Experimental model of nephropathy associated with diabetes mellitus in mice

Purpose: Nontransmissible chronic diseases, such as diabetes mellitus (DM) and nephropathy, affect a significant portion of the population, often treated due to injuries that require healing and regeneration. To create an experimental model of associated comorbidities, for healing and regeneration studies, protocols for induction of nephropathy by ischemia and reperfusion (I/R) and induction of DM by injection of streptozotocin (STZ) were associated. Methods: Sixty-four mice (Mus musculus), female, adult, Swiss strain, weighing approximately 20 g, were divided into four groups: G1: control (n = 24), G2: nephropathy group (N) (n = 7), G3, DM (n = 9), and G4: N+DM (n = 24). Arteriovenous stenosis (I/R) of the left kidney was performed as the first protocol. The animals received a hyperlipidemic diet for 7 days after the injection of STZ (150 mg/kg, via i.p.) and an aqueous glucose solution (10%) for 24 h. The animals in the G3 and G4 groups were observed for 14 days before receiving the diet and STZ. The evolution of nephropathy was observed using a urine test strip and the DM, through the analysis of blood glucose with a reagent strip on a digital monitor. Results: The ischemic induction protocols of nephropathy and DM with STZ, associated, were sustainable, low-cost, and without deaths. There were alterations compatible with initial renal alterations, in the first 14 days, such as increased urinary density, pH alteration, presence of glucose, proteins and leukocytes, when compared to the control group. DM was confirmed by the presence of hyperglycemia 7 days after induction and its evolution after 14 days. The animals in the G4 group showed constant weight loss when compared to the other groups. It was possible to observe morphological alterations in the kidneys submitted to I/R, regarding coloration, during surgery and after the end of the observation period, in the volume and size of the left kidney, when compared to the contralateral kidney. Conclusion: It was possible to induce nephropathy and DM associated in the same animal, in a simple way, confirmed with rapid tests, without losses, providing a basis for future studies.

Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus / Zinco-alfa2-glicoproteina (ZAG) como biomarcador precoce de nefropatia diabética em pacientes com diabetes mellitus tipo 2

Abstract Introduction: Although microalbuminuria remains the gold standard for early detection of diabetic nephropathy (DN), it is not a sufficiently accurate predictor of DN risk. Thus, new biomarkers that would help to predict DN risk earlier and possibly prevent the occurrence of end-stage kidney disease are being investigated. Objective: To investigate the role of zinc-alpha-2-glycoprotein (ZAG) as an early marker of DN in type 2 diabetic (T2DM) patients. Methods: 88 persons were included and classified into 4 groups: Control group (group I), composed of normal healthy volunteers, and three patient groups with type 2 diabetes mellitus divided into: normo-albuminuria group (group II), subdivided into normal eGFR subgroup and increased eGFR subgroup > 120 mL/min/1.73m2), microalbuminuria group (group III), and macroalbuminuria group (group IV). All subjects were submitted to urine analysis, blood glucose levels, HbA1c, liver function tests, serum creatinine, uric acid, lipid profile and calculation of eGFR, urinary albumin creatinine ratio (UACR), and measurement of urinary and serum ZAG. Results: The levels of serum and urine ZAG were higher in patients with T2DM compared to control subjects and a statistically significant difference among studied groups regarding serum and urinary ZAG was found. Urine ZAG levels were positively correlated with UACR. Both ZAG levels were negatively correlated with eGFR. Urine ZAG levels in the eGFR ˃ 120 mL/min/1.73m2 subgroup were higher than that in the normal eGFR subgroup. Conclusion: These findings suggest that urine and serum ZAG might be useful as early biomarkers for detection of DN in T2DM patients, detectable earlier than microalbuminuria.

Resumo Introdução: Embora a microalbuminúria continue sendo o padrão ouro para a detecção precoce da nefropatia diabética (ND), ela não é um preditor suficientemente preciso do risco de ND. Assim, novos biomarcadores para prever mais precocemente o risco de ND e possivelmente evitar a ocorrência de doença renal terminal estão sendo investigados. Objetivo: Investigar a zinco-alfa2-glicoproteína (ZAG) como marcador precoce de ND em pacientes com debates mellitus tipo 2 (DM2). Métodos: Os 88 indivíduos incluídos foram divididos em quatro grupos: grupo controle (Grupo I), composto por voluntários saudáveis normais; e três grupos de pacientes com DM2 assim divididos: grupo normoalbuminúria (Grupo II), subdivididos em TFG normal e TFG > 120 mL/min/1,73 m2), grupo microalbuminúria (Grupo III) e grupo macroalbuminúria (Grupo IV). Todos foram submetidos a urinálise e exames para determinar glicemia, HbA1c, função hepática, creatinina sérica, ácido úrico, perfil lipídico, cálculo da TFG, relação albumina/creatinina (RAC) e dosagem urinária e sérica de ZAG. Resultados: Os níveis séricos e urinários de ZAG foram mais elevados nos pacientes com DM2 em comparação aos controles. Foi identificada diferença estatisticamente significativa entre os grupos estudados em relação aos níveis séricos e urinários de ZAG. Os níveis urinários de ZAG foram positivamente correlacionados com a RAC. Ambos os níveis de ZAG foram negativamente correlacionados com TFG. Os níveis urinários de ZAG no subgrupo com TFG ˃ 120 mL/min/1,73m2 foram maiores do que no subgrupo com TFG normal. Conclusão: Constatamos que a ZAG sérica e urinária pode ser um útil biomarcador precoce para detecção de ND em pacientes com DM2, sendo detectável mais precocemente que microalbuminúria.

Kidney Disease in Diabetes Mellitus: Cross-Linking between Hyperglycemia, Redox Imbalance and Inflammation / Doença Renal do Diabetes: Cross-Linking entre Hiperglicemia, Desequilíbrio Redox e Inflamação

Abstract Chronic hyperglycemia is the key point of macro- and microvascular complications associated with diabetes mellitus. Excess glucose is responsible for inducing redox imbalance and both systemic and intrarenal inflammation, playing a critical role in the pathogenesis of diabetic kidney disease, which is currently the leading cause of dialysis in the world. The pathogenesis of the disease is complex, multifactorial and not fully elucidated; many factors and mechanisms are involved in the development, progression and clinical outcomes of the disease. Despite the disparate mechanisms involved in renal damage related to diabetes mellitus, the metabolic mechanisms involving oxidative/inflammatory pathways are widely accepted. The is clear evidence that a chronic hyperglycemic state triggers oxidative stress and inflammation mediated by altered metabolic pathways in a self-perpetuating cycle, promoting progression of cell injury and of end-stage renal disease. The present study presents an update on metabolic pathways that involve redox imbalance and inflammation induced by chronic exposure to hyperglycemia in the pathogenesis of diabetic kidney disease.

Resumo A hiperglicemia crônica é o ponto-chave das complicações macro e microvasculares associadas ao diabetes mellitus. O excesso de glicose é responsável por induzir desequilíbrio redox e inflamação sistêmica e intra-renal, desempenhando um papel crítico na patogênese da doença renal do diabetes, configurada atualmente como a principal causa de doença renal dialítica em todo o mundo. A patogênese da doença é complexa, multifatorial e, não totalmente elucidada, estando vários fatores e mecanismos associados ao seu desenvolvimento, progressão e desfechos clínicos. Apesar dos mecanismos díspares envolvidos nos danos renais durante o diabetes, os caminhos metabólicos pela via oxidativa/inflamatória são amplamente aceitos e discutidos. As evidências acentuam que o estado hiperglicêmico crônico desencadeia o estresse oxidativo e a inflamação mediada por diversas vias metabólicas alteradas em um ciclo-vicioso de autoperpetuação, promovendo aumento da injúria celular e progressão para a doença renal dialítica. O presente artigo traz, portanto, uma atualização sobre os caminhos metabólicos que envolvem o desequilíbrio redox e a inflamação induzidos pela exposição crônica à hiperglicemia na patogênese da doença renal do diabetes.

Association of different biomarkers of renal function with D-dimer levels in patients with type 1 diabetes mellitus (renal biomarkers and D-dimer in diabetes)

ABSTRACT Objective This study aimed to evaluate the association between different renal biomarkers with D-Dimer levels in diabetes mellitus (DM1) patients group classified as: low D-Dimer levels (< 318 ng/mL), which included first and second D-Dimer tertiles, and high D-Dimer levels (≥ 318 ng/mL), which included third D-Dimer tertile. Materials and methods D-Dimer and cystatin C were measured by ELISA. Creatinine and urea were determined by enzymatic method. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Albuminuria was assessed by immunoturbidimetry. Presence of renal disease was evaluated using each renal biomarker: creatinine, urea, cystatin C, eGFR and albuminuria. Bivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels and odds ratio was calculated. After, multivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels (after adjusting for sex and age) and odds ratio was calculated. Results Cystatin C presented a better association [OR of 9.8 (3.8-25.5)] with high D-Dimer levels than albuminuria, creatinine, eGFR and urea [OR of 5.3 (2.2-12.9), 8.4 (2.5-25.4), 9.1 (2.6-31.4) and 3.5 (1.4-8.4), respectively] after adjusting for sex and age. All biomarkers showed a good association with D-Dimer levels, and consequently, with hypercoagulability status, and cystatin C showed the best association among them. Conclusion Therefore, cystatin C might be useful to detect patients with incipient diabetic kidney disease that present an increased risk of cardiovascular disease, contributing to an early adoption of reno and cardioprotective therapies.

Fisiopatología de la nefropatía diabética: una revisión de la literatura / Pathophysiology of diabetic nephropathy: a literature review

La enfermedad renal crónica es una complicación frecuente en la diabetes mellitus. Su importancia radica en la alta prevalencia y la proyección a futuro que ésta tiene. Se asocia a altos gastos en salud y además a deterioro cardiovascular global. La fisiopatología del desarrollo de esta enfermedad está siendo estudiada y se sabe que en ella participan una serie de vías moleculares complejas que determinan una enfermedad microvascular. En esta revisión se intenta abordar las vías conocidas en el desarrollo de nefropatía diabética, con el fin de comprender mejor posibles blancos terapéuticos que se podrían desarrollar.

Chronic kidney disease is a common complication of diabetes. Its importance lies in its high prevalence and future projection. It is associated with high health costs and global cardiovascular deterioration as well. The development of this disease pathophysiology is being studied and it is known that a series of complex molecular pathways determining a microvascular disease are involved. This review addresses the known pathways in the development of diabetic nephropathy aiming to improve the understanding of potential therapeutic targets that could be developed in the future.

Role of advanced glycation end products in the onset of diabetic kidney disease complications

Advanced glycation end products are known to play an important role in diabetes complications, such as diabetic nephropathy. Most known pathways of diabetic complications involve oxidative stress, that have pivotal role in cell dysfunction onset and progression of angiopathies. This review will explore how AGEs cause endothelial dysfunction in diabetes and what current biochemical mechanisms have been proposed as an explanation for the development of diabetic nephropathy (AU)

The Impact of Diabetes Mellitus on Vascular Biomarkers in Patients with End-Stage Renal Disease

PURPOSE: Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) and an important risk factor for cardiovascular (CV) disease. We investigated the impact of DM on subclinical CV damage by comprehensive screening protocol in ESRD patients. MATERIALS AND METHODS: Echocardiography, coronary computed tomography angiogram, 24-h ambulatory blood pressure monitoring, and central blood pressure with pulse wave velocity (PWV) were performed in 91 ESRD patients from the Cardiovascular and Metabolic disease Etiology Research Center-HIgh risk cohort. RESULTS: The DM group (n=38) had higher systolic blood pressure than the non-DM group (n=53), however, other clinical CV risk factors were not different between two groups. Central aortic systolic pressure (148.7±29.8 mm Hg vs. 133.7±27.0 mm Hg, p= 0.014), PWV (12.1±2.7 m/s vs. 9.4±2.1 m/s, p<0.001), and early mitral inflow to early mitral annulus velocity (16.7±6.4 vs. 13.7±5.9, p=0.026) were higher in the DM group. Although the prevalence of coronary artery disease (CAD) was not different between the DM and the non-DM group (95% vs. 84.4%, p=0.471), the severity of CAD was higher in the DM group (p=0.01). In multivariate regression analysis, DM was an independent determinant for central systolic pressure (p=0.011), PWV (p<0.001) and the prevalence of CAD (p=0.046). CONCLUSION: Diabetic ESRD patients have higher central systolic pressure and more advanced arteriosclerosis than the non-DM control group. These findings suggest that screening for subclinical CV damage may be helpful for diabetic ESRD patients.

Factores de progresión de disfunción renal en diabéticos ingresados en Medicina Interna / Renal disease´s progression factors in diabetic people admitted in Internal Medicine

Introducción: la nefropatía diabética es un factor de riesgo para desarrollar eventos cardiovasculares. Debido a que si su presencia se establece se reduce el filtrado glomerular y se acelera la aterosclerosis. Existen muchos factores de progresión que comprometen aun más sus aspectos fisiopatológicos y el pronóstico. Objetivo: caracterizar factores de progresión de disfunción renal en diabéticos ingresados en el Servicio de Medicina Interna, período 2012 a 2013. Materiales y Métodos: se realizó un estudio descriptivo, transversal y observacional en diabéticos ingresados en Servicio de Medicina Interna, Hospital Militar de Matanzas, con menos de diez años de evolución, en el período de 2012 a 2013; con consentimiento informado de pacientes y Jefe del Servicio. Se caracterizó la función renal para detectar precozmente factores de progresión de nefropatía diabética, en cada uno, en cuanto a filtrado glomerular y microalbuminuria. Para ello se revisaron historias clínicas. Las variables de afectación renal con factores de riesgo de progresión, tanto clínicos como paraclínicos fueron: edad, microalbuminuria, alteraciones del filtrado glomerular, hiperuricemia, dislipidemia, hiperglucemia, nivel de tensión arterial, sedentarismo, dieta y hábitos tóxicos. Usando la planilla de recolección de datos y la representación mediante tablas, números y por ciento. Resultados: la hipertrigliceridemia, hiperuricemia e hiperglucemia constituyeron los más asociados a descenso del filtrado glomerular y microalbuminuria positiva con 94,44 %, 80,33 % y 48,24 % respectivamente; en tan solo diez años de evolución de la diabetes. Conclusiones: evidente presencia de factores de progresión de enfermedad renal crónica en pacientes diabéticos.

Introduction: Diabetic Nephropathy is a very important risk factor for the development of cardiovascular disorders. It´s related with glomerular filtrate reduction and atherosclerosis. Then also many renal disease´s progression factors affect their physiophatological aspects and the prognosis. Objective: To caracterize renal disease´s progression factors in diabetic people admitted in Internal Medicine period of 2012 to2013. Materials and Methods: A retrospective descriptive longitudinal study was carried out. The sample was formed by 496 patients entered in the Internal Medicine Service, Military Hospital of Matanzas, and they haved less than ten years of evolution of their illness, in the understood period of 2012 at 2013. The used variables of chronic renal disease´s progression factors were: age, microalbuminuria, glomerular filtrate, toxic habits, diet, sedentarism, blood pressure level, serum uric acid and lipid levels. For organizing the obtained indicators authors applied the descriptive statistic method, analyzing the information through distribution tables. The results were represented in numbers and percent. Results: The most associated renal disease´s progression factors were hypertrygliceridemia, hyperuricemia and hyperglucemia. They respectively showed about 94,44 %, 80,33 % and 48,24 %. They were also associated with the worst affectation on glomerular filtrate and microalbuminuria in less than ten years old of diabetes evolution. Conclusions: there is a high presence of chronic renal disease´s progression factors in diabetic people.

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

ABSTRACT Objective The objective of this study was to evaluate the role of oxidative stress in an experimental model of streptozotocin-induced diabetic nephropathy in rats. Materials and methods Wistar, adult, male rats were used in the study. Animals were divided in the following groups: Citrate (control, citrate buffer 0.01M, pH 4.2 was administrated intravenously - i.v - in the caudal vein), Uninephrectomy+Citrate (left uninephrectomy-20 days before the study), DM (streptozotocin, 65 mg/kg, i.v, on the 20th day of the study), Uninephrectomy+DM. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight, and relative kidney weight); renal function (creatinine clearance), urine albumin (immunodiffusion method); oxidative metabolites (urinary peroxides, thiobarbituric acid reactive substances, and thiols in renal tissue), and kidney histology were evaluated. Results Polyphagia, polydipsia, hyperglycemia, and reduced body weight were observed in diabetic rats. Renal function was reduced in diabetic groups (creatinine clearance, p < 0.05). Uninephrectomy potentiated urine albumin and increased kidney weight and relative kidney weight in diabetic animals (p < 0.05). Urinary peroxides and thiobarbituric acid reactive substances were increased, and the reduction in thiol levels demonstrated endogenous substrate consumption in diabetic groups (p < 0.05). The histological analysis revealed moderate lesions of diabetic nephropathy. Conclusion This study confirms lipid peroxidation and intense consumption of the antioxidant defense system in diabetic rats. The association of hyperglycemia and uninephrectomy resulted in additional renal injury, demonstrating that the model is adequate for the study of diabetic nephropathy.

Evaluation of biochemical and clinical markers of endothelial dysfunction and their correlation with urinary albumin excretion in patients with type 1 diabetes mellitus

ABSTRACT Objective Endothelial dysfunction (ED) plays an important role in the pathogenesis of diabetic nephropathy. The purpose of the study was to determine flow mediated endothelial dependent vasodilatation (FMD) measurements and serum soluble (s) endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) levels in patients with type 1 diabetes mellitus (T1DM) with or without increased urinary albumin excretion (UAE) and compare them with the healthy controls. Subjects and methods Seventy three patients with T1DM were enrolled. Patients were divided into two subgroups according to microalbumin measurements in 24-hr urine collections. The diabetic patients without microalbuminuria (41 patients) were defined as Group I and those with microalbuminuria (32 patients) were defined as group II. A hundred age and sex matched healthy subjects participated as the control group (Group III). Serum sET-1, sICAM-1, sVCAM-1 levels and FMD measurements were determined in all participants. Results Median FMD measurement was significantly lower in the diabetic groups compared with the control group (6.6, 6.4 and 7.8% in Group I, II and III, respectively) (p < 0.05). FMD was negatively correlated with age (p = 0.042). Median serum sICAM-1 level was higher in the patient groups compared to the control group (p < 0.05). Median serum sVCAM-1 level was higher in the group of patients with increased albuminuria compared to the normoalbuinuric and the control group (p < 0.05). Serum sVCAM-1 level was found to be positively correlated with degree of urinary albumin excretion (p < 0.001). Conclusion We assume that sVCAM-1 may be used as a predictive marker for risk stratification for nephropathy development and progression.

Effect of maternal diabetes on female offspring / Efeito do diabetes materno na prole feminina

Objective To evaluate the effect of maternal diabetes on the blood pressure and kidney function of female offspring, as well as if such changes exacerbate during pregnancy. Methods Diabetes mellitus was induced in female rats with the administration of streptozotocin in a single dose, one week before mating. During pregnancy, blood pressure was measured through plethysmography. On the 20th day of pregnancy, the animals were placed for 24 hours in metabolic cages to obtain urine samples. After the animals were removed from the cages, blood samples were withdrawn. One month after pregnancy, new blood and urine sample were collected. Kidney function was evaluated through proteinuria, plasma urea, plasma creatinine, creatinine excretion rate, urinary flow, and creatinine clearance. Results The female offspring from diabetic mothers showed an increase in blood pressure, and a decrease in glomerular filtration rate in relation to the control group. Conclusion Hyperglycemia during pregnancy was capable of causing an increase in blood pressure and kidney dysfunction in the female offspring. .

Objetivo Avaliar o efeito do diabetes materno sobre a pressão arterial e a função renal da prole feminina, bem como verificar se as alterações observadas se exacerbam durante a prenhez. Métodos O diabetes mellitus foi induzido em ratas com a administração de estreptozocina em dose única, uma semana antes do cruzamento. Durante a prenhez, foram feitas medidas da pressão arterial por pletismografia. No 20o dia da prenhez, os animais foram colocados durante 24 horas em gaiolas metabólicas para obtenção de amostras de urina. Após a retirada dos animais das gaiolas, foram obtidas amostras de sangue. Um mês após a prenhez, foram obtidas novas amostras de sangue e urina para as determinações. A função renal foi avaliada por meio de proteinúria, ureia plasmática, creatinina plasmática, carga excretada de creatinina, fluxo urinário e clearance de creatinina. Resultados As fêmeas da prole de mães diabéticas apresentaram elevação da pressão arterial e redução do ritmo de filtração glomerular em relação ao grupo controle. Conclusão A hiperglicemia durante a gestação foi capaz de causar elevação da pressão arterial e disfunção renal na prole de sexo feminino. .

Comparación entre las fórmulas Cockcroft-Gault y MDRD para estimar velocidad de filtración glomerular en diabéticos / Comparison between Cockcroft-Gault and MDRD formulas to estimated glomerular filtration rate in diabetic people

INTRODUCCIÓN: La nefropatía diabética es una complicación relevante de la Diabetes Mellitus. Por esto, la American Diabetes Association (ADA) recomienda la determinación de la velocidad de filtración glomerular (VFG) como screening de nefropatía. Existe una fórmula, la MDRD (Modification of Diet in Renal Disease), que permite hacer una estimación bastante exacta dela VFG. La utilización de ésta ha sido comparada permanentemente con la Cockcroft-Gault. OBJETIVO: comparar ambas fórmulas para la VFG en la realidad local. MATERIAL Y MÉTODO: se realizó un estudio retrospectivo sobre 243 pacientes, seleccionados al azar, de un total de 1.057 pacientes diabéticos tipo 2 registrados en el Plan de Salud Cardiovascular en el CESFAM San Rafael de la comuna La Pintana que contaban con medición seriada de Creatinina plasmática en sus controles periódicos. Se consideraron los valores de creatinina plasmática más recientes tomados en el período Enero 2010-Octubre 2011 y obtuvimos la VFG aplicando ambas fórmulas. RESULTADOS: del total de pacientes seleccionados, 158 fueron mujeres (65 por ciento) y 85 hombres (35 por ciento), con una media de edad de 53 años (DE 8,08). La VFG media estimada con MDRD fue de 89 ml/min/1,73 m2 (DE 21) y con la Cockcroft-Gault fue de 108 ml/min (DE 32), p<0,001. Realizamos un estudio de correlación entre ambas fórmulas. DISCUSIÓN: ambas mostraron correlación aceptable para estimar la VFG, aunque en pacientes obesos las estimaciones de VFG fueron más elevadas con Cockcroft-Gault que con MDRD. Por otro lado, en pacientes añosos la tendencia fue a que la fórmula MDRD diera estimaciones más altas.

INTRODUCTION: Diabetic Nephropathy is a significant complication of Diabetes Mellitus. That’s why, the American Diabetes Association (ADA) recommended for screening the determination of the glomerular filtration rate (GFR). MDRD (Modification of Diet in Renal Disease), is a formula which allows a very exactly estimation of GFR. Permanently, it had always been compared with Cockcroft-Gault formula. OBJECTIVE: Compare both formulas in the local reality. MATERIAL AND METHOD: It was done a retrospective studio over 243 patients, randomly selected, of a total of 1,057 type 2 diabetes patients registered in Cardiovascular program of San Rafael CESFAM that had serial measurement of plasmatic creatinine in their periodic controls. It was considered the most recent values of plasmatic creatinine taken between January 2010 – October 2011. RESULTS: Of the patients selected, 158 women (65 percent) and 85 men (35 percent), with average age of 53 years (SD 8,08), the GFR estimated with MDRD was of 89 ml/min/1.73 m2 (SD 21) and 108 ml/min (SD 32) for Cockcroft-Gault formula, p<0.001. We realized a correlation studio between both formulas. DISCUSSION: Both formulas demonstrated an acceptable correlation to estimated GFR, although obese patients had higher estimations with Cockcroft-Gault formula, on the other side, elderly patients had elevated results with MDRD.

Efeito do exercício resistido intradialítico em pacientes renais crônicos em hemodiálise / Effect of resistance exercise intradialytic in renal patients chronic in hemodialysis

INTRODUÇÃO: Pacientes com doença renal crônica (DRC) quando submetidos ao exercício resistido (ER) apresentam substancial melhorias de muitas funções, em especial os relacionados ao sistema cardiovascular, respiratório, muscular e na qualidade de vida (QV). Não existem avaliações do impacto de exercício simples e factíveis em pacientes com DRC associada ao Diabetes Mellitus (DM) durante o período intradialítico. OBJETIVO: Estudar o papel do exercício resistido no tratamento e na qualidade de vida em pacientes submetidos à hemodiálise crônica (HD). Assim, submetemos pacientes com DRC e DM ao ER durante a hemodiálise. MÉTODOS: Quinze pacientes em cada grupo: 1: DM com DRC submetidos ao ER; 2: DM com DRC sedentários; 3: DRC e ER e, 4: DRC sedentários. Avaliações durante oito semanas, com ER três vezes na semana. Avaliação laboratorial, teste de força muscular (FM) e QV (SF-36). RESULTADOS: O ER induziu melhoria na glicemia e na FM com discretas, mas significantes alterações na uréia e, K (p < 0,0001). Foi de impacto a melhoria na avaliação dos parâmetros de QV (p < 0,001) com o ER, como a Capacidade Funcional, o Aspecto Físico, redução das Dores (de uma maneira geral), Saúde Geral, Vitalidade, a Função Social, Estado Emocional e na Saúde Mental. Conclusão: O programa de ER (simples e factível) no período intradialítico alterou parâmetros clínicos, na FM e uma significante melhoria na avaliação da QV. O impacto na QV foi importante para o paciente, inclusive envolvendo melhoria em nível familiar e de relacionamento social quando submetidos ao ER.

INTRODUCTION: Patients with chronic kidney disease (CKD) when subjected to resistance exercise (RE) show substantial improvements in many functions, especially those related to the cardiovascular system, respiratory, muscular and quality of life (QOL). There are no evaluations of the impact of exercise simple and feasible in patients with CKD associated with Diabetes Mellitus (DM) during the intradialytic period. Thus, patients with CKD and submit to the DM + RE during hemodialysis. OBJECTIVE: To study the role of resistance exercise in the treatment and quality of life in patients undergoing chronic hemodialysis (HD). METHODS: 15 patients in each group: 1: DM with CKD and RE; 2: DM + CKD sedentary; 3: CKD + RE and 4: DRC sedentary. They were evaluated during eight weeks, with RE three times a week. Parameters: Laboratory assessments, muscle strength testing (FM) and QV (SF-36). RESULTS: RE induced improvement in glucose and FM with subtle but significant changes in urea, or even in the K (p < 0.0001). It was an improvement in the impact assessment of QOL parameters (p < 0.001) with the RE, such as Functional Capacity, Physical Aspect, Reduction of Pain (in general), General Health, Vitality, Social Function, Emotional State and Mental Health. CONCLUSION: The RE program (simple and feasible) during intradialytic clinical parameters changed FM and a significant improvement in QOL assessment were observed. The impact on QOL was important for the patient, including those involving improvement in level of family and social relationships when subjected to RE.

Nephropathy following Type 2 diabetes mellitus in Tunisian population / Nefropatía tras la diabetes mellitus tipo 2 en la población Tunesina

OBJECTIVE: The purpose was to compare the characteristics of Tunisians with Type 2 diabetes mellitus (Type 2 DM) and nephropathy with those without nephropathy. This study assessed whether or not phenotypic characteristics can predict nephropathy development in Type 2 DM. The prevalence of nephropathy in Tunisian Type 2 DM patients, and their relationship with clinical and biochemical factors as well as chronic complications of the disease were determined. METHODS: This was a cross-sectional study of patients with diabetes diagnosed between January 2008 and December 2010. Altogether, 73 Type 2 DM and 42 healthy volunteers from the Basic Health Group of Sousse, were targeted for the study. Clinical, biochemical data, as well as complications of diabetes were collected. Kidney malfunction was defined by glomerular filtration rate (GFR). RESULTS: Diabetic patients were older. Diabetic women were more likely to have higher body mass index than men (p = 0.004). Obesity was more in women than men (60/23%). Complications including hypertension and dyslipidaemia were co-associated in women. Urinary creatinine clearance in Type 2 DM patients without nephropathy was significantly lower than in healthy participants (p < 0.0001). Microalbuminuria and urinary creatinine clearance were associated only in women with Type 2 DM with nephropathy (R² = 0.95); 1.5% of Type 2 DM patients without nephropathy had GFR < 60 mL/min/1.73m² and 76% had a GFR between 60 and 89 mL/min/1.73m². Glomerular filtration rate difference between Type 2 DM patients with/without nephropathy, as well as between Type 2 DM patients with nephropathy/Type 2 DM without nephropathy, and with retinopathy was not significant. CONCLUSIONS: By analysing factors associated with nephropathy in Type 2 DM Tunisian patients, this study demonstrated their susceptibility to nephropathy. In addition, retinopathy is potentially associated with incipient nephropathy in Type 2 DM Tunisian patients.

OBJETIVO: El propósito fue comparar las características de los tunesinos con diabetes mellitus tipo 2 (DMT2) y nefropatía, con aquéllos que no padecen nefropatía. Este estudio evaluó la posibilidad de saber si las características fenotípicas pueden predecir el desarrollo de una nefropatía en pacientes de DMT2. Se determinó la prevalencia de la nefropatía en los pacientes tunesinos con DMT2, y su relación con factores clínicos y bioquímicos, así como las complicaciones crónicas de la enfermedad. MÉTODOS: Se realizó un estudio transversal de pacientes con diabetes diagnosticada entre enero de 2008 y diciembre de 2010. En total, 73 voluntarios con DMT2 y 42 saludables del Grupo Básico de Salud de Sousse, fueron escogidos para el estudio. Se recogieron los datos clínicos y bioquímicos, así como las complicaciones por diabetes. El grado de mal funcionamiento renal fue determinado por la tasa de filtrado glomerular (GFR). RESULTADOS: Los pacientes diabéticos tenían más edad. Las mujeres diabéticas presentaban una mayor probabilidad de tener un índice de masa corporal más alto que los hombres (p = 0.004). Hubo mayor obesidad en las mujeres que en los hombres (60/23%). Las complicaciones - incluyendo hipertensión y dislipidemia - estuvieron co-asociadas en las mujeres. La depuración de la creatinina urinaria en los pacientes de DMT2 sin nefropatía fue significativamente más baja (p < 0.0001) que en los participantes saludables. La microalbuminuria y la depuración de la creatinina urinaria estuvieron asociadas en las mujeres con DMT2 con nefropatía (R² = 0.95); 1.5% de los pacientes con DMT2 sin nefropatía, tuvo una tasa GFR < 60 mL/min/1.73m² y 76% tuvo una GFR entre 60 y 89 mL/min/1.73m². La diferencia de la tasa de filtrado glomerular entre los pacientes de DMT2 con/sin nefropatía, así como entre los pacientes de DMT2 con nefropatía/DMT2 sin nefropatía, y con retinopatía, no fue significativa. CONCLUSIONES: Analizando factores asociados con la nefropatía en pacientes tunesinos con DMT2, este estudio demostró que estos últimos son susceptibles a la nefropatía. Además, la retinopatía se halla potencialmente asociada con la nefropatía incipiente en los pacientes tunesinos que padecen DMT2.

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN), a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs). The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

Complicações microvasculares e disfunção autonômica cardíaca em pacientes com diabete melito tipo 1 / Microvascular complications and cardiac autonomic dysfunction in patients with diabetes mellitus type 1 / Complicaciones microvasculares y disfunción autonómica cardíaca en pacientes con diabetes mellittus tipo 1

FUNDAMENTO: A presença de neuropatia autonômica cardíaca (NAC) em pacientes com diabete melito (DM) está associada a aumento da mortalidade e a complicações crônicas microvasculares do diabete. OBJETIVO: Investigar uma possível associação entre achados sugestivos de NAC durante a realização do teste ergométrico (TE) e nefropatia e retinopatia em pacientes com DM tipo 1. MÉTODOS: Realizamos um estudo transversal com 84 pacientes com DM tipo 1. Todos os pacientes foram submetidos à avaliação clínica e laboratorial e realizaram TE, sendo que aqueles que apresentaram achados sugestivos de isquemia miocárdica foram excluídos da análise dos dados (n = 3). A avaliação de complicações microvasculares (retinopatia e nefropatia) foi realizada na amostra. RESULTADOS: Os pacientes com nefropatia e aqueles com retinopatia atingiram uma frequência cardíaca (FC) durante o pico de exercício (FC máxima) menor e apresentaram aumento menor da FC em relação ao repouso (ΔFC pico) quando comparados com aqueles sem estas complicações. Esses pacientes também apresentaram menor redução da FC no segundo e 4º minutos após o final do teste (ΔFC recuperação dois e 4 minutos). Após realização de análise multivariada com controle para os possíveis fatores de confusão, os ΔFC recuperação em dois e 4 minutos, FC máxima e o ΔFC pico permaneceram significativamente associados à retinopatia; e os ΔFC recuperação no segundo e 4º minutos permaneceram associados à presença de nefropatia. CONCLUSÃO: O TE pode ser considerado um instrumento adicional para a detecção precoce de NAC e para identificar pacientes em maior risco para complicações microvasculares do diabete.

BACKGROUND: The presence of cardiac autonomic neuropathy (CAN) in patients with diabetes mellitus (DM) is associated with increased mortality and chronic microvascular complications of diabetes. OBJECTIVE: To investigate a possible association between specific findings of CAN during exercise testing (ET) and nephropathy and retinopathy in patients with type 1 DM. METHODS: We conducted a cross-sectional study of 84 patients with type 1 DM. All patients underwent clinical laboratory evaluation and performed ET, and those who presented findings suggesting myocardial ischemia were excluded from data analysis (n = 3). The assessment of microvascular complications (retinopathy and nephropathy) was performed in the sample. RESULTS: Patients with nephropathy and those with retinopathy achieved a lower heart rate (HR) at peak exercise (HR max) and smaller increase in HR in relation to rest (Peak ΔHR) compared with those without these complications. These patients also had a smaller reduction in HR in the second and 4th minutes after the end of the test (ΔHR recovery 2 and 4 minutes). After performing a multivariate analysis with control for possible confounding factors, the ΔHR recovery in two and four minutes, maximum HR and Peak ΔHR remained significantly associated with retinopathy; and ΔHR recovery in the second and 4th minutes remained associated with the presence of nephropathy. CONCLUSION: The ET can be considered an additional tool for early detection of CAN and to identify patients at increased risk for microvascular complications of diabetes.

BACKGROUND: LA presencia de neuropatía autonómica cardíaca (NAC) en pacientes con diabetes mellittus (DM) está asociada a aumento de la mortalidad y a complicaciones crónicas microvasculares de diabetes. OBJECTIVE: Investigar una posible asociación entre hallazgos sugestivos de NAC durante la realización de la prueba ergométrica (PE) y nefropatía y retinopatía en pacientes con DM tipo 1. METHODS: Realizamos un estudio transversal con 84 pacientes con DM tipo 1. Todos los pacientes fueron sometidos a evaluación clínica y laboratorial y llevaron a cabo PE, siendo que aquellos que presentaron hallazgos sugestivos de isquemia miocárdica fueron excluidos del análisis de los datos (n = 3). La evaluación de complicaciones microvasculares (retinopatía y nefropatía) se realizó en la muestra. RESULTS: Los pacientes con nefropatía y aquellos con retinopatía alcanzaron una frecuencia cardíaca (FC) durante el nivel máximo de ejercicio (FC máxima) menor y presentaron aumento menor de FC con relación al reposo (ΔFC pico) cuando comparados con aquellos sin estas complicaciones. Estos pacientes también presentaron una menor reducción de la FC en el segundo y 4º minutos tras el final de la prueba (ΔFC recuperación 2 y 4 minutos). Tras la realización de análisis multivariado con control para los posibles factores de confusión, los ΔFC recuperación en dos y 4 minutos, FC máxima y el ΔFC pico permanecieron significativamente asociados a la retinopatía; y los ΔFC recuperación en el segundo y 4º minutos permanecieron asociados a la presencia de nefropatía. CONCLUSION: Se puede considerar la PE como un instrumento adicional para la detección precoz de NAC y para identificar pacientes en un mayor riesgo para complicaciones microvasculares de la diabetes.

Factors affecting the progression of diabetic nephropathy and its complications: a single-center experience in Saudi Arabia

One out of five Saudi diabetics develops end-stage renal disease [ESRD]. Factors associated with progressive loss of renal function have not been extensively studied and reported in our community. We sought to evaluate the pattern and progression in glomerular filtration rate [GFR] and investigate the potential risk factors associated with progression to diabetic nephropathy [DN] among Saudi patients. Hospital-based retrospective analysis of type 2 diabetic patients seen between January 1989 and January 2004 at Security Forces Hospital and King Saud University in Riyadh, Saudi Arabia. DN was defined as persistent proteinuria assessed by urine dipstick [at least twice for at least two consecutive years and/or serum creatinine >130 micromol/L; and/or GFR <60 mL/min/1.73m[2]. Of 1952 files reviewed, 621 [31.8%] met the criteria for DN, and 294 [47%] were males. The mean [SD] age of the patients at baseline was 66.9 [11.4] years, and mean duration of diabetes was 15.4 [7.5] years. GFR deteriorated from a baseline value of 78.3 [30.3] mL/min/1.73m[2] to 45.1 [24.1] mL/min/1.73m[2] at the last visit, with a mean rate of decline in GFR of 3.3 mL/min/year. Progression of nephropathy was observed in 455 [73.3%] patients, with 250 [40.3%] patients doubling their first-hospital-visit serum creatinine level in a mean of 10.0 [6.0] years. At the end of the study, 1 6.5% of the cohort developed ESRD and were dialyzed. GFR >90 mL/min/1.73m[2] at the first hospital visit; duration of diabetes >10 years; persistent proteinuria; systolic blood pressure >130 mm Hg; and presence of retinopathy were significant markers associated with progression of nephropathy. Diabetic nephropathy tends to be progressive among Saudis, with GFR deteriorating at a rate of 3.3 mL/year and with a doubling of serum creatinine level in 40.3% of patients in 9.9 years