To investigate the changes of renal type IV collagen turnover in diabetic nephropathy, urinary type IV collagen was measured by a highly sensitive one-step sandwich enzyme immunoassay (EIA). Urinary samples were obtained from 698 diabetic patients and 191 healthy adults. Among the patients, 264 had urinary albumin levels of less than 29 mg/g.creatine (Cr) (Stage I: normoalbuminuric stage), 169 had microalbuminuria from 30 to 299 mg/g.Cr (Stage II: microalbuminuric stage), 84 patients had macroalbuminuria of more than 300 mg/g.Cr and serum Cr of less than 1.1 mg/dl (Stage IIIA: macroalbuminuric stage without renal dysfunction), 97 had macroalbuminuria of more than 300 mg/g.Cr and serum Cr of more than 1.2 mg/dl (Stage IIIB: macroalbuminuric stage with renal dysfunction), and 84 had renal failure (Stage IV). The levels of urinary type IV collagen in Stages II, IIIA, IIIB, and IV were significantly higher than those in Stage I (P < 0.0001). The level of urinary type IV collagen in Stage I (5.00 +/- 0.23 microg/g.Cr; mean +/- SE) was also higher than that in normal adults (3.44 +/- 0.11 microg/g.Cr; mean +/- SE). These levels increased gradually due to progression of the clinical stage of diabetic nephropathy. It appears that the levels of urinary type IV collagen can be a useful marker for detecting renal injuries in diabetes according to our Asian multicenter trials.
Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.
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