Acute kidney injury (AKI) poses an increased risk factor for new AKI episodes, progression to chronic kidney disease, and death. A worsened evolution has been linked to an incomplete renal repair beyond the apparent functional recovery based on plasma creatinine (pCr) normalization. However, structural sequelae pass largely unnoticed due to the absence of specific diagnostic tools. The urinary kidney injury molecule 1 (KIM-1) participates in renal tissue damage and repair and is proposed as a biomarker of early and subclinical AKI. Thus, we study in this paper the evolution of KIM-1 urinary excretion alongside renal tissue sequelae after an intrinsic AKI episode induced by cisplatin in Wistar rats. Creatinine clearance, pCr, proteinuria and the fractional excretion of Na+ and glucose were used to monitor renal function. Renal tissue damage was blindly scored in kidney specimens stained with hematoxylin-eosin and periodic acid-Schiff. KIM-1 urinary excretion and renal mRNA expression were also assessed. Finally, we analyzed urinary KIM-1 in patients apparently recovered from AKI. Our results show that, after the normalization of the standard markers of glomerular filtration and tubular function, the extent of persistent histological findings of tissue repair correlates with the renal expression and urinary level of KIM-1 in rats. In addition, KIM-1 is also elevated in the urine of a significant fraction of patients apparently recovered from an AKI. Besides its potential utility in the early and subclinical diagnosis of renal damage, this study suggests a new application of urinary KIM-1 in the non-invasive follow-up of renal repair after AKI.
Acute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.
Acute Kidney Injury/urine , Insulin-Like Growth Factor Binding Proteins/urine , Tissue Inhibitor of Metalloproteinase-2/urine , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Animals , Antineoplastic Agents/toxicity , Biomarkers/urine , Cisplatin/toxicity , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Male , Rats , Rats, Wistar
Simultaneous administration of certain antihypertensive (renin-angiotensin system inhibitors and diuretics) and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a renal toxicity syndrome known as "triple whammy" acute kidney injury (TW-AKI), yet poorly characterized at the pathophysiological level, as no specific experimental model exists on which to conduct preclinical research. Herein, we generated and characterized a rat model of TW-AKI (0.7 mg/kg/day trandolapril +400 mg/kg/day ibuprofen +20 mg/kg/day furosemide). Double treatments involving the NSAID caused a subclinical acute kidney injury, as they reduced glomerular filtration rate to a significant but not sufficient extent to increase Crpl concentration. Only the triple treatment generated an overt AKI with increased Crpl provided that animals were under partial water ingestion restriction. Histological examination revealed no evidence of tissue renal injury, and no proteinuria or makers of renal damage were detected in the urine. These findings, along with a normal fractional excretion of sodium and glucose, indicated that these drug combinations produce a prerenal type of AKI. In fact, blood pressure and renal blood flow were also reduced (most markedly following the triple combination), although renal dysfunction was more pronounced than expected for the corresponding pressure drop, supporting a key pathological role of the interference with renal autoregulation mechanisms. In summary, prerenal TW-AKI only occurs when volemia is challenged (i.e., by furosemide in partially water-deprived animals) under the effects of renin-angiotensin system inhibitors and NSAIDs. This model will facilitate further pathophysiological knowledge for a better diagnosis and clinical handling of this syndrome.
Acute Kidney Injury/chemically induced , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Disease Models, Animal , Diuretics/adverse effects , Animals , Blood Pressure/drug effects , Drug Therapy, Combination/adverse effects , Furosemide/adverse effects , Ibuprofen/adverse effects , Indoles/adverse effects , Male , Rats, Wistar , Renal Circulation/drug effects
Introducción: La enfermedad cardiovascular constituye una comorbilidad importante y a la vez, la primera causa de muerte en los pacientes con enfermedad renal crónica. Objetivo: Describir la asociación entre los factores de riesgo y la enfermedad cardiovascular en pacientes en plan continuo de hemodiálisis. Método: Estudio descriptivo, longitudinal y retrospectivo con 49 pacientes que participaron en el plan continuo de hemodiálisis del Hospital Calixto García en el 2012. Para la asociación de las variables se utilizó el índice de probabilidades (odds ratio), con su intervalo de confianza y la prueba exacta de Fisher. Resultados: El 83,7 por ciento de los pacientes fueron hipertensos y el 71,4 por ciento tuvo hipertrofia del ventrículo izquierdo. La edad avanzada fue el factor de riesgo que más se asoció con dicha hipertrofia [OR=4,35 (IC=1,03-18,37); p=0.036]. Los factores de riesgo que se asociaron con la disfunción diastólica, fueron la hipertensión arterial [OR=9,88 (IC=1,11-87,90); p=0.021], la diabetes mellitus [OR=12,94 (IC=1,49-112,44); p=0.006] y la hipoalbuminemia [OR=4,67 (IC=1,09-19,90); p=0.030]. Ningún factor de riesgo se asoció con la valvulopatía mitral. Conclusiones: El antecedente patológico más prevalente fue la hipertensión arterial y la mayor parte de la población tenía hipertrofia del ventrículo izquierdo, que se asoció con la edad avanzada; de la misma forma, la hipertensión arterial, la diabetes mellitus y la hipoalbuminemia se asociaron con la disfunción diastólica. No se encontró asociación estadística entre la valvulopatía mitral y ninguno de los factores de riesgo analizados(AU)
Humans , Kidney Failure, Chronic/epidemiology , Cardiovascular Diseases/epidemiology , Risk Factors , Renal Dialysis , Comorbidity , Epidemiology, Descriptive , Longitudinal Studies , Retrospective Studies
