Alteration of urine pH

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penicillamine when the patient has made an immune response to the drug. The degree of renal impairment is best reflected in the creatinine clearance which measures the glomerular filtration rate because creatinine is eliminated entirely by this process.

Tubule damage. By concentrating 1801 of glomerular filtrate into 1.51 of urine each day renal tubule cells are exposed to much greater amounts of solutes and environmental toxins than are other cells in the body. The proximal tubule, through which most water is reabsorbed, experiences the greatest concentration and so suffers most drug-induced injury. Specialised transport processes concentrate acids, e.g. salicylate (aspirin), cephalosporins, and bases, e.g. aminoglycosides, in renal tubular cells. Heavy metals and radiographic contrast media also cause damage at this site. Proximal tubular toxicity is manifested by leakage of glucose, phosphate, bicarbonate and aminoacids into the urine.

The counter current multiplier and exchange systems of urine concentration (see p. 530) cause some drugs to accumulate in the renal medulla. Analgesic nephropathy is often first evident at this site partly because of high tissue concentration and partly, it is believed, because of ischaemia through inhibition of locally produced vasodilator prostaglandins by NSAIDs. The distal tubule is the site of lithium-induced nephrotoxicity; damage to the medulla and distal nephron is manifested by failure to concentrate the urine after fluid deprivation and by failure to acidify urine after ingestion of ammonium chloride.

Tubule obstruction. Given certain physicochemical conditions, crystals can deposit within the tubular lumen. Methotrexate, for example, is relatively insoluble at low pH and can precipitate in the distal nephron when the urine is acid. Similarly the uric acid produced by the metabolism of nucleic acids released during rapid tumour cell lysis can cause a fatal urate nephropathy. This was a particular problem with the introduction of chemotherapy for leukaemias until the introduction of allopurinol; it is now routinely given before the start of chemotherapy to block xanthine oxidase so that the much more soluble uric acid precursor, hypoxanthine, is excreted instead. Crystal-nephropathy is also a problem with the widely used antiretroviral agent indinavir.

Other drug-induced lesions of the kidney include:

• Vasculitis, caused by allopurinol, isoniazid, sulphonamides

• Allergic interstitial nephritis, caused by penicillins (especially), thiazides, allopurinol, phenytoin, sulphonamides

• Drug-induced lupus erythematosus, caused by hydralazine, procainamide, sulfasalazine.

Drugs may thus induce any of the common clinical syndromes of renal injury, namely:

Acute renal failure, e.g. aminoglycosides, cisplatin Nephrotic syndrome, e.g. penicillamine, gold, Captopril (only at higher doses than now recommended) Chronic renal failure, e.g. NSAIDs Functional impairment, i.e. reduced ability to dilute and concentrate urine (lithium), potassium loss in urine (loop diuretics), acid-base imbalance (acetazolamide).

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