Diabetic nephropathy, a renal microvascular complication of DM characterized by albuminuria and progressive loss of kidney function, is a leading cause of ESRD [1–4, 13]. As a marker for glomerular disease, albuminuria is often the first clinical indicator of DN and is utilized as a clinical tool for predicting prognosis and monitoring therapeutic response [1, 10]. The absence of albuminuria in patients with a reduced eGFR and DM raises the possibility of nondiabetic CKD [1].
Concurrent with HTN, which occurs in approximately 65% of patients with DM, hyperglycemia, and genetic predisposition are key factors in the development and progression of kidney disease [8, 13]. DN is characterized by the development of proteinuria with a subsequent decline in eGFR [6, 8, 11]. Although increasing urinary albumin excretion and serum Cr levels accompanied with diminished eGFR are likely important markers of kidney decline, it is unclear whether these biomarkers are independent risk factors for the progression of kidney disease or subsequent outcomes in patients with type 2 DM [8, 16].
In a study of patients with type 2 DM, Berhane et al. reported that the risk of progression to ESRD was 2.1 fold higher in patients with microalbuminuria and 9.3 fold higher in those with macroalbuminuria, compared to those without albuminuria [17]. Conversely, Norris et al. reported that albuminuria, serum Cr, and eGFR were significant factors associated with renal outcomes [8]. In the present study, the rate of reduction in eGFR per year was 1.47 ± 6.61 mL/min/1.73 m2 in the microalbuminuria group and 6.10 ± 9.83 mL/min/1.73 m2 in the macroalbuminuria group, indicating a significant decrease in renal function in patients with macroalbuminuria. Additionally, comparison of the patients according to the severity of macroalbuminuria revealed that the rate of reduction in eGFR per year was significantly higher in those with severe albuminuria (4.10 ± 8.98 mL/min/1.73 m2 in the moderately increased albuminuria group; 9.19 ± 10.39 mL/min/1.73 m2 in the severely increased albuminuria group). Consistent with these results, > 50% reduction in eGFR compared to baseline eGFR, CKD, and HD due to the deterioration of renal function were also significantly more frequent in patients with more severe albuminuria.
A study by Yokoyama et al. found that cardiovascular events were more frequent in patients with microalbuminuria and macroalbuminuria compared to those with normal albuminuria and that lower eGFR was associated with higher frequency of cardiovascular events [18]. Moreover, a study by Solomon et al. showed that the higher the urine ACR, the greater the cardiovascular death and all-cause mortality [19]. In the present study, there was statistically significant difference in the incidence of CVD. However, no statistically significant difference was found in the incidences of heart failure, cerebrovascular disease, and PAD.
In the present study, renal outcomes were compared by classifying the cohort of patients with DN into three groups according to the degree of albuminuria. All patients in the study had a relatively preserved renal function with an initial eGFR > 60 mL/min/1.73 m2. The patients with microalbuminuria and those with macroalbuminuria showed significant differences in the rates of progression to CKD, > 50% reduction in eGFR compared to baseline, and HD due to deterioration of renal function. In particular, even within the macroalbuminuria group, the severely increased albuminuria group exhibited more severe renal dysfunction compared with the moderately increased albuminuria group. The rate of reduction in eGFR per year was also significantly different depending on the degree of albuminuria.
In agreement with the present study findings, the poor prognosis of renal function in patients with macroalbuminuria compared to those with microalbuminuria has been shown in previous studies [17, 19, 20]. In the present study, the prognosis of renal function was worse in patients with severely increased albuminuria (urine ACR > 900 mg/g Cr) compared to those with moderately increased albuminuria (urine ACR 300–900 mg/g Cr). There was no significant difference in the prevalence of HTN between the moderately increased albuminuria and the severely increased albuminuria. However, there were significant differences in the rates of progression to CKD (p = 0.003), > 50% reduction in eGFR compared to baseline (p < 0.001), and HD due to deterioration of renal function (p = 0.004). Therefore, faster deterioration of renal function is expected in patients with severely increased albuminuria. In previous studies, albuminuria was reported to affect cardiovascular outcomes [8, 18, 19, 21]. In the incidence of CVD, there was a significant difference according to the level of albuminuria; however, no significant difference was found in the incidences of heart failure, cerebrovascular disease, and PAD among the groups in the present study.
Several limitations of the present study should be acknowledged. First, this was a single-center study and there were differences in the number of patients among the three groups. As the number of patients was not sufficient, the current study findings should be confirmed in future studies with larger cohorts. Second, DN was not diagnosed by kidney biopsy in most patients, and only 3 (0.9%) patients were diagnosed with DN based on kidney biopsy. Although the DN diagnosis was based on clinical findings, it is known that there are cases in which kidney biopsy is diagnosed as other glomerular disease in approximately 10–85% [22–25], and there may be a bias for this. Third, the DN diagnosis was based on the date of first urine ACR test; however, accurate confirmation of the duration of DM and presence of DN were difficult due to the retrospective study design [21]. Fourth, the prevalence rate of HTN and RASi treatment were different between the microalbuminuria and macroalbuminuria groups. HTN and RASi treatment can affect renal prognosis and might have introduced a bias [6, 26, 27]. However, there was no significant difference in the prevalence rate of HTN and RASi treatment between the moderately increased albuminuria group and severely increased albuminuria group despite the significant difference in renal prognosis between the moderately increased albuminuria group and severely increased albuminuria group. Finally, whether the patients had HTN and were on RASi treatment could be confirmed; however, it was difficult to confirm the degree of blood pressure control in patients. Therefore, although HTN is a risk factor that can impact renal prognosis [27], there is a limitation that can act as a bias because the efficacy of blood pressure control could not be evaluated.