Early urinary markers of diabetic kidney disease: a nested case-control study from the Diabetes Control and Complications Trial (DCCT)

Abstract

Background: Urinary markers were tested as predictors of macroalbuminuria or microalbuminuria in patients with type 1 diabetes.

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

Setting & participants: 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.

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

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

Measurements: 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.

Limitations: 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.

Figure 1

Each panel on the left (A–D) depicts the change across time, from baseline to the event of macroalbuminuria, for each urinary marker. Each panel on the right (E–H) depicts the change across time, from baseline to the event of microalbuminuria. Values shown are the median, and error bars represent the interquartile range.