G. Lemm et al., MONITORING OF PROTEINURIA IN PHASE-I STUDIES IN HEALTHY MALE-SUBJECTS, European Journal of Clinical Pharmacology, 54(4), 1998, pp. 287-294
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.