Intellectual performance of kidney transplant recipients' offspring: a cross-sectional, multicenter study.

OBJECTIVE: The number of successful pregnancies in kidney transplant (KT) recipients has increased in recent years. Little evidence is available about the risk of in utero immunosuppressive exposure for long-term cognitive consequences. The aim of this study was to evaluate the impact of immunosuppression during pregnancy on intellectual performance of children born to KT recipients. METHODS: Using a cross-sectional design, women who had undergone KT and their children (aged 4+ years) were recruited at the outpatient follow-up in five transplant centers. Women who did not receive immunosuppression during pregnancy with similar distributions of socioeconomic status and length of gestation and their children were also recruited. Children were assessed with Wechsler Intelligence Scales. RESULTS: The study sample included 50 exposed and 50 unexposed children. No differences between groups in all the proposed confounding factors were found. Full-scale IQ did not differ significantly between both groups. Also, significant differences in any index or subscale score were not observed, with the exception of time required to complete the Wechsler preschool and primary scale of intelligence (WPPSI) Zoo locations subtest, which was done quicker in the unexposed group (p = .007). Exposure to immunosuppression during pregnancy was not a significant predictor of low IQ in logistic regression after adjustment for other factors. CONCLUSIONS: Immunosuppression therapy during pregnancy of KT women did not affect global intellectual performance of their offspring, except maybe for visuospatial working memory in preschool children.

Classification of Acute Rejection Episodes in Kidney Transplantation: a Proposal Based on Factor Analysis.

INTRODUCTION: Kidney transplantation is considered the ideal treatment for end-stage renal disease. Acute rejection can influence graft survival. The aim of this study was to propose a classification system for acute rejection based on factor analysis. MATERIALS AND METHODS: Data were collected from kidney transplant recipients with acute rejection diagnosis based on standard histological variables, the presence of peritubular eosinophils, and immunolabeling for lysozyme and myeloperoxidase in kidney tissue. Factor analysis was employed for data reduction and generation of a new case classification, with orthogonal rotation as a strategy to simplify factors, and principal component analysis was used as an extraction method. RESULTS: Seventy-nine kidney biopsies were obtained from 74 patients. The total population was divided into humoral rejection (39.2%), cellular rejection (34.1%), and mixed acute rejection (26.7%). No significant differences were found between the three groups in clinical and biochemical variables. We extracted 4 factors using factor analysis. The 1st factor was characterized by the presence of capillaritis, plasma cells infiltration, tubulitis, and inflammation. The 2nd factor included positivity for lysozyme and myeloperoxidase, while the 3rd factor included the presence of eosinophils and glomerulitis. The 4th component consisted of the presence of C4d and endarteritis. The cases belonging to the 3rd factor showed the greatest increase in serum creatinine. The cases belonging to the 4th factor exhibited greater urinary excretion of proteins. CONCLUSIONS: This proposal of classification of acute rejection could contribute to evaluate the prognosis of kidney transplant recipients.

Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients.

Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/-FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ "naïve" Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.

Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment.

OBJECTIVE: Regulatory Foxp3-expressing T cells (Tregs), IL-10-producing B cells (Bregs), and IDO-expressing dendritic cells (DCregs) downregulate inflammatory processes and induce peripheral tolerance, while Th17A and Th22 cell subpopulations are of proinflammatory nature. The aims of the study were to characterize and to enumerate peripheral Tregs, Bregs, and DCregs and Th17A and Th22 cell subpopulations in kidney transplant recipients (KTRs) under belatacept or cyclosporine treatment. METHODS: Forty-one KRT patients (30 under belatacept treatment and 11 under cyclosporine treatment) and 26 healthy donors (HDs) were included in the study. CD19(+)-expressing peripheral B lymphocytes were purified by positive selection. IL-10-producing B cells, CD4(+)/CD25(high)Foxp3(+), and CD8(+)/CD28(-)Foxp3(+) Tregs, CCR6(+)/CD123(+)/IDO(+) DCs, as well as Th17A and Th22 cell subpopulations were quantitated by flow cytometry. RESULTS: Of the IL-10-producing Bregs, CD19(+)/CD24(high)/CD38(high)/CD5(+), CD19(+)/CD24(high)/CD38(high)/CD10(+), CD19(+)/CD24(high)/CD38(high)/CD20(+), and CD19(+)/CD24(high)/CD38(high)/CD27(-) had significant higher frequency in patients under belatacept treatment when compared with those under cyclosporine. Only CD19(+)/CD24(high)/CD38(high)/CD27(+) and CD19(+)/CD24(high)/CD38(high)/CXCR7(+) cells had significant higher frequency in patients under cycloporine treatment when compared to those under belatacept. The percentages of IDO-expressing pDC, CD4(+)/CD25(high)Foxp3(+), and CD8(+)/CD28(-)Foxp3(+) were significantly higher in the belatacept group when compared the cyclosporine one, while Th17A and Th22 cells had significant higher frequency in the latter group. CONCLUSION: Belatacept seems to maintain and enhance, at least systemically, a tolerant profile to renal allograft in transplant recipients by means of higher circulatory frequencies of regulatory B, T and pDC subpopulations.

Aldosterone synthase gene polymorphism and renal histopathologic changes in kidney transplant patients receiving a calcineurin inhibitor.

INTRODUCTION: Aldosterone participates in the pathogenesis of calcineurin inhibitor nephrotoxicity (CIN), producing renal vasoconstriction and transforming growth factor beta (TGFß) expression. The objective of this study was to assess aldosterone polymorphisms and relationships to plasma aldosterone levels and the development of renal histological lesions in kidney transplant patients. MATERIAL AND METHODS: Patients with kidney graft biopsy were divided according to the presence or absence of CIN. We determined aldosterone synthase (AS) -344 T/C and int 2 W/C gene polymorphisms and plasma aldosterone levels. Histological, biochemical and clinical variables were measured. RESULTS: Calcineurin inhibitor (CI) levels were significantly higher in patients with the int 2 WW genotype than in patients with WC or CC genotypes. There was a greater degree of interstitial fibrosis in patients with int 2 CC genotype. No relationship was found between the different polymorphisms and a higher degree and/or frequency of CIN. There was also no relationship with plasma aldosterone levels. CONCLUSION: The frequency of the different polymorphisms studied was not related to plasma aldosterone levels or the development of CIN; however, the int 2 CC genotype was related to a greater degree of interstitial fibrosis, whereas the WW genotype was related to higher CI serum levels.

CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing.

BACKGROUND AND AIMS: Variability in CYP3A5 expression associated with differences in tacrolimus bioavailability has been documented. The wild-type allele CYP3A5*1 expresses the functional protein, whereas the CYP3A5*3 allele is a splice variant with a premature stop codon and encodes a truncated nonfunctional protein. The aim of the study was to determine the frequency of CYP3A5*1 and CYP3A5*3 in 291 (124 adults, 167 pediatric) Mexican renal transplant recipients, evaluate the tacrolimus dose requirements by genotype and compare genotype frequency data with that of other populations. METHODS: We carried out a multicenter study. Patients were recruited from three institutions located in Mexico City. Genotyping of the CYP3A5*1 and CYP3A5*3 alleles was performed by direct DNA sequencing. RESULTS: Eighteen patients (6.2%) were CYP3A5*1*1 homozygous carriers or functional protein expresser homozygous, 121 patients (41.6 %) were CYP3A5*1*3 were heterozygous carriers or heterozygous expressers, and 152 patients (52.2%) were CYP3A5*3*3 homozygous carriers or homozygous nonexpressers. There was a statistically significant difference in frequency of the functional and nonfunctional expresser phenotypes from those reported for Black and Caucasian, but not for South Asian populations. The CYP3A5 phenotype had a significant impact in tacrolimus bioavailability, as wild-type carriers required higher dosing compared to mutated carriers to achieve similar drug trough levels. Patients with CYP3A5*1*1 genotype had a median dose requirement of 0.16 mg/kg/day, CYP3A5*1*3 patients had a median tacrolimus dose of 0.13 mg/kg/day and CYP3A5*3*3 had a median dose of 0.07 mg/kg/day (Kruskal-Wallis, p <0.0001). CONCLUSIONS: Of the Mexican transplant recipients, 52.2% were CYP3A5*3*3 and required significantly lower tacrolimus dose than those with CYP3A5*1 allele.

Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies).

BACKGROUND: Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants. METHODS: Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT). RESULTS: A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P ≤ 0.002) across both studies at month 12. Non-HDL cholesterol was lower in the belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA). CONCLUSIONS: At month 12, belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of belatacept will continue to be assessed over the 3-year trials.

Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study.

BACKGROUND AND OBJECTIVES: Prolonged use of calcineurin inhibitors (CNIs) in kidney transplant recipients is associated with renal and nonrenal toxicity and an increase in cardiovascular risk factors. Belatacept-based regimens may provide a treatment option for patients who switch from CNI-based maintenance immunosuppression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a randomized, open-label Phase II trial in renal transplant patients with stable graft function and receiving a CNI-based regimen. Patients who were ≥6 months but ≤36 months after transplantation were randomized to either switch to belatacept or continue CNI treatment. All patients received background maintenance immunosuppression. The primary end point was the change in calculated GFR (cGFR) from baseline to month 12. RESULTS: Patients were randomized either to switch to belatacept (n=84) or to remain on a CNI-based regimen (n=89). At month 12, the mean (SD) change from baseline in cGFR was higher in the belatacept group versus the CNI group. Six patients in the belatacept group had acute rejection episodes, all within the first 6 months; all resolved with no allograft loss. By month 12, one patient in the CNI group died with a functioning graft, whereas no patients in the belatacept group had graft loss. The overall safety profile was similar between groups. CONCLUSIONS: The study identifies a potentially safe and feasible method for switching stable renal transplant patients from a cyclosporine- or tacrolimus-based regimen to a belatacept-based regimen, which may allow improved renal function in patients currently treated with CNIs.

Extended major histocompatibility complex haplotypes, ancestry and acute kidney transplant rejection in Mexicans.

INTRODUCTION: Extended major histocompatibility complex (MHC) haplotypes are associated with several autoimmune diseases, and these appear to depend on ancestry. OBJECTIVE: To evaluate the association of extended MHC gene frequencies, ancestry, and acute rejection. MATERIAL AND METHODS: 127 living kidney transplant recipients who underwent kidney transplantation in Mexico City between January 2004 and October 2007 with follow up until October 2008. The primary outcome was biopsy proven acute rejection. Ancestry was considered as either Amerindian or admixtures with Caucasian, African or Oriental genes. Allele and haplotype frequencies were estimated for HLA A, B and DR loci. Hardy Weinberg (HW) and delta values were analyzed to test for linkage disequilibrium (LD). RESULTS: There were no significant differences in the baseline characteristics between groups. 50% were men, and 28, 61 and 10% of the patients shared zero, one or two haplotypes, respectively. The whole population was Hispanic and born in Mexico. Median PRA was 0%. Allelic variance in all MCH loci was in HW equilibrium, 14% developed acute rejection. There was a high frequency of Amerindian haplotypes; admixture genes and LD were higher in the group with acute rejection. When compared to the group without acute rejection, the haplotype A1*B8*DR3 was more frequent in donors in whom their recipients had acute rejection (p = 0.008), while A28*B39*DR4 was more common in the recipients with acute rejection (p = 0.003). Multivariate Cox regression models did not attenuate these associations. CONCLUSIONS: Ancestry and LD may be associated with risk of acute rejection and may therefore be useful in directing immunosuppression.

[Kidney transplant program at the Instituto Nacional de Cardiologia Ignacio Chavez]. / Programa de trasplante renal en el Instituto Nacional de Cardiología Ignacio Chávez.

The first renal transplant was done on July 22, 1968 and until December, 2010 a total of 865 procedures have been performed. Immunosuppressive protocols have changing with time: from 1968 to 1984 azathioprine + prednisone plus total radiation in some cases; from 1985 to 1998 cyclosporine + azathioprine + prednisone; in 1998 tacrolimus is used for first time; Mofetil micofenolate was available at 2005 and practically has displaced to azathioprine. As far as possible we use some induction therapy. Primary ESRD etiologies were: unknown (74.9%), glomerulonephritis (9.7%) and diabetic nephropathy (4.2%). Recipient's mean age was 29.9 +/- 11.6 years (12-70) and 35 +/- 9.8 years (18-62) in donors. Analysis group for graft and patient survival included 292 transplants (censured for death with functional graft) with a follow-up of 103 months (CI 95%: 99-108). Survival at 1, 5 and 10 years were: 95, 85 and 60% for graft as well as 100, 94 and 90% for patient. In year 2000 we started to perform renal biopsies at transplant (time zero biopsies), those results have been published and at present are a worldwide reference. In September, 2005 laparoscopic donor nephrectomy is initiated, 180 procedures have been done with excellent results. In year 2006, training in renal transplant acquires the endorsement as a Medicine Posgrade recognized by the UNAM School of Medicine. We have participated in 9 national clinical trials and 6 international multicentric ones. Our renal transplant program offers a good choice for patients with low resources with similar results reported in the literature using current immunosuppressive schemes and surgical procedures. Institutional authorities and humanitarian associations support in addition to participation on investigation studies have been of vital importance.

[Clinical baseline and post-nephrectomy characteristics of renal donors with IgA nephropathy diagnosed by time-zero renal biopsy (T0-RBx) compared with donors with normal T0-RBx]. / Características clínicas basales y post-nefrectomía de donadores renales con nefropatía por IgA diagnosticada mediante biopsia "cero" comparados con donadores con biopsia "cero" normal.

BACKGROUND: The renal manifestations of IgA nephropathy are wide, including patients with asymptomatic disease. The probability of developing advanced renal disease after 20 years of diagnosis varies. The prevalence of mesangial deposits of IgA in otherwise healthy people has been studied previously and there are only 2 reports in which the diagnosis is made by time-zero renal biopsy (TO-RBx). MATERIAL AND METHODS: We compared clinical characteristics (baseline and at followup) of renal donors with IgA nephropathy diagnosed by TO-RBx compared with 20 donors with normal TO-RBx. RESULTS: From 1999 to 2006 151 T0-RBx were analyzed. Of these 10 cases (6.62%) had IgA nephropathy. There were two patients with stage II and 8 with stage I according to HASS classification of IgA nephropathy. All donors in both groups (n=30) had normal urinary tests, however urinary protein excretion was significantly higher in the IgA nephropathy group compared with the normal group from baseline to the end of follow-up (three years). The glomerular filtration rate at three years of follow-up was significantly higher in the normal group (80 +/- 14 vs. 65 +/- 8 mL/min, p = 0.001). CONCLUSIONS: Donors with IgA nephropathy on TO-RBx had no urinary abnormalities during pre donation screening. At three years of follow-up patients with IgA nephropathy showed a greater loss of renal function as well as increased urinary protein excretion.

El paciente altamente sensibilizado: Alternativas terapéuticas para el trasplante renal / The highly sensitized patient therapeutic alternatives for kidney transplantation

Patients become sensitized after exposure to non-self human leukocyte antigen (HLA) during pregnancy, blood transfusion, and organ transplantation. Performing transplantation in highly sensitized receptors represents a challenge for transplant programs, organ allocation organizations and usually patients are forced to stay on transplant waiting lists for many years and ultimately may never find a donor. There are various approaches that can be adopted in order to transplant these patients such as plasmapheresis, immunoadsorption, intravenous immune globulin, anti-timocitic agents, monoclonal antibodies (anti CD-20) and splenectomy with similar results as obtained in non highly sensitized patients with the increased risk of severe and recurrent rejection which may carry implications for long-term graft outcomes. Thus a positive crossmatch test is not necessarily an absolute contraindication and allows access for transplantation.

El paciente candidato a trasplante renal puede sensibilizarse hacia su donador cuando se expone a antígenos humanos leucocitarios (HLA) no propios principalmente durante las siguientes circunstancias: embarazo, transfusiones sanguíneas y trasplante previo. La realización de trasplantes en este tipo de pacientes representa un reto para el grupo médico y comités encargados de asignar los órganos, por lo que generalmente este tipo de pacientes permanecen en listas de espera por años e incluso pueden nunca ser trasplantados. Múltiples procedimientos terapéuticos han sido desarrollados con la finalidad de permitir la realización del trasplante en estos pacientes, siendo los principales: plasmaféresis, inmunoadsorción, inmunoglobulina intravenosa, agentes antitimocíticos, anticuerpos monoclonales (antiCD20) y esplenectomía. Estos procedimientos terapéuticos han permitido a ciertos grupos de trasplante obtener resultados similares a los observados en pacientes trasplantados no sensibilizados aunque el riesgo para rechazo severo o recurrente sigue siendo mayor, lo cual puede tener implicaciones negativas en la sobrevida a largo plazo. De lo anteriormente expuesto se concluye que una prueba cruzada positiva no necesariamente es una contraindicación absoluta para la realización de un trasplante.

Inmunosupresión para receptores de trasplante renal: estrategias actuales / Immunosuppression for kidney transplant recipients: current strategies

Immunosuppressive therapy aims to protect transplanted organs from host responses. The success achieved during the last two decades in patient and graft survival is mainly related to the development and clinical use of efficacious immunosuppressive drugs. Nevertheless, the challenge of achieving a balance of adequate graft protection while minimizing the adverse consequences of excessive immunosuppression in the long-term continues. Current maintenance immunosuppression for renal transplant recipients generally consists of a calcineurin inhibitor plus an adjunctive antiproliferative agent, and steroids. The addition of induction therapy with a variety of monoclonal or polyclonal antibodies provides a more potent immunosuppression and its use is more relevant in patients with a high immunological risk. More recently, mammalian target of rapamycin inhibitors have been incorporated in different schemes proven its efficacy in a number of protocols. The incidence of acute rejection is now in its lower historical percentage and excellent results are reported from many transplant centers all over the world due mainly to a judicious combination of these drugs evaluated through many clinical studies. However, long-term use of immunosuppressive drugs convey inherent risks which translate in an increase of cancers and infections, among others. Ongoing investigations and clinical protocols involving new immunosuppressive drugs and biological agents are yielding important information on how to obtain tolerance or the nearest to this goal. Furthermore, there should be a continuous improvement in patient and graft survival, as the use of different immunosuppressive agents for induction and maintenance are individualized (adapted to each patient).

La terapia inmunosupresora empleada en receptores de trasplante tiene el objetivo de proteger el injerto de la respuesta inmunoloógica generada por parte del huésped. El éxito logrado en el transcurso de las últimas dos décadas en la supervivencia de receptores e injertos, ha dependido en gran medida del desarrollo y uso clínico de fármacos inmunosupresores de probada eficacia. Empero el enorme beneficio que han representado, el reto continúa para mantener un balance adecuado entre la protección inmunológica del injerto y la minimización de las consecuencias adversas derivadas de su indispensable utilización a largo plazo. La terapia inmunosupresora actual de mantenimiento en receptores de trasplante renal consiste habitualmente en la administración de un inhibidor de calcineurina, un agente antiproliferativo, como adyuvante, y esteroides. La adición de terapia de inducción, con modalidades biológicas de anticuerpos mono o policlonales, proveen un mayor grado de inmunosupresión y su empleo adquiere gran relevancia en pacientes con mayor riesgo inmunológico. En una etapa más reciente, los inhibidores del blanco de rapamicina han sido introducidos en varios esquemas después de probar su eficacia en múltiples protocolos. La incidencia de rechazo agudo ha alcanzado sus más bajos índices históricos y los resultados alcanzados en muchos centros de trasplante del mundo son excelentes, derivados en gran medida de la combinación juiciosa de estos fármacos, evaluados en una gran variedad de estudios. El empleo crónico de estos fármacos conlleva riesgos inherentes que se traducen en riesgos incrementados para el desarrollo de infecciones y neoplasias, entre otros. Así, mientras esperamos nuevos avances derivados de una gran profusión de estudios de investigación y protocolos clínicos con nuevas drogas inmunosupresoras y compuestos biológicos, encaminados a obtener tolerancia o lo más cercano a este propósito, deberemos ser capaces de continuar mejorando la vida funcional de la mayoría de los injertos y, desde luego, de sus receptores, "individualizando" (de acuerdo con los riesgos de cada paciente) el empleo de los agentes inmunosupresores disponibles para inducción y mantenimiento.

[The highly sensitized patient. Therapeutic alternatives for kidney transplantation]. / El paciente altamente sensibilizado. Alternativas terapéuticas para el trasplante renal.

Patients become sensitized after exposure to non-self human leukocyte antigen (HLA) during pregnancy, blood transfusion, and organ transplantation. Performing transplantation in highly sensitized receptors represents a challenge for transplant programs, organ allocation organizations and usually patients are forced to stay on transplant waiting lists for many years and ultimately may never find a donor. There are various approaches that can be adopted in order to transplant these patients such as plasmapheresis, immunoadsorption, intravenous immune globulin, anti-thymocyte agents, monoclonal antibodies (anti CD-20) and splenectomy with similar results as obtained in non highly sensitized patients with the increased risk of severe and recurrent rejection which may carry implications for long-term graft outcomes. Thus a positive crossmatch test is not necessarily an absolute contraindication and allows access for transplantation.