Clinicopathological characteristics of non-diabetic renal disease in patients with type 2 diabetes mellitus in a northeastern Chinese medical center: a retrospective analysis of 273 cases

With the rising prevalence of diabetes mellitus (DM), diabetic nephropathy (DN) is now the most common cause of end stage-renal disease (ESRD) worldwide [1]. The condition imposes a heavy economic burden on the healthcare system in China [2]. Type 2 diabetes is associated with more heterogeneous renal lesions than those in type 1 diabetes [2‐5]. Moreover, non-diabetic renal disease such as IgA nephropathy (IgAN), membranous nephropathy (MN) and mesangioproliferative glomerulonephritis (MPGN) may coexist with DN. Differentiation between DN and non-diabetic renal disease (NDRD) may not be possible without renal biopsy.

DN is typically irreversible, while NDRDs may be amenable to cure with early diagnosis and treatment; therefore, management and prognosis of NDRD and DN are quite different. Identification of NDRD with renal biopsy may help guide specific alteration in treatment and, thereby, improve prognosis [6, 7]. The indications for renal biopsy in type 2 diabetic patients with NDRD include a recent history of DM, lower HbA1c levels, and normal blood pressure (BP), absence of DR, rapid decline in renal function, increasing proteinuria, active urine sediment or acute onset of nephrotic syndrome (NS) [6, 8, 9].

Occurrence of NDRD in type 2 diabetic patients has been increasingly documented in recent years [10‐12]; prevalence of NDRD shows considerable regional variations worldwide [2, 6, 13]. The estimated prevalence of NDRD among Chinese type 2 diabetic patients is between 13.4 and 82.9 % [14‐18]. The global prevalence of NDRD superimposed on DN is believed to be less than 50 % [2], yet the prevalence of NDRD combined with DN in northeastern China is not clear.

In this retrospective, single-center study, we assessed the prevalence of DN alone, isolated NDRD, and NDRD superimposed on DN in type 2 diabetic patients. Detailed analysis of clinical and histopathological features of NDRD with or without DN in T2D patients is presented to characterize the different nature of NDRD in northeastern China.

We assessed the clinical and pathological characteristics of DN, NDRD, and NDRD superimposed on DN in type 2 diabetic patients in a single medical center of northeastern China; the relationship between clinical or laboratory data and renal pathological characteristics is assessed.

The number of renal biopsy performed in T2D patients of northeastern China is increasing year by year. Renal biopsies revealed that 75 % cases had NDRD among those tested; this finding is in the range of other reports (17–85 %) [6, 12, 14, 15, 17, 18, 21‐26] and a high incidence of NDRD complicating DN (11.0 %). A variety of renal lesions can occur in T2D patients, the most common primary pathological types in NDRD group was MN (29.7 %), followed by IgAN (22.9 %), and the most secondary pathologic type was LN (5.1 %) in this group. This finding is consistent with Asian results reported earlier [6, 13, 27]. In the DN + NDRD group, all patients had pathologic hallmarks of DN and the most common NDRD lesion was hypertensive renal arteriolar sclerosis (63.3 % of all cases) followed by MN (20 %). Overall, the common lesions in NDRD and DN + NDRD groups were MN (28.3 %), IgAN (20 %), hypertensive renal arteriolar sclerosis (12.2 %), MPGN (6.8 %), and interstitial nephritis. Our findings differ from those reported earlier in southeastern Asia, in which IgAN was the most common NDRD (up to 65 %) [6, 21, 22, 26]. In contrast, FSGS have been proven to be the most common pathological type in USA [28], New Zealand [9], and Croatia [29], while AIN was the most prevalent pathological type in India, Taiwan, and Malaysia [6, 25, 26, 30]. A study showed hypertensive renal damage to be the most common pathology in China [18], and IgAN is the most common lesion in NDRD superimposed on DN [2, 17] in another medical center. The disease spectrum of NDRD with or without DN in northeastern China may differ from that in other parts of the world. Hereditary and racial predisposition to different glomerulopathies, plus different eligibility criteria for renal biopsy in T2D patients, may have contributed to the variability in the reported findings.

Duration of DM at the time of renal biopsy was reported to be shorter among patients with NDRD as compared to that in patients with DN superimposed on NDRD, which was broadly accepted as one of the hallmarks of NDRD in a previous literature review. Our results are in agreement with those of previous studies [6‐8]. 40.3 % of the entire study population received insulin treatment.

In this study, the NDRD patients had a higher rate of baseline proteinuria (>90 %) and a lower rate of NS (42.3 %); however, the incidence rates in NDRD group did not differ from other groups, which is contrary to a previous study [7], where the degree of proteinuria in DN patients was higher compared to that in patients with NDRD. Likewise, the lack of between-group differences with respect to hematuria in our study (about 70 %) is not consistent with earlier studies which found degree of hematuria helped to distinguish NDRD from DN [6, 27, 30]. However, on subgroup analysis by degree of hematuria, more NDRD patients had urine RBC ˃ 20/HP although the difference was not statistically significant. Further, in a newly published report, detection of dysmorphic erythrocytes was a stronger correlation of NDRD in T2D as compared to hematuria [31]. It may be better to replace hematuria to distinguish NDRD from DN in the future. In this study, NDRD group had a higher baseline level of eGFR than DN ± NDRD group, which is consistent with the lower rate of renal failure in NDRD group reported earlier [30].

No significant differences were observed with respect to dyslipidemia between DN, NDRD, and DN + NDRD groups; the average total cholesterol levels in patients with DN did not differ from that in other groups, which is in agreement with previous studies [13, 21, 32, 33]. Another finding in the present study was the lack of difference in BMI between the 3 groups, which is in accordance with the results of several studies [26, 29], while two conflicting results have been reported in this respect in the Chinese context [32, 34]. Large prospective studies may help to understand the BMI change in Chinese T2D patients with NDRD ± DN in the future.

The frequency of hypertension in the NDRD group (45 cases, 25.7 %) was significantly lower as compared to that in the DN ± NDRD group, which is consistent with earlier reports [8, 13, 21, 29, 34]. This suggests that absence of hypertension in DM is one of the diagnostic features of NDRD, which may be linked to high dietary intake of salt northeastern China [35, 36]. 41.4 % patients were receiving RAAS blockade therapy at the time of renal biopsy; the proportion of patients receiving RAAS blockade is lower than that reported from previous two studies [26, 37]. This suggests that blood pressure control may be preventing progression of renal disease.

The retrospective study design and small sample size are foremost limitations of our study. Of note, selection bias is inevitable in any biopsy-based study. In general, our results can be applicable to T2D patients who were willing to undergo renal biopsy, the likelihood of which is relatively low in the Jilin Province (<10 %) due to the invasive nature of the investigation and, to some extent, reluctance on the part of nephrologists to perform renal biopsy owing to the associated risk of complications. The present study involved T2D patients only in one medical center of Jilin province, which could result in sampling bias. The pathological diagnoses in the patients included in this study were made by the same pathologist, which could have introduced an element of subjectivity. DR has been classically regarded as the indicator of DN, but the reported DR rate was only 15.4 %, which is another shortcoming that limits the generalizability of our findings. Previous studies have shown an association between low serum complement levels (C3/C4) and NDRD [7]; however, due to lack of data we did not assess this association. Such limitations indicate the need for prospective studies to understand the natural history of NDRD superimposed on DN in China.

In this study, 11.0 % of northeastern Chinese T2D patients had NDRD superimposed on DN. The most common pathological diagnosis was hypertensive renal arteriolar sclerosis. Patients with isolated NDRD tended to have a shorter history of DM and lack of DR. Larger, multicenter randomized prospective studies are therefore needed to confirm preliminary changes in T2D patients in order to distinguish NDRD from NDRD superimposed on DN at an early stage, which will help in initiating specific treatment, and thereby, improving kidney survival and reducing the incidence of chronic kidney disease (CKD).