The 2021–2022 position of Brazilian Diabetes Society on diabetic kidney disease (DKD) management : an evidence-based guideline to clinical practice. Screening and treatment of hyperglycemia, arterial hypertension, and dyslipidemia in the patient with DKD

Background: Diabetic kidney disease is the leading cause of end-stage renal disease and is associated with increased morbidity and mortality. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021–2022. This evidence-based guideline provides guidance on the correct management of Diabetic Kidney Disease (DKD) in clinical practice. Methods: The methodology was published elsewhere in previous SBD guidelines and was approved by the internal institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, with the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to DKD diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease]. Results: The extensive review of the literature made by the 14 members of the Central Committee defined 24 recommendations. Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity ( I2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies, exploratory analyses, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panelists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa 75–89% of agreement; IIb 50–74% of agreement, and III, when most of the panelist recommends against a defined treatment. Conclusions: To prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin–angiotensin–aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients’ survival

2009 CKD-EPI glomerular filtration rate estimation in Black individuals outside the United States: a systematic review and meta-analysis

peer reviewedABSTRACT Background The 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most used equation to estimate glomerular filtration rate (GFR), with race being a factor thereof, increasing GFR by 16% in self-identified Black persons compared with non-Black persons. However, recent publications indicate that it might overestimate GFR for Black adults outside the USA. In this meta-analysis, we assessed the accuracy, evaluated by the percentage of estimated GFR within 30% of measured GFR (P30), of the 2009 CKD-EPI equation in estimating GFR with and without the race coefficient in Black individuals outside the United States of America (USA). Methods We searched MEDLINE and Embase from inception to 9 July 2022, with no language restriction, supplemented by manual reference searches. Studies that assessed the CKD-EPI P30 accuracy with or without the race coefficient in Black adults outside the USA with an adequate method of GFR measurement were included. Data were extracted by independent pairs of reviewers and were pooled using a random-effects model. Results We included 11 studies, with a total of 1834 Black adults from South America, Africa and Europe. The race coefficient in the 2009 CKD-EPI equation significantly decreased P30 accuracy {61.9% [95% confidence interval (CI) 53–70%] versus 72.9% [95% CI 66.7–78.3%]; P = .03}. Conclusions Outside the USA, the 2009 CKD-EPI equation should not be used with the race coefficient, even though the 2009 CKD-EPI equation is not sufficiently accurate either way (<75%). Thus we endorse the Kidney Disease: Improving Global Outcomes guidelines to use exogenous filtration markers when this may impact clinical conduct

Non-classical effects of androgens on testes from neonatal rats

a b s t r a c t The intratesticular testosterone concentration is high during the early postnatal period although the intracellular androgen receptor expression (iAR) is still absent in Sertoli cells (SCs). This study aimed to evaluate the non-classical effects of testosterone and epitestosterone on calcium uptake and the electrophysiological effects of testosterone (1 lM) on SCs from rats on postnatal day (pnd) 3 and 4 with lack of expression of the iAR. In addition, crosstalk on the electrophysiological effects of testosterone and epitestosterone with follicle stimulating hormone (FSH) in SCs from 15-day-old rats was evaluated. SCs on pnd 4. FSH application followed by testosterone and epitestosterone reduced the depolarization of the two hormones. Application of epitestosterone 5 min after FSH resulted in a delay of epitestosteronepromoted depolarization. The cell resistance was also reduced. Thus, in SCs from neonatal Wistar rats, both testosterone and epitestosterone act through a non-classical mechanism stimulating calcium uptake in whole testes, and testosterone produces a depolarizing effect on SC membranes. Testosterone and epitestosterone stimulates non-classical actions via a membrane mechanism, which is independent of iAR. FSH and testosterone/epitestosterone affect each other&apos;s electrophysiological responses suggesting crosstalk between the intracellular signaling pathways

Análise da inclusão do coeficiente racial na estimativa da taxa de filtração glomerular : revisão sistemática e metanálise e avaliação em uma amostra sul-brasileira

A doença renal crônica (DRC) é um grande problema de saúde pública em todo o mundo e que frequentemente cursa com desfechos desfavoráveis, com eventual desenvolvimento de doença renal terminal (DRT) em uma parcela significativa desses pacientes. A taxa de filtração glomerular (TFG) é o melhor índice geral da função renal. Na prática clínica, a TFG é usualmente estimada através de equações baseadas na medida da creatinina sérica, como a Chronic Kidney Disease Epidemiology Collaboration de 2009 (CKD-EPI), Modification of Diet in Renal Disease (MDRD), European Kidney Function Consortium (EKFC). Dentre essas equações, a CKD-EPI de 2009 e a MDRD incluem em suas fórmulas um coeficiente de ajuste racial (CR), acrescendo 16% e 21%, respectivamente, na estimativa da TFG em negros. No entanto, sabe-se que a população negra é quase 3 vezes mais propensa a desenvolver DRT, e em média 5 anos mais cedo do que adultos brancos nos EUA. Por isso, o uso do CR tem sido amplamente criticado como uma fonte potencial de discriminação e desigualdade em saúde, impedindo o acesso precoce aos cuidados de saúde para pacientes negros. Nesse sentido, foram recentemente desenvolvidas a CKD-EPI 2021 e a EKFC, que não empregam o CR. Dessa forma, o presente trabalho se dedicou a investigar a acurácia da CKD-EPI 2009 com e sem o CR na população negra através de uma revisão sistemática e metanálise de estudos observacionais, bem como o desempenho das equações CKD-EPI 2009 (com CR), CKD-EPI 2021 e EKFC em uma amostra de voluntários brancos e negros autodeclarados do Rio Grande do Sul. Na nossa metanálise pesquisamos por artigos no MEDLINE e EMBASE até 9 de julho de 2022, sem restrição de idioma, complementadas por pesquisas manuais de referências. Foram incluídos estudos que avaliaram a acurácia P30 da CKD-EPI 2009 com ou sem o CR em adultos negros fora dos EUA comparada a um método padrão adequado de medida da TFG. Os dados foram extraídos por pares independentes de revisores e agrupados usando um modelo de efeitos aleatórios. Foram incluídos 11 estudos, com um total de 1.834 adultos negros da América do Sul, África e Europa. O CR presente na fórmula da equação CKDEPI de 2009 diminuiu significativamente os resultados de precisão do P30 (61,9% [IC 95%, 53% a 70%] vs. 72,9% [IC 95%, 66,7% a 78,3%]; p=0,03). 9 No estudo transversal, comparamos as equações da TFGe com o método padrão-ouro de medida da TFG por 51Cr-EDTA. A análise de concordância das equações com a TFG medida mostrou que a CKD-EPI 2009 apresentou o maior valor de acurácia P30 em negros (77%) bem como o menor viés (4,04) e o maior coeficiente de correlação de concordância (CCC: 0,819). Por outro lado, a CKDEPI de 2021 teve o melhor desempenho entre os pacientes brancos, com acurácia P30 adequada (76%), menor viés (1,45) e maior CCC (0,747). Embora evidenciada pela análise de Bland-Altman a tendência de subestimar os valores da TFG medida para todas as equações, o pior desempenho observado foi da equação EKFC, seguido da CKD-EPI 2021, em negros. A CKD-EPI 2009 calculada com o CR teve um desempenho pior do que sem o CR para adultos negros fora dos EUA em nossa metanálise, embora tenha tido o melhor desempenho com o CR na avaliação transversal da nossa população. Portanto, concluímos que ainda não é possível afirmar que a CKDEPI 2021 deva ser adotada em detrimento da CKD-EPI 2009. Estudos maiores e mais bem conduzidos, incluindo negros de diferentes países, são necessários e darão uma valiosa contribuição para confirmar esses resultados. Por fim, endossamos as diretrizes da KDIGO e recomendamos fortemente que a TFG seja medida por meio de marcadores exógenos quando uma estimativa mais precisa da TFG for impactar claramente as decisões clínicas.Chronic kidney disease (CKD) is a major public health problem worldwide with frequent unfavorable outcomes. A significant proportion of these patients eventually develops end-stage renal disease (ESRD). Glomerular filtration rate (GFR) is the best overall index of kidney function. In clinical practice, GFR is usually estimated using equations based on the measurement of serum creatinine, such as the Chronic Kidney Disease Epidemiology Collaboration 2009 (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and European Kidney Function Consortium (EKFC). Among these equations, the 2009 CKD-EPI and the MDRD include a racial adjustment coefficient (RC) in their formulas, adding 16% and 21%, respectively, to the estimate of GFR in Blacks. However, it is known that the Black population is almost 3 times more likely to develop ESRD, and on average 5 years earlier than White adults in the US. Therefore, the use of RC has been widely criticized as a potential source of discrimination and health inequality, preventing early access to health care for Black patients. In this sense, the CKD-EPI 2021 and EKFC equations, that do not use the RC, were recently developed. Thus, the present work aimed to investigate the accuracy of the CKD-EPI 2009 with and without the RC in the Black population through a systematic review and meta-analysis of observational studies, as well as the performance of the CKD-EPI 2009 equations (with RC), CKD-EPI 2021, and EKFC in a sample of self-declared Whites and Blacks from Rio Grande do Sul. In our meta-analysis, we searched for articles in MEDLINE and EMBASE since July 9, 2022, without language restrictions, supplemented by manual reference searches. Studies that evaluated the P30 accuracy of the CKD-EPI 2009 with or without RC in non-US Black adults with an adequate standard method of measuring GFR were included. Data were extracted by independent pairs of reviewers and pooled using a random effects model. Eleven studies were included, with a total of 1,834 Black adults from South America, Africa, and Europe. The RC in the 2009 CKD-EPI equation formula significantly decreased the P30 accuracy results (61.9% [95% CI, 53% to 70%] vs. 72.9% [95% CI, 66, 7% to 78.3%]; p=0.03). 11 In the cross-sectional study, we compared eGFR equations with the goldstandard method of measured GFR (mGFR) by 51Cr-EDTA. The equations performance was assessed using Bland-Altman plot, concordance correlation coefficient (CCC), bias, and P30 accuracy. The analysis of agreement of the equations with the measured GFR showed that the CKD-EPI 2009 presented the highest P30 accuracy value in Blacks (77%) as well as the lowest bias (4.04) and the highest CCC (0.849). On the other hand, the 2021 CKD-EPI performed best among White patients, with the highest P30 accuracy (83%), lowest bias (1.45), and highest CCC (0.790). Although the Bland-Altman analysis showed a tendency to underestimate the measured GFR values for all equations, the worst performance observed was for the EKFC equation in both groups, followed by the CKD-EPI 2021, in Blacks. Our meta-analysis showed that 2009 CKD-EPI calculated with the RC performed worse than without the RC for non-US Black adults, although it performed better with the RC in our Black population. Therefore, we conclude that it is not yet possible to state that CKD-EPI 2021 should be adopted to the detriment of CKD-EPI 2009. Larger and better-conducted studies, including Blacks from different countries, are necessary and will make a valuable contribution to confirm these results. Finally, we endorse the KDIGO guidelines and strongly recommend that clinicians measure GFR using exogenous markers when a more accurate GFR can clearly impact clinical decisions

Ações da insulina e do IGF-I sobre marcadores de ação hormonal em células de Sertoli de ratos em diferentes estágios de desenvolvimento

A insulina e o IGF-I são hormônios que possuem alta homologia, isto é, apresentam grande semelhança estrutural no que se refere a sequencia de aminoácidos. Assim como os hormônios, seus receptores de membrana também são semelhantes, e a similaridade de suas sequencias de aminoácidos é em torno de 50%. Essas semelhanças permitem que ambos os hormônios se liguem aos seus receptores com alta afinidade e ao receptor do outro hormônio com menor afinidade. Tanto insulina como IGF-I desencadeiam uma série de efeitos sobre as células de Sertoli, como transporte de glicose e produção de lactato. Dessa forma, este estudo tem por objetivo investigar a ação do IGF-I e da insulina sobre a captação de cálcio, o transporte de aminoácido e glicose, além de suas ações eletrofisiológicas em células de Sertoli de ratos de 12 a 15 dias e de 30 dias de idade. Para o registro do potencial de membrana foram utilizados túbulos seminíferos isolados de testículos de ratos Wistar machos de 12 a 15 dias de idade e de 30 dias de idade. O registro intracelular da célula de Sertoli foi realizado utilizando microcapilares de borossilicato preenchidos com KCl 3 M acoplados a um eletrômetro. Foi realizada a aplicação tópica de IGF-I (100 ng/ml) e insulina (100 μM) isoladamente e também após a perfusão com a verapamil (100 μM) e JB1 (1 μg/ml). A captação de 45Ca2+ foi investigada se utilizando testículos inteiros. Os tecidos foram pré-incubados em KRb com 45Ca2+ por 60 minutos para equilibrar o meio intra e extracelular de 45Ca2+. Em seguida, as gônadas foram incubadas por 2 minutos em KRb com 45Ca2+ com ou sem IGF-I ou insulina. O transporte de [14C]MeAIB e [14C]2-DG também foram investigados se utilizando de testículos inteiros. Com pré-incubação de 30 minutos em KRb sem [14C]MeAIB ou [14C]2-DG, e posterior incubação de 45 minutos com [14C]MeAIB ou de 120 minutos com [14C]2-DG, com ou sem o respectivo hormônio a ser investigado. Os resultados foram dados como média ± SEM. Os dados foram analisados pelo teste T student para comparação entre dois grupos ou ANOVA para medidas repetidas com o pós-teste de Bonferroni. IGF-I e insulina produziram um efeito despolarizante sobre o potencial de membrana das células de Sertoli de ratos imaturos. Este efeito é dependente do influxo de cálcio, uma vez que a perfusão com verapamil bloqueou a ação dos dois hormônios. A reposta despolarizante do IGF-I foi bloqueada pelo JB1, enquanto que a resposta à insulina foi parcialmente bloqueada. Em ratos de 30 dias, apenas a insulina apresentou uma despolarização significativa. IGF-I e insulina também estimularam a captação de cálcio, aminoácido e glicose. A ação da insulina sobre o transporte de cálcio foi totalmente bloqueada pelo JB1 enquanto que do IGF-I foi apenas parcialmente bloqueado. Já sobre o transporte de aminoácido, o JB1 não exerceu qualquer efeito sobre a ação da insulina, enquanto que o efeito do IGF-I foi parcialmente bloqueado. E a estimulação do transporte de glicose pelo IGF-I não foi bloqueada pelo JB1, e a da insulina parcialmente bloqueada. Esses dados mostram que IGF-I e insulina, em diferentes parâmetros, se utilizam não apenas de seus receptores cognatos, mas também de outros receptores de membrana. Dessa forma, ficou claro que a sinalização gerada por esses hormônios nas células de Sertoli depende da presença dos receptores de ambos os hormônios na membrana celular para que eles sejam capazes de interferir nos processos metabólicos e funcionais dessas células.Insulin and IGF-I are hormones which have high homology. In other words, they have high structural similarity with regard to the sequence of amino acids. As well as the hormones, their membrane receptors are also similar, and the similarity of their amino acid sequences is around 50%. These similarities allow both hormones bind to their receptors with high affinity and to each other's receptor with lower affinity. Both insulin and IGF-I trigger a number of effects on the Sertoli cells, such as transporting glucose and lactate production. Thus, this study aims to investigate the action of IGF-I and insulin on calcium uptake, transport of amino acids and glucose, as well as their electrophysiological actions in Sertoli cells from 12- to 15- and 30-days-old rats. To record the membrane potential were used isolated seminiferous tubules from 12- to 15- and 30-days-old rats. The intracellular recording of Sertoli cells was performed using microcapillaries filled with 3 M KCl coupled to an electrometer. Was performed topical application of IGF-I (100 ng/ml) and insulin (100 mM) alone and also after infusion with verapamil (100 mM) and JB1 (1 μg/ml). The uptake of 45Ca2+ was investigated using whole testes. Tissues were pre-incubated in KRb with 45Ca2+ for 60 minutes to equilibrate intra and extracellular medium. Then, the gonads were incubated for 2 minutes in KRb with 45Ca2+ and with or without IGF-I or insulin. The transport of [14C]MeAIB and [14C]2-DG were also investigated using whole testes. Which was pre-incubated for 30 minutes in KRb without [14C]MeAIB or [14C]2-DG, and further was incubated for 45 minute in KRb with [14C]MeAIB or 120 minutes with [14C]2-DG, with or without the respective hormone to be investigated. The results are given as mean ± SEM. Data were analyzed by Student's t test for comparison between two groups or ANOVA for repeated measures with Bonferroni post-test. IGF-I and insulin produced a depolarizing effect on the membrane potential of Sertoli cells from immature rats. This effect is calcium influx dependent, since the verapamil infusion blocked the action of the two hormones. The depolarizing response of IGF-I was blocked by JB1, whereas the depolarizing response of insulin was partially blocked. In 30-day-old rats, only insulin showed a significant depolarization. Insulin and IGF-I also stimulated the uptake of calcium, amino acids and glucose. The action of insulin on calcium uptake was completely blocked by JB1 while IGF-I was only partially blocked. On amino acid transport, JB1 had no effect on the insulin action, while IGF-I effect was partially blocked. And stimulation of glucose transport by IGF-I was blocked by JB1 and partially blocked the insulin effect. These data show that IGF-I and insulin on different parameters, use not only their cognate receptors, but also other membrane receptors. Thus, it became clear that the signal generated by these hormones in Sertoli cells depends on the presence of receptors for both hormones in the cell membrane to they are able to interfere on the functional and metabolic processes of these cells