RESUMEN
Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.
Asunto(s)
Biomarcadores Farmacológicos/orina , Moléculas de Adhesión Celular/orina , Pruebas de Función Renal/métodos , Riñón , Acetilglucosaminidasa/orina , Animales , Biomarcadores Farmacológicos/metabolismo , Nitrógeno de la Urea Sanguínea , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Cisplatino/toxicidad , Creatinina/sangre , Ciclosporina/toxicidad , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Gentamicinas/toxicidad , Histocitoquímica , Riñón/efectos de los fármacos , Riñón/lesiones , Pruebas de Función Renal/normas , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Curva ROC , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Daño por Reperfusión , Tioacetamida/toxicidadRESUMEN
Guidance for the use of biomarkers in pharmaceutical development and clinical trial optimization will reduce developmental cycle time. A 'fit-for-purpose' guidance for biomarker use is considered herein when the same biomarker is applied in very different contexts in drug development and after regulatory approval. Recent approved use of renal safety biomarkers in Good Laboratory Practice studies lacks sufficient guidance for the use of these markers across the drug development pipeline. In lead optimization, renal injury biomarkers are possible anchors for promising new prodromal metabolic biomarkers, which are applied before lead candidate selection. Renal injury biomarkers can now be evaluated as potential efficacy and pharmacodynamic biomarkers in clinical trial proof-of-concept studies for diabetic nephropathy.