Drugs and the kidney

Drug-induced impairment of renal function


Impaired perfusion of the kidneys can result from drugs that cause:
1 Hypovolaemia due to:
(a) Potent loop diuretics such as frusemide, especially in elderly patients
(b) Renal salt and water loss, e.g. from hypercalcaemia induced by vitamin D therapy (since hypercalcaemia adversely affects renal tubular salt and water conservation)
2 Decrease in cardiac output, which impairs renal perfusion, e.g. due to {3-blockers}
3 Decreased renal blood flow, e.g. ACE inhibitors Renal.
Several mechanisms of drug-induced renal damage exist and may coexist. These include:
ACUTE TUBULAR NECROSIS PRODUCED BY DIRECT NEPHROTOXICITY. Examples include prolonged or excessive treatment with aminoglycosides (kanamycin, gentamicin, streptomycin), amphotericin Band cephaloridine, heavy metals or carbon tetrachloride. The combination of aminoglycosides or cephaloridine with frusemide is particularly nephrotoxic.
ACUTE TUBULO-INTERSTITIAL NEPHRITIS  WITH INTERSTITIAL OEDEMAAND INFLAMMATORY CELL INFILTRATION. This cell-mediated hypersensitivity nephritis occurs with many drugs, including penicillins, particularly methicillin, sulphonamides and some NSAIDS.
Postrenal Retroperitoneal fibrosis with urinary tract obstruction may result from the use of methysergide. Use of drugs in patients with impaired renal function.
Many aspects of drug handling are altered in patients with renal impairment.

ABSORPTION. This may be unpredictable in uraemia as nausea and vomiting are frequently present. METABOLISM. Oxidative metabolism of drugs by the liver may be altered in uraemia. This is rarely of clinical significance.
The rate of drug metabolism by the kidney may be reduced as a result of two factors:
1 Reduced drug catabolism. Insulin, for example, is in part catabolized by the normal kidney. In renal disease, insulin catabolism is reduced. The insulin requirements of diabetics decline as renal function deteriorates for this reason.
2 Reduced conversion of a precursor to a more active metabolite, e.g. the conversion of 25-hydroxycholecalciferol to the more active 1,25-(OH)2D3. The Iohydroxylase enzyme responsible for this conversion is located in the kidney. In renal disease, production of the enzyme declines and deficiency of 1,25-(OH)2D3 results.
PROTEIN BINDING. Reduced protein binding of a drug potentiates its activity and increases the potential for toxic side-effects. Measurement of the total plasma concentration of such a drug can give misleading results. For example, the serum concentration of phenytoin required to produce an anti epileptic effect is much higher in normal individuals than in those with renal failure, since in the latter proportionately more drug is present in the free form.

Safe prescribing in renal disease
Safe prescribing in renal disease

Some patients with renal disease are hypoproteinaemic and reduced drug-binding to protein results. This is not the sole mechanism of reduced drug-binding in such patients. For example, hydrogen ions, which are retained in renal failure, bind to receptors for acidic drugs such as sulphonamides, penicillin and salicylates, thus enhancing their potential for causing toxicity.
VOLUME OF DISTRIBUTION. Salt and water overload or depletion may occur in patients with renal disease. This affects the concentration of drug obtained from a given dose.
END-ORGAN SENSITIVITY. The renal response to drug treatment may be reduced in renal disease. For example, mild thiazide diuretics have little diuretic effect in patients with severe renal impairment.
RENAL ELIMINATION. By far the most important problem in the use of drugs in renal failure concerns the reduced elimination of many drugs normally excreted by the kidneys.
Water-soluble drugs such as gentamicin that are poorly absorbed from the gut, typically given by injection and are not metabolized by the liver give rise to far more problems than lipid-soluble drugs such as propranolol, which are well absorbed and principally metabolized by the liver. Metabolites of lipid-soluble drugs, however,  may themselves be water-soluble and potentially toxic. Drugs causing uraemia by effects upon protein anabolism and catabolism.
Tetracyclines, with the exception of doxycycline, have acatabolic effect and as a result the concentration of nitrogenous waste products is increased. They may also cause impairment of GFR by a direct effect. Corticosteroids have a catabolic effect and so also increase the production of nitrogenous wastes. A patient with moderate impairment of renal function may therefore become severely uraemic if given tetracyclines or corticosteroid therapy.
Drugs and toxic agents causing specific renal tubular syndromes include mercury, lead, cadmium and vitamin D.

Problem patients

Particular problems are presented by patients in whom renal function is altering rapidly, such as those with recovering acute tubular necrosis and those on regular dialysis treatment. In addition, drugs may be removed by dialysis, which will affect the dosage required.

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