Nonalbuminuric Renal Insufficiency: Can It Be a Novel Category of Diabetic Nephropathy?

Diabetic nephropathy is a major cause of chronic kidney disease (CKD) and a common underlying cause of hemodialysis. In order to prevent hemodialysis due to diabetic nephropathy, early detection and treatment of diabetic nephropathy are indispensable. Because the risk for cardiovascular diseases (CVDs) and treatment strategies, especially protein restriction level, differ by stage of diabetic nephropathy, an accurate evaluation of disease severity is important. In Japan, the Joint Committee on Diabetic Nephropathy revised its Classification on Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) [1]. Diabetic nephropathy is classified into five stages on the basis of albuminuria/proteinuria and estimated glomerular filtration rate (eGFR) as follows. Stage 1 (pre-nephropathy): normoalbuminuria (<30 mg/g Cr); stage 2 (incipient nephropathy): microalbuminuria (30 to 299 mg/g Cr); stage 3 (overt nephropathy): macroalbuminuria (≥300 mg/g Cr) or persistent proteinuria (≥0.5 g/g Cr); stage 4 (kidney failure): any albuminuria/proteinuria status and eGFR <30 mL/min/1.73 m2; and stage 5 (dialysis therapy): any status on continued dialysis therapy.

Both the occurrence of albuminuria and reduction in eGFR are independent risk factors for CVD [234], although their clinical characteristics are somewhat different. It is accepted worldwide that albuminuria is very important biomarker of incipient diabetic nephropathy [5]. On the other hand, decline in eGFR is not useful as a diagnostic marker of incipient diabetic nephropathy [6]. Severely decreased eGFR is reported to predict renal failure or CVD regardless of the presence or absence of albuminuria [3]; therefore, it is useful as a marker of the progression of diabetic nephropathy.

Although diabetic nephropathy is classified into five stages in “Classification of Diabetic Nephropathy 2014” [1], it does not always proceed from one stage to the next orderly; there is a group of diabetic patients whose eGFR declines without the occurrence of albuminuria [78].

In this issue of Endocrinology and Metabolism, Lee et al. [9] reported that nonalbuminuric stage ≥3 CKD group (<60 mL/min/1.73 m2) was a significant category of diabetic nephropathy, and that the patients belonging to this category showed higher prevalence of CVD and retinopathy than those with preserved eGFR (≥60 mL/min/1.73 m2). Because this group had shorter diabetic duration than the albuminuric stage ≥3 CKD group, nonalbuminuric stage probably proceed to albuminuric stage. Since the rate of treatment with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers of the nonalbuminuric CKD group is higher than that of the albuminuric CKD group, by treating with renin-angiotensin system antagonists, regression from albuminuric CKD to nonalbuminuric CKD might be expected.

According to the KNHANES (Korea National Health and Nutritional Examination Survey), 8.6% of diabetic patients belonged to the category of CKD defined as eGFR <60 mL/min/1.73 m2 [10]. This proportion seemed quite low compared with the 39% reported in this paper [9]. This discrepancy might indicate that the subjects of this retrospective study did not represent the patients observed in the real clinical settings. Although the findings of Lee et al. [9] are worthwhile from a viewpoint of early detection and intervention of the patients at high risk, a prospective study with a larger number of patients is needed to confirm and establish the significance of nonalbuminuric renal insufficiency.