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.

Associação entre artrite reumatoide e citrulinização proteica por porphyromonas gingivalis: revisão de literatura / Association between Rheumatoid Arthritis and protein citrulinization by Porphyromonas gingivalis: Literature Review

A presença de peptidil-arginina deaminase (PADs), enzimas de Porphyromonas gingivalis (P. gingivalis), encontradas em pacientes com periodontite, são capazes de quebrar a tolerância imune, mediante citrulinização proteica, culminando, em um paciente suscetível, ao desenvolvimento da artrite reumatoide (AR). O objetivo desta revisão de literatura é avaliar uma possível correlação entre a periodontite e AR por meio da citrulinização proteica realizada por P. gingivalis. Para o desenvolvimento desta revisão de literatura, foi realizada uma busca na base de dados eletrônicas PUBMED, no período de maio a agosto de 2017. Foi utilizada uma estratégia de busca otimizada com as seguintes palavraschave: rheumatoid arthritis, periodontal disease e P. gingivalis. Assim, foram encontrados um total de 83 artigos, sendo selecionados inicialmente por título e resumo por um revisor e, posteriormente, por outro revisor, selecionando pelos critérios de inclusão: artigos completos escritos em língua portuguesa, espanhola ou inglesa; ter 10 anos ou menos de publicação. Ao final da seleção foram obtidos 22 artigos; destes, 15 incluídos por serem estudos clínicos em animais ou humanos. De acordo com este estudo, foi possível correlacionar positivamente a periodontite e a AR por meio da citrulinização proteica realizada pela bactéria P. gingivalis. Contudo, a mediação por PADs não é a única e exclusiva forma de correlação entre essas doenças, sendo necessários mais estudos para estabelecer outras possíveis correlações. (AU)

The presence of peptidyl arginine deaminase (PADs), an enzyme associated to Porphyromonas gingivalis (P. gingivalis), found in patients with periodontitis, can lead to the breakdown of immune tolerance by means of protein citrulinization, leading to a development of rheumatoid arthritis (RA) in susceptible patients. The objective of this literature review is to evaluate a possible correlation between periodontitis and RA through protein citrulinization performed by P. gingivalis. For the development of this literature review, a search was performed on the electronic database PUBMED from May to August 2017. An optimized search strategy was used with the following keywords: rheumatoid arthritis, periodontal disease and P. gingivalis. A total of 83 articles were found, being initially selected by title and abstract by one reviewer and later by another reviewer selecting by inclusion criteria: Complete articles written in Portuguese, Spanish or English; have 10 years or less of publication. At the end of the selection, 22 articles were obtained; of these, 15 included by being clinical studies in animals or humans. According to this study, it is possible to positively correlate periodontitis and RA with protein citrulinization performed by P. gingivalis. However, mediation by PADs is not the only and exclusive form of correlation between these diseases, and further studies are needed to establish other possible correlations. (AU)

Meta-analysis of the association between PADI4 -92C/G polymorphism and rheumatoid arthritis in the Chinese population

Many studies have evaluated the correlation between peptidylarginine deiminase 4 (PADI4) -92C/G polymorphism and rheumatoid arthritis (RA), but the results remain inconclusive. Therefore, we performed a meta-analysis in the Chinese population to provide comprehensive data on the association between PADI4 -92C/G polymorphism and RA. Eligible studies published before May 2016 were identified in PubMed and Chinese databases. The strengths of these associations were assessed by pooled odds ratios (OR) and 95% confidence interval (CI). Eight studies documenting a total of 1351 RA cases and 1585 controls were included in this meta-analysis. In the overall analysis, a significant association between the PADI4 -92C/G polymorphism and RA was found in the Chinese population (G vs C: OR=1.32, 95%CI=1.02-1.71; GG+CG vs CC: OR=1.75, 95%CI=1.20-2.53). The subgroup analyses stratified by geographic area(s) and source of controls revealed significant results in South China, in hospital-based studies and population-based studies. In summary, this meta-analysis suggested that PADI4 -92C/G polymorphism may be associated with the RA incidence in the Chinese population, especially for South China. Further studies conducted on other ethnic groups are required for definite conclusions.