MONITORING OF PROTEINURIA IN PHASE-I STUDIES IN HEALTHY MALE-SUBJECTS

Objective. The quantitative measurement of urinary marker proteins may improve the sensitivity of monitoring renal function in healthy male subjects in phase I studies. Little is known about the variability of physiological proteinuria in young, healthy male subjects. Thus, the b iological and analytical variability of three marker proteins, i.e. al bumin, alpha(1)-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG ), were investigated in this population. Methods: Seven young, healthy male subjects participated in a prospective two-way cross-over study, and 139 in a retrospective study. Albumin and alpha-microglobulin wer e determined by immunological methods (radial immunodiffusion and/or k inetic nephelometry), and NAG by enzyme activity in a colorimetric ass ay.Results: The inter-assay precision of NAG, albumin and alpha-microg lobulin is good (<15%) if automated kinetic nephelometry is applied fo r albumin and al-microglobulin determination, but less impressive (<25 %) with radial immunodiffusion. The highest frequency of detectable pr oteinuria and highest creatinine-adjusted protein levels are found in the second morning urine voided after a night's rest. The intra-indivi dual biological variability of NAG excretion from day to day is low (C V: 15-25%), irrespective of outpatient or inpatient settings. By contr ast, albumin and alpha(1)-microglobulin excretion can differ by a fact or of 2-3 from day to day, and higher levels are predominantly found i n outpatient settings. The reference ranges for young, healthy male su bjects are generally lower than published in cross-sectional studies i n the total healthy population. Conclusion: These findings and establi shed reference ranges for young, healthy male subjects may assist in t he evaluation of proteinuria in clinical pharmacological phase I trial s.