Early urinary markers of diabetic kidney disease: a nested case-control study from the Diabetes Control and Complications Trial (DCCT).
BACKGROUND
Urinary markers were tested as predictors of macroalbuminuria or microalbuminuria in patients with type 1 diabetes.


METHODS
Nested case-control of participants in the Diabetes Control and Complications Trial (DCCT).


METHODS
87 cases of microalbuminuria were matched to 174 controls in a 1:2 ratio, while 4 cases were matched to 4 controls in a 1:1 ratio, resulting in 91 cases and 178 controls for microalbuminuria. 55 cases of macroalbuminuria were matched to 110 controls in a 1:2 ratio. Controls were free of micro-/macroalbuminuria when their matching case first developed micro-/macroalbuminuria.


METHODS
Urinary N-acetyl-beta-d-glucosaminidase (NAG), pentosidine, advanced glycation end product (AGE) fluorescence, and albumin excretion rate (AER).


RESULTS
Incident microalbuminuria (2 consecutive annual AERs > 40 but < or = 300 mg/d) or macroalbuminuria (AER > 300 mg/d).


METHODS
Stored urine samples from DCCT entry and 1-9 years later when macro- or microalbuminuria occurred were measured for the lysosomal enzyme NAG and the AGE pentosidine and AGE fluorescence. AER and adjustor variables were obtained from the DCCT.


RESULTS
Submicroalbuminuric AER levels at baseline independently predicted microalbuminuria (adjusted OR, 1.83; P < 0.001) and macroalbuminuria (adjusted OR, 1.82; P < 0.001). Baseline NAG excretion independently predicted macroalbuminuria (adjusted OR, 2.26; P < 0.001) and microalbuminuria (adjusted OR, 1.86; P < 0.001). Baseline pentosidine excretion predicted macroalbuminuria (adjusted OR, 6.89; P = 0.002). Baseline AGE fluorescence predicted microalbuminuria (adjusted OR, 1.68; P = 0.02). However, adjusted for NAG excretion, pentosidine excretion and AGE fluorescence lost the predictive association with macroalbuminuria and microalbuminuria, respectively.


CONCLUSIONS
Use of angiotensin-converting enzyme inhibitors was not directly ascertained, although their use was proscribed during the DCCT.


CONCLUSIONS
Early in type 1 diabetes, repeated measurements of AER and urinary NAG excretion may identify individuals susceptible to future diabetic nephropathy. Combining the 2 markers may yield a better predictive model than either one alone. Renal tubule stress may be more severe, reflecting abnormal renal tubule processing of AGE-modified proteins, in individuals susceptible to diabetic nephropathy.
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4951, USA. elizabeth.kern@case.edu
Elizabeth F O
EF
Kern
Penny
P
Erhard
Wanjie
W
Sun
Saul
S
Genuth
Miriam F
MF
Weiss
D000118:Acetylglucosaminidase / Q000652:urine; D000293:Adolescent; D000328:Adult; D000419:Albuminuria / Q000175:diagnosis; D001120:Arginine / Q000031:analogs & derivatives / Q000652:urine; D015415:Biomarkers / Q000652:urine*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1; D003928:Diabetic Nephropathies / Q000175:diagnosis* / Q000503:physiopathology; D005260:Female; D017127:Glycation End Products, Advanced / Q000652:urine; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000652:urine; D008297:Male; D011237:Predictive Value of Tests; D055815:Young Adult
D015415:Biomarkers; D017127:Glycation End Products, Advanced; D001120:Arginine; C062187:pentosidine; D000118:Acetylglucosaminidase; D008239:Lysine