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 biological and analytical variability of three marker proteins, i.e. albumin, 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(1)-microglobulin were determined by immunological methods (radial immunodiffusion and/or kinetic nephelometry), and NAG by enzyme activity in a colorimetric assay.


RESULTS
The inter-assay precision of NAG, albumin and alpha(1)-microglobulin is good (< 15%) if automated kinetic nephelometry is applied for albumin and alpha(1)-microglobulin determination, but less impressive (< 25%) with radial immunodiffusion. The highest frequency of detectable proteinuria and highest creatinine-adjusted protein levels are found in the second morning urine voided after a night's rest. The intra-individual biological variability of NAG excretion from day to day is low (CV: 15-25%), irrespective of outpatient or inpatient settings. By contrast, albumin and alpha(1)-microglobulin excretion can differ by a factor of 2-3 from day to day, and higher levels are predominantly found in outpatient settings. The reference ranges for young, healthy male subjects are generally lower than published in cross-sectional studies in the total healthy population.


CONCLUSIONS
These findings and established reference ranges for young, healthy male subjects may assist in the evaluation of proteinuria in clinical pharmacological phase I trials.
Lemm
G
G
Bayer AG, Pharma Research Centre, Institute of Clinical Pharmacology, Department Biochemical Pharmacology, Wuppertal, Germany. GEORG.LEMM.GL@bayer-ag.de
Küppers
J
J
Frey
R
R
Wingender
W
W
Kuhlmann
J
J
D000118:Acetylglucosaminidase / Q000652:urine; D000328:Adult; D000419:Albuminuria / Q000652:urine; D000510:Alpha-Globulins / Q000652:urine; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D005082:Physical Exertion; D011446:Prospective Studies; D011507:Proteinuria / Q000652:urine*; D012016:Reference Values; D012189:Retrospective Studies
D000510:Alpha-Globulins; C016001:alpha-1-microglobulin; D003404:Creatinine; D000118:Acetylglucosaminidase