APOL1 Gene Variants and Risk for Cardiovascular Disease.

INTRODUCTION: The association of APOL1 risk variants with cardiovascular risk and cardiovascular disease (CVD) in observational and clinical trials has had inconsistent results. We aim to assess the relationship between the presence of APOL1 risk variants and the CVD risk in Afro-descendant patients with end-stage renal disease (ESRD). METHODS: We performed an observational, cross-sectional study of Afro-descendant adult patients with ESRD who were on the waitlist for a kidney transplant. Associations of APOL1 genotypes (high-risk [HR] = 2 alleles; low-risk [LR] = 0 or 1 allele) with cardiovascular risk were the primary clinical endpoint. The relation was evaluated using univariate and multivariate analysis. RESULTS: We enrolled a total of 102 patients with ESRD; 37% (38 patients) had APOL1 HR status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form and 63% (64 patients) had APOL1 LR status. No significant association was found between HR APOL1 genotypes and high cardiovascular risk (in adjusted Colombia Framingham Risk Score). APOL1 HR versus LR variants were not independently associated with left ventricular hypertrophy or systolic dysfunction. No cardiovascular deaths occurred during the follow-up. CONCLUSION: In Afro-descendent patients with ESRD, APOL1 HR status is not associated with the increase in cardiovascular risk profile and metabolic disturbances.

Nefronoptisis: reporte de un caso pediátrico / Nephronophthisis: a pediatric case report

La nefronoptisis es una enfermedad renal quística, de herencia autosómica recesiva, causada por mutaciones en genes que codifican proteínas involucradas en la función de cilios primarios, lo que resulta en enfermedad renal y manifestaciones extrarrenales como degeneración retiniana y fibrosis hepática. Según la edad de desarrollo de enfermedad renal crónica terminal, se describen tres formas clínicas de presentación: infantil, juvenil y adolescente. El diagnóstico se realiza por una prueba genética positiva o una biopsia de riñón que demuestre cambios tubulointersticiales crónicos con un engrosamiento de las membranas basales tubulares. No existe hasta la actualidad una terapia curativa, por lo que el trasplante renal oportuno es determinante en cuanto al pronóstico. Se presenta un paciente de 13 meses de edad con poliuria de 3 meses de evolución, insuficiencia renal, anemia y elevación de transaminasas. Con hallazgos histológicos compatibles en la biopsia renal, se arribó al diagnóstico de nefronoptisis infantil, con afectación hepática

Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. According to the age of development of end-stage chronic kidney disease, three clinical forms of presentation are described: infantile, juvenile and adolescent. Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis.We present a 13-month old male patient with polyuria, kidney failure, anemia and elevated aminotransferases over three months. With compatible histological kidney biopsy, the diagnosis of infantile nephronophthisis with liver involvement was reached.

[Nephronophthisis: a pediatric case report]. / Nefronoptisis: reporte de un caso pediátrico.

Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. According to the age of development of end-stage chronic kidney disease, three clinical forms of presentation are described: infantile, juvenile and adolescent. Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis. Nefronoptisis: reporte de un caso pediátrico Nephronophthisis: a pediatric case report We present a 13-month old male patient with polyuria, kidney failure, anemia and elevated aminotransferases over three months. With compatible histological kidney biopsy, the diagnosis of infantile nephronophthisis with liver involvement was reached.

La nefronoptisis es una enfermedad renal quística, de herencia autosómica recesiva, causada por mutaciones en genes que codifican proteínas involucradas en la función de cilios primarios, lo que resulta en enfermedad renal y manifestaciones extrarrenales como degeneración retiniana y fibrosis hepática. Según la edad de desarrollo de enfermedad renal crónica terminal, se describen tres formas clínicas de presentación: infantil, juvenil y adolescente. El diagnóstico se realiza por una prueba genética positiva o una biopsia de riñón que demuestre cambios tubulointersticiales crónicos con un engrosamiento de las membranas basales tubulares. No existe hasta la actualidad una terapia curativa, por lo que el trasplante renal oportuno es determinante en cuanto al pronóstico. Se presenta un paciente de 13 meses de edad con poliuria de 3 meses de evolución, insuficiencia renal, anemia y elevación de transaminasas. Con hallazgos histológicos compatibles en la biopsia renal, se arribó al diagnóstico de nefronoptisis infantil, con afectación hepática.

NOS3 gene intron 4 a/b polymorphism is associated with ESRD in autosomal dominant polycystic kidney disease patients.

INTRODUCTION: Endothelial nitric oxide synthase (eNOS) genes have been implicated in renal hemodynamics as potent regulators of vascular tone and blood pressure. It has been linked to a reduction in plasma nitric oxide levels. Several studies have recently been conducted to investigate the role of NOS3 gene polymorphisms and end-stage renal disease (ESRD). However, the results are still unclear and the mechanisms are not fully defined. As a result, we conducted a meta-analysis to examine the relationship between NOS3 gene polymorphism and ESRD in autosomal polycystic kidney disease (ADPKD) patients. METHODS: To assess the relationship between NOS3 gene polymorphism and ESRD, relevant studies published between September 2002 and December 2020 were retrieved from the PubMed (Medline), EMBASE, Google Scholar, and Web of Science databases. The pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using a fixed-effect model. To assess the heterogeneity of studies, we used Cochrane's Q test and the Higgins and Thompson I2 statistics. RESULTS: Our meta-analysis of 13 studies showed that the presence of the two NOS3 gene polymorphisms significantly increased ESRD risk in ADPKD patients with 4a/b gene polymorphism (aa+ab vs. bb: OR=1.95, 95% CI=1.24-3.09, p=0.004). In addition, no significant association was found between the NOS3 894G>T (Glu298Asp) polymorphism and the risk of ESRD in ADPKD patients (GT+TT vs. GG: OR=1.21, 95% CI=0.93-1.58, p=0.157). There was no evidence of publication bias. CONCLUSIONS: The findings of the current meta-analysis suggest that NOS3 intron 4a/b polymorphism plays a vital role in the increasing risk of ESRD in ADPKD patients.

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury.

Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-ß1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment.

Arg913Gln variation of SLC12A3 gene is associated with diabetic nephropathy in type 2 diabetes and Gitelman syndrome: a systematic review.

BACKGROUND: Diabetic nephropathy is a global common cause of chronic kidney disease and end-stage renal disease. A lot of research has been conducted in biomedical sciences, which has enhanced understanding of the pathophysiology of diabetic nephropathy and has expanded the potential available therapies. An increasing number of evidence suggests that genetic alterations play a major role in development and progression of diabetic nephropathy. This systematic review was focused on searching an association between Arg913Gln variation in SLC12A3 gene with diabetic nephropathy in individuals with Type 2 Diabetes and Gitelman Syndrome. METHODS: An extensive systematic review of the literature was completed using PubMed, EBSCO and Cochrane Library, from their inception to January 2018. The PRISMA guidelines were followed and the search strategy ensured that all possible studies were identified to compile the review. Inclusion criteria for this review were: 1) Studies that analyzed the SLC12A3 gene in individuals with Type 2 Diabetes and Gitelman Syndrome. 2) Use of at least one analysis investigating the association between the Arg913Gln variation of SLC12A3 gene with diabetic nephropathy. 3) Use of a case-control or follow-up design. 4) Investigation of type 2 diabetes mellitus in individuals with Gitelman's syndrome, with a history of diabetic nephropathy. RESULTS: The included studies comprised 2106 individuals with diabetic nephropathy. This review shows a significant genetic association in most studies in the Arg913Gln variation of SLC12A3 gene with the diabetic nephropathy, pointing out that the mutations of this gene could be a key predictor of end-stage renal disease. CONCLUSIONS: The results showed in this systematic review contribute to better understanding of the association between the Arg913Gln variation of SLC12A3 gene with the pathogenesis of diabetic nephropathy in individuals with T2DM and GS.

Vitamin D Receptor Gene Polymorphisms and Environment Influencing the Impact on Survival in Hemodialysis Patients.

INTRODUCTION: The vitamin D-receptor axis is involved in multiple physiological functions and altered states such as hypertension, mineral metabolism disorders, and inflammation. These disturbances are major risk factors for progression to end-stage kidney disease and cardiovascular disease. In addition, changes in internal systemic environment could be influencing the impact of survival in patients with kidney disease. This study aimed to evaluate the impact of vitamin D receptor (VDR) polymorphisms on hemodialysis patients' survival. MATERIAL AND METHODS: A total of 122 hemodialysis patients and 120 healthy controls were compared for VDR gene polymorphism. Markers for full coverage in the VDR gene were selected and genotyped. The hemodialysis patients were followed until death event, which was considered the primary endpoint for the survival analysis. RESULTS: Two tag SNPs (rs10875695 and rs11168293) showed significant differences between the hemodialysis and healthy patients. In survival analysis, the CC genotype for rs2248098, compared to the TT genotype, was associated with a worse mortality rate. After adjustments for age, sex, diabetes mellitus, and cardiovascular disease, the genotype CC (rs2248098) was associated with a higher risk of mortality in a multivariable analysis. CONCLUSIONS: Polymorphisms specific to patients with kidney disease could be influencing different conditions associated with mortality. Thus, these genetic markers, rs2248098 for example, would act in a specific time in the history of kidney disease and would bring different results of patient survival outcomes.

Polymorphism related to cardiovascular risk in hemodialysis subjects: a systematic review.

Cardiovascular disease (CVD) is one of the leading causes of mortality in hemodialysis (HD) subjects. In addition to the traditional risk factors that are common in these individuals, genetic factors are also involved, with emphasis on single nucleotide polymorphs (SNPs). In this context, the present study aims to systematically review the studies that investigated the polymorphisms associated with cardiovascular risk in this population. In general, the SNPs present in HD individuals are those of genes related to inflammation, oxidative stress and vascular calcification, also able of interfering in the cardiovascular risk of this population. In addition, polymorphisms in genes related to recognized risk factors for CVD, such as dyslipidemia, arterial hypertension and left ventricular hypertrophy, also influence cardiovascular morbidity and mortality.

Polymorphism related to cardiovascular risk in hemodialysis subjects: a systematic review / Polimorfismos associados ao risco cardiovascular em indivíduos em hemodiálise: uma revisão sistemática

ABSTRACT Cardiovascular disease (CVD) is one of the leading causes of mortality in hemodialysis (HD) subjects. In addition to the traditional risk factors that are common in these individuals, genetic factors are also involved, with emphasis on single nucleotide polymorphs (SNPs). In this context, the present study aims to systematically review the studies that investigated the polymorphisms associated with cardiovascular risk in this population. In general, the SNPs present in HD individuals are those of genes related to inflammation, oxidative stress and vascular calcification, also able of interfering in the cardiovascular risk of this population. In addition, polymorphisms in genes related to recognized risk factors for CVD, such as dyslipidemia, arterial hypertension and left ventricular hypertrophy, also influence cardiovascular morbidity and mortality.

RESUMO A doença cardiovascular (DCV) é uma das principais causas de mortalidade de indivíduos em hemodiálise (HD). Além dos fatores de risco tradicionais, que são frequentes nesses indivíduos, também estão envolvidos fatores genéticos, com destaque para os polimorfismos de nucleotídeo único (do inglês, single nucleotide polymorphism, SNP). O presente trabalho tem como objetivo revisar sistematicamente os estudos que investigaram os polimorfismos associados ao risco cardiovascular nessa população. De modo geral, os SNPs presentes em indivíduos em HD são aqueles de genes relacionados à inflamação, estresse oxidativo e calcificação vascular, também capazes de interferir no risco cardiovascular dos pacientes. Polimorfismos em genes relacionados a fatores de risco reconhecidos para DCV, como dislipidemia, hipertensão arterial e hipertrofia ventricular esquerda, também influenciam a morbidade e mortalidade cardiovascular.

Structural impact analysis of missense SNPs present in the uroguanylin gene by long-term molecular dynamics simulations.

The guanylate cyclase activator 2B, also known as uroguanylin, is part of the guanylin peptide family, which includes peptides such as guanylin and lymphoguanylin. The guanylin peptides could be related to sodium absorption inhibition and water secretion induction and their dysfunction may be related to various pathologies such as chronic renal failure, congestive heart failure and nephrotic syndrome. Besides, uroguanylin point mutations have been associated with essential hypertension. However, currently there are no studies on the impact of missense SNPs on uroguanylin structure. This study applied in silico SNP impact prediction tools to evaluate the impact of uroguanylin missense SNPs and to filter those considered as convergent deleterious, which were then further analyzed through long-term molecular dynamics simulations of 1µs of duration. The simulations suggested that all missense SNPs considered as convergent deleterious caused some kind of structural change to the uroguanylin peptide. Additionally, four of these SNPs were also shown to cause modifications in peptide flexibility, possibly resulting in functional changes.

Association of vitamin D receptor gene polymorphisms with end-stage renal disease and the development of high-turnover renal osteodystrophy in a Chinese population.

Two single nucleotide polymorphisms (SNPs; TaqI and ApaI) in the vitamin D receptor (VDR) gene have been identified as risk factors for the progression of end-stage renal disease (ESRD). The purpose of our study was to confirm the reported association of these two SNPs with ESRD risk and progression of renal osteodystrophy in a Chinese Han population. A total of 452 ESRD patients and 904 matched-pair controls (based on age, gender, and body mass index) were included. Identification of VDR gene polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method with TaqI and ApaI restriction enzymes. There was no association of the TaqI polymorphism with ESRD risk. However, significant associations were seen between ApaI (rs7975232) polymorphism and ESRD risk in the heterozygote model (AC/ AA; P = 0.002; OR = 1.4, 95%CI = 1.14-1.83), homozygote model (CC/AA; P = 0.007; OR = 1.8, 95%CI = 1.17-2.85) genotypes for rs7975232, allelic model (P < 0.001; OR = 1.4, 95%CI = 1.15-1.64), dominant model (P = 0.001; OR = 1.5, 95%CI = 1.19-1.87), and recessive model (P = 0.046; OR = 0.6, 95%CI = 0.42-1.00) between cases and healthy controls Moreover, we found a significant correlation between the genotype and allele distribution of ApaI and intact parathyroid hormone (iPTH) levels, where allele C carriers have increased iPTH levels. The ApaI polymorphism in the VDR gene appears to be a susceptibility locus for ESRD in Chinese individuals, and allele C carriers may have an increased risk of high-turnover renal osteodystrophy.

Vascular endothelial growth factor as an angiogenesis biomarker for the progression of autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary nephropathy characterized by abnormal growth of epithelial cells. Genetic factors, including the vascular endothelial growth factor (VEGF) gene, play an important role in its progression. The main aim of this study was to evaluate the influence of VEGF-C936T polymorphism in the development and progression of ADPKD. In total, 302 individuals were studied and divided into two groups: G1 (73 patients with ADPKD) and G2 (229 individuals without the disease). Among the patients, 46 (63%) progressed to end-stage renal disease (ESRD), and required hemodialysis and/or renal transplant. These patients were re-grouped into G1-A for progression analysis. A peripheral blood sample was obtained from all subjects; the DNA was extracted and the VEGF-C936T polymorphism analyzed using polymerase chain reaction/restriction fragment length polymorphism. The significance level was set at P < 0.05. The homozygous wild-type genotype (C/C) was predominant in G1 (78%) and G2 (79%; P = 0.9249). We observed a significant reduction in the mean age of patients with the risk allele (C/T + T/T = 44.3 ± 13.4 years) compared to the C/C genotype (52.2 ± 9.6 years; P = 0.047) in G1-A. In conclusion, the VEGF-C936T polymorphism does not discriminate patients from controls. However, the presence of the T allele appears to accelerate the progression of ADPKD, anticipating ESRD, thereby suggesting its importance in the prognosis of the disease. However, the importance role played by VEGF gene variants in different populations and larger sample sizes must be verified.

Allelic variations in the CYBA gene of NADPH oxidase and risk of kidney complications in patients with type 1 diabetes.

Oxidative stress plays a pivotal role in the pathophysiology of diabetic nephropathy, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system is an important source of reactive oxygen species in hyperglycemic conditions in the kidney. Plasma concentration of advanced oxidation protein products (AOPP), a marker of oxidative stress, is increased in patients with diabetic nephropathy. We investigated associations of variants in the CYBA gene, encoding the regulatory subunit p22(phox) of NADPH oxidase, with diabetic nephropathy and plasma AOPP and myeloperoxidase (MPO) concentrations in type 1 diabetic patients. Seven SNPs in the CYBA region were analyzed in 1357 Caucasian subjects with type 1 diabetes from the SURGENE (n=340), GENEDIAB (n=444), and GENESIS (n=573) cohorts. Duration of follow-up was 10, 9, and 6 years, respectively. Cox proportional hazards and logistic regression analyses were used to estimate hazard ratios (HR) or odds ratios (OR) for incidence and prevalence of diabetic nephropathy. The major G-allele of rs9932581 was associated with the incidence of renal events defined as new cases of microalbuminuria or the progression to a more severe stage of nephropathy during follow-up (HR 1.59, 95% CI 1.17-2.18, P=0.003) in SURGENE. The same allele was associated with established/advanced nephropathy (OR 1.52, 95% CI 1.22-1.92, P=0.0001) and with the incidence of end-stage renal disease (ESRD) (HR 2.01, 95% CI 1.30-3.24, P=0.001) in GENEDIAB/GENESIS pooled studies. The risk allele was also associated with higher plasma AOPP concentration in subsets of SURGENE and GENEDIAB, with higher plasma MPO concentration in a subset of GENEDIAB, and with lower estimated glomerular filtration rate (eGFR) in the three cohorts. In conclusion, a functional variant in the promoter of the CYBA gene was associated with lower eGFR and with prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. These results are consistent with a role for NADPH oxidase in the pathophysiology of kidney complications of diabetes.

Familial mixed nephrocalcinosis as a cause of chronic kidney failure: two case reports.

INTRODUCTION: Nephrocalcinosis consists of the deposition of calcium salts in the renal parenchyma and is considered the mixed form when it involves the renal cortex and medulla. The main etiological agents of this condition are primary hyperparathyroidism, renal tubular acidosis, medullary sponge kidney, hyperoxaluria and taking certain drugs. These factors can lead to hypercalcemia and/or hypercalciuria, which can give rise to nephrocalcinosis. CASE PRESENTATIONS: Patient 1 was a 48-year-old Caucasian woman with a history of bilateral nephrocalcinosis causing chronic kidney failure. Imaging examinations (X-ray, ultrasound and computed tomography of the abdomen) revealed extensive calcium deposits in the renal parenchyma, indicating nephrocalcinosis as the causal factor of the disease. Patient 2 is the 45-year-old brother of patient 1. He exhibited an advanced stage of chronic kidney failure. As nephrocalcinosis is considered to have a genetic component, a family investigation revealed this condition in patient 2. CONCLUSION: Nephrocalcinosis may be detected incidentally through diagnostic imaging studies. Whenever possible, treatment should include the base disease that caused the appearance of the calcification, as the precise etiological determination is extremely important.

Survival and Predictive Factors of Lethality in Hemodyalisis: D/I Polymorphism of The Angiotensin I-Converting Enzyme and of the Angiotensinogen M235T Genes / Sobrevida e Fatores Preditores de Letalidade em Hemodiálise: Polimorfismos D/I do Gene da Enzima Conversora da Angiotensina I e o M235T do Angiotensinogênio

Background: End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes. Objective: To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis. Methods: Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study. Results: The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34%) and infections (15%). Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038), TT angiotensinogen (p = 0.08261), and family income greater than five times the minimum wage (p = 0.03089), the latter being a protective factor. Conclusions: The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene. .

Fundamento: Os pacientes em hemodiálise continuam tendo um significativo aumento na morbiletalidade, especialmente a causada por doenças cardiovasculares. A análise dos fatores genéticos ligados ao sistema renina-angiotensina que influenciam na sobrevivência destes pacientes poderá ajudar na busca por melhores resultados. Objetivo: Avaliar a sobrevida em hemodialisados e sua associação com polimorfismo dos genes do sistema reninaangiotensina: deleção/inserção do gene que codifica a enzima conversora da angiotensina I e o M235T do angiotensinogênio. Métodos: Estudo observacional desenhado para ver o papel dos genes do sistema renina-angiotensina. Foram analisados 473 pacientes tratados com hemodiálise crônica em quatro unidades de diálise do Estado do Rio de Janeiro. As taxas de sobrevida foram calculadas pelo método de Kaplan-Meier e as diferenças entre as curvas avaliadas pelos testes de: Tarone-Ware, Peto-Prentice e Log-rank. Foram utilizados também modelos de regressão logística e multinomial. Um valor de p ≤ 0,05 foi considerado estatisticamente significativo. O comitê de ética aprovou este estudo. Resultados: A idade média dos pacientes foi de 45,8%. A taxa de sobrevida global foi de 48% em 11 anos. As principais causas de óbito foram: doenças do aparelho circulatório (34 %) e infecções (15%). A análise de regressão logística encontrou significância estatística para as seguintes variáveis: idade, o TT do angiotensinogênio e a renda familiar acima de cinco salários mínimos, esta última como fator de proteção (p valor: 0,000038, 0,08261 e 0,03089, respectivamente). Conclusões: Nossos dados sugerem que o risco de letalidade em pacientes em hemodiálise pode ser influenciado também pelo polimorfismo ...

Survival and predictive factors of lethality in hemodialysis: D/I polymorphism of the angiotensin I-converting enzyme and of the angiotensinogen M235T genes.

BACKGROUND: End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes. OBJECTIVE: To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis. METHODS: Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study. RESULTS: The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34%) and infections (15%). Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038), TT angiotensinogen (p = 0.08261), and family income greater than five times the minimum wage (p = 0.03089), the latter being a protective factor. CONCLUSIONS: The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene.

Catalase activity, allelic variations in the catalase gene and risk of kidney complications in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. RESULTS: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CONCLUSIONS/INTERPRETATION: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.

Renin-angiotensin system, hypertension, and chronic kidney disease: pharmacogenetic implications.

About 80% of CKD (chronic kidney disease) patients are hypertensive, and kidney function and blood pressure are clearly related to both physiologic and pathologic conditions in a "vicious cycle". In this pathologic scenario, there is a renin-angiotensin system (RAS) hyperactivity associated to progression of renal damage. Current guidelines indicate as the first choice of antihypertensive intervention, the pharmacologic blockade of the RAS. Nonetheless, both response to treatment and renal protection have considerable inter-individual variability. The main aims of this review are to describe the genetic characteristics of RAS components and to identify the possible pharmacogenetic implications for RAS-blocker drugs in the hypertension-CKD scenario. To date, RAS polymorphisms have not been consistently associated to antihypertensive response and studies focusing on CKD are scarce. Nonetheless, pharmacogenetic studies for the RAS-blocker drugs could still be further explored, especially with new generation tools and focusing not only on the antihypertensive response, but also on renal protection as well.

Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels.

BACKGROUND: Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis. METHODS: We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C(-1562)T, rs3918242; -90 (CA)(14-24), rs2234681; and Q279R, rs17576) were determined by Taqman® Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1. RESULTS: Hemodialysis increased MMP-9 and TIMP-1 levels (P<0.05). Genotypes had no effects on baseline MMP-9 and TIMP-1 levels (P>0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C(-1562)T polymorphism (P<0.05), and increased MMP-9 levels in subjects with the QQ (but not QR or RR) genotype for the Q279R polymorphism (P<0.05), whereas the CA(n)(14-24) polymorphism had no major effects. While MMP-9 haplotypes had no effects on baseline MMP-9 levels (P>0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P=0.0012 and P=0.0045, respectively). CONCLUSION: ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors.