Association of polymorphisms in leptin and adiponectin genes with long-term outcomes in renal transplant recipients.

The effect of polymorphims in leptin and adiponectin genes on long-term outcomes of renal transplantation is unknown. In 349 renal transplant recipients (RTR), we aimed to determine associations between five SNPs in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes and these outcomes. Follow-up time ranged from 2 to 25 years (mean 10.29 ± 5.16 years). Two SNPs showed associations with long-term outcomes and their statistical significance greatly increased after 39 RTR with a history of cardiovascular events prior to transplantation were removed from the analysis. Adjusted odds ratios (OR) for LEPR rs1805094 and ADIPOQ rs1501299 and risk of graft loss were 0.35 (0.16-0.74) p = 0.006 and 2.37 (1.28-4.37) p = 0.006, respectively. The assessment of risk for global mortality revealed OR values of 0.20 (0.06-0.62), p = 0.005, and 2.43 (1.08-5.44), p = 0.031 for LEPR rs1805094 and ADIPOQ rs1501299, respectively. Our results show that polymorphism in genes involved in leptin and adiponectin function modify long-term outcomes in renal transplantation.

CYP3A genotypes of donors but not those of the patients increase the risk of acute rejection in renal transplant recipients on calcineurin inhibitors: a pilot study.

PURPOSE: We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs). METHODS: One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs. Clinical and pharmacokinetic parameters were recorded at four time-points after transplant (1 week and 1, 5 and 12 months). RESULTS: Nineteen patients (13.86%) experienced ARE. Patients who received a kidney from a donor carrying the CYP3A4*1B or CYP3A5*1 variant experienced ARE more frequently than those whose donor carried wild-type genotypes [OR = 6.29 (1.62-24.39), p = 0.008 and OR = 3.42 (1.06-11.01), p = 0.039, respectively]. The combined analysis of the CYP3A4*1B/3A5*1 alleles also revealed an increased risk in patients whose donors carried both variants [OR = 6.24 (1.60-24.33), p = 0.007]. The CYP3A genotype of the recipient did not affect ARE risk, although it did determine the degree of exposure to CNI throughout the first year after transplant. Patients with one or two variant alleles displayed lower concentration-to-dose ratios (CDRs) than non-carriers, with differences increasing with time after transplant (p values = 0.039, 0.004, 6.0 e-04 and 2.7 e-07 in the four time-points). CONCLUSIONS: Our preliminary findings suggest that the determination of the CYP3A genotype of the donor, but not that of the recipient, may be useful to predict the incidence of acute rejection in renal transplantation.

Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism.

Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetraenoic acid (20-HETE), which play an important role both in renal transplant and diabetes mellitus (DM). We searched for associations between polymorphisms in this metabolic pathway and the risk of post-transplant diabetes mellitus (PTDM) in kidney recipients. One-hundred-sixty-four patients were genotyped for common SNPs in this route, namely CYP2C8*3, CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2J2*7, CYP4A11 F434S and CYP4F2 V433M. Demographic and clinical parameters were retrospectively collected at four time-points in the first year after grafting. Thirty-four patients (20.73%) developed PTDM, which was more prevalent among older patients [OR for older age = 1.06 (1.03-1.10), p < 0.001] and in those with higher body mass index (BMI) [OR for higher average BMI in the first year = 1.13 (1.04-1.23); p < 0.01]. Creatinine clearance [OR = 0.97 (0.95-0.99); p < 0.01] and exposure to tacrolimus [OR = 3.25 (1.15-9.19); p < 0.05] were also relevant for PTDM risk. With regard to genetic variants, logistic regression analysis controlling for significant demographic and clinical variables showed that the V433M polymorphism in CYP4F2, responsible for 20-HETE synthesis, was an independent risk factor for PTDM [OR = 3.94 (1.08-14.33); p < 0.05]. We have shown that a genetic variant in the CYP4F2 gene, the main gene implicated in 20-HETE synthesis, is associated with the risk for PTDM. Our findings suggest that genes in the metabolic pathways of AA may become good candidates in genetic association studies for PTDM.

A 3'-UTR Polymorphism in Soluble Epoxide Hydrolase Gene Is Associated with Acute Rejection in Renal Transplant Recipients.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms in the gene encoding soluble epoxy hydrolase (EPHX2), which metabolizes EETs to less active compounds, may play a role in the outcome of renal transplantation. METHODS: In a group of 259 Caucasian renal transplant recipients and 183 deceased donors, we determined the presence of three common EPHX2 SNPs, namely rs41507953 (K55R), rs751141 (R287Q) and rs1042032 A/G. Associations with parameters of graft function and the incidence of acute rejection were retrospectively investigated throughout the first year after grafting by logistic regression adjusting for clinical and demographic variables. RESULTS: Carriers of the rs1042032 GG genotype displayed significantly lower estimated glomerular filtration rate (eGFR) (38.15 ± 15.57 vs. 45.99 ± 16.05; p = 0.04) and higher serum creatinine values (1.57 ± 0.58 vs. 1.30 ± 0.47 g/dL; p=0.02) one year after grafting, compared to patients carrying the wildtype A-allele. The same GG genotype was also associated to increased risk of acute rejection. Interestingly, this association was observed for the genotype of both recipients [OR =6.34 (1.35-29.90); p = 0.015] and donors [OR = 5.53 (1.10-27.80); p=0.042]. A statistical model including both genotypes along with other meaningful demographic and clinical variables resulted in an increased significance for the association with the recipients' genotype [OR=8.28 (1.21-74.27); p=0.031]. CONCLUSIONS: Our results suggest that genetic variability in the EETs-metabolizing gene, EPHX2, may have a significant impact on the outcome of deceased-donor renal transplantation.

Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation.

BACKGROUND: Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) enzymes to vasoactive metabolites (mainly epoxyeicosatrienoic acids) which are known to play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms along these metabolic routes may play a role in the outcome of renal transplantation. DESIGN: One-hundred and forty Caucasian renal transplant recipients and 137 donors were included. We determined the presence of seven common functional polymorphisms in the five genes governing the CYP-mediated AA metabolic pathway (CYP2C8, CYP2C9, CYP2J2, CYP4A11 and CYP4F2). Associations with parameters and events related to graft function and survival were retrospectively investigated throughout the first year after grafting. RESULTS: The CYP2J2*7 allele of the donor was significantly associated with higher risk for delayed graft function [OR = 4·40 (1·45-13·37), P < 0·01] and lower death-censored graft survival [107·90 (84·19-131·62) vs. 176·89 (166·47-187·32) months for CYP2J2*1/*1 grafts; log-rank P = 0·015]. In addition, patients whose donors carried the CYP4A11 434S variant of the F434S polymorphism displayed impaired creatinine clearance, with statistically significant differences vs. 434FF subjects throughout the whole period of study (P < 0·05, P < 0·01, P < 0·001 and P < 0·05 for 1 week, 1 month, 5 months and 1 year after grafting, respectively). CONCLUSIONS: Taken together, these results indicate that variability in the CYP450 genes involved in the synthesis of eicosanoids from AA may have a significant impact on graft function and survival in renal transplantation.

Utilidad del recuento e inmunofenotipaje de los linfocitos intraepiteliales de la mucosa intestinal en el diagnóstico de la enfermedad celiaca / Usefulness of intraepithelial lymphocytes immunophenotyping in intestinal mucosa for the diagnosis of coeliac disease

Introducción. Se han observado cambios característicos en las poblaciones de linfocitos intraepiteliales (LIE) de la mucosa intestinal en pacientes celiacos infantiles y adultos. Objetivos. Determinar el rango normal de las poblaciones de LIE por citometría de flujo y establecer su rentabilidad diagnóstica en la enfermedad celiaca (EC). Material y métodos. Estudio retrospectivo de 246 niños y 461 adultos con sospecha de EC a los que se había realizado estudio de poblaciones de LIE. El grupo de EC (221 niños y 98 adultos) lo forman individuos con serología celiaca positiva e histología con lesión grado Marsh 1 o mayor. El grupo control (25 niños y 363 adultos) lo constituyen individuos sin lesión intestinal y serología celiaca negativa a los que también se había realizado inmunofenotipo de LIE por citometría de flujo. Resultados. En el grupo de pacientes celiacos se observa un aumento significativo de LIE totales y LIE TCRγδ y un descenso significativo de LIE NK-like en comparación con los grupos control. En función de las curvas ROC, los puntos de corte en la población infantil fueron: %LIE > 14,2%, %LIE TCRγδ > 16,5% y %LIE NK-like < 10,1%. Los puntos de corte en la población adulta fueron: %LIE > 14,2%, %LIE TCRγδ > 16,1% y %LIE NK-like < 4,4%. En ambas poblaciones se obtienen una especificidad y VPP cercano o igual al 100%, con unos CP+ > 5 y CP− < 2 o próximos. Conclusiones. En el presente trabajo se han establecido los valores de corte para los tres parámetros analizados de los LIE. Estos parámetros permiten diagnosticar con una especificidad cercana al 100% la EC en el niño y en el adulto. Los valores de CP+ y CP− obtenidos muestran que estos parámetros son muy útiles en el diagnóstico de EC activa infantil y del adulto. Por lo tanto, el análisis de las poblaciones de LIE por medio de la citometría de flujo es una nueva herramienta diagnóstica de la EC que complementa el estudio anatomopatológico clásico aumentando su especificidad (AU)

Introduction: The intestinal mucosa of children and adult with coeliac disease shows characteristic changes in intraepithelial lymphocyte (IEL) populations. Objectives: Determination of the normal range of IEL populations by flow cytometry and its diagnostic usefulness in coeliac disease (CD). Methods: A retrospective study of 246 children and 461 adults with suspected CD with IEL immunophenotype results. The CD group (221 children and 98 adults) are individuals with positive coeliac serology and a histology lesion Marsh grade 1 or greater. The control group included 25 children and 363 adults without bowel lesion, negative serology and with IEL immunophenotype results. Results: The group of coeliac patients, adults and children, shows a significant increase in total IEL and TCRdeltagamma IEL, and a significant decrease in NK-like IEL compared with control groups. Based on ROC curves, the cut-off in coeliac children was: %IEL >14.2%, %TCRdeltagamma IEL>16.5% and %NK-like IEL<10.1%. The cut-off in the adult coeliac population was: %IEL >14.2%, %TCR IEL>16.1% and %NK-like IEL<4.4%. In both populations the specificity and PPV are close or equal to 100%, a CP+ >5 and a CP− <2 or near. Conclusions: The cut-off values of the LIE population analysed has been established in this study. The values of CP+ and CP− show that these parameters are very useful for the diagnosis of celiac disease in children and adults, with a specificity of approximately 100%. The immunophenotyping of LIE is a very useful technique in the diagnosis of CD, and complements the classical pathological study, thus increasing the specificity (AU)