Nephrotic Syndrome in Diabetic Kidney Disease: An Evaluation and Update of the Definition

Abstract

Background Nephrotic syndrome is defined as urine total protein >3.5 g/d or total protein-creatinine ratio of >3.5 g/g, low serum albumin, high serum cholesterol, and peripheral edema. These threshold levels have not been rigorously evaluated in diabetic kidney disease or using urine albumin, the preferred measure of proteinuria in diabetes. Study Design Diagnostic test study Setting and Participants Adults with type 2 diabetes, hypertension and urine total protein >0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial. Index Test Baseline measures of proteinuria (total protein, albumin, and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures. Reference Test Other signs and symptoms of nephrotic syndrome at baseline (serum albumin <3.5g/dl, serum total cholesterol >260mg/dl or use of a statin, edema or use of a loop diuretic); progression of chronic kidney disease during follow up (doubling of baseline serum creatinine or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests. Results Among 1608 participants, total urine protein of 3.5 g/d was equivalent to urine albumin of 2.2 (95% confidence interval 1.4–3.5) g/d. Of 1467 participants, 641 (44%) had urine total protein ≥3.5 g/d at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline and 385 (26%) had progression of kidney disease over a mean follow-up interval of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. The threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes. Limitations Study population limits generalizability; inability to adjust for several variables known to affect serum albumin; lack of spot urine samples Conclusions The historical definition for nephrotic-range proteinuria appears reasonable in diabetic kidney disease. The equivalent thresholds for nephrotic-range albuminuria and albumin-creatinine ratio are 2.2 g/d and 2.2 g/g, respectively.

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