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The Nephrotoxic Potential of Drugs and Chemicals Pharmacological Basis and Clinical Relevance

  • Gideon Koren
Adverse Drug Experience

Summary

Scores of drugs in common clinical use are capable of inflicting various degrees of damage to the kidney. Similarly, a large number of widely employed chemicals may adversely affect renal tissue as part of their toxic potential. A xenobiotic may damage the kidney by more than one mechanism. For example, NSAIDs may cause decreased renal perfusion, interstitial nephritis, primary glomerulopathy and/or altered potassium homeostasis. A large number of drugs and chemicals inflict their damage on the renal tubular cell secondary to intracellular accumulation to concentrations substantially higher than in the plasma or in other tissues. These include aminoglycosides, mercury and carbon tetrachloride and cephaloridine.

Drug-induced interstitial nephritis is characterised by inflammatory lesions of the renal interstitium developed after at least 7 to 10 days of therapy. The immunological nature of this reaction is suggested by the associated fever, maculopapular rash and arthralgia observed in some of the patients. Although eosinophilia, eosinophiluria, and raised blood IgE levels are characteristic, immunoglobulins are not deposited in renal tissue, and the basic mechanism has not been elucidated. Renal biopsy demonstrates oedema and interstitial inflammatory reaction, mainly with lymphocytes, monocytes, eosinophils and plasma cells. Less frequent, vasculitis of small vessels or granulomatous reaction may develop, leading to necrotising glomerulonephritis. The drugs most commonly causing acute interstitial nephritis are methicillin, ampicillin, cephalosporins, rifampicin (rifampin), sulphonamides, phenindione and allopurinol. Other penicillins, NSAIDs, phenytoin, thiazides and frusemide (furosemide) are less frequently associated with this syndrome.

Drugs and chemicals may affect renal function by pharmacologically decreasing glomerular filtration rate and/or renal blood flow. These include the NSAIDs, radiological contrast media and cyclosporin.

Normal renal function depends upon an intact glomerular apparatus. Many drugs and chemicals are capable of damaging the glomerulus, causing its increased permeability to large molecules such as proteins. Several drugs including d-penicillamine, thiopronine, captopril, pyrithioxine and methimazole, are believed to exert their damage through their sulfhydryl group which bind with high affinity to glomerular structures.

A variety of xenobiotics or their metabolites may be deposited in the renal tubule causing obstruction of urine flow and a secondary damage to tubular epithelium. Sulphonamides, methotrexate and ethylene glycol are good examples.

Drugs and chemicals may adversely affect renal handling of water and electrolytes by a variety of mechanisms. While chlorpropamide enhances the secretion and pharmacological action of antidiuretic hormone, lithium may lead to nephrogenic diabetes insipidus.

The most important step in approaching drug- or chemical-induced nephrotoxicity is the recognition of the role played by the specific agent.

Before institution of therapy with a known nephrotoxin, it is imperative to obtain baseline measurements of renal function (plasma creatinine and urea, creatinine clearance and uronalysis). Drug-induced nephrotoxicity is often augmented by dehydration and preexisting renal failure; maintaining adequate urine output with mannitol minimises the nephrotoxic risk of radiocontrast media, methotrexate and cisplatin. The clinician should be aware of possible drug interactions which are likely to increase the nephrotoxic risk of a given agent. Similarly, disease states may augment renal toxicity in a specific manner.

Following exposure to a known nephrotoxin, it is important to assure that dose schedules of drugs excreted by the kidney are modified to correct for changes in their clearance rate.

Keywords

Renal Blood Flow Methoxyflurane Phenacetin Nephrogenic Diabetes Insipidus Acute Interstitial Nephritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© ADIS Press Limited 1989

Authors and Affiliations

  • Gideon Koren
    • 1
    • 2
    • 3
  1. 1.Division of Clinical PharmacologyThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of PediatricsThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Pediatrics and PharmacologyUniversity of TorontoTorontoCanada

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