Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Uremic neuropathy: an overview of the current literature

SUMMARY INTRODUCTION: Peripheral neuropathy is a disorder that affects the cell body, axon or myelin of motor or peripheral sensory neurons and occurs in 60-100% of patients who are submitted to dialysis due to chronic kidney disease. Uremic neuropathy is attributed to the accumulation of organic waste, evident in patients with reduced glomerular filtration rate. Objectives: This review aims to make clinical characteristics of uremic neuropathy evident enabling early diagnosis and treatment. Methods: This is a literature review of articles published on PubMed over the last 10 years using "Uremic Neuropathy" as "Title/Abstract". Results: A total of nine articles that met the inclusion criteria were included. UN is a distal symmetric sensorimotor polyneuropathy that occurs due to the accumulation of uremic toxins associated with an oxidative stress-related free radical activity. Hyperkalemia is thought to play an important role in its pathophysiology. Diagnosis depends on nerve conduction studies, and treatment includes dialysis or renal transplant. Conclusion: Clinical presentations of UN are broad and non-specific; nonetheless, it is important to detect early changes in order to avoid its progression. The earlier UN is diagnosed and treated, the more successful are the clinical outcomes.

RESUMO INTRODUÇÃO: A neuropatia periférica (NU) é um distúrbio que afeta o corpo celular, o axônio ou a mielina do motor ou neurônios sensoriais periféricos e ocorre em 60%-100% dos pacientes que são submetidos à diálise por doença renal crônica. A neuropatia urêmica é atribuída à acumulação de resíduos orgânicos, evidente em pacientes com taxa de filtração glomerular reduzida. Objetivo: O objetivo desta revisão é fazer com que as características clínicas da neuropatia urêmica sejam evidenciadas, permitindo o diagnóstico e tratamento precoce. Método: Esta é uma revisão da literatura de artigos publicados no PubMed nos últimos dez anos usando "Neuropatia Urêmica" como "Título/Resumo". Resultados: No total, foram incluídos nove artigos que atendem aos critérios de inclusão. A NU é uma polineuropatia sensório-motora simétrica distal que ocorre devido ao acúmulo de toxinas urêmicas associadas à atividade de radicais livres relacionados ao estresse oxidativo. A hipercalemia tem um papel importante na sua fisiopatologia. O diagnóstico depende de estudos de condução nervosa e o tratamento inclui diálise ou transplante renal. Conclusão: As apresentações clínicas das NU são amplas e não específicas; no entanto, é importante detectar mudanças iniciais para evitar sua progressão. Quanto mais precoce for a detecção e tratamento da NU, melhor será o resultado clínico.

The importance of homocysteine levels in the prognosis of patients with chronic renal disease and in hemodialysis patients / Importância dos níveis de homocisteína no prognóstico de pacientes com doença renal crônica e em pacientes em hemodiálise

ABSTRACT Introduction: Homocysteine (Hcy) is one of the metabolites of methionine (Met), an essential diet-derived amino acid. There is a close relationship between high plasma Hcy levels and declining renal function. Plasma and urinary Hcy level has been the target of studies as a biomarker that forecasts poor outcome in renal patients and in hemodialysis patients. This review evaluates the main studies that sought to correlate Hcy and poor prognosis in renal disease as well as the treatments proposed for the reduction of plasma Hcy levels in these patients. Conclusion: Hcy could be an important biomarker of renal disease progression mainly in hemodialysis patients. We emphasize the importance of normalizing plasma levels of this amino acid to ensure a better prognosis in kidney disease.

RESUMO Introdução: A homocisteína (Hcy) é um dos metabólitos da metionina (Met), um aminoácido essencial proveniente da dieta. Existe uma estreita relação entre os altos níveis plasmáticos de Hcy e o declínio da função renal. A Hcy plasmática e urinária tem sido alvo de estudos como um biomarcador capaz de sinalizar o prognóstico em doentes renais e em pacientes em hemodiálise. Esta revisão avalia os principais estudos que buscaram correlacionar a Hcy e o prognóstico da doença renal e descreve os tratamentos propostos para a redução dos níveis plasmáticos de Hcy nesses pacientes. Conclusão: A Hcy pode ser um biomarcador da progressão na doença renal, principalmente em pacientes hemodialíticos. Ressaltamos a importância da normalização dos níveis plasmáticos desse aminoácido para garantir um melhor prognóstico na doença renal.

Serum NGAL and Cystatin C Comparison With Urinary Albumin-to-Creatinine Ratio and Inflammatory Biomarkers as Early Predictors of Renal Dysfunction in Patients With Type 2 Diabetes.

INTRODUCTION: Diabetic nephropathy is associated with specific histological changes. Early detection of poor glomerular and tubular function can be achieved with biomarkers of diabetes. The aim of this study was to evaluate the accuracy of kidney dysfunction biomarkers in type 2 diabetes (T2D). METHODS: Patients with T2D were grouped according to their glycated hemoglobin level. Patients' urine and blood samples were taken to measure cystatin C (CysC), neutrophil gelatinase-associated lipocalin, beta-trace protein levels, and the first morning void albumin-to-creatinine ratio. Patients in the end stage of renal disease or receiving dialysis were not included. Receiver operating characteristic curves were generated, and the areas under the curve were compared with the performance of the biomarkers used to evaluate kidney dysfunction in T2D. RESULTS: Ninety patients with T2D were chosen. CysC was positively correlated with creatinine (P < 0.001), estimated glomerular filtration rate (P < 0.001), and urinary beta-trace protein (P = 0.01). The area under the curve was 0.635 for CysC, 0.621 for serum neutrophil gelatinase-associated lipocalin, and 0.660 for the albumin-to-creatinine ratio. A crude logistic regression model showed a positive association between serum CysC (P = 0.01) and serum neutrophil gelatinase-associated lipocalin (P < 0.001). A linear regression model showed a positive association between serum CysC, creatinine, and estimated glomerular filtration rate (P < 0.001) but did not show a positive association with glycated hemoglobin (P = 0.892). DISCUSSION: Neutrophil gelatinase-associated lipocalin and serum CysC were positively associated with the presence of renal dysfunction and had better performance on receiver operating characteristic analysis than the other markers evaluated in patients with T2D without kidney dysfunction.

AIDS and the pancreas in the HAART era: a cross sectional study.

BACKGROUNDS: The aim of this study is identify the main morphological patterns of the pancreas in AIDS patients in use of Higly Active Antiretorviral Therapy (HAART). METHODS: We conducted a cross sectional study in the year of 2010. The inclusion criteria were patients older than 18 years who died of AIDS with the use of HAART (2006-2009) and underwent to autopsy . They were compared with a group of 109 patients who died of AIDS in 1995 before the HAART therapy. All the autopsies were made in the Death Verification Service of São Paulo. RESULTS: The HAART group presented pancreas abnormalities lighter than no HAART users. In the HAART group, histology shows: reduction of zymogen granules in the acinar cells (ZG) higher percentage of cases, "dysplasia-like" presents lower and pancreatic acinar atrophy, presents higher percentage of cases compared to no HAART group. The exocrine pancreas in treated patients was distinguished by the high level of atrophy, sharp reduction of zymogen granules and high level of apoptosis, reflecting degeneration and lower level of protein-caloric malnutrition. CONCLUSIONS: The islets of Langerhans in HAART group were increased in number and volume and with high level of nuclear dysplasia. The antiviral therapy and a longer survival resulted in a higher atrophy and reduction of enzymes, increasing the apoptosis and generated important changes in the pancreatic islets, probably resulting in clinical laboratory repercussion.We found no evidence of pancreatic histopathological lesions secondary to antiretroviral therapy.