Co-administration of co-trimoxazole does not augment tacrolimus-induced impairment in kidney function in rats.

Co-trimoxazole is an antibiotic that is frequently used in organ transplant patients. Our objective was to determine the effect of co-trimoxazole on tacrolimus-mediated functional impairment of the kidney in rats. Sprague Dawley rats were divided into three groups. Group 1 (dextrose) received 5% dextrose and Group 2 (tacrolimus) received tacrolimus (1 mg/kg/day) as a continuous intravenous infusion for seven days. Group 3 (combination) received tacrolimus as above and co-trimoxazole (30 mg/kg/day trimethoprim and 150 mg/kg/day sulfamethoxazole) intraperitoneally for six or seven days. Biochemical and functional parameters were measured pre- and post-drug infusion. On day 7, glomerular filtration rate (GFR) was evaluated using 3H-inulin while the effective renal plasma flow (ERPF)/cationic tubular secretion was assessed using 14C-tetraethylammoniumbromide(TEA). GFR (mL/min/kg) as measured by inulin clearance was higher (p < or = 0.05) in the dextrose (12.0 +/- 1.4) group as compared to tacrolimus group (6.0 +/- 1.3) and combination group (6.4 +/- 1.6), but there was no difference between the tacrolimus and combination group. ERPF/cationic tubular secretion (mL/min/kg) was also significantly higher in the dextrose group (62.6 +/- 10.3) as compared to the other two groups. ERPF/cationic tubular secretion was not different between the combination (33.3 +/- 5.9) and the tacrolimus (35.1 +/- 6.7) groups when there was no co-trimoxazole in the body. However, in the presence of co-trimoxazole ERPF/cationic tubular secretion was significantly reduced in the combination (23.1 +/- 3.5) group as compared to the tacrolimus group (35.1 +/- 6.7). These results indicate that co-trimoxazole does not further potentiate tacrolimus induced impairment in kidney function but is likely to further inhibit cationic tubular secretion in patients on tacrolimus therapy.

Alterations in function and phenotype of monocytes from patients with septic disease--predictive value and new therapeutic strategies.

Recently we described the predictive value of the proportion of HLA-DR+ peripheral blood monocytes for the clinical outcome of septic disease in immunosuppressed patients (allograft recipients) and surgical patients mostly with peritonitis as septic focus (following perforation of gastrointestinal tract). The experiments described here show that the loss of HLA-class II antigen expression and other phenotypical abnormalities of monocytes from septic patients with fatal outcome are associated with functional defects (antigen presentation, formation of reactive oxygen species, cytokine secretion). The picture of phenotypical and functional defects of monocytes was termed "immunoparalysis" (leading parameter: loss of HLA-DR antigen expression less than 20%). Interferon-gamma as well as GM-CSF normalized in vitro the surface antigen expression on monocytes derived from septic patients with "immunoparalysis". However, sera from patients with "immunoparalysis" prevented the cytokine-mediated effects on HLA-DR antigen expression. The inhibitory activity in septic sera was not dialysable. In order to remove such factors we started a plasmapheresis study in septic patients selected for "immunoparalysis". The preliminary data of this clinical trial suggest an improved survival rate.