Tubular toxicity of proteinuria and the progression of chronic kidney disease.

Proteinuria is a well-established biomarker of chronic kidney disease (CKD) and a risk predictor of associated disease outcomes. Proteinuria is also a driver of CKD progression toward end-stage kidney disease. Toxic effects of filtered proteins on proximal tubular epithelial cells enhance tubular atrophy and interstitial fibrosis. The extent of protein toxicity and the underlying molecular mechanisms responsible for tubular injury during proteinuria remain unclear. Nevertheless, albumin elicits its toxic effects when degraded and reabsorbed by proximal tubular epithelial cells. Overall, healthy kidneys excrete over 1000 individual proteins, which may be potentially harmful to proximal tubular epithelial cells when filtered and/or reabsorbed in excess. Proteinuria can cause kidney damage, inflammation and fibrosis by increasing reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. Here we summarize toxic proteins reported in proteinuria and the current understanding of molecular mechanisms of toxicity of proteins on proximal tubular epithelial cells leading to CKD progression.

Nephrotoxicity of iopamidol is associated with mitochondrial impairment in human cell and teleost models.

Iopamidol is a nonionic, low-osmolar iodinated contrast agent used for angiography. Its clinical use is associated with renal dysfunction. Patients suffering from preexisting kidney disease have an increased risk of renal failure upon iopamidol administration. Studies in animals confirmed renal toxicity, but the involved mechanisms remain unclear. Therefore, the aim of the present study was to use human embryonic kidney cells (HEK293T) as a general cell model of mitochondrial damage, as well as, zebrafish larvae, and isolated proximal tubules of killifish to investigate factors promoting renal tubular toxicity of iopamidol with a focus on mitochondrial damage. Results from in vitro HEK293T cell-based assays indicate that iopamidol affects mitochondrial function Treatment with iopamidol induces ATP depletion, reduces the mitochondrial membrane potential, and elevates mitochondrial superoxide and reactive oxygen species accumulation. Similar results were obtained with gentamicin sulfate and cadmium chloride, two well-known model compounds associated with renal tubular toxicity. Confocal microscopy confirms changes in mitochondrial morphology, such as mitochondrial fission. Importantly, these results were confirmed in proximal renal tubular epithelial cells using ex vivo and in vivo teleost models. In conclusion, this study provides evidence for iopamidol-induced mitochondrial damage in proximal renal epithelial cells. Teleost models allow studying proximal tubular toxicity with translational relevance for humans.

Cisplatin Nephrotoxicity: Novel Insights Into Mechanisms and Preventative Strategies.

Cisplatin is a highly effective chemotherapeutic agent that has been used for more than 50 years for a variety of cancers; however, its use is limited by toxicity, including nephrotoxicity. In this in-depth review, we discuss the incidence of cisplatin-associated acute kidney injury, as well as common risk factors for its development. Cisplatin accumulates in the kidney tubules and causes AKI through various mechanisms, including DNA damage, oxidative stress, and apoptosis. We also discuss the spectrum of nephrotoxicity, including acute and chronic impairment of kidney function, electrolyte disturbances, and thrombotic microangiopathy. We discuss the limited options for the diagnosis, prevention, and management of these complications, along with factors that may impact future therapy with or without cisplatin. We conclude with directions for future research in this expanding and important area.

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury.

Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI.

Late renal toxicity of treatment for childhood malignancy: risk factors, long-term outcomes, and surveillance.

Chronic glomerular and tubular nephrotoxicity is reported in 20-50% and 20-25%, respectively, of children and adolescents treated with ifosfamide and 60-80% and 10-30%, respectively, of those given cisplatin. Up to 20% of children display evidence of chronic glomerular damage after unilateral nephrectomy for a renal tumour. Overall, childhood cancer survivors have a ninefold higher risk of developing renal failure compared with their siblings. Such chronic nephrotoxicity may have multiple causes, including chemotherapy, radiotherapy exposure to kidneys, renal surgery, supportive care drugs and tumour-related factors. These cause a wide range of chronic glomerular and tubular toxicities, often with potentially severe clinical sequelae. Many risk factors for developing nephrotoxicity, mostly patient and treatment related, have been described, but we remain unable to predict all episodes of renal damage. This implies that other factors may be involved, such as genetic polymorphisms influencing drug metabolism. Although our knowledge of the long-term outcomes of chronic nephrotoxicity is increasing, there is still much to learn, including how we can optimally predict or achieve early detection of nephrotoxicity. Greater understanding of the pathogenesis of nephrotoxicity is needed before its occurrence can be prevented.