SGLT-2 inhibitors in diabetes: a focus on renoprotection

SUMMARY Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.

Metabolic and volume status evaluation of hemodialysis patients with and without residual renal function in the long interdialytic interval / Avaliação metabólica e volêmica no maior intervalo interdialítico de pacientes em hemodiálise com e sem função renal residual

Abstract Introduction: It is unclear whether residual renal function (RRF) in dialysis patients can attenuate the metabolic impact of the long 68-hour interdialytic interval, in which water, acid, and electrolyte accumulation occurs. Objective: to evaluate serum electrolyte levels, water balance, and acid-base status in dialytic patients with and without RRF over the long interdialytic interval (LII). Methodology: this was a single-center, cross-sectional, and analytical study that compared patients with and without RRF, defined by diuresis above 200 mL in 24 hours. Patients were weighed and serum samples were collected for biochemical and gasometric analysis at the beginning and at the end of the LII. Results: 27 and 24 patients with and without RRF were evaluated, respectively. Patients without RRF had a higher increase in serum potassium during the LII (2.67 x 1.14 mEq/L, p < 0.001), reaching higher values at the end of the study (6.8 x 5.72 mEq/L, p < 0.001) and lower pH value at the beginning of the interval (7.40 x 7.43, p = 0.018). More patients with serum bicarbonate < 18 mEq/L (50 x 14.8%, p = 0.007) and mixed acid-base disorder (57.7 x 29.2%, p = 0.042), as well as greater interdialytic weight gain (14.67 x 8.87 mL/kg/h, p < 0.001) and lower natremia (137 x 139 mEq/L, p = 0.02) at the end of the interval. Calcemia and phosphatemia were not different between the groups. Conclusion: Patients with RRF had better control of serum potassium, sodium, acid-base status, and volemia throughout the LII.

Resumo Introdução: Não se sabe ao certo se a função renal residual (FRR) de pacientes dialíticos pode atenuar o impacto metabólico do maior intervalo interdialítico (MII) de 68 horas, no qual ocorre acúmulo de volume, ácidos e eletrólitos. Objetivo: Avaliar os níveis séricos de eletrólitos, balanço hídrico e status ácido-básico de pacientes dialíticos com e sem FRR ao longo do MII. Metodologia: Tratou-se de estudo unicêntrico, transversal e analítico, que comparou pacientes com e sem FRR, definida como diurese acima de 200 mL em 24 horas. Para tal, os pacientes foram pesados e submetidos à coleta de amostras séricas para análise bioquímica e gasométrica no início e fim do MII. Resultados: Foram avaliados 27 e 24 pacientes com e sem FRR, respectivamente. Pacientes sem FRR apresentaram maior aumento de potássio sérico durante o MII (2,67 x 1,14 mEq/L, p < 0,001) atingindo valores mais elevados no fim (6,8 x 5,72 mEq/L, p < 0,001); menor valor de pH no início do intervalo (7,40 x 7,43, p = 0,018), maior proporção de pacientes com bicarbonato sérico < 18 mEq/L (50 x 14,8 %, p = 0,007) e distúrbio ácido-básico misto (70,8 x 42,3 %, p = 0,042), além de maior ganho de peso interdialítico (14,67 x 8,87 mL/kg/h, p < 0,001) e menor natremia (137 x 139 mEq/L, p = 0,02) no fim do intervalo. A calcemia e fosfatemia não foram diferentes entre os grupos. Conclusão: Pacientes com FRR apresentaram melhor controle dos níveis séricos de potássio, sódio, status ácido-básico e da volemia ao longo do MII.

Cardiovascular Mortality in Chronic Kidney Patients: the Role of Uremic Toxins / Mortalidade Cardiovascular em Pacientes Renais Crônicos: o Papel das Toxinas Urêmicas

A doença cardiovascular (DCV) é a maior causa de morte nos pacientes com doença renal crônica (DRC) nomundo. Vários fatores estão associados a essa elevada mortalidade e, recentemente, as toxinas urêmicas produzidas pela microbiota intestinal têm recebido bastante atenção, já que a falência renal cursa com o acúmulo dessas toxinas no plasma. Essas toxinas têm relação com estresse oxidativo, inflamação, disfunção endotelial e induçãoda aterosclerose e, recentes estudos têm observado que pacientes com elevados níveis de tais toxinas têm aumento na mortalidade por DCV. Assim, o objetivo da presente revisão foi discutir o papel das toxinas urêmicasprovenientes da microbiota intestinal e seu impacto na mortalidade cardiovascular em pacientes renais crônicos, bem como as possíveis perspectivas terapêuticas que podem ser elucidadas a partir do conhecimento aprofundado do tema...

The cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) in the world. Several factors are associated with this high mortality. Recently, the uremic toxins produced by intestinal microbiota have received extensiveattention from researchers, since kidney failure evolves with the accumulation of these toxins in the plasma. These toxins are related to oxidative stress, inflammation, endothelial dysfunction, and induction of atherosclerosis, and recent studies have noted thatpatients with high levels of these toxins have increased mortality due to CVD. Therefore, the purpose of this review was to discuss the role of uremic toxins from the intestinal microbiota and their impact on cardiovascular mortality in CKD patients, as well as the possible therapeutic perspectives that can be explained based on an in-depth understanding of the subject...

Superoxide overproduction and kidney fibrosis: a new animal model / Produção aumentada de superóxido e fibrose renal: novo modelo animal

Objective To establish whether the mutation in the Immp2L gene induces renal fibrosis and whether aging exacerbates renal morphology in mice. Methods Female mutant mice with mutation in the inner mitochondrial membrane peptidase 2-like protein at 3 and 18 months of age were used. Renal fibrosis was analyzed using classic fibrosis score, Masson’s trichrome staining, and analysis of profibrotic markers using real time polymerase chain reaction (superoxide dismutase 1, metalloproteinase-9, erythropoietin, transforming growth factor beta), and immunostaining (fibroblasts and Type IV collagen). Oxidative stress markers were determined by immunohistochemistry. The number of renal apoptotic cells was determined. Renal function was estimated by serum creatinine. Results Young mutant mice had significantly more glomerulosclerosis than age-matched mice (p=0.034). Mutant mice had more tubular casts (p=0.025), collagen deposition (p=0.019), and collagen type IV expression (p<0.001). Superoxide dismutase 1 expression was significantly higher in young mutants (p=0.038). Old mutants exhibited significantly higher expression of the fibroblast marker and macrophage marker (p=0.007 and p=0.012, respectively). The real time polymerase chain reaction of metalloproteinase-9 and erythropoietin were enhanced 2.5- and 6-fold, respectively, in old mutants. Serum creatinine was significantly higher in old mutants (p<0.001). Conclusion This mutation altered renal architecture by increasing the deposition of extracellular matrix, oxidative stress, and inflammation, suggesting a protective role of Immp2L against renal fibrosis. .

Objetivo Estabelecer se a mutação no gene Immp2L induz à fibrose renal e se o envelhecimento exacerba a morfologia renal em camundongos. Métodos Foram usadas fêmeas de camundongos mutantes para proteína semelhante à peptidase 2 da camada interna da mitocôndria, com 3 e 18 meses de idade. Para analisar a fibrose renal, foram usados o escore clássico de fibrose, a coloração com tricrômio de Masson, e a análise de marcadores profibróticos, por meio da reação em cadeia de polimerase em tempo real (superóxido dismutase 1, metalonoproteinase-9, eritropoietina e fator transformador de crescimento beta), e a imunocoloração (fibroblastos e colágeno IV). Marcadores de estresse oxidativo foram determinados por imuno-histoquímica. O número de células apoptóticas renais foi analisado. A função renal foi estimada por creatinina sérica. Resultados Camundongos mutantes jovens apresentaram glomeruloesclerose em quantidade significativamente maior que animais da mesma idade (p=0,034). Os mutantes mostraram maior formação de cilindros tubulares (p=0,025), deposição de colágeno (p=0,019) e maior expressão de colágeno do tipo IV (p<0,001). A expressão de superóxido dismutase 1 foi maior em mutantes jovens (p=0,038). Mutantes idosas exibiram maior expressão dos marcadores de fibroblastos e macrófagos (p=0,007 e p=0,012, respectivamente). As reações da cadeia de polimerase em tempo real da metalanoproteinase-9 e da eritropoietina estavam aumentadas em 2,5 e 6 vezes, respectivamente, em mutantes idosas. A creatinina sérica foi significantemente maior em animais idosos mutantes (p<0,001). Conclusão Essa mutação alterou a arquitetura renal pelo aumento da deposição de matriz extracelular, estresse oxidativo e inflamação, sugerindo papel de proteção de Immp2L contra a fibrose renal. .

El litio y su relación con la acuaporina-2 y el canal de sodio ENaC / Lithium and its relation with the epithelial sodium channel and aquaporin-2

Desde hace más de cuarenta años que el litio es usado para el tratamiento de la enfermedad bipolar; recientes estudios sugieren también su utilidad en el trastorno cognitivo mínimo tipo amnésico. El litio es filtrado en el glomérulo y un 65-75% del mismo es reabsorbido en el túbulo contorneado proximal y en el asa ascendente de Henle por el transportador Na+, K+, 2Cl- y vía paracelular. Una pequeña fracción del litio entra en las células principales del túbulo colector por medio del canal epitelial de sodio sensible al amiloride (ENaC) localizado en la membrana apical de la célula. Luego de 10- 20 años de tratamiento con litio los enfermos pueden desarrollar poliuria, acidosis tubular e insuficiencia renal crónica que puede terminar en una forma de diabetes que no responde a la arginina vasopresina llamada diabetes insípida nefrogénica. Se cree que estas fallas renales son consecuencias de una reducción en el número de moléculas de acuaporina 2 en la membrana apical. Las causas para esto son complejas. El litio es un poderoso inhibidor de la isoforma beta de la enzima glicógeno sintetasa quinasa y esto está asociado a una menor actividad de la adenilato ciclasa que lleva a una disminución en la concentración intracelular de cAMP. Esto finalmente interferiría con la síntesis de nuevas moléculas de acuaporina 2 y con el tráfico de ellas desde la zona subapical de la célula hacia la membrana celular, causando la disminución en la reabsorción de agua en la parte distal del nefrón.

For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3β and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney.

Filtração glomerular e fatores associados em hipertensos atendidos na atenção básica / Glomerular filtration and associated factors in hypertensive individuals treated at primary care level

FUNDAMENTO: No Brasil, a hipertensão arterial (HA) constitui-se um dos principais fatores de risco para doença renal crônica (DRC). Recomenda-se o monitoramento da filtração glomerular (FG) para avaliação da função renal em hipertensos, posto que sua redução precede o aparecimento de sintomas. OBJETIVO: Avaliar a FG e fatores associados em hipertensos. MÉTODOS: Realizou-se estudo transversal no período de janeiro a junho de 2008, com 297 hipertensos com ou sem diabete melito (DM) tratados em uma unidade básica de saúde em São Luís-MA. Foram incluídos pacientes >20 anos e de ambos os sexos. Avaliaram-se dados sociodemográficos, estado nutricional, FG e microalbuminúria em urina de 24h, controle pressórico e glicêmico, creatinina sérica e lipidograma. RESULTADOS: A idade média foi 60,6 × 11,5 anos com predomínio do sexo feminino (75,1 por cento), sobrepeso/obesidade (65,0 por cento) e circunferência da cintura elevada (60,6 por cento). A prevalência de FG < 60 ml/min foi 24,6 por cento no grupo HA sem DM e 18,3 por cento no HA com DM, sem diferença significante. Para o grupo HA sem DM houve associação apenas da FG reduzida com idade > 65 anos, que permaneceu após ajustamento. Para o grupo HA com DM houve associação da redução da FG com idade > 65 anos, tabagismo e obesidade, porém, após ajustamento, permaneceram idade e tabagismo. CONCLUSÃO: Nestes pacientes, a prevalência de FG < 60 ml/min foi elevada e, após ajustamento, apenas idade > 65 anos e tabagismo apresentaram-se como fatores associados à FG. Isto reforça a necessidade da avaliação sistemática da FG em hipertensos visando a prevenção secundária da doença renal crônica.

BACKGROUND: In Brazil, arterial hypertension (AH) constitutes one of the main risk factors for chronic kidney disease (CKD). The monitoring of glomerular filtration (GF) is recommended for the assessment of kidney function in hypertensive individuals, as GF decrease precedes symptom onset. OBJECTIVE: To assess GF and its associated factors in hypertensive individuals. METHODS: A cross-sectional study was carried out from January to June 2008 in 297 individuals with arterial hypertension (AH) with or without diabetes mellitus (DM), treated at a primary care facility in the city of São Luís, Maranhão. Patients older than 20 years and of both sexes were included in the study. Sociodemographic and nutritional status data, GF rate and microalbuminuria levels in 24-hour urine were assessed, as well as blood pressure, glucose and serum creatinine levels and a lipidogram. RESULTS: Mean age was 60.6 × 11.5 years, with a predominance of the female sex (75.1 percent), overweight/obesity (65.0 percent) and large waist circumference (60.6 percent). The prevalence of GF < 60 ml/min was 24.6 percent in the AH group without DM and 18.3 percent in the AH group with DM, with no significant difference. For the AH group without DM, there was an association only between reduced GF and age > 65 years, which remained after adjustment. For the AH group with DM, there was an association between reduced GF and age > 65 years, smoking habit and obesity. However, after the adjustment, age and smoking habit remained as associated factors. CONCLUSION: In these patients, the prevalence of GF < 60 ml/min was high and after the adjustment, only age > 65 years and smoking habit were shown to be factors associated to GF. This reinforces the need to systematically evaluate GF in hypertensive individuals, aiming at the secondary prevention of chronic kidney disease.

Prediction of differential creatinine clearance in chronically obstructed kidneys by non-contrast helical computerized tomography

PURPOSE: We investigate the use of non-contrast helical computerized tomography (NCHCT) in the measurement of differential renal parenchymal volume as a surrogate for differential creatinine clearance (CrCl) for unilateral chronically obstructed kidney. MATERIALS AND METHODS: Patients with unilateral chronically obstructed kidneys with normal contralateral kidneys were enrolled. Ultrasonography (USG) of the kidneys was first done with the cortical thickness of the site with the most renal substance in the upper pole, mid-kidney, and lower pole of both kidneys were measured, and the mean cortical thickness of each kidney was calculated. NCHCT was subsequently performed for each patient. The CT images were individually reviewed with the area of renal parenchyma measured for each kidney. Then the volume of the slices was summated to give the renal parenchymal volume of both the obstructed and normal kidneys. Finally, a percutaneous nephrostomy (PCN) was inserted to the obstructed kidney, and CrCl of both the obstructed kidney (PCN urine) and the normal side (voided urine) were measured two 2 after the relief of obstruction. RESULTS: From March 1999 to February 2001, thirty patients were enrolled into the study. Ninety percent of them had ureteral calculi. The differential CrCl of the obstructed kidney ( percentCrCl) was defined as the percentage of CrCl of the obstructed kidney as of the total CrCl, measured 2 weeks after relief of obstruction. The differential renal parenchymal volume of the obstructed kidney ( percentCTvol) was the percentage of renal parenchymal volume as of the total parenchymal volume. The differential USG cortical thickness of the obstructed kidney ( percentUSGcort) was the percentage of mean cortical thickness as of the total mean cortical thickness. The Pearson's correlation coefficient (r) between percentCTvol and percentCrCl and that between percentUSGcort and percentCrCl were 0.756 and 0.543 respectively. The regression line was percentCrCl = (1.00) x percentCTvol - 14.27. The percentCTvol overestimated the differential creatinine clearance by about 14 percent, but the correlation is good. CONCLUSION: The differential renal parenchymal volume measured by NCHCT provided a reasonable prediction of differential creatinine clearance in chronically obstructed kidneys.

Desarrollo de un instrumento para medir la calidad de vida en pacientes con insuficiencia renal crónica y diálisis. Una experiencia en Honduras / Development of an instrument to measure quality of life in patients with chronic renal failure and dialysis. An experience in Honduras

ANTECEDENTES. La insuficiencia renal crónica (IRC) impacta severamente en la calidad de vida del paciente, sin embargo no existe un instrumento uniforme que la evalúe. OBJETIVO. Determinar el impacto de la IRC en la vida de los pacientes hospitalizados para diálisis peritoneal en el Hospital Escuela durante el primer semestre del año 2000. El instrumento evalúa 11 áreas de la vida (emocional, social, laboral, económica, familiar, conyugal, independencia, función cognitiva, energía, efectos secundarios de la diálisis y calidad de vida en general). se siguió los lineamientos de la Organización Mundial de la Salud para el diseño de las escalas de calidad de vida, así como otros parámetros de otras escalas utilizadas internacionalmente para otras enfermedades. RESULTADOS. Se encontró que la IRC impacta todos los aspectos evaluados, especialmente en las áreas social (83), laboral (77), económica y cognitiva (75 cada una) y emocional (73). eL 30.2 calificó su calidad de vida en el último mes como mala, el 41.5 la calificó como regular, el 26.4 de buena y el 1.9 como muy buena. La vida familiar se afecta importantemente en varios aspectos. CONCLUSION. Se encontro que el cuestionario fue comprensible e internamente consistente. La mayoría de los pacientes manifestó afectación en importantes áreas de su vida, por lo que se requiere un manejo integral del problema.

Aldosterona plasmática y urinaria: la actividad de la renina plasmática en sujetos normales / Aldosterone plasmatic and urinary: plasma renin activity in elderly normal subject

Con el objeto de estudiar las variaciones de los índices AP/ARP y AU/ARP en sujetos normales de edad avanzada, así como la influencia que ejercen sobre ellos la edad y la función renal, se seleccionaron 21 sujetos ancianos (79 ñ 9 años), nueve hombres y doce mujeres, y se compararon con 24 sujetos normales de menor edad (39 ñ 10 años), trece hombres y once mujeres, estudiados bajo las mismas condiciones. El hallazgo más importante que se encontró en este trabajo, fue una correlación inversa y estadísticamente muy significativa entre dichos índices y la función renal (p < 0,001), por lo que deducimos que en los ancianos la caída de la función renal debe ejercer alguna influencia sobre el incremento de los valores de estos índices. Los valores de la AP, relativamente más elevados, que presentan estos sujetos, podrían ser un mecanismo compensatorio para mantener la homeostasis del potasio en ancianos