Evaluation of peptidylarginine deiminase 4 and PADI4 polymorphisms in sepsis-induced acute kidney injury

SUMMARY BACKGROUND: The aim of this study is to evaluate the peptidylarginine deiminase 4 (PAD 4) concentration and PADI4 polymorphisms as predictors of acute kidney injury (AKI) development, the need for renal replacement therapy (RRT), and mortality in patients with septic shock. METHODS: We included all individuals aged ≥ 18 years, with a diagnosis of septic shock at ICU admission. Blood samples were taken within the first 24 hours of the patient's admission to determine serum PAD4 concentration and its PADI4 polymorphism (rs11203367) and (rs874881). Patients were monitored during their ICU stay and the development of SAKI was evaluated. Among the patients in whom SAKI developed, mortality and the need for RRT were also evaluated. RESULTS: There were 99 patients, 51.5% of whom developed SAKI and of these, 21.5% needed RRT and 80% died in the ICU. There was no difference between PAD4 concentration (p = 0.116) and its polymorphisms rs11203367 (p = 0.910) and rs874881 (p = 0.769) in patients in whom SAKI did or did not develop. However, PAD4 had a positive correlation with plasma urea concentration (r = 0.269 and p = 0.007) and creatinine (r = 0.284 and p = 0.004). The PAD4 concentration and PADI4 polymorphisms were also not associated with RRT and with mortality in patients with SAKI. CONCLUSION: PAD4 concentration and its polymorphisms were not associated with SAKI development, the need for RRT, or mortality in patients with septic shock. However, PAD4 concentrations were associated with creatinine and urea levels in these patients.

RESUMO OBJETIVO: Avaliar a concentração da peptidilarginina deiminase 4 (PAD4) e os polimorfismos de PADI4, como preditores de desenvolvimento de lesão renal aguda, necessidade de terapia renal substitutiva (TRS) e mortalidade em pacientes com choque séptico. MÉTODOS: Foram incluídos indivíduos com idade ≥18 anos, com diagnóstico de choque séptico na admissão na Unidade de Terapia Intensiva (UTI). Amostras de sangue foram coletadas nas primeiras 24 horas após a admissão do paciente para determinar a concentração sérica de PAD4 e seus polimorfismos PADI4 (rs11203367) e (rs874881). Os pacientes foram acompanhados durante a internação na UTI e tiveram avaliados desenvolvimento da lesão renal aguda séptica (Sepsis-induced acute kidney injury - Saki), necessidade TRS e mortalidade. RESULTADOS: Foram avaliados 99 pacientes; 51,5% desenvolveram Saki e, desses, 21,5% necessitaram de TRS e 80% morreram na UTI. Não houve diferença entre a concentração de PAD4 (p=0,116) e seus polimorfismos rs11203367 (p=0,910) e rs874881 (p=0,769) entre os pacientes. No entanto, o PAD4 apresentou correlação positiva com a concentração plasmática de ureia (r=0,269; p=0,007) e creatinina (r=0,284; p=0,004). A concentração de PAD4 e os polimorfismos da PADI4 também não foram associados à TRS e à mortalidade em pacientes com Saki. CONCLUSÕES: A concentração de PAD4 e seus polimorfismos não foram associados ao desenvolvimento de Saki, à necessidade de TRS ou à mortalidade em pacientes com choque séptico. No entanto, as concentrações de PAD4 foram associadas às concentrações de creatinina e ureia nesses pacientes.

Genes Expression in the Early Stage of Acute Renal Ischemia-reperfusion Injury in Rats / 法医学杂志

OBJECTIVES@#To study the differential genes expression in the early stage of acute renal ischemia-reperfusion injury and explore potential molecular mechanisms.@*METHODS@#The ischemia-reperfusion model was made via clamping renal artery of rat. The microarray detection and bioinformatics analyzing of the genes expression were performed. Differentially expressed genes were screened and related cellular activities and signaling pathways were analyzed in early stage of acute kidney injury. Meanwhile, molecules closely relative to acute kidney injury were explored by establishing a biological network of the differentially expressed genes, and the results were verified by real-time PCR.@*RESULTS@#A total of 151 genes showed differential expression in this study, including 132 up-regulated and 19 down-regulated genes. Cell proliferation, cytokines mediated signaling transduction and immune responses were greatly enriched by GO and KEGG analysis. The results of real-time PCR showed that compared with control groups, three selected genes （ANXA1, PHLDA1 and KLF6） which related to the acute kidney injury had an obvious differential expression in the early stage of disease. The multiple of increase was essentially the same as the multiple detected by microarray.@*CONCLUSIONS@#This study shows differential gene expression profile, related biological processes and signaling pathways involved in the early stage of acute kidney injury. ANXA1, PHLDA1 and KLF6 may play a role in the pathogenesis of acute kidney injury.

Análise da tendência temporal de dano renal agudo entre pacientes graves conforme polimorfi smos I/D e -262A > T da enzima conversora da angiotensina / Temporal trends in acute renal dysfunction among critically ill patients according to I/D and -262A > T ACE polymorphisms

A síndrome de disfunção de múltiplos órgãos e sistemas (DMOS) e a disfunção renal aguda compartilham muitos dos fatores fisiológicos envolvidos em seu desenvolvimento. Estudos recentes correlacionam suscetibilidades individuais, determinadas geneticamente, à disfunção de órgãos em pacientes criticamente enfermos, situação em que o gene da enzima conversora da angiotensina (ECA) poderia ser um candidato para elucidar predisposição ou risco genético. Nosso objetivo foi examinar os efeitos da presença de dois polimorfismos, I/D e -262A > T, na disfunção renal em pacientes agudamente graves do Sul do Brasil. O escore SOFA (sequential organ failure assessment) à admissão e a tendência da função renal (medida pelo escore renal diário do SOFA) foram determinados em pacientes de unidade de terapia intensiva (UTI). Um total de 153 pacientes adultos (79 homens) foi incluído no estudo. Houve monitoração diária da função renal durante toda a permanência na UTI e também pós-UTI. Observou-se a progressão para insuficiência renal (SOFA 3 e 4) nos primeiros sete dias de internação em UTI, bem como necessidade de diálise. As frequências genotípicas gerais em nossa amostra foram II = 0,17; ID = 0,46; DD = 0,37; e AA = 0,30; AT = 0,55; TT = 0,15; e as frequências alélicas foram I = 0,40, D = 0,60; e A = 0,56; T = 0,44. Este é o primeiro estudo para verificar a influência de polimorfismos I/D e -262A > T da ECA em disfunção renal aguda em pacientes críticos. Nenhuma associação significativa foi encontrada entre os genótipos ou as frequências alélicas e a evolução da função renal. Os polimorfismos I/D e -262A > T da ECA não têm impacto significativo sobre a evolução da função renal durante a primeira semana de internação na UTI nem exercem qualquer influência sobre a mortalidade em pacientes graves.

Multiple organ failure syndrome and acute renal dysfunction share many of physiologic factors involved in their development. Recent studies correlate the susceptibility to organ dysfunction in critically ill patients with genetic inheritance. Many of them consider ACE gene could be a possible candidate to elucidate a genetic predisposition or a genetic risk factor. We aimed to examine the effects of I/D and -262A > T ACE polymorphisms in the renal function in severely ill southern Brazilians patients. A multi-organic worldwide known failure score, the SOFA (sequential organ failure assessment), was used to determine the basal health state at first day (ICU admission). Considering admission SOFA score and trend of renal function (measured by daily renal SOFA scores, with daily measure of serum creatinine and diuresis), we hypothesize that ACE polymorphisms could influence in the trend of renal function in ICU patients. A total of 153 critically ill adult patients (79 men) were included in this study. We monitored the patients daily during their entire ICU and post-ICU (hospital) stay (measured from the ICU admission day to a maximum of 224 days). We observed progression to renal failure (SOFA scores 3 and 4) in first seven days of ICU stay and need for dialysis. The general genotypic frequencies in our sample were II = 0.17; ID = 0.46; DD = 0.37 and AA = 0.30; AT = 0.55; TT = 0.15, and the allelic frequencies were I = 0.40; D = 0.60 and A = 0.56; T = 0.44. This is the first study to verify the influence of I/D and -262A > T ACE polymorphisms in acute renal dysfunction among critically ill patients. No significant association was found between genotypes or allele frequencies and the trend of the renal function. The I/D and -262A > T ACE polymorphisms have no significant impact on the trend of renal function during the first week of ICU stay, neither any influence in mortality in critically ill patients.

Association between hyperhomocysteinemia and vascular dysfunction on molecular basis in acute and chronic models of experimental renal failure-possible role of folic acid

Hyperhomocysteinemia [HHcy] has recently been suggested as a risk factor for atherosclerosis [AS] in patients with chronic renal disease. Several mechanisms for HHcy-induced AS have been proposed but the molecular pathogenesis of this relation is still unclear. So far, there are no reports showing the changes in homocysteine levels in acute renal failure. We investigated whether HHcy is a common finding in acute and chronic renal failure, its relation to the pathogenesis of vascular dysfunction and its possible treatment by folic acid. 35 rats were divided into 5 groups [Gp]: Gp1 [sham operated]; Gp2 [acute ischemic renal failure]; Gp3 [treated acute ischemic renal failure]; Gp4 [chronic renal failure]; Gp5 [treated chronic renal failure]. Blood samples were collected for determination of urea, creatinine and homocysteine. Aortae were harvested for assessment of vascular endothelial growth factor [VEGF] expression and aortic content of tumor necrosis factor alpha [TNF]. Both acute [Gp2] and chronic [Gp4] models of renal failure showed higher homocysteine concentrations; increased VEGF expression and increased TNF alpha than Gpl. Folic acid treatment caused significantly lower homocysteine levels and VEGF expression in Gp3 and Gp5 than Gp2 and Gp4, while its reducing effect on TNF was only evident in acute treated model compared to Gp2. Homocysteine significantly correlates with creatinine and VEGF expression in acute models [Gp2 and 3], with urea, creatinine, TNF alpha in chronic model [Gp4] and with TNF alpha in Gp5. Our findings demonstrate that HHcy is evident in acute and chronic renal failure. Increased VEGF expression in acute failure and enhanced vascular inflammation in chronic failure could be possible mechanisms by which HHcy accelerates AS. However, the direct causal relationship between them needs further investigations. Folic acid decreases HHcy and could be useful in reducing cardiovascular risk factors in uremic patients