Does nondiabetic renal disease exacerbate diabetic nephropathy in patients with type 2 diabetes?

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Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). It is estimated that 20% to 40% of DM patients will develop a diabetic renal disease. Currently, DN is the leading cause of end-stage renal disease worldwide, including in Korea, and has become a serious economic burden to the healthcare system in Korea [1]. However, renal diseases other than DN, a heterogeneous group of renal lesions, also occur frequently in patients with diabetes.

Renal biopsy is considered to be a major part of the clinical practice of nephrology, because the information it provides is critical in making a specific diagnosis and decisions for patient management and for the evaluation of disease activity and prognosis [2]. Due to its invasiveness, however, renal biopsy is not routinely performed in diabetic patients presenting with proteinuria alone.

Thus, the diagnosis of DN is almost always based on clinical findings and supported by persistent proteinuria without hematuria, hypertension, and progressive decline in renal function. The validity of this clinical approach is well-established in type 1 diabetes, but not in those with type 2 diabetes [3]. It is not uncommon for patients with a 7- to 10-year history of type 1 DM to have demonstrated diabetic retinopathy (DR) and a history of microalbuminuria. These patients present no evidence of sudden-onset marked proteinuria, hematuria, abnormal kidney size, or other renal disease [4-7].

Unfortunately, most of our knowledge of DN in type 2 diabetes patients is derived from studies of patients with type 1 DM [2,3]. Furthermore, nondiabetic renal diseases (NDRD), either isolated or superimposed on an underlying DN, have been reported, and the prevalence of biopsy-proven NDRD in type 2 patients varies from 10% to 85% [8-10]. It is well-known and generally accepted that it is difficult to reverse DN, whereas some cases of NDRD are readily treatable and remittable with appropriate treatment. However, DN and NDRD coexist in some diabetic patients. In summary, it is important to distinguish NDRD from DN and to identify features that discriminate between NDRD and DN, because this could assist clinicians in making a rapid and appropriate diagnosis, resulting in more effective management.

In this issue of The Korean Journal of Internal Medicine, Byun et al. [11] found that shorter duration of diabetes, higher hemoglobin A1c (HbA1c), and the absence of DR are independent predictors of NDRD, and that NDRD is associated with better renal outcomes with specific treatment, such as steroids and immunosuppressants. Additionally, patients with a history of hematuria were more likely to have NDRD. A large meta-analysis study showed that clinical predictors allowing discrimination of NDRD from DN were: 1) absence of DR, 2) shorter DM duration, 3) lower HbA1c, and 4) lower blood pressure. They also found no difference in age, 24-hour urinary protein excretion, serum creatinine, glomerular filtration rate, or blood urea nitrogen concentrations in patients with NDRD and DN [12]. The results of that study are quite similar to those of the authors [13] with the exception of blood pressure. Byun et al. [11] also found that immunoglobulin A (IgA) nephropathy was the most common lesion, followed by membranous nephropathy, crescentic glomerulonephritis, and tubulointerstitial nephritis, in order of frequency. In contrast, a report from Malaysia showed that the causes of NDRD in type 2 diabetes, in decreasing order of frequency, were acute interstitial nephritis, glomerulonephritis, hypertensive renal disease, and acute tubular necrosis [14]. A recent study from China reported that IgA nephropathy was the most common NDRD, followed by tubulointerstitial lesion, membrano-proliferative glomerulonephritis, and membranous nephropathy [12]. The high prevalence of IgA nephropathy as the most common NDRD in type 2 diabetes patients in these two studies is consistent with their geographic distribution, in which IgA nephropathy is the most common glomerulonephritis in the general population. This reflects the prevalence patterns of glomerular disease in adults in the general population [15,16]. From the results of these studies, we may cautiously conclude that IgA nephropathy is the most common NDRD in East Asian diabetic patients. Another interesting finding of Byun et al. [11] was that the rate of decline in renal function was faster in patients with DN compared with those with NDRD alone or with DN. The authors' explanation was that patients with DN had a shorter duration and lower degree of severity of diabetes and a higher incidence of potentially treatable renal diseases, such as IgA nephropathy and membranous nephropathy. These findings are consistent with a previous report demonstrating that a shorter duration of diabetes and the presence of potentially treatable NDRD had a favorable prognosis in type 2 diabetes [14].

Several studies have suggested that there are distinct clinical and pathological features in diabetic patients with DN complicating NDRD. These patients have some of the clinical and pathological features of DN, which include a high prevalence of DR, a long duration of diabetes, poor glycemic control, and a lack of history of hematuria [8-12]. As some cases of NDRD are remittable and, in some cases, treatable if correctly intercepted, leading to completely different renal outcomes, the importance of accurate diagnosis cannot be understated. It is well-known that the only way to distinguish NDRD from DN is renal histology. However, the prevalences of NDRD are not uniform, which is likely to be due to differences in study populations and/or selection criteria. Thus, larger, multicenter, randomized, prospective studies are needed to confirm these preliminary findings. There is an urgent need to identify features that can discriminate between NDRD and DN; this could provide clinicians with more objective, reliable, and safe diagnoses, leading to more effective medical management.