A 2-year-old boy has been treated for tuberculosis with isoniazid, rifampicin, ethambutol and pyraz

Fråga: A 2-year-old boy has been treated for tuberculosis with isoniazid, rifampicin, ethambutol and pyrazinamide for two months. During the treatment serum urea has increased. The other blood values have remained unchanged. The questioner wants to know about the documentation concerning these drugs and nephrotoxicity. Ethambutol and pyrazinamide have now been withdrawn.

Sammanfattning: Renal failure is considered a rare complication due to treatment with isoniazid, rifampicin, ethambutol and pyrazinamide. Rifampicin is associated with the largest number of documented cases of renal failure. Ethambutol has been judged as a possible cause for some cases of nephrotoxicity. However, all of drugs mentioned have in some cases been associated with interstitial nephritis.

In this case it seems most probable that rifampicin or ethambutol may have affected the kidneys and caused the increase of serum urea.

Svar: Isoniazid is acetylated in the liver. The acetylator phenotype should be the most important factor for the elimination. The kidneys are of less importance, as normally only 10-30 per cent is excreted unchanged in the urine. Pre-existing renal failure necessitates adequate control of urea and creatinine serum levels. Nephrotoxicity is rarely observed, but may be induced in combined therapy with rifampicin, or in patients developing hypersensitivity reactions (1).

Rifampicin is a macrocyclic antibiotic which has been, for a long time, a drug of choice in the treatment of tuberculosis. A large number of cases have been documented of acute renal failure due to rifampicin (2) but it is still considered a rare complication. The exact mechanism for the renal abnormality is not known. Sensitisation and continuous formation of antigen-antibody complexes with deposition in the kidney is the most commonly proposed mechanism. This toxicity is considered reversible and is overrepresented in patients intermittently treated with rifampicin (7). Early symptoms of renal failure are oliguria and anuria, haematuria or haemoglobinuria. These symptoms are often preceded by haemolysis or "flu-like" syndrome (7). Acute interstitial nephritis has also been described (3). In the files of Swedish Adverse Reactions Advisory Drug Committee (SADRAC) there are four cases of renal failure reported and two cases of increased creatinine possibly related to rifampicin (4).

Ethambutol is rarely associated with nephrotoxicity. There are two cases of nephrotoxicity possibly related to ethambutol and five patients on treatment with ethambutol and isoniazid with reported interstititial nephritis (5).

Pyrazinamide is a pyrazine analogue and is not registered in Sweden. Hyperuricaemia is commonly reported during therapy with pyrazinamide and may be due to inhibition of uric acid excretion. In Medline 89 we found one report of tubulointerstitial nephritis associated with pyrazinamide (6). 1 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1992; 12th ed: 753

2 Drugline nr 05369 (year 1986)
3 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1992; 12th ed: 756
4 Swedis
5 Martindale, The extra pharmacopoeia. 1993; 30th ed: 165
6 Martindale, The extra pharmacopoeia. 1993; 30th ed: 195

7 Drugline nr 09965 (year 1993)