Nondiabetic Renal Disease in Type 2 Diabetic Patients: A Review of our Experience in 220 Cases

Abstract

Background: The purpose of this retrospective study was to evaluate the renal biopsies performed on type 2 diabetic patients for suspicion of nondiabetic renal disease (NDRD) and to correlate the pathological finding with the clinical and laboratory findings. Methods: From January 1999 to December 2009, 220 people with type 2 diabetes for clinically suspected NDRD underwent renal biopsy. The case records of these patients were retrospectively analyzed. Based on the biopsy findings, patients were divided into two groups: Group I, isolated diabetic glomerulosclerosis (DGS), and Group II, NDRD with underlying DGS. Clinical and laboratory data were analyzed in relation to the histopathological findings. Results: Of the 220 patients studied, 153 were males and 67 were females. The average age was 51.35 years (30–79). Renal biopsy showed that 100 patients (45.5%) had NDRD with underlying DGS. Group II had a significantly higher level of proteinuria and hematuria but less frequent diabetic retinopathy. There was no significant difference between the two groups in age, duration of diabetes, presence of hypertension, serum creatinine, and glomerular filtration rate. IgA nephropathy was the most common, accounting for 34% of Group II, membranous nephropathy ranked second accounting for 22.0%, followed by mesangial proliferative nephritis for 14%. Conclusion: This study showed that IgA nephropathy is the commonest NDRD among diabetics. The absence of retinopathy, especially when associated with nephritic proteinuria and hematuria, strongly predicts NDRD superimposed on DGS. Renal biopsy should be performed in diabetics when the clinical scenario is atypical.

• nondiabetic renal disease
• type 2 diabetes mellitus
• renal biopsy
• diabetic glomerulosclerosis
• diabetic retinopathy

INTRODUCTION

The prevalence of type 2 diabetes is rising rapidly among Asian populations, partly due to the westernization of diet and urbanization of lifestyle. It is estimated that by the year 2050 the prevalence of diabetes will reach 50 million in China alone.¹ About 20–40% of patients suffering from diabetes mellitus eventually develop diabetic renal disease.² The diagnosis of diabetic nephropathy (DN) is almost always based on clinical grounds and supported by a long history of diabetes, evidence of target organ damage, and proteinuria preceding azotemia. The validity of this clinical approach is well established in type 1 diabetes but none in type 2 diabetes.³ The characteristic pathological findings in DN are diffuse or nodular mesangial sclerosis and glomerular basement membrane (GBM) thickening, accompanied by chronic tubular atrophy, interstitial fibrosis, and prominent arteriosclerosis. However, nondiabetic renal disease (NDRD) in diabetic patients, either isolated or superimposed on an underlying diabetic glomerulosclerosis (DGS), has been reported with different spectrum of diseases identified in different series. The nature of NDRD in people with type 2 diabetes is not widely documented in China or other developing countries. The aim of this study was to identify NDRD in type 2 diabetic patients who underwent renal biopsy in our hospital and to correlate the pathological finding with the clinical presentation and laboratory parameters.

SUBJECTs AND METHODS

All native kidney biopsies performed at the Second Xiangya Hospital of the Central South University from January 1999 to December 2009 were retrospectively reviewed. Biopsies performed on patients with type 2 diabetes for clinically suspected NDRD were selected and reviewed. Percutaneous renal biopsy was performed in these patients after obtaining informed consent as they were suspected to have NDRD due to absence of diabetic retinopathy (DR) and/or presence of microscopic hematuria or any other atypical clinical finding. The histopathological glass slides were reviewed and the pathology reports were retrieved from the department of pathology computerized filing system. Tissue was separated and allocated for immunofluorescence microscopy. Tissue for immunofluorescence was surrounded with optimal cutting temperature (OCT) compound and frozen, then stained with fluorescein-tagged antibodies against IgG, IgA, IgM, complement C3, C4, C1q, fibrin-related antigen and hepatitis B virus (HBV)-associated antigens. Tissue for light microscopy (LM) was placed into formalin and dehydrated and then placed in a paraffin block, and sections were stained by hematoxylin and eosin, periodic acid-Schiff, silver methenamine, and Masson's trichrome. Electron microscopy (EM) is not routinely done on all cases in our institution; however, on selected cases EM was performed and the films were retrieved and reviewed along with the EM report. NDRD was categorized following orthodox pathological criteria.⁴ As a result of the investigation, we may find mild-to-moderate thickening of GBM or effacement of the podocyte foot processes as features of the diabetic glomerulopathy or minimal change disease, or we may find nothing special; in this case minor glomerular abnormalities were diagnosed. Patients were grouped by isolated DGS (Group I) and NDRD with underlying DGS (Group II). None of the studied population had isolated NDRD because of the confirmative DN in diabetic patients. Patients data such as age, gender, duration of diabetes, presence of retinopathy on fundus examination, presence of hypertension (defined as systolic blood pressure above 140 mmHg, or diastolic blood pressure above 80 mmHg, or intake of antihypertensive medications), and presence of hyperlipidemia and hyperuricemia were included. Serum creatinine, glomerular filtration rate as estimated by MDRD (Modification of Diet in Renal Disease study) formula, presence of hematuria defined as three or more red blood cells per high-power field in a centrifuged urine sample prior by biopsy, and proteinuria using 24 hours urine protein were all considered.

STATISTICAL ANALYSIS

The descriptive statistics were presented as mean ± SD for measurement data and percentage for enumeration count data. Differences between groups were assessed by ANOVA for normally distributed measurement data, Wilcoxon's test for nonnormally distributed measurement data, and the chi-square test for enumeration data. Significance was evaluated using a two-sided p < 0.05. Statistical analysis was performed using SPSS for Windows version 17.

RESULTS

Demographic Profile

Renal biopsy showed that among the studied population 120 (54.5%) cases were found to have isolated DGS whereas the remaining 100 (45.5%) subjects had NDRD superimposed on DGS. Mean age (at biopsy) was 51.35 years (30–79). Sex ratio was 2.3:1 (male:female). Group I patients had an average age of 52.13 (13.2) years whereas Group II had 49.3 (9.4) years. The median diabetes duration (from diagnosis of diabetes to kidney biopsy) was long in both groups with a mean of 10.06 (3.31) and 8.27 (3.8) years, respectively. No statistically significant difference was detected between the two groups in age at the time of biopsy, duration of diabetes, creatinine level, or creatinine clearance at the time of presentation (Table 1).

Table 1. Comparison of patients with isolated diabetic glomerulosclerosis (Group I) and patients with nondiabetic lesions on top of diabetic glomerulosclerosis (Group II) in the demographic, clinical, and laboratory characteristics

Parameter	Group I	Group II	p
Age in years [mean (SD)]	52.13 (13.2)	49.3 (9.4)	>0.05
Sex ratio (male/female)	78/42	75/25	>0.05
Duration of diabetes in years [mean (SD)]	10.06 (3.31)	8.27 (3.8)	>0.05
Serum creatinine μmol/L [mean(SD)]	395.56 (335.09)	376.2 (266.58)	>0.05
GFR mL/min/1.73 m^2 [mean (SD)]	35.21 (17.5)	41.7 (15.02)	>0.05
Urinary proteins g/24 h [mean (SD)]	2.72 (1.09)	4.97 (2.08)	<0.05

Reasons for Renal Biopsy

Indications for renal biopsy were the presence of hematuria in 88 (40.0%) patients, unexplained rapid deterioration of renal function in 43 (19.5%) patients, and sudden onset of massive proteinuria without retinopathy in 76 (34.5%) cases.

Clinical Manifestations

Table 2 shows that most patients had hematuria in Group II, which accounted for 68%, whereas the proportion in Group I was relatively low (16.7%). Similarly, severe proteinuria was common in Group II. Half of the patients had proteinuria of nephritic range. In addition, DR was predominant in DN (76.7%). No statistically significant difference was detected between the two groups in renal insufficiency, hypertension, hyperlipidemia, and hyperuricemia.

Table 2. Clinical features

Clinical manifestations	Group I (n = 120)	Group II (n = 100)
Hematuria	20 (16.7%)	68 (68.0%)
Proteinuria	26 (21.7%)	50 (50.0%)
Renal insufficiency	28 (23.3%)	15 (15%)
Hypertension	78 (65.0%)	76 (76%)
Hyperlipidemia	78 (65.0%)	76 (76.0%)
Hyperuricemia	48 (21.7%)	50 (50.0%)
Diabetic retinopathy	92 (76.7%)	10 (10.0%)

Note: *p < 0.05 versus Group I.

Pathological Types

Histopathological findings in Group II patients showed IgA nephropathy as the commonest finding seen in 34 cases (34.0%), Membranous nephropathy in 22 cases (22.0%), followed by mesangial proliferative glomerulonephritis (14%, not including IgA nephropathy). Other pathological findings are summarized in Table 3.

Table 3. Histopathological findings in Group II (n = 100)

Pathological types	Case	Percentage (%)
IgA nephropathy	34	34.0
Membranous nephropathy	22	22.0
Mesangial proliferative GN^a	14	14.0
HBV-associated GN	8	8.0
Minor glomerular abnormalities	6	6.0
Minimal change disease	4	4.0
Hypertensive nephrosclerosis	4	4.0
FSGS	4	4.0
Crescentic GN	2	2.0
Lupus GN	2	2.0

Notes: GN: glomerulonephritis; HBV-associated GN: hepatitis B virus-associated glomerulonephritis; FSGS: focal segmental glomerulonephritis.

^aIgA nephropathy not included in this part.

DISCUSSION

The prevalence of NDRD in the diabetic patients who underwent kidney biopsy varies from 10% to 85% in different reports.^5–8 It widely depends on the selection criteria and the populations being studied.^9,10 Our study showed that 45.5% of biopsied type 2 diabetic patients were diagnosed as NDRD. This was in accordance with the previous studies where the prevalence of NDRD was found to range from 45% to 57%,^9,11–13 but different from other studies where the prevalence of NDRD was around 7–10%.^5,14 This low prevalence could be explained by the different selection criteria for doing renal biopsy in such patients.

In this study no significant difference was found between the two groups in age at the time of biopsy. In contrast, Soni et al.¹⁵ reported that patients with NDRD on the background of DGS were older than those with isolated DGS. Diabetic duration is an indicator of DN in type 2 diabetic mellitus. Patients with persistent proteinuria and a relatively short period of diabetes should be examined carefully to identify NDRD.¹⁶ This study did not show significant difference in the duration of diabetes between the two groups. This was in accordance with Amal et al.,¹⁷ whereas Soni et al.¹⁵ reported a shorter duration of diabetes with NDRD. Our study was in accordance with the previous study that showed no significant difference in the incidence of associated hypertension between the two groups.¹⁷ There was also no significant difference between the two studied groups in serum creatinine or creatinine clearance. This was in contrast to the results of Soni et al.¹⁵ and Taft et al.,¹⁸ where azotemia was higher in patients with NDRD on top of DGS. Our results were also in contrast to the previous studies that showed a significantly higher proteinuria in patients with DGS than in patients with NDRD on top of DGS.^9,17 In this study, the prevalence of hematuria was quite different between the two groups (17% vs. 68%). Severe proteinuria is common in DN, but hematuria is rarely found. Meanwhile, many entities of NDRD, such as IgA nephropathy, often manifest microscopic or gross hematuria. Thus, hematuria becomes an important differential indicator, which is supported by the study of Zhou et al.¹⁶ But, this study disagrees with Amal et al.¹⁷ in showing that hematuria is not a useful predictor of diabetic or NDRDs. DR is one of the microvascular complications of diabetic mellitus, which might have the same pathogenetic pathway as DN. Retinopathy, when if coexists with nephropathy, is thought to be a window of renal complication. Our study confirmed the accepted view that one of the important predictors of NDRD is the absence of retinopathy.^12,15,19 However, the presence of retinopathy should not rule out the need for renal biopsy, especially if the clinical scenario is atypical. A study by Wong et al.¹⁹ also showed that the association of hematuria or proteinuria with the absence of retinopathy constitutes the strongest indication for a nondiabetic lesion (positive predictive values of 94%). Thus, combination of indications constitutes a more sensitive predictor of NDRD than any of the indications alone.¹⁵

IgA nephropathy was the most common, accounting for 34% of all the NDRD. This indicated that we should pay more attention to the probability of nondiabetic renal injuries, especially IgA nephropathy in diabetic patients. Moreover, together with non-IgA mesangial proliferative glomerulonephritis (14%), all 48% of NDRD were predominantly mesangial proliferative glomerulonephritis. The number was similar to those in other Asian reports. Moreover, IgA nephropathy was found to be the commonest NDRD in other studies.^20,21 But other studies^15,17 showed that crescentic glomerulonephritis or acute tubulointerstitial nephr- itis and postinfectious glomerulonephritis were the commonest NDRD. Several observations suggest that common occurrence of IgA nephropathy in diabetic patients is not coincidental.^20–22 Diabetic itself by affecting either glomerular structure and functioning and/or nonenzymatic glycation of immunoglobulin may facilitate the development of immunopathological alterations.²³ In support of this notion, superimposed IgA nephropathy on DN was associated with higher IgA levels when compared with DN alone.²⁴ The characters, such as hematuria and proteinuria, mesangial proliferation, and tubulointerstitial lesions, were more frequently observed in diabetic patients with IgA, compared with IgA nephropathy. These findings could be indicative of a superimposed glomerular injury. Siu-Ka Mak et al.²⁵ indicated that the medium-term renal and patients outcome of type 2 diabetic patients with combined IgA nephropathy and DGS were similar to that of type 2 DGS alone. But a few reports have documented a rapid deterioration of renal function in patients with superimposed IgA nephropathy on top of DN, and diabetic microvascular complications are also worsened by superimposition of IgA nephropathy.^26,27 Because the inclusion criteria for renal biopsy in these retrospective series have included atypical clinical course like rapid loss of renal function among diabetic patients with renal involvement, selection bias leading to IgA nephropathy patients with aggressive renal outcome being picked up is a distinct possibility. It is apparent that only by prospectively recruiting type 2 diabetic patients with defined criteria for renal biopsy, although subsequently observing the clinical course of these patients, could one determine the true difference between the outcome of patients with DGS alone and those with superimposed IgA nephropathy.

The mechanism implicated in the development of NDRD in diabetic patients remains speculative. The predisposition of DGS to superimposed nephritis has been attributed to enhanced exposure of antigenic cellular components that trigger immune responses. Also, preexisting glomerular alterations might favor an immune reaction in the subepithelial space.¹⁵ Lai et al.,²⁸ however, found no difference in the prevalence of NDRD between patients with and without diabetes and that the coexistence of a different glomerulonephritis in the diabetic kidney might be coincidental.

Therapeutic decisions based on the results of the biopsy may differ – treatment of diabetic patients with nondiabetic nephropathy may be adjusted to eliminate the primary trigger causing the renal pathology with a potential to halt or reverse the decline in renal function. Lesions such as focal segmental glomerulosclerosis, minimal change disease, and membranous glomerulonephritis may be successfully treated with corticosteroids or other immunosuppressive agents. But diabetic patients were probably less likely than their nondiabetic counterparts to receive immunosuppressive agents, because of the tendency of hyperglycemia and infection. Although aggressive treatment of these lesions may not always lead to complete remission of the underlying disease, induction of even partial remission could prolong renal survival in a patient with chronic kidney disease. Therefore, clinicians must consider the risk/benefit ratio before initiating specific treatment.

In conclusion, this study showed that NDRD was seen in 45.5% of the studied diabetic population and IgA nephropathy is the commonest NDRD among diabetic patients. A higher level of proteinuria and hematuria with the absence of retinopathy strongly predicts NDRD superimposed on DGS. Therefore, we recommended an individual physician's judgment of renal biopsy in type 2 diabetics to identify those patients with a treatable lesion and for better determining the renal outcome. Our study has some limitations. It was a retrospective single center study that concluded a small number of patients from the same geographical area. A more longitudinal study needs to be done on a larger number of diabetic patients to evaluate the actual prevalence of NDRD in diabetic patients.

Declaration of interest: The authors acknowledge the assistance of Fang Wang, Na Li, Xinke Yuan and all the workers in the medical record library for assistance with the records collection and data analysis. The authors report no conflicts of interest.