-up of 17 kidney transplant recipients

BACKGROUND Subcutaneous phaeohyphomycosis in solid organ recipients may have an adverse outcome. OBJECTIVE We sought to describe the disease course, treatment, and outcome of allograft function in kidney transplant recipients with phaeohyphomycosis. METHODS Seventeen patients were followed for a mean period of 25.4 months to analyze the clinical response to treatment. RESULTS There was no treatment failure or relapsing disease among 12 patients who completed treatment. Two patients were still in treatment with disease remission. One patient discontinued the study during treatment with partial remission, one died after finishing treatment with disease remission, and one was dropped from the study because contact was lost. Immunosuppressive regimens were not changed. Two of 17 patients had a significant reduction in allograft function. LIMITATIONS The follow-up time was short and the number of patients was small. CONCLUSIONS The outcome of phaeohyphomycosis in kidney transplant recipients was favorable with minimal impact on renal allograft function.

Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients

AIM Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. The extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C₀/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation. MATERIALS & METHODS Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5*3 (rs776746, 6986A>G), *6 (rs10264272, 14690G>A) and *7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C₀/dose under a two-step data analysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model. RESULTS C₀/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C₀/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected. CONCLUSION Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5*3, *6 and *7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials.

Transplantation with kidneys retrieved from deceased donors with acute renal failure.

Background The discard rate of kidneys recovered from deceased donors with acute renal failure (ARF) is higher compared with those without ARF mainly due to the uncertainty regarding short-term and long-term outcomes. Methods We retrospectively analyzed 1-year patient, graft, and rejection-free survivals and renal function of transplantations performed with kidneys recovered from deceased donors with or without ARF, defined as serum creatinine level of more than 1.5 mg/dL. We performed multivariable analysis to evaluate whether ARF was an independent risk factor associated with inferior outcomes. Results Of a total of 1518 patients, 253 received kidneys from expanded-criteria donors (ECD; with ARF [n=116] and without ARF [n=137]) and 1265 from standard-criteria donors (SCD; with ARF [n=369] and without ARF [n=896]). The incidence of delayed graft function was higher in ECD (68.1% vs. 58.4%; P=0.072) and SCD (69.9% vs. 50.6%; P<0.001) recipients of kidneys with ARF compared with those without ARF, respectively. At 1 year, patient, graft, and rejection-free survivals were not statistically different in SCD or ECD recipients with or without ARF. Renal function at 1 year was similar in recipients of ECD (41.9±26.3 vs. 40.1±21.7 mL/min; P=0.565) or SCD (50.9±29.9 vs. 53.6±28.5 mL/min; P=0.131) kidneys with and without ARF, respectively. Compared with kidneys without ARF, receiving a kidney allograft with ARF was not associated with increased risk of death, graft lost, or inferior renal function 1 year after transplantation. Conclusion In this cohort of patients, kidneys from deceased donors with ARF provided graft survival and renal function comparable with kidneys from donors without ARF 1 year after transplantation.