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Dissecting the Causes of Proteinuria

Question: When should I consider etiologies other than diabetic nephropathy in proteinuric patients with type 2 diabetes?

Answer: Although diabetes can cause proteinuria and renal insufficiency, it is not the only culprit that causes kidney damage. In some patients, diagnosis of diabetic nephropathy is easy—the classic scenario is diabetes duration of 10–15 years and diabetic retinopathy with or without measurable neuropathy. If untreated and followed over time, these patients will progress from normal urinary sediment to microalbuminuria to overt proteinuria to renal failure. Patients who don't fit the mold may have other causes for their proteinuria, such as a shorter duration of disease and no evidence of other complications, especially if they have features consistent with other disease states, such as multiple myeloma or lupus.

EXAMINING URINE FOR WHITE AND RED CELLS AND CASTS CAN HELP DETERMINE THE PROTEINURIA'S CAUSE.

Proteinuria can be transient, orthostatic, or persistent. The persistent form generally indicates the most severe disease. Types of glomerular disease include focal glomerulonephritis, diffuse glomerulonephritis, and nephrotic syndrome.¹ To differentiate these from diabetic nephropathy check the urine for red blood cells, white cells, and casts, although in many cases a renal biopsy will be needed.

If I see a patient—particularly with a diabetes duration <10 years—who doesn't have the classic picture of gradually evolving diabetic nephropathy (from normal to microalbuminuria to proteinuria over a period of years), I am suspicious. I also consider alternative diagnoses in patients who exhibit any evidence of an autoimmune disease, malignancy, or HIV. Additionally, patients who have normal renal function after having had diabetes for >25 years are very unlikely to develop microalbuminuria and proteinuria due to diabetes (approximately 1% per year).² So if an individual with a long duration of diabetes develops rapidly progressive proteinuria and renal insufficiency, an alternative cause should be considered.

Patients with type 1 diabetes who have nephropathy almost invariably have other manifestations of microvascular disease, usually in the form of diabetic retinopathy.³ The relationship of nephropathy and retinopathy in patients with type 2 diabetes is less clear. In a cross-sectional study where renal biopsies were performed in patients with type 2 diabetes and persistent proteinuria, 77% of patients were found to have changes consistent with diabetic nephropathy while 23% had nondiabetic causes for their nephropathy.⁴ Fifty-six percent of the patients with diabetic nephropathy had retinopathy, whereas none of the patients with nondiabetic renal disease had retinopathy. Another study revealed similar findings.⁵

Therefore patients who develop persistent proteinuria with a short duration of diabetes (<10 years) or a long duration without complications should be considered at risk for having a nondiabetic cause for their proteinuria. Patients with proteinuria in the absence of diabetic retinopathy should be considered for renal biopsy as well (more strongly true for type 1 than type 2 diabetes). Examining urine sediment for white cells, red cells, and casts can help determine the proteinuria's cause. Physicians should seek and evaluate signs and symptoms of other systematic diseases, such as lupus and cancer, as indicated.

Footnotes

Anne Peters, MD, is a professor of medicine at the University of Southern California's Keck School of Medicine, director of the USC Westside Center for Diabetes, and director of the Comprehensive Diabetes Center at Roybal Community Medical Center, all in Los Angeles.

References

1. Haas M, Meehan SM, Karrison TG, et al.: Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976–1979 and 1995–1997. Am J Kidney Dis 30:621–631, 1997.[Medline]

2. Simon P, Ramee MP, Boulahrouz R, et al.: Epidemiologic data of primary glomerular diseases in western France. Kidney Int 66:905–908, 2004.[Medline]

3. Orchard TJ, Dorman JS, Maser RE, et al.: Prevalence of complications in IDDM by sex and duration: Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes 39: 1116–1124, 1990.[Abstract]

4. Parving HH, Gall MA, Skott P, et al.: Prevalence and causes of albuminuria in noninsulin-dependent diabetic patients. Kidney Int 41:758–762, 1992.[Medline]

5. Christensen PK, Larsen S, Horn T, et al.: Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy. Kidney Int 58:1719–1731, 2000.[Medline]

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This Article Full Text (PDF) Services Email this article to a friend Similar articles in this journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Social Bookmarking                What's this?