title: Distal tubular acidosis induced by FK506.
abstract: This study was designed to investigate the effect of tacrolimus (FK506) and of cyclosporine (CsA) on tubular function in renal graft recipients. Patients were randomised after renal transplantation to immunosuppressive treatment with FK506 (n = 8) or CsA (n = 8). Patients had a mean age of 45.7 +/- 3.4 yr; there was no difference in age, sex, HLA status or CMV mismatches. Neither was there any difference in the frequency of episodes of acute kidney failure between the groups, nor was there a significant difference in the frequency of episodes of kidney rejection within the first year. The mean FK506 level at the time lay at 14.7 +/- 14.4 ng/mL whole blood, and the mean CsA level at the time of study was 162 +/- 25 ng/mL whole blood. We performed renal function studies 6 months after transplantation: CIn, CPAH, NaHCO3 loading, and Na2SO4 loading. There was no significant impairment of GFR in patients treated with FK506 with 53.6 +/- 2.5 mL/min as compared to 58 +/- 6 mL in group 2. Plasma renin activity (0.6 +/- 0.4 ng/mL vs 2.3 +/- 3; p < 0.01) and aldosterone (69 +/- 17 vs 157 +/- 28.2 pg/mL; p < 0.05) were significantly decreased during treatment with FK506. Fractional HCO3 excretion was low in both groups, indicating that bicarbonate reabsorption in the proximal nephron was unimpaired. Distal renal tubular acidosis was demonstrated in 4 patients of group 1 but in only 1 of group 2. Potassium levels were slightly increased in patients treated with FK506 (5.4 +/- 0.2 mmoL/L) as compared to cyclosporine (4.9 +/- 0.3 mmoL/L; p < 0.05). Distal hydrogen ion secretion, evaluated by the ability to increase urinary pCO2 in a highly alkaline urine, was impaired in patients treated with FK506 (U-B pCO2: 16.1 +/- 4 vs 36 +/- 5.8; p < 0.05) as compared to patients treated with CsA. The maximum acidification capability (NAE) was slightly lowered during therapy with FK506 (67.5 +/- 11.8 versus 86.6 +/- 16.5 mumoL/min, ns). We conclude that FK506 administration results in a decrease in the rate of hydrogen ion secretion by the collecting tubules. This defect was disclosed by the finding of a subnormal pCO2 in a highly alkaline urine. These results show that FK506 is able to induce distal tubular acidosis. Distal tubular acidosis is part of FK506 induced nephrotoxicity, the pathogenesis of this type of hyperkalemic metabolic acidosis found in patients treated with FK506 after renal transplantation has to be further elucidated.
authors.affiliation: Klinik f. Nephrologie und Rheumatologie, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Heering
authors.forename: K
authors.initials: K
authors.lastname: Ivens
authors.forename: S
authors.initials: S
authors.lastname: Aker
authors.forename: B
authors.initials: B
authors.lastname: Grabensee
mesh_terms: D000141:Acidosis, Renal Tubular / Q000139:chemically induced* / Q000503:physiopathology / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000503:physiopathology; D008875:Middle Aged; D017693:Sodium Bicarbonate; D013431:Sulfates; D016559:Tacrolimus / Q000009:adverse effects*
chemical_list: D007166:Immunosuppressive Agents; D013431:Sulfates; C012036:sodium sulfate; D016572:Cyclosporine; D017693:Sodium Bicarbonate; D016559:Tacrolimus