Direct (Toxic Nephropathy)



Immunological Drug-Associated Renal Dis­ease. Drugs such as penicillins, sulfonamides, phenytoin, and allopurinol may be associated with the development of hypersensitivity vascu­litis. This is a systemic disorder characterized by the deposition of immune complexes in the small blood vessels of the kidney and the skin. The renal histopathology is that of a proliferative glomer­ulonephritis. The renal prognosis of this disease is good, and the lesion usually resolves when the offending agent is discontinued.

By contrast to systemic immunological disease with glomerular involvement, primary glomerular injury is associated with drugs such as gold salts and penicillamine. The histological lesion is that of membranous glomerulonephritis. The clinical manifestations of proteinuria and hematuria as well as the histological abnormalities frequently resolve when the drugs are stopped.

The interstitium of the kidney may also be in­volved in an immunologically mediated renal in­flammatory response associated with the inges­tion of certain drugs. Agents such as the penicillin derivatives, particularly methicillin, are associ­ated with the development of acute interstitial ne­phritis. Allopurinol, cimetidine, phenytoin, rif­ampin, and sulfonamides, as well as a variety of other drugs, have been associated with the de­velopment of acute interstitial nephritis. On his­tological examination of the kidney, there is an interstitial inflammatory response characterized by infiltration of eosinophils. The patient may have fever, rash, and eosinophilia in addition to renal dysfunction. Many patients with this drugrelated syndrome, however, manifest only the renal functional impairment. The prognosis is generally good, and renal function improves when there is no longer an exposure to the of­fending agent. Occasionally, a short course of cor­ticosteroids is indicated to hasten the resolution of the disease.

Nonsteroidal anti-inflammatory drugs have also been associated with the development of acute in­terstitial nephritis. The inflammatory cell seen on histological examination of the kidney is the lym­phocyte. Nonsteroidal anti-inflammatory drug-induced interstitial nephritis may also be accom­panied by the development of the nephrotic syn­drome. Discontinuance of the drug, with or with­out the administration of corticosteroids, usually results in resolution of the injury.

Direct Tubular Toxicity. Certain classes of drugs appear to have the capability of causing di­rect damage to the renal tubular cells. The clinical presentation is that of the acute renal failure syn­drome. The aminoglycoside antibiotics and the cancer chemotherapeutic agent, cis-platinum, are common causes ci the acute renal failure syn­drome. The clinical characteristics of this syn­drome are discussed in Chapter 32. Although the mechanism of injury differs with different drugs, there is, ultimately, a disturbance in the function of the renal tubular cells.

In addition to the morphological and functional disturbances associated with the development of acute renal insufficiency, a number of drugs are associated with impairments of specific tubular functions. In these conditions, the glomerular fil­tration rate may or may not be normal. Derange­ments in proximal tubular function occur with ex­posure to heavy metals and outdated tetracycline. The manifestations may include renal tubular aci­dosis, phosphaturia, and glycosuria. Impairment in the ability to concentrate the urine may be seen in patients taking lithium carbonate, demethyl-chlortetracycline, or amphotericin B. Diabetes in­sipidus is the clinical expression of this defect. Drugs such as vincristine, cyclophosphamide, and chlorpropamide may be associated with im­pairment in the ability to excrete a water load and to dilute the urine. Hyperkalemia and distal renal tubular acidosis may be seen in patients receiving amphotericin B, beta-adrenergic blocking agents, and nonsteroidal anti-inflammatory drugs.