Drug toxicity in the proximal tubule: new models, methods and mechanisms

Abstract

The proximal tubule (PT) reabsorbs most of the glomerular filtrate and plays an important role in the uptake, metabolism and excretion of xenobiotics. Some therapeutic drugs are harmful to the PT, and resulting nephrotoxicity is thought to be responsible for approximately 1 in 6 of cases of children hospitalized with acute kidney injury (AKI). Clinically, PT dysfunction leads to urinary wasting of important solutes normally reabsorbed by this nephron segment, leading to systemic complications such as bone demineralization and a clinical scenario known as the renal Fanconi syndrome (RFS). While PT defects can be diagnosed using a combination of blood and urine markers, including urinary excretion of low molecular weight proteins (LMWP), standardized definitions of what constitutes clinically significant toxicity are lacking, and identifying which patients will go on to develop progressive loss of kidney function remains a major challenge. In addition, much of our understanding of cellular mechanisms of drug toxicity is still limited, partly due to the constraints of available cell and animal models. However, advances in new and more sophisticated in vitro models of the PT, along with the application of high-content analytical methods that can provide readouts more relevant to the clinical manifestations of nephrotoxicity, are beginning to extend our knowledge. Such technical progress should help in discovering new biomarkers that can better detect nephrotoxicity earlier and predict its long-term consequences, and herald a new era of more personalized medicine.

Keywords: Drug toxicity; Fanconi syndrome; Proximal tubule.

Fig. 1

Drug transport in the proximal tubule. The reabsorption of filtered solutes (S) across the apical membrane of the proximal tubule (PT) is coupled to that of sodium (Na⁺), utilizing intracellular gradients generated by the basolateral Na⁺/K⁺-ATPase. Drugs are taken up from the blood via basolateral organic anion and cation transporters (OATs and OCTs, respectively) and excreted into the urine via apically expressed ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance proteins (MRPs) and human multidrug and toxin compound extrusion-1 (hMATE1). Receptor-mediated endocytosis provides an apical entry route for filtered drugs such as aminoglycosides. Some drugs passing through PT cells are toxic to mitochondria, and can disrupt the supply of ATP to the basolateral Na⁺/K⁺-ATPase, resulting in a breakdown in transport and wasting of solutes in the urine (renal Fanconi syndrome). DT distal tubule, CD collecting duct, G Glomerulus