Body Fat Distribution, Adipocytokines Levels and Variability in Associated Genes and Kidney Transplant Outcomes.

Introduction: Body fat distribution is known to contribute to a variety of pathologies. Research Questions: We aimed to assess whether this distribution is associated with clinical outcomes in renal transplant recipients (RTR) and to examine its relationship with leptin and adiponectin gene variants and plasma concentrations. Design: Bioelectrical impedance analyses were performed in 236 RTR. Leptin/adiponectin levels were measured by immunoassay and relevant polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes were identified. Associations were assessed by logistic regression modeling. Results: The waist-to-height ratio (WHr) displayed a significant association with delayed graft function, acute rejection and post-transplant diabetes mellitus, with OR values of 2.04 (1.02-4.08) p = 0.045; 3.08 (1.22-7.79) p = 0.017 and 2.79 (1.16-6.74) p = 0.022, respectively. Waist circumference was linked to delayed graft function [OR = 1.03 (1.01-1.05), p = 0.025] and AR [OR = 1.041 (1.01-1.07), p = 0.009]. Leptin levels were significantly higher in patients who experienced rejection [19.91 ± 23.72 versus 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01-1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs 96.38 ± 14.65 for GG/GT genotypes; p = 0.021). Conclusion: WC, and especially WHr, are associated with adverse outcomes in renal transplantation and are affected by variability in the ADIPOQ gene.

Alfa-1-microglobulina: valor pronóstico en la enfermedad renal crónica / Alpha-1-microglobulin: Prognostic value in chronic kidney disease

Objetivos: La alfa-1-microglobulina (α1M) es una proteína tubular usada para detectar lesiones agudas del túbulo proximal. Se ha evaluado el uso de α1M como marcador de progresión de la enfermedad renal crónica (ERC) y de supervivencia vital.Diseño y métodosSe seleccionaron 163 pacientes (90 hombres), con una edad media de 61,6±16,4 años. La excreción de α1M en orina se analizó por nefelometría. Los pacientes se dividieron en 2 grupos según la excreción de α1M (valor de corte: 32,85mg/24h).ResultadosLa supervivencia libre de ERC terminal fue del 94,2% a los 5 años en pacientes con α1M baja. Para pacientes con una excreción más elevada la supervivencia fue del 72,7% (p=0,011). La supervivencia fue del 94,4% en pacientes con α1M baja; para los pacientes con una excreción elevada de α1M, la supervivencia fue del 54,2% (p=0,001). La regresión de Cox mostró una asociación independiente de la α1M con la progresión de la ERC.ConclusionesLa excreción urinaria de α1M se asoció con una progresión más rápida de la ERC y una mayor mortalidad. Serán precisos estudios más amplios para confirmar la relación causal entre α1M y mortalidad general. (AU)

Objectives: α1-microglobulin (α1M) is a tubular protein used for detecting acute lesions of proximal tubules. This study evaluated the use of urine α1M excretion as a marker of chronic kidney disease (CKD) progression and life survival.Design and methodsIn all 163 patients were recruited (90 men), mean age 61.6±16.4 years. Urinary α1M was evaluated using an immunonephelometric assay. Patients were divided into 2 groups according to urinary α1M excretion (cut-off value: 32.85mg/24h).ResultsEnd stage renal disease-free survival was 94.2% at 5 years for patients with lower α1M. For patients in the highest percentile, renal function survival was 72.7% (P=.011). Life survival was 94.4% for patients with α1M in the lower percentiles. For patients in the upper percentile, live survival was 54.2% (P=.001). The Cox regression analysis showed an independent association of CKD progression with high α1M excretion (P=.043).Conclusionsα1M urinary excretion was associated with faster CKD progression and higher mortality. Further studies are needed to determine whether the association between α1M urinary excretion and excess mortality risk represents a causal link. (AU)

Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy.

Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48-0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05-9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.

Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease.

Preclinical studies indicate that arachidonic acid (AA)-derived eicosanoids contribute to hyperglycemia-induced kidney injury. We aimed to determine whether plasma and/or urinary levels of dihydroxyeicosatrienoic (DHETs) and 20-hydroxyeicosatetraenoic (20-HETE) acids are associated with diabetic kidney disease (DKD). A total of 334 subjects (132 DKD patients and 202 non-diabetic individuals) were studied. Plasma levels of 11,12-DHET, 14,15-DHET and 20-HETE were measured by LC/MS/MS. Urinary 20-HETE concentrations were determined by immunoenzymatic assay. Subjects with normoalbuminuria had larger 20-HETE-to-creatinine urinary ratios (20-HETE/Cr) than those with micro and macroalbuminuria (p=0.012). Likewise, participants with eGFR>60 ml/min/1.73 m2 had higher plasma levels of 14,15-DHET (p=0.039) and 20-HETE/Cr ratios (p=0.007). Concentrations of 14,15-DHET, 11,12-DHET and 20-HETE/Cr were significantly lower in DKD patients. Median values for non-diabetic vs. DKD were, respectively, 493 (351.0-691.5) vs. 358 (260.5-522) ng/L, p=3e-5; 262 (183.5-356.0) vs. 202 (141.5-278.0) ng/L, p=1e-4 and 5.26 (1.68-11.65) vs. 2.53 (1.01-6.28) ng/mgCr, p=0.010. In addition, 20-HETE/Cr ratios were higher in patients with non-proteinuric DKD than in those with typical DKD (p=0.020). When only individuals with impaired filtration were considered, 14,15-DHET and 11,12-DHET levels were still higher in non-diabetic subjects (p=0.002 and p=0.006, respectively). Our results indicate that AA-derived eicosanoids may play a relevant role in DKD.

Alpha-1-microglobulin: Prognostic value in chronic kidney disease. / Alfa-1-microglobulina: valor pronóstico en la enfermedad renal crónica.

OBJECTIVES: α1-microglobulin (α1M) is a tubular protein used for detecting acute lesions of proximal tubules. This study evaluated the use of urine α1M excretion as a marker of chronic kidney disease (CKD) progression and life survival. DESIGN AND METHODS: In all 163 patients were recruited (90 men), mean age 61.6±16.4 years. Urinary α1M was evaluated using an immunonephelometric assay. Patients were divided into 2 groups according to urinary α1M excretion (cut-off value: 32.85mg/24h). RESULTS: End stage renal disease-free survival was 94.2% at 5 years for patients with lower α1M. For patients in the highest percentile, renal function survival was 72.7% (P=.011). Life survival was 94.4% for patients with α1M in the lower percentiles. For patients in the upper percentile, live survival was 54.2% (P=.001). The Cox regression analysis showed an independent association of CKD progression with high α1M excretion (P=.043). CONCLUSIONS: α1M urinary excretion was associated with faster CKD progression and higher mortality. Further studies are needed to determine whether the association between α1M urinary excretion and excess mortality risk represents a causal link.

Combined donor-recipient genotypes of leptin receptor and adiponectin gene polymorphisms affect the incidence of complications after renal transplantation.

BACKGROUND: We aimed to examine whether combined donor/recipient variants in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes may affect outcomes in renal transplantation. METHODS: A total of 233 donors and their corresponding 307 recipients were genotyped for LEPR rs1805094, rs1137100 and rs1137101, and ADIPOQ rs1501299 and rs224176. Combined donor/recipient genetic scores were created to investigate associations with delayed graft function (DGF), graft loss and estimated glomerular filtration rate (eGFR). RESULTS: Recipients whose donors carried variant alleles of LEPR rs1137100 and rs1137101 had lower risk of DGF [OR = 0.48 (0.24-0.97), p = 0.040] and [OR = 0.47 (0.23-0.95), p = 0.035], respectively. In addition, rs1137101 also showed an inverse association with lower incidence of graft loss [OR = 0.44 (0.31-0.97), p = 0.040]. The analysis of genetic scores of donor/recipients showed that again rs1137101 was inversely associated with both outcomes: OR = 0.46 (0.23-0.92), p = 0.029 and OR = 0.45 (0.11-0.81), p = 0.009, respectively. With regard to graft function, the T-allele of ADIPOQ rs1501299 in the donor was related to higher eGFR values (75.26 ± 29.01 vs. 67.34 ± 25.39 ml/min for wild-type grafts, p = 0.012). Higher combined genetic scores in this same polymorphism were also associated with better function (78.33 ± 31.87 vs. 68.25 ± 24.32 ml/min, p = 0.018). Finally, eGFR values were similar between paired kidneys but they were different when comparing grafts with or without the rs1501299 T-variant (77.87 ± 26.50 vs. 69.27 ± 26.73 ml/min, p = 0.016). CONCLUSIONS: Our study has shown for the first time to our knowledge that variants in LEPR and ADIPOQ genes of the donors and/or their combination with those in the recipients may affect the outcome of renal transplantation.

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.

Variability in the leptin receptor gene and other risk factors for post-transplant diabetes mellitus in renal transplant recipients.

Aim: Post-transplant diabetes mellitus (PTDM) is one of the main complications after kidney transplantation. It is known that leptin plays an important role in glucose metabolism and mutations in the leptin receptor gene (LEPR) are responsible for different complications in renal transplant recipients. We aimed to analyse the association of polymorphisms in LEPR with the development of PTDM in these patients. Methods: A total of 315 renal transplant recipients were genotyped for the Lys109Arg, Gln223Arg and Lys656Asn polymorphisms. The impact of these genetic variables together with other clinical and demographic parameters on PTDM risk was evaluated in a multivariate regression analysis. Results: The 223Arg variant showed a significant association with PTDM risk [OR = 3.26 (1.35-7.85), p = 0.009] after correcting for multiple testing. Carriers of this variant also showed higher BMI values (26.95 ± 4.23) than non-carriers (25.67 ± 4.43, p = 0.025). In addition, it was BMI at transplant and not the BMI increment in the first year after grafting that was associated with PTDM (p > 0.00001). Haplotype analyses did not reveal significant associations. Conclusions: Our result show, for the first time to our knowledge, that genetic variability in the LEPR may contribute significantly to the risk for PTDM in renal transplant recipients. KEY MESSAGES The LEPR Gln223Arg polymorphism significantly contributes to the development of PTDM in renal transplant recipients. The effect of the 223Arg variant on PTDM is strongly modulated by the age of the recipient. The 223Arg variant in the leptin receptor is related to higher BMI in renal transplant recipients.

Polymorphisms in genes involved in vasoactive eicosanoid synthesis affect cardiovascular risk in renal transplant recipients.

OBJECTIVE: Arachidonic acid metabolism by cytochrome P450 (CYP) epoxygenases leads to epoxyeicosatrienoic acids (EETs), which are eicosanoids with vasodilator and anti-inflammatory properties. We aim to determine whether genetic variability in these routes may contribute to cardiovascular (CV) risk in renal transplant recipients. METHODS: In a cohort of 355 patients, we determined the presence of two polymorphisms, CYP2C8*3 and CYP2J2*7, known to affect eicosanoid levels. Associations with CV mortality, CV event-free long-term survival and graft survival were retrospectively investigated by logistic regression models. RESULTS: CYP2J2*7 showed a statistical trend towards higher CV mortality (p = .06) and lower cardiac or cerebral event-free long-term survival (p = .05), whilst CYP2C8*3 displayed a significant inverse association with the risk of CV event (hazard ratio [HR] = 0.34 [0.15-0.78], p = .01). The association of CYP2J2*7 with CV mortality became significant when the analysis was restrained to 316 patients without a history of CV events prior to transplantation (HR = 15.72 [2.83-91.94], p = .005). In this subgroup of patients both single nucleotide polymorphisms (SNPs) were significantly associated with event-free survival. HR values were 5.44 (1.60-18.51), p = .007 and 0.26 (0.09-0.75), p = .012 for CYP2J2*7 and CYP2C8*3, respectively. CONCLUSIONS: Our results show, for the first time to our knowledge, that two SNPs in CYP2C8 and CYP2J2, which synthesize EETs, may modify CV outcomes in renal transplant recipients, a population that is already at a high risk of suffering these events.

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.