Clinical correlates and pathology of non-diabetic renal disease in diabetes mellitus

INTRODUCTION

Diabetic nephropathy (DN), also known as diabetic kidney disease, is a devastating complication of diabetes mellitus (DM) and is a leading cause of end-stage renal disease worldwide. Its prevalence across studies conducted globally lies between 11% and 38%. A cross-sectional study in India reported an incidence of more than 34%.^[1,2] Non-diabetic renal disease (NDRD) is also reported in patients with type 2 DM within a broad range of 8–85% of biopsied cases.^[3] A recently published observational study reported NDRD in more than 50% of patients with diabetes.^[3] Thus, the prevalence of NDRD in patients with diabetes is high. Unlike DN, which is usually diagnosed based on the clinical and biochemical profile of the patients, NDRD requires a biopsy. It is critical to identify and differentiate patients with NDRD from DN or those with NDRD superimposed on DN because the management of both these conditions varies considerably. In addition, early diagnosis of NDRD improves the prognosis and reduces associated morbidity.

Therefore, the present study was planned to analyze the spectrum of NDRD in clinically indicated patients with atypical renal involvement and DM.

MATERIALS AND METHODS

The primary objective of the study was to assess patients with T2D with atypical renal involvement suggestive of non-diabetic etiology for NDRD. The clinical profile and nature of renal involvement of patients with isolated NDRD and those with NDRD superimposed on DN were compared. The secondary objective was to determine and compare the etiopathogenesis of nephropathy in these patients by renal biopsy.

It is a descriptive study which enrolled 50 patients with T2D and renal involvement suggestive of non-diabetic etiology per inclusion criteria for further evaluation with renal biopsy. Adult patients with T2D for <5 years who demonstrated either nephrotic range proteinuria with normal renal function, declining renal function in the absence of diabetic retinopathy (DR), sudden unexplained deterioration of renal function, active urinary sediment, gross microscopic hematuria, or proven NDRD were included in the study. Patients with signs of infections, such as renal abscesses, acute and chronic pyelonephritis, those with renal calculi causing hydronephrosis, and those with signs of DN alone were excluded from the study.

After renal biopsy reports were available, they were classified into either NDRD alone or DN with co-existing NDRD. For each of the eligible patients, a detailed medical history was obtained, and a physical examination was performed. Data for patients and their features were documented on a standard pro forma, including demographics and the underlying primary renal disease. The patient features consist of demographic parameters (age and gender), body mass index (BMI) (kg/m²), years of diabetes, the occurrence of DR, hypertension (%), hypothyroidism, ischemic heart disease (IHD %), glycated hemoglobin (HbA1c %), 24-h urinary protein (mg/day), hematuria, creatinine (mg/dL), estimated glomerular filtration rate (GFR) (mL/min), and urine protein creatine ratio. Patient characteristics were compared between the groups for analysis.

The etiological diagnosis was confirmed by histopathology. Glomerulonephritis was diagnosed in patients with a history of edema hypertension and documented a nephritic or nephrotic range of proteinuria. DN was also considered etiology in the presence of DR with albuminuria with a classical history of slow progression. NDRD was suspected in patients with sudden deterioration of renal function, hematuria, and worsening creatinine in the absence of DR. However, confirmation of DN and NDRD was obtained with a renal biopsy.

Written informed consent was obtained from each patient before the initiation of the study regarding the use of their clinical data for the publication, excluding any identifiable details. The research/study was approved by the Institutional Review Board at St John’s Medical College Hospital, number IEC/1/931/2018/277, dated October 15, 2018.

RESULTS

During the study period from September 2018 to January 2020, 50 patients were found to be eligible and included in the study analysis. The mean age of the patients was 55.57 ± 12.28 years, with 66% males. Among the 50 patients, histopathological analysis revealed that all patients had NDRD, with 36% superimposed on DN, while 64% had NDRD alone.

The demographics, clinical characteristics, and laboratory findings between these two groups are depicted in Table 1.

There was no significant difference in the mean age, gender, and BMI between the two groups. However, the duration of diabetes and incidence of DR were significantly greater in patients with both NDRD and DN than in those with NDRD alone. The proportion of patients with hypertension, IHD, and hypothyroidism was not significantly different between the two groups.

There was no significant difference between the two groups in the laboratory parameters investigating renal function and HbA1C [Table 1].

On comparison of the histopathological features [Table 2], it was observed that immunoglobulin A (IgA) nephropathy was the most common microscopic finding, followed by membranous nephropathy, acute tubular necrosis (ATN), and rapid progression of glomerular nephritis (RPGN), with no significant differences between the two groups. However, global glomerulosclerosis, membranoproliferative glomerulonephritis, Henoch-Schonlein purpura nephritis, light chain disease, and lupus nephritis were seen exclusively in patients in the NDRD group, while FSGS, thrombotic microangiopathy, hypertensive nephrosclerosis, and C3 glomerulonephropathy were exclusively seen in NDRD + DN group.

The patient profiles in both groups are shown in Table 3. The incidence of atypical features, namely, gross, microscopic hematuria, acute urinary sediment, sudden unexplained deterioration of renal function (elevated creatinine, decreased GFR, and proteinuria), declining renal function in the absence of DR, and nephrotic range of proteinuria was significantly greater in the isolated NDRD group than the group with NDRD + DN.

DISCUSSION

In our study of patients with diabetes, histopathological analysis revealed 36% with NDRD superimposed on DN and 64% with NDRD alone. Since the clinical profile prompts the conduct of a biopsy, the existing literature demonstrates a wide variation in the proportion of patients with an overlap of NDRD and DN between 8% and 85%; others found 12–79%, depending on criteria for biopsy. The widely varying data further underscore the need for more evidence generation in diabetic patients manifesting renal disease. Two observational studies have previously reported an incidence of isolated NDRD in 18–20% and NDRD and DN in 29–33% of biopsied patients.^[3,4] The results of our study are similar to that reported in India and other regions where incidence was more than 50% by Wilfred et al. (68.81%) and Yang et al. (61%) Prakash in their respective studies.^[5-7] The wide variation in previously reported results would also be explained by the inclusion criteria of the duration of diabetes. We applied a cutoff of <5 years and, therefore, possibly had more patients with NDRD than DN. The mean duration overall of diabetes in our study was between 3.1 years, while in other studies, it was 3–8 years and 4–6 years.^[3,4] The duration of diabetes was clearly longer in those with NDRD superimposed on DN compared to isolated NDRD. This observation is in agreement with the previously reported studies, which also found a significant difference in the duration of diabetes between these groups.^[3-8] The lesser duration of diabetes in patients with renal manifestations per se is suggestive of NDRD than DN.^[4]

The incidence of DR was also significantly higher in those with DN than without. In the isolated NDRD group, merely one patient had DR. Absence of retinopathy has been stated to be one of the predictors of NDRD, but presence does not exclude NDRD, as noted in our study.^[8] The presence of retinopathy in those with DN also corroborates the association between the duration of diabetes and microvascular complications.

Surprisingly, there was no difference between the incidence of hypertension, glycemic control mean levels of proteinuria, or mean renal function parameters between the two groups. Other studies have reported similar findings, while still others have found direct associations.^[4,8,9] This further highlights the need for histopathological analysis and discourages complete reliance on clinical parameters for prompting suspicion of NDRD, which could be inconsistent.

The most common finding in isolated NDRD was membranous nephropathy, followed by IgA nephropathy and RPGN, while in the NDRD and DN group, maximum patients displayed IgA nephropathy, followed by ATN and RPGN. These are common nephropathies reported previously in diabetic patients with NDRD.^[4,10-13] Overall, IgA was the most frequent NDRD, as also demonstrated by a meta-analysis of 48 studies.^[14]

Among the two patient groups, there were significant differences in the patient profiles. The atypical characteristics were significantly greater in patients with isolated NDRD than in the NDRD+DN group. The incidence of atypical features was almost twice in the isolated NDRD group than in the group with NDRD+DN. Thus, NDRDs are highly prevalent and may superimpose DN. Therefore, histopathological analysis seems essential to diagnose NDRD in diabetic patients to reduce the probability of missed NDRD diagnosis.

Our study has certain limitations. We selected patients based on a higher likelihood of NDRD with a short duration of diabetes. A DN-only group would have provided more clear comparisons between NDRD and non-NDRD.

CONCLUSION

Our data show that a considerable proportion of patients have DN-superimposed NDRD. Atypical features of renal impairment with lower incidence or absence of retinopathy with nephrotic range proteinuria and shorter duration of diabetes are clinical indicators of NDRD. However, though there was a significant difference in atypical renal manifestation among patients with isolated NDRD and combined NDRD with DN, recognizing NDRD solely on the basis of clinical indicators is challenging. Therefore, histopathological analysis is key.