Article Figures & Data
Figures
- Figure 1.
Kidney specific factors that enhance nephrotoxic risk are noted. First, high RBF increases drug delivery to the kidney. High metabolic rates of cells increase risk for nephrotoxicity with certain drugs. Renal biotransformation of drugs to toxic metabolites and ROS overwhelms local anti-oxidants. Increased concentration of drugs in the medulla and interstitium causes nephrotoxicity. Finally, apical uptake of certain drugs (aminoglycosides, sucrose) and basolateral transport of drugs through the OAT (tenofovir) and OCT (cisplatin) transporters increases renal toxicity. Abbreviations: RBF, renal blood flow; OAT, organic anion transporter; OCT, organic cation transporter; ROS, reactive oxygen species.
- Figure 2.
Apical membrane handling of substances, in this example aminoglycosides, by proximal tubular cells. Aminoglycosides interact with anionic phospholipids/megalin on the apical surface where they are endocytosed and enter the cell. The drug is then translocated into lysosomes, where it is associated with various forms of cellular injury. Abbreviations: AG (+), aminoglycoside; (-) PL, anionic phospholipids; M, megalin; Lys, lysosome; Na+, sodium; K+, potassium.
- Figure 3.
Basolateral handling of substances, in this example tenofovir, by proximal tubular cells. Tenofovir (TDF) is delivered to the basolateral membrane, transported into the cell via the organic anion transporter-1 (OAT-1), and excreted by various apical transporters into the urinary space. In this example, transport by the multidrug-resistance protein (MRP2) transporter is inhibited or dysfunctional, causing intracellular accumulation of drug and nephrotoxicity. Abbreviations: Pgp, P-glycoprotein; PEPT1/2, peptide transporters; OA, organic anions; OC, organic cations; OAT, organic anion transporter, OCT, organic cation transporter; Na+, sodium; K+, potassium.
Tables
Therapeutic Agents Alternative Products Diagnostic Agents Environmental Exposures Antimicrobial Herbal remedies Radiocontrast Heavy metals Aminoglycosides Aristolochic acid High osmolar Lead Antiviral agents Ephedrasp. Low osmolar Mercury Amphotericin B Glycyrrhizasp. Iso-osmolar Cadmium Colistin Datura sp. Uranium Sulfadiazine Taxus celebica Other agents Copper Ciprofloxacin Uno degatta Gadolinium (in high dose) Bismuth Cape aloes Oral NaP solution Chemotherapy (colonoscopy prep) Solvents Platins Adulterants Hydrocarbons Ifosfamide Mefenamic acid Mitomycin Dichromate Other toxins Gemcitabine Cadmium Silicon Methotrexate Phenylbutazone Germanium Pentostatin Melamine Interleukin-2 Anti-angiogenesis agents Analgesics NSAIDs Selective COX-2 inhibitors Phenacetin Analgesic combinations Immunosuppressives Sirolimus Calcineurin inhibitors Other ACE inhibitors/ARBs Methoxyflurane Sucrose, Hydroxyethyl starch, Mannitol Pamidronate, Zolendronate Topiramate, Zonisamide Orlistat Statins Mesalamine ↵a NaP, sodium phosphate; NSAIDs, nonsteroidal anti-inflammatory drugs; ARBs, angiotensin-receptor blockers; ACE, angiotensin-converting enzyme.
Patient-Specific Factors Female sex Old age (>65 yr) Nephrotic syndrome Cirrhosis/obstructive jaundice Acute/Chronic kidney disease True or effective volume depletion Decreased glomerular filtration rate Enhanced proximal tubular toxin reabsorption Sluggish distal tubular urine flow rates Metabolic perturbations Hypokalemia, hypomagnesemia, hypercalcemia Alkaline or acid urine pH Immune response genes Pharmacogenetics favoring drug toxicity Gene mutations in hepatic and renal P450 system Gene mutations in renal transporters and transport proteins Kidney-Specific Factors High rate of blood delivery (20-25% of cardiac output) Increased toxin concentration in renal medulla & interstitium Biotransformation of substances to reactive oxygen species High metabolic rate of tubular cells (loop of Henle) Proximal tubular uptake of toxins Apical uptake via endocytosis/pinocytosis Basolateral transport via OAT and OCT Drug-Specific Factors Prolonged dosing periods and toxin exposure Potent direct nephrotoxic effects of the drug or compound Combinations of toxins/drugs promoting enhanced nephrotoxicity Competition between endogenous and exogenous toxins for transporters, increasing toxin accumulation within the tubular cell Insoluble parent compound and metabolite with intratubular crystal precipitation ↵a OAT, organic anion transporters; OCT, organic cation transporters.
Tubulopathies Renal Tubular Acidosis/Fanconi Syndrome Sodium Wasting Potassium Wasting Nephrogenic Diabetes Insipidus Nephrotic Syndrome/Proteinuria Glomerular Disease Minimal Change Glomerulonephritis Focal Segmental Glomerulosclerosis Membranous Glomerulonephritis Other Thrombotic Microangiopathy HUS/TTP Acute Kidney Injury Hemodynamic Disturbances Parenchymal Kidney Disease Collecting System Disease Chronic Kidney Disease Analgesic Nephropathy Chronic Tubulointerstitial Nephritis Secondary Progression of Toxin-induced Kidney Disease ↵a HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.
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