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.

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.

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.

Muerte súbita en pacientes con enfermedad renal crónica avanzada / Sudden cardiac death in non-dialysis chronic kidney disease patients

Antecedentes: Una alta proporción de fallecimientos en pacientes tratados mediante diálisis ocurre de forma súbita e inesperada. La incidencia de muerte súbita (MS) en pacientes con enfermedad renal crónica (ERC) en estadios prediálisis es menos conocida. Objetivos: Determinar la incidencia y factores asociados a la MS en una cohorte de 1.078 pacientes con ERC avanzada. Métodos: Estudio de cohortes prospectivo y de observación, que incluyó a pacientes con ERC estadio 4-5 prediálisis. La asociación entre las variables basales y la MS fue analizada mediante modelos de regresión de Cox y de competencia de riesgo (Fine y Gray). Los datos demográficos, clínicos, la medicación y los parámetros bioquímicos basales de potencial interés fueron incluidos como covariables en el análisis predictivo. Resultados: Durante el periodo de estudio (mediana de seguimiento 12 meses), fallecieron 210 pacientes (19%) y de forma súbita 34 casos (16% total de muertes). Las tasas de incidencia de muerte por cualquier causa y de MS fueron: 113 (IC 95%: 99-128) y 18 (IC 95%: 13-26) eventos por 1.000 pacientes/año, respectivamente. Mediante análisis de regresión de Cox, la edad, el índice de comorbilidad y el tratamiento con antiagregantes plaquetarios fueron las covariables que se asociaron significativamente con MS. Esta última covariable mostró un efecto beneficioso sobre el desarrollo de MS. En los modelos de regresión por competencia de riesgo, en los que el evento competidor fue la muerte no súbita por cualquier causa, solo la edad y el índice de comorbilidad se asociaron significativamente con la MS. Conclusiones: La MS es relativamente frecuente en pacientes con ERC prediálisis. La MS se asoció significativamente con la edad y la comorbilidad, y varios datos indirectos de este estudio muestran que un infradiagnóstico o infratratamiento de la enfermedad cardiovascular podría predisponer a un mayor riesgo de MS (AU)

BACKGROUND: A relatively high proportion of deaths in dialysis patients occur suddenly and unexpectedly. The incidence of sudden cardiac death (SCD) in non-dialysis advanced chronic kidney disease (CKD) stages has been less well investigated. OBJECTIVE: This study aims to determine the incidence and predictors of SCD in a cohort of 1078 patients with CKD not yet on dialysis. METHODS: Prospective observational cohort study, which included patients with advanced CKD not yet on dialysis (stage 4-5). The association between baseline variables and SCD was assessed using Cox and competing-risk (Fine and Grey) regression models. Demographic, clinical information, medication use, and baseline biochemical parameters of potential interest were included as covariates. RESULTS: During the study period (median follow-up time 12 months), 210 patients died (19%), and SCD occurred in 34 cases (16% of total deaths). All-cause mortality and SCD incidence rates were 113 (95% CI: 99-128), and 18 (95% CI: 13-26) events per 1000 patients/year, respectively. By Cox regression analysis, covariates significantly associated with SCD were: Age, comorbidity index, and treatment with antiplatelet drugs. This latter covariate showed a beneficial effect over the development of SCD. By competing-risk regression, in which the competing event was non-sudden death from any cause, only age and comorbidity index remained significantly associated with SCD. CONCLUSIONS: SCD is relatively common in non-dialysis advanced CKD PATIENTS: SCD was closely related to age and comorbidity, and some indirect data from this study suggest that unrecognised or undertreated cardiovascular disease may predispose to a higher risk of SCD (AU)

Sudden cardiac death in non-dialysis chronic kidney disease patients. / Muerte súbita en pacientes con enfermedad renal crónica avanzada.

BACKGROUND: A relatively high proportion of deaths in dialysis patients occur suddenly and unexpectedly. The incidence of sudden cardiac death (SCD) in non-dialysis advanced chronic kidney disease (CKD) stages has been less well investigated. OBJECTIVE: This study aims to determine the incidence and predictors of SCD in a cohort of 1078 patients with CKD not yet on dialysis. METHODS: Prospective observational cohort study, which included patients with advanced CKD not yet on dialysis (stage 4-5). The association between baseline variables and SCD was assessed using Cox and competing-risk (Fine and Grey) regression models. Demographic, clinical information, medication use, and baseline biochemical parameters of potential interest were included as covariates. RESULTS: During the study period (median follow-up time 12 months), 210 patients died (19%), and SCD occurred in 34 cases (16% of total deaths). All-cause mortality and SCD incidence rates were 113 (95% CI: 99-128), and 18 (95% CI: 13-26) events per 1000 patients/year, respectively. By Cox regression analysis, covariates significantly associated with SCD were: Age, comorbidity index, and treatment with antiplatelet drugs. This latter covariate showed a beneficial effect over the development of SCD. By competing-risk regression, in which the competing event was non-sudden death from any cause, only age and comorbidity index remained significantly associated with SCD. CONCLUSIONS: SCD is relatively common in non-dialysis advanced CKD patients. SCD was closely related to age and comorbidity, and some indirect data from this study suggest that unrecognised or undertreated cardiovascular disease may predispose to a higher risk of SCD.

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.

¿Qué intervenciones terapéuticas durante el estadio prediálisis de la enfermedad renal crónica se asocian a una mejor supervivencia en diálisis? / During the pre-dialysis stage of chronic kidney disease, which treatment is associated with better survival in dialysis?

Introducción: El cuidado especializado de los pacientes en estadios avanzados de la enfermedad renal crónica (ERC) se asocia a una mejor supervivencia en diálisis, pero se desconoce qué tratamientos favorecen específicamente esta evolución. Objetivos: Analizar las intervenciones terapéuticas habituales en el estadio de ERC avanzada y establecer cuáles de ellas se asocian a una mejor supervivencia en diálisis y su relación con las causas de muerte. Material y métodos: Estudio de cohortes, prospectivo y de observación, que incluyó a 591 pacientes que iniciaron diálisis (491 hemodiálisis y 100 diálisis peritoneal), que habían sido controlados previamente en la consulta de ERC. Las intervenciones terapéuticas analizadas fueron: tratamientos antihipertensivos, estatinas, antiagregantes plaquetarios, inhibidores de la xantina-oxidasa, corrección de la acidosis metabólica, tratamiento con captores de fósforo (cálcicos o no), vitamina D (calcitriol o paricalcitol), eritropoyetina y disponibilidad de fístula arterio-venosa interna (FAVI). La asociación independiente de cada uno de estos tratamiento con la mortalidad en diálisis fue analizada mediante modelos de regresión de Cox con ajuste a edad, sexo, tiempo de seguimiento prediálisis, función renal al inicio de diálisis, comorbilidad, albumina sérica y proteína C reactiva, y con estratificación al tipo de diálisis. Resultados: Con una mediana de seguimiento de 28 meses, la cifra total de fallecidos fue de 191 (32 %). En los modelos multivariantes se observó que, además de la edad, el índice de comorbilidad y la albúmina sérica, el tratamiento prediálisis con inhibidores de la enzima de conversión y/o antagonistas de los receptores de la angiotensina, la corrección de la acidosis con bicarbonato sódico y la FAVI al inicio de la hemodiálisis se asociaron de forma significativa con una mejor supervivencia en diálisis. No se observaron diferencias en las causas de muerte entre los diferentes tratamientos analizados. Conclusión: Estos resultados sugieren un posible beneficio diferido de algunos tratamientos en estadios prediálisis sobre la evolución en diálisis. Además, el inicio de hemodiálisis sin una FAVI, y por tanto la necesidad de utilización de catéteres endovenosos, empeora el pronóstico de estos pacientes (AU)

Introduction: Specialised care of patients in advanced stages of chronic kidney disease (CKD) is associated with better survival in dialysis, but it is not known which treatments specifically favour this outcome. Objectives: To analyse normal treatment in advanced stages of CKD and establish which treatments are associated with better survival in dialysis as well as their relationship with causes of death. Material and method: Cohort, prospective observational study of 591 patients who started dialysis (491 haemodialysis and 100 peritoneal dialysis), who had previously been monitored in the CKD clinic. The treatments analysed were: antihypertensive treatments, statins, antiplatelet drugs, xanthine oxidase inhibitors, correction of metabolic acidosis, treatment with (calcium or non-calcium) phosphate binders, vitamin D (calcitriol or paricalcitol), erythropoietin and the availability of an internal arteriovenous fistula (IAVF). The independent association of each of these treatments with mortality in dialysis was analysed using Cox regression models adjusted for age, sex, pre-dialysis monitoring time, renal function at the start of dialysis, comorbidity, serum albumin and C-reactive protein, and with stratification of the type of dialysis. Results: With a median follow-up period of 28 months, the total number of patients who died was 191 (32%). In the multivariate models, we observed that, in addition to age, the comorbidity index, serum albumin, pre-dialysis treatment with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers, correction of acidosis with sodium bicarbonate and IAVF at the start of haemodialysis were significantly associated with better survival in dialysis. We did not observe differences in causes of death between the different treatments analysed. Conclusion: These results suggest a potential delayed benefit of some treatments in pre-dialysis stages on the outcome of dialysis. Furthermore, beginning dialysis without an IAVF, resulting in the need for intravenous catheters, worsens prognosis in these patients (AU)

During the pre-dialysis stage of chronic kidney disease, which treatment is associated with better survival in dialysis?

INTRODUCTION: Specialised care of patients in advanced stages of chronic kidney disease (CKD) is associated with better survival in dialysis, but it is not known which treatments specifically favour this outcome. OBJECTIVES: To analyse normal treatment in advanced stages of CKD and establish which treatments are associated with better survival in dialysis as well as their relationship with causes of death. MATERIAL AND METHOD: Cohort, prospective observational study of 591 patients who started dialysis (491 haemodialysis and 100 peritoneal dialysis), who had previously been monitored in the CKD clinic. The treatments analysed were: antihypertensive treatments, statins, antiplatelet drugs, xanthine oxidase inhibitors, correction of metabolic acidosis, treatment with (calcium or non-calcium) phosphate binders, vitamin D (calcitriol or paricalcitol), erythropoietin and the availability of an internal arteriovenous fistula (IAVF). The independent association of each of these treatments with mortality in dialysis was analysed using Cox regression models adjusted for age, sex, pre-dialysis monitoring time, renal function at the start of dialysis, comorbidity, serum albumin and C-reactive protein, and with stratification of the type of dialysis. RESULTS: With a median follow-up period of 28 months, the total number of patients who died was 191 (32%). In the multivariate models, we observed that, in addition to age, the comorbidity index, serum albumin, pre-dialysis treatment with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor blockers, correction of acidosis with sodium bicarbonate and IAVF at the start of haemodialysis were significantly associated with better survival in dialysis. We did not observe differences in causes of death between the different treatments analysed. CONCLUSION: These results suggest a potential delayed benefit of some treatments in pre-dialysis stages on the outcome of dialysis. Furthermore, beginning dialysis without an IAVF, resulting in the need for intravenous catheters, worsens prognosis in these patients.

Use of α1-microglobulin for diagnosing chronic interstitial nephropathy.

α1-Microglobulin (α1M) is a low molecular weight protein and has been best characterized for detecting acute lesions of proximal tubules (Bonventre in Contrib Nephrol 156:213-219, 2007). This study has tried to evaluate the use of α1M for the differential diagnosis of chronic interstitial nephropathy. 145 patients were recruited [81 men and 64 women, mean age 61.8 ± 16.7 years, 64.8 % have an estimated glomerular filtration (GFR) <60 ml/min]. Urinary α1M was evaluated using an immunonephelometric assay. 82 patients were diagnosed as having chronic interstitial nephritis (CIN), and 46 patients have been previously diagnosed of glomerulonephritis (GN). A group of hypertensive patients without renal disease was used as control (n = 17). Patients in GN group had the highest α1M excretion (15.05 mg/24 h). When the α1M/albuminuria rates were calculated, the CIN group had the highest rate (1.03 mg/mg) and the GN group had the lowest rate (0.04 mg/mg) (p < 0.001). When the α1M/proteinuria rates were calculated, the results were rather similar. The AUC for CIN group was 0.785, and the one for GN group was 0.139. Patients with estimated GFR <60 ml/min showed a higher excretion of α1M (18.75, 8.75-40.00 mg/24 h). Nevertheless, α1M/albuminuria and α1M/proteinuria rates were still higher in CIN patients with GFR ≥60 ml/min. α1M urinary excretion is increased in chronic interstitial nephropathy and glomerulonephritis as well as in patients with GFR <60 ml/min. The α1M/albuminuria rate and the α1M/proteinuria quotient are increased in chronic interstitial nephropathies but decreased in glomerular diseases.

Concentraciones más elevadas de fósforo sérico en pacientes con enfermedad renal crónica avanzada tratados con diuréticos / Increased serum phosphate concentrations in patients with advanced chronic kidney disease treated with diuretics

INTRODUCCIÓN: Las concentraciones séricas de fósforo muestran una gran variabilidad en los pacientes con enfermedad renal crónica avanzada (ERCA) no en diálisis. El tratamiento con diuréticos puede influir en la severidad de las alteraciones óseo-minerales relacionadas con la ERCA, pero su efecto sobre los niveles de fósforo sérico es menos conocido. OBJETIVOS: Determinar si existe una asociación independiente entre los niveles de fósforo sérico y el tratamiento con diuréticos, e investigar los mecanismos por los que los diuréticos podrían afectar el metabolismo del fósforo. MATERIAL Y MÉTODOS: Estudio transversal en el que fueron incluidos 429 pacientes con ERCA. Además de las determinaciones analíticas convencionales, se incluyeron los siguientes parámetros: excreción urinaria de fósforo en 24 horas, reabsorción tubular máxima de fósforo (TmP) y fracción de excreción de fósforo (FEP). RESULTADOS: El 55 % de los pacientes estaba en tratamiento con diuréticos. Con respecto a los no tratados con diuréticos, los que recibieron este tratamiento mostraron una concentración media de fósforo sérico significativamente superior (4,78 ± 1,23 vs. 4,24 ± 1,04 mg/dl; p < 0,0001), así como una mayor TmP (2,77 ± 0,72 vs. 2,43 ± 0,78 mg/dl; p < 0,0001). Por regresión lineal y logística múltiple, las asociaciones entre diuréticos y concentraciones de fósforo sérico o hiperfosfatemia (fósforo sérico > 4,5 mg/dl) mantuvieron las significaciones estadísticas tras ajuste con las principales variables confundentes. En los pacientes con la máxima carga de fósforo ajustada a función renal, aquellos tratados con diuréticos mostraron una FEP significativamente menor que los no tratados con diuréticos. CONCLUSIÓN: El tratamiento con diuréticos en la ERCA se asocia a concentraciones más elevadas de fósforo sérico. Los diuréticos podrían interferir de forma indirecta con la máxima capacidad compensatoria renal de excretar fósforo. El tratamiento con diuréticos debería ser tenido en cuenta en los estudios que relacionan las concentraciones de fósforo sérico y las alteraciones cardiovasculares

BACKGROUND: Serum phosphate concentrations usually show great variability in patients with advanced chronic kidney disease (CKD) not requiring dialysis. Diuretics can alter mineral metabolism, and according to previous clinical observations, they may increase serum phosphate levels. OBJECTIVES: This study aims to confirm whether diuretics are independently associated with increased serum phosphate concentrations, and to investigate by which mechanisms diuretics may affect phosphate metabolism. METHODS: In this cross-sectional, singlecentre study, 429 Caucasian patients with advanced CKD not on dialysis were included. In addition to conventional serum biochemical measures, the following parameters of renal phosphate excretion were assessed: 24 hours urinary phosphate excretion, tubular maximum phosphate reabsorption (TmP) per GFR, and fractional excretion of phosphate (FEP). RESULTS: Fiftyeight percent of patients were on diuretics. Patients on diuretics showed significantly higher mean serum phosphate concentration (4.78±1.23 vs. 4.24±1.04mg/dl; p<.0001), and higher TmP per GFR (2.77±0.72 vs. 2.43±0.78mg/dl; p<.0001) than those of patients untreated with diuretics. By multivariate linear and logistic regression, significant associations between diuretics and serum phosphate concentrations or hyperphosphatemia remained after adjustment for potential confounding variables. In patients with the highest phosphate load weighted to kidney function, those treated with diuretics showed significantly lower FEP than that of patients untreated with diuretics. CONCLUSIONS: Diuretic treatment is associated with increased serum phosphate concentrations in patients with advanced CKD. Diuretics may indirectly interfere with the maximum renal compensatory capacity to excrete phosphate. Diuretics should be considered potential confounders in the relationship between serum phosphate concentrations and cardiovascular outcomes in patients with CKD

Increased serum phosphate concentrations in patients with advanced chronic kidney disease treated with diuretics.

BACKGROUND: Serum phosphate concentrations usually show great variability in patients with advanced chronic kidney disease (ACKD) not on dialysis. Diuretics treatment can have an influence over the severity of mineral-bone metabolism alterations related to ACKD, but their effect on serum phosphate levels is less known. OBJECTIVES: This study aims to determine whether diuretics are independently associated with serum phosphate levels, and to investigate the mechanisms by which diuretics may affect phosphate metabolism. MATERIAL AND METHOD: 429 Caucasian patients with CKD not on dialysis were included in this cross-sectional study. In addition to conventional serum biochemical measures, the following parameters of renal phosphate excretion were assessed: 24-hours urinary phosphate excretion, tubular maximum phosphate reabsorption (TmP), and fractional excretion of phosphate (FEP). RESULTS: 58% of patients were on treatment with diuretics. Patients on diuretics showed significantly higher mean serum phosphate concentration (4.78 ± 1.23 vs. 4.24 ± 1.04 mg/dl; P<.0001), and higher TmP per GFR (2.77 ± 0.72 vs. 2.43 ± 0.78 mg/dl; P<.0001) than those not treated with diuretics. By multivariate linear and logistic regression, significant associations between diuretics and serum phosphate concentrations or hyperphosphataemia remained after adjustment for potential confounding variables. In patients with the highest phosphate load adjusted to kidney function, those treated with diuretics showed significantly lower FEP than those untreated with diuretics. CONCLUSIONS: Treatment with diuretics is associated with increased serum phosphate concentrations in patients with ACKD. Diuretics may indirectly interfere with the maximum renal compensatory capacity to excrete phosphate. Diuretics should be considered in the studies linking the relationship between serum phosphate concentrations and cardiovascular alterations in patients with CKD.