The des-Arg9-bradykinin/B1R axis: Hepatic damage in COVID-19.

Patients infected by the SARS-CoV-2 virus are commonly diagnosed with threatening liver conditions associated with drug-induced therapies and systemic viral action. RNA-Seq data from cells in bronchoalveolar lavage fluid from COVID-19 patients have pointed out dysregulation of kallikrein-kinin and renin-angiotensin systems as a possible mechanism that triggers multi-organ damage away from the leading site of virus infection. Therefore, we measured the plasma concentration of biologically active peptides from the kallikrein-kinin system, bradykinin and des-Arg9-bradykinin, and liver expression of its proinflammatory axis, bradykinin 1 receptor (B1R). We measured the plasma concentration of bradykinin and des-Arg9-bradykinin of 20 virologically confirmed COVID-19 patients using a liquid chromatography-tandem mass spectrometry-based methodology. The expression of B1R was evaluated by immunohistochemistry from post-mortem liver specimens of 27 COVID-19 individuals. We found a significantly higher blood level of des-Arg9-bradykinin and a lower bradykinin concentration in patients with COVID-19 compared to a healthy, uninfected control group. We also observed increased B1R expression levels in hepatic tissues of patients with COVID-19 under all hepatic injuries analyzed (liver congestion, portal vein dilation, steatosis, and ischemic necrosis). Our data indicate that des-Arg9-bradykinin/B1R is associated with the acute hepatic dysfunction induced by the SARS-CoV-2 virus infection in the pathogenesis of COVID-19.

Impact of the immunotherapy induction on allograft outcome and survival in kidney transplant patients with donor-specific antibodies to HLA-DQB1.

BACKGROUND: The presence of donor-specific antibodies (DSAs) against HLA-DQB1 is considered a significant barrier to good outcome and allograft survival in kidney transplantation (KT). This study aimed to assess the impact of induction immunotherapy on the outcome and allograft survival in KT patients with HLA-DQB1-DSA. METHODOLOGY: Thirty-two patients who had undergone KT and found to be positive for HLA-DQB1-DSA were monitored at least one to 10 years. They were allocated into two groups of patients: G1 received induction immunotherapy (n = 14 patients; 43.75%), and G2 did not (n = 18 patients; 56.25%). RESULTS: In G1, 6 (42.86%) patients experienced rejection episodes (RE), 2 (14.29%) due to antibody-mediated rejection (ABMR) and 4 (28.57%) due to T-cell-mediated rejection (TCMR). In G2, 13 (72.22%) patients experienced RE, 3 (16.67%) due to ABMR, and 10 (55.56%) due to TCMR. Graft loss occurred in 4 patients from G1, 2 (14.29%) due to ABMR and 2 (14.29%) due to non-immunological causes. In G2, 9 (50.00%) patients lost their grafts, 2 (11.11%) due to TCMR, 2 (11.11%) due to ABMR, and 5 (27.78%) due to non-immunological causes. The graft survival rate was 64.29% in G1 and 45.83% in G2. Glomerulitis and peritubular capillaritis were observed in 3 and C4d-positive patients with/or without induction who lost their grafts by ABMR by HLA-DQ DSA. Two patients from G2 lost their graft by TCMR due to interstitial lymphocytic infiltrate (i1), foci of mild tubulitis (t2), interstitial edema, moderate interstitial fibrosis and tubular atrophy. Better graft survival rates were shown in patients from G1 who received induction immunotherapy. CONCLUSION: Our study suggests that patients with an immunological profile of HLA-DQ+ DSA+ treated by immunotherapy induction have a decreased risk of ABMR and increased allograft survival, and the presence of anti-HLA-DQB1 DSA+ detected before and after KT were associated with ABMR episodes and failure.

The Oxford Classification predictors of chronic kidney disease in pediatric patients with IgA nephropathy / Preditores da doença renal crônica segundo a Classificação de Oxford em pacientes pediátricos com nefropatia por IgA

Abstract Objective: The Oxford Classification for Immunoglobulin A nephropathy (IgAN) identifies pathological variables that may predict the decline of renal function. This study aimed to evaluate the Oxford Classification variables as predictors of renal dysfunction in a cohort of Brazilian children and adolescents with IgAN. Methods: A total of 54 patients with IgAN biopsied from 1982 to 2010 were assessed. Biopsies were re-evaluated and classified according to the Oxford Classification. Multivariate analysis of laboratory and pathological data was performed. The primary outcomes were decline of baseline estimated glomerular filtration rate (eGFR) greater than or equal to 50%. Results: Mean follow-up was 7.6 ± 5.0 years. Mean renal survival was 13.5 ± 0.8 years and probability of decline ≥50% in baseline eGFR was 8% at five years of follow-up and 15% at ten years. Ten children (18.5%) had a decline of baseline eGFR ≥ 50% and five (9.3%) evolved to end-stage renal disease. Kaplan-Meier analysis showed that baseline proteinuria, proteinuria during follow-up, endocapillary proliferation, and tubular atrophy/interstitial fibrosis were associated with the primary outcome. Multivariate Cox analysis showed that only baseline proteinuria (HR, 1.73; 95% CI, 1.20-2.50, p = 0.003) and endocapillary hypercellularity (HR, 37.18; 95% CI, 3.85-358.94, p = 0.002) were independent predictors of renal dysfunction. No other pathological variable was associated with eGFR decline in the multivariate analysis. Conclusion: This is the first cohort study that evaluated the predictive role of the Oxford Classification in pediatric patients with IgAN from South America. Endocapillary proliferation was the unique pathological feature that independently predicted renal outcome.

Resumo Objetivo: A Classificação Oxford para a Nefropatia por Imunoglobulina A (IgAN) identificou variáveis patológicas de risco para disfunção renal. O presente estudo teve como objetivo avaliar as variáveis da Classificação de Oxford como preditores de disfunção renal em crianças brasileiras com IgAN. Métodos: Foram analisados 54 pacientes com diagnóstico de IgAN entre 1982-2010. As biópsias renais foram reavaliadas pela Classificação de Oxford. Foram feitas análises uni e multivariada das variáveis clínicas e patológicas. O desfecho primário foi queda da taxa de filtração glomerular (TFG) ≥ 50% da filtração basal. Resultados: O acompanhamento médio foi de 7,6 ± 5,0 anos. A sobrevida renal média foi de 13,5 ± 0,8 anos e a probabilidade de atingir o desfecho primário foi de 8% em cinco anos e 15% em 10 anos de seguimento. Dez crianças (18,5%) apresentaram queda na TFG basal ≥ 50% e cinco (9,3%) evoluíram para doença renal crônica terminal. A análise de Kaplan-Meier mostrou que a proteinúria basal e de seguimento, a proliferação endocapilar e a atrofia tubular/fibrose intersticial foram associadas com o desfecho primário. A análise multivariada de Cox mostrou que a proteinúria basal (HR = 1,73; IC95% 1,20-2,50, p = 0,003) e a proliferação endocapilar (HR = 37,18; IC95% 3,85-358,94, p = 0,002) foram preditores independentes de disfunção renal. Nenhuma outra variável patológica foi associada com declínio da TFG na análise multivariada. Conclusão: Este é o primeiro estudo brasileiro que avaliou a Classificação Oxford em crianças com IgAN. A proliferação endocapilar foi a única característica patológica capaz de predizer independentemente o declínio da função renal.

The Oxford Classification predictors of chronic kidney disease in pediatric patients with IgA nephropathy.

OBJECTIVE: The Oxford Classification for Immunoglobulin A nephropathy (IgAN) identifies pathological variables that may predict the decline of renal function. This study aimed to evaluate the Oxford Classification variables as predictors of renal dysfunction in a cohort of Brazilian children and adolescents with IgAN. METHODS: A total of 54 patients with IgAN biopsied from 1982 to 2010 were assessed. Biopsies were re-evaluated and classified according to the Oxford Classification. Multivariate analysis of laboratory and pathological data was performed. The primary outcomes were decline of baseline estimated glomerular filtration rate (eGFR) greater than or equal to 50%. RESULTS: Mean follow-up was 7.6±5.0 years. Mean renal survival was 13.5±0.8 years and probability of decline ≥50% in baseline eGFR was 8% at five years of follow-up and 15% at ten years. Ten children (18.5%) had a decline of baseline eGFR≥50% and five (9.3%) evolved to end-stage renal disease. Kaplan-Meier analysis showed that baseline proteinuria, proteinuria during follow-up, endocapillary proliferation, and tubular atrophy/interstitial fibrosis were associated with the primary outcome. Multivariate Cox analysis showed that only baseline proteinuria (HR, 1.73; 95% CI, 1.20-2.50, p=0.003) and endocapillary hypercellularity (HR, 37.18; 95% CI, 3.85-358.94, p=0.002) were independent predictors of renal dysfunction. No other pathological variable was associated with eGFR decline in the multivariate analysis. CONCLUSION: This is the first cohort study that evaluated the predictive role of the Oxford Classification in pediatric patients with IgAN from South America. Endocapillary proliferation was the unique pathological feature that independently predicted renal outcome.

Serum levels of sTNF-R1, sTNF-R2 and CXCL9 correlate with disease activity in adult type paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is the most common systemic mycosis in Latin America. A major problem in the management of PCM is to determine the best time to discontinue therapy due to the high relapse rate among patients. Soluble TNF receptors (sTNF-R) levels and chemokines are associated with disease activity in several infectious, inflammatory and autoimmune disorders. The aim of the present work was to evaluate levels of sTNF-R1, sTNF-R2 and chemokines in serum of patients with adult type of PCM, before and after antifungal therapy, and to correlate those levels to disease activity. Concentrations of sTNF-R1, sTNF-R2 and CXCL9 were higher in untreated patients and decreased progressively with treatment. The serum marker with the best accuracy to discriminate PCM cases from controls was sTNF-R2. sTNF-R1 did not drop to control levels before 36 months of treatment. CCL2 and CCL3 levels were low at baseline in PCM patients, raised significantly after 12 months of treatment and diminished thereafter. CCL24 levels were higher after 36 months of antifungal therapy in PCM patients. CCL11 levels were not statistically different from control subjects. sTNF-R1, sTNF-R2 and CXCL9 may be useful as laboratory parameters to assess disease activity in PCM patients.