| Abstract|| |
Diabetes mellitus is the most common cause of chronic kidney disease worldwide. The prevalence of nondiabetic renal disease (NDRD) among patients with type 2 diabetes mellitus (T2DM) varies widely. This study aimed to evaluate the renal biopsies performed on type 2 diabetic patients for suspicion of NDRD and to correlate clinicopathological findings. All T2DM patients aged > 18 years were included in this study, who had renal biopsy performed for the following reasons: recent-onset nephrotic syndrome, unexplained rapid deterioration of renal function, proteinuria not accompanied by retinopathy, and unexplained hematuria. Renal biopsy was analyzed by light microscopy and immunofluorescence. Based on biopsy findings, the patients were grouped into three: (i) isolated NDRD, (ii) NDRD ± diabetic nephropathy (DN), and (iii) isolated DN. A total of 140 patients were enrolled in this study. Recent-onset nephrotic syndrome was the most common indication for biopsy, followed by the presence of active urine sediment. Forty-two percent of the patients had isolated DN, while NDRD was seen in 34% and DN ± NDRD in 24%. Focal segmental glomerulosclerosis (FSGS) and IgA nephropathy were the most common causes of isolated NDRD, while chronic tubulointerstitial nephritis (CTIN) was common in NDRD plus DN. Short duration of diabetes, absence of diabetic retinopathy, and lower glycated hemoglobin were predictive of NDRD. NDRD was seen in 58% of the patients with atypical presentations. FSGS and CTIN were common in NDRD diseases. Judicious use of biopsy in diabetic patients with atypical presentation may help in the diagnosis of NDRD.
|How to cite this article:|
Sharma M, Parry MA, Jeelani H, Mahanta PJ, Doley PK, Pegu G. Prevalence of Nondiabetic Renal Disease in Patients with Type 2 Diabetes Mellitus with Clinicopathological Correlation: A Study from a Tertiary Care Center of Assam, India. Saudi J Kidney Dis Transpl 2020;31:831-9
|How to cite this URL:|
Sharma M, Parry MA, Jeelani H, Mahanta PJ, Doley PK, Pegu G. Prevalence of Nondiabetic Renal Disease in Patients with Type 2 Diabetes Mellitus with Clinicopathological Correlation: A Study from a Tertiary Care Center of Assam, India. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Sep 23];31:831-9. Available from: http://www.sjkdt.org/text.asp?2020/31/4/831/292318
| Introduction|| |
Around 415 million people were estimated to have diabetes mellitus (DM) worldwide in 2015, and it is projected to increase to 642 million, with disproportionate growth in low- to middle-income countries driven by an increase in the prevalence of type 2 diabetes mellitus (T2DM) secondary to obesity and metabolic syndrome., DM is the most common cause of end-stage renal disease (ESRD) requiring renal replacement therapy with co-existence of DM and renal damage increasing the risk of death and cardiovascular events. Diabetic nephropathy (DN) refers to specific pathologic structural and functional changes seen in the kidneys of patients with DM that result from the effects of DM on the kidney. These changes result in a clinical presentation that is characterized by protei- nuria, hypertension (HTN), and progressive reduction in kidney function.
About 30%–40% of the patients with diabetes with at least 10 years of history of the disease present with a frank DN characterized by peculiar histological features at the glomerular level including nodular or diffuse mesangial sclerosis, arteriolar hyalinosis, microaneurysms, and exudative lesions. This histopathological pattern is frequently seen in young and lean patients with type 1 DM, but biopsy samples from patients with T2DM often indicate the presence of other pathogenic factors, such as primary glomerulopathies, aging-related nephro- pathy, or previous episodes of acute kidney injury (AKI).
Increased longevity, changes in diet and lifestyle, and an increased incidence of episodes of AKI (ischemic and toxic) have increased the global prevalence of chronic kidney disease (CKD) independent of DM.,,, Higher prevalence of CKD in adults with DM may in part be attributable to the presence of nondiabetic renal disease (NDRD) which may not be suspected on the basis of clinical signs or urine abnormality., Many patients with diabetes erroneously labeled as having progressive forms of DN are rather developing NDRD or “mixed” conditions where typical features of DN overlap with other kinds of histological damage. Thus, coincident CKD in a patient with DM can be true DN (as a result of the DM), NDRD, or a combination of NDRD and DN: these three entities can be reliably distinguished only by kidney biopsy.,
The utility of kidney biopsy in patients with diabetes is currently an object of debate. Since there is no overall consensus on timing and indications, the decision to perform kidney biopsy is usually based on personal opinions or single-center policies. The aim of this study to determine the spectrum of kidney biopsy performed on patients with T2DM for clinical suspicion of NDRD and to determine the predictability of diagnosing NDRD with or without DN versus isolated DN in patients with T2DM based on clinical and laboratory data.
| Material and Methods|| |
This was a cross-sectional observational study conducted in Gauhati Medical College and Hospital, Guwahati, from January 1, 2016, to December 31, 2018. All patients with T2DM who presented with clinical suspicion of NDRD were subjected to kidney biopsy after informed consent about the need of the same and were included in the study. Data regarding age, gender, duration of diabetes, presence or absence of diabetic retinopathy (DR), and arterial HTN were recorded for all patients. The indications for renal biopsy in our study were active urinary sediment (hematuria with dysmorphic red blood cells or red blood cell casts), recent onset of nephrotic syndrome (with nephrotic syndrome defined as proteinuria of > 3.5 g/day/1.73 m2 body surface area with edema and/or serum albumin <3.5 g/dL), proteinuria without retinopathy, unexplained AKI (AKI defined as increase in serum creatinine by > 0.3 mg/dL within 48 h or > 1.5 times baseline that is presumed to have occurred within the prior 7 days), and rapidly progressive renal failure.
Fasting blood glucose, serum urea, crea- tinine, sodium, potassium, glycosylated hemoglobin (HbA1C), urine routine examination, urine culture sensitivity, 24-h urine protein, and ultrasonography of the whole abdomen were evaluated in all patients. Glomerular filtration rate (GFR) was estimated using four- variable modification of diet in renal disease study formula. Serological tests for antinuclear antibodies, anti-double-stranded DNA, complement levels (C3 and C4), and antineutrophil cytoplasmic antibodies were performed in selected patients. Funduscopic examination was performed in all patients by an ophthalmologist.
All kidney biopsies were performed under ultrasonographic guidance using an 18G kidney biopsy needle. Two cores of tissue were obtained: one was submitted for light microscopy and other for immunofluorescence studies. Electron microscopy was not performed due to nonavailability. For light microscopic examination, 3 μm thick paraffin sections were stained with periodic acid–Schiff, hematoxylin-eosin, Jones’ methenamine silver, and Gomori’s trichrome. Immunofluorescence staining was performed for the detection of antibodies to IgG, IgA, IgM, C1q, and C3. DN was defined as findings of mesangial expansion, diffuse intercapillary glomerulosclerosis and/or nodular Kimmelstiel–Wilson formation, basement membrane thickening, the presence of fibrin cap, or capsular drops. The determination of specific renal histopathological findings was accepted as NDRD. Acute tubular necrosis (ATN) was diagnosed if nonatrophic tubules displayed diffuse acute tubular injury, including epithelial simplification, loss of brush border, and focal cytoplasmic shedding and acute interstitial nephritis (AIN) if interstitial inflammatory cell infiltrates included eosinophils and involved areas without tubular atrophy/interstitial fibrosis.
Based on biopsy findings, patients were categorized into three groups:
- Group I: Isolated DN
- Group II: Isolated NDRD
- Group III: NDRD superimposed on underlying DN.
Patients with the typical clinical course of DN and the presence of DR, patients with urinary tract infection, urinary tract obstruction, acute/chronic liver disease, and active malignancy, patients aged <18 years, patients with secondary causes for diabetes, patients with inadequate biopsy, and patients without consent were excluded.
The IBM SPSS Statistics software version 23.0 (IBM Corp., Armonk, NY, USA) was used for the analyses. Continuous data were expressed as mean ± standard deviation and noncontinuous data in percentage and numerical values. Differences between the groups were assessed using the Pearson’s Chi-square test for categorical variables and Kruskal–Wallis/Mann–Whitney U-test for numerical variables. Logistic regression analysis was done using the Wald test. P < 0.05 was considered statistically significant.
| Results|| |
A total of 140 patients with T2DM who were suspected of having NDRD underwent renal biopsy from January 2016 to December 2018. The mean age of our study population was 49.04 ± 7.31 years. Approximately 64% of the patients were males. The mean duration of diabetes was 6.29 ± 2.03 years. In our study population, the mean serum creatinine was 2.78 ± 1.89 mg/dL and estimated GFR was 35.95 ± 21.44 mL/min/1.73 m2. The mean proteinuria of the study population was 2.83 ± 1.99 g/day, with 59 patients (42%) having nephrotic range proteinuria. Fifty-nine patients (42%) had isolated DN, 48 (34%) had isolated NDRD, and 33 (23.5%) had DN plus NDRD. [Table 1] and [Table 2] summarize the clinical and laboratory parameters of the whole study population and of the three histology groups. Patients with isolated DN had a significantly longer duration of diabetes than patients with isolated NDRD (7.61 ± 1.62 years vs. 4.88 ± 1.43 years, P < 0.001). The prevalence of DR was significantly higher in patients with isolated DN (52.5%) than patients with isolated NDRD (22.9%) and patients with DN plus NDRD (42.8%), with P = 0.008. Patients with DN had significantly higher serum creatinine than those with isolated NDRD or DN plus NDRD (P = 0.003). Significantly higher HbA1C and serum total cholesterol were seen in patients with isolated DN than patients with isolated NDRD. Proteinuria was significantly (P = 0.003) higher in patients with isolated DN (3.33 ± 2.01 g/day) than patients with isolated NDRD (2.79 ± 1.84 g/day) and patients with DN plus NDRD (2.02 ±1.94 g/day).
|Table 2: Demographic and clinical characteristics of the study patients at the time of renal biopsy.|
Click here to view
Indications for renal biopsy [Figure 1] included recent onset of nephrotic syndrome in 57 patients (40.7%), rapidly progressive renal failure in 23 patients (16.4%), active urinary sediment in 31 patients (22.14%), AKI in 11 patients (7.8%), and renal failure without retinopathy in 18 patients (12.8%). Among patients who underwent renal biopsy, most of the patients who had presented with recent onset of nephrotic syndrome turned out to have isolated DN (56.14%), while most of the patients who presented with active urine sediment had NDRD (54.8%). All patients with AKI turned out to have DN plus NDRD picture in biopsy. Moreover, in patients presenting with rapidly progressive renal failure, DN was seen in 60% and NDRD in 40%.
In our study, pure DN was seen in 59 patients (42.14%), while NDRD (either isolated NDRD or superimposed on DN) was seen in 81 patients (57.85%). Isolated NDRD was seen in 48 patients (34%), and NDRD superimposed on DN was seen in 33 patients (23.57%). [Table 3] shows the renal histological lesions identified in patients with isolated DN and in those with NDRD superimposed on DN. The most common NDRDs with concomitant DN were chronic tubulointerstitial nephritis (CTIN) (39.4%), AIN (18.2%), IgA nephropathy (IgAN, 15.2%), and ATN (15.2%). In patients with isolated NDRD, focal segmental glome- rulosclerosis (FSGS, 33.3%), and IgAN (20.8%) were the most common histology seen. Membranous nephropathy and myeloma cast nephropathy were seen in six patients (12.5%) each in isolated NDRD.
|Table 3: Renal pathology of nondiabetic kidney disease, with and without diabetic nephropathy, in type 2 diabetes patients.|
Click here to view
Univariate analysis in our study indicated that short duration of diabetes, absence of DR, lower serum cholesterol levels, lower serum albumin levels, lower glycated hemoglobin, lower proteinuria, and active sediment in urine were significantly associated with NDRD (± DN). In the multivariate regression analysis [Table 4], duration of diabetes and the presence of diabetic retinopathy were present more associated with DN but did not reach statistical significance.
|Table 4: Multivariate analysis of clinical parameters in patients with nondiabetic kidney disease with or without diabetic nephropathy.|
Click here to view
| Discussion|| |
DN is one of the important and frequent complications of DM and has become the most common cause of ESRD worldwide., The likelihood that some patients with suspected DN, in fact, have NDRD or NDRD plus DN has not been appropriately acknowledged in preclinical or clinical studies despite the need for these disease entities to be distinguished in order to improve understanding of disease pathogenesis and develop appropriate pre- clinical models for drug development. In the absence of a diagnostic biopsy, registries often assign a diagnosis of DN or diabetic kidney disease (DKD) to patients with DM plus CKD, increasing the prevalence of DKD. The prevalence of NDRD can vary from 12% to 79%, depending on the selection criteria and the population being studied.,,,,, Predictive factors for NDRD identified in various studies include abrupt onset of nephrotic syndrome, rapid decline of renal function, absence of DR, and presence of active urinary sediment.,
In our study, the mean duration of diabetes before the biopsy was 6.29 ± 2.03 years. In the DN group, it was 7.6 ± 1.62 years, in the NDRD group, it was 4.88 ± 1.43 years, and in the mixed group, it was 5.97 ± 1.96 years, which was statistically significant. This was similar to the study by Soni et al, in which duration of diabetes was significantly less in the NDRD group compared to the mixed or DN group. In another study by Sharma et al, the median duration of DM in patients with NDRD alone was five years, which was significantly shorter than in patients with DN alone (13 years) and DN plus NDRD (10 years), and DM duration > 12 years was predictive of DN alone., Tone et al found that short duration of diabetes (<5 years) carried high sensitivity (75%) and specificity (70%) for predicting NDRD, and Chang et al reported a mean DM duration of 5.9 years in patients with NDRD versus 10.6 years in patients with DN alone (P < 0.001). Similar results were seen in other studies.,, However, some studies with a smaller cohort reported no difference of diabetes duration between the groups with DN and NDRD., In our study, proteinuria was significantly higher in patients with DN compared to patients with isolated NDRD. This was similar to other studies.,,,, Serum albumin was significantly lower in patients with DN which can be explained by higher proteinuria in this group of patients. There was no significant difference in the prevalence of hypertension in all the three groups in our study; this finding is similar to other studies., In our study, the most frequent indication for renal biopsy was recent onset of nephrotic syndrome, rapidly progressive renal failure, and active urinary sediment. Most of the patients with recent-onset nephrotic syndrome had isolated DN in renal biopsy. This could be due to poorly controlled blood sugar in these patients that lead to the development of microvascular complications and progressive increase in proteinuria.
In our study, isolated DN was seen in 59 patients (42.1%), isolated NDRD was seen in 48 patients (34.3%), and mixed DN plus NDRD was seen in 33 patients (23.5%). The prevalence of NDRD (either alone or superimposed on DN) in our study was comparable to that of other studies. In a large cohort of T2DM patients who underwent biopsy, studied by Sharma et al, 67% had NDRD (either DN with NDRD or NDRD alone) and 37% had isolated DN. In another study by Soni et al, out of 160 T2DM patients who underwent kidney biopsy, 72.5% had either NDRD alone or superimposed on DN. In the isolated NDRD group, FSGS was the most common histological lesion (33.3%), followed by IgAN (20.8%); IgAN and cast nephropathy were seen in 12.5%. In the mixed group, CTIN was the most common biopsy finding (39.4%), followed by ATN and AIN. In a study by Soni et al, FSGS and membranous nephropathy were the most common biopsy findings in the NDRD group, while AIN and post-infectious glomerulonephritis were more common in the mixed group. FSGS was also the most common diagnosis in patients with NDRD cohort in the study by Sharma et al with ATN common in the mixed group. While FSGS is the main diagnosis of NDRD in Western countries, IgAN is the predominant histo- logical lesion in the studies from China and Korea accounting for around 50% of non- diabetic glomerular diagnosis.,, Higher prevalence of IgAN as a primary glomerular disease in these countries can account for this higher prevalence of IgAN in NDRD. Thus, the prevalence of different categories of biopsy- proven renal disease in diabetic patients depends on the usual prevalence of renal disease in the total population according to the geographical area and ethnic characteristics of the population.
In our study, DR was significantly correlated with the presence of DN (P = 0.008). However, in multivariate analysis, it was not an independent predictor of DN. In a study by Soni et al, the absence of retinopathy predicted NDRD in 68% of the cases. Similar findings were reported on other studies.,, In a meta-analysis by He et al, the sensitivity and specificity of DR in predicting DN were 65% [95% confidence interval (CI): 0.62-0.68] and 75% (95% CI: 0.73–0.78), respectively. Predictive role of diabetic retinopathy with respect to DN was questioned by Liang et in a study, since the absence of DR was also associated with DN. In a study by Prakash et al, DN was present in about 50% of the diabetics without diabetic retinopathy, while 40% of the patients with DR had other renal diseases. Similarly, the absence of correlation between DR and NDRD was seen in two studies by Mak et al and Lin et al., Discordance in the occurrence of DR and DN reported has been suggested to be due to dissimilar genetic predispositions.
| Conclusion|| |
In our study, DN was the most common histological pattern with NDRD seen in one- third of patients and mixed pattern in around one-fourth of patients. FSGS was the most common pattern in the pure NDRD group, while CTIN was common in the mixed group. Short duration of diabetes, lower glycated hemoglobin, absent DR, and active urinary sediment were independent predictors of NDRD (± DN) on univariate analysis. However, on multivariate analysis, none were significantly predictive of NDRD. Thus, we can conclude that NDRD cannot be predictive on clinical grounds and judicious use of renal biopsy can be useful.
| Acknowledgments|| |
The authors would like to thank all the supporting staff at the Nephrology Department, Gauhati Medical College and Hospital, for their help in conducting this study. Furthermore, we would like to pay our gratitude to Dr. Sheema Samreen for help in statistical analysis.
| Source(S) of Support|| |
Gauhati Medical College and Hospital, Guwahati Assam, India.
Conflict of interest: None declared.
| References|| |
International Diabetes Federation: Diabetes Atlas. 7th
ed. Brussels, Belgium: IDF Executive Office; 2015.
World Health Organization. Global Status Report on Noncommunicable Diseases, Geneva, Switzerland: World Health Organization; 2014.
Navaneethan SD, Schold JD, Jolly SE, Arrigain S, Winkelmayer WC, Nally JV Jr. Diabetes control and the risks of ESRD and mortality in patients with CKD. Am J Kidney Dis 2017;70:191-8.
Liang S, Zhang XG, Cai GY. Identifying parameters to distinguish nondiabetic renal diseases from diabetic nephropathy in patients with type 2 diabetes mellitus: A meta-analysis. PLoS One 2013;8:e64184.
Bolignano D, Mattace-Raso F, Sijbrands EJ, Zoccali C. The aging kidney revisited: A systematic review. Ageing Res Rev 2014; 14:65-80.
ERA-EDTA Registry. ERA-EDTA Registry Annual Report, Department of Medical Informatics, Amsterdam, The Netherlands; 2016.
Bello AK, Levin A, Tonelli M, et al. Assessment of global kidney health care status. JAMA 2017;317:1864-81.
Saran R, Robinson B, Abbott KC, et al. US renal data system 2016 annual data report: Epidemiology of kidney disease in the United States. Am J Kidney Dis 2017;69:A7-A8.
Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of chronic kidney disease — A systematic review and meta-analysis. PLoS One 2016;11:e0158765.
Gonzalez Suarez ML, Thomas DB, Barisoni L, Fornoni A. Diabetic nephropathy: Is it time yet for routine kidney biopsy? World J Diabetes 2013;4:245-55.
Sharma SG, Bomback AS, Radhakrishnan J, et al. The modern spectrum of renal biopsy findings in patients with diabetes. Clin J Am Soc Nephrol 2013;8:1718-24.
Fiorentino M, Bolignano D, Tesar V, et al. Renal biopsy in patients with diabetes: A pooled meta-analysis of 48 studies. Nephrol Dial Transplant 2017;32:97-110.
Collins AJ, Foley RN, Gilbertson DT, Chen SC. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl (2011) 2015;5:2-7.
Soni SS, Gowrishankar S, Kishan AG, Raman A. Non diabetic renal disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; 11:533-7.
Gambara V, Mecca G, Remuzzi G, Bertani T. Heterogeneous nature of renal lesions in type II diabetes. J Am Soc Nephrol 1993;3:1458- 66.
Mak SK, Gwi E, Chan KW, et al. Clinical predictors of nondiabetic renal disease in patients with non-insulin dependent diabetes mellitus. Nephrol Dial Transplant 1997;12: 2588-91.
Ruggenenti P, Gambara V, Perna A, Bertani T, Remuzzi G. The nephropathy of non-insulin- dependent diabetes: Predictors of outcome relative to diverse patterns of renal injury. J Am Soc Nephrol 1998;9:2336-43.
Pham TT, Sim JJ, Kujubu DA, Liu IL, Kumar VA. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol 2007;27:322- 8.
Chang TI, Park JT, Kim JK, et al. Renal outcomes in patients with type 2 diabetes with or without coexisting non-diabetic renal disease. Diabetes Res Clin Pract 2011;92:198- 204.
Tone A, Shikata K, Matsuda M, et al. Clinical features of nondiabetic renal disease in patients with Type 2 diabetes. Diab Res Clin Pract 2005;69:237-42.
Kanodia KV, Vanikar AV, Nigam L, Patel RD, Suthar KS, Patel H. Clinicopathological study of nondiabetic renal disease in type 2 diabetic patients: A single center experience from India. Saudi J Kidney Dis Transpl 2017;28: 1330-7.
] [Full text]
Kritmetapak K, Anutrakulchai S, Pongchaiyakul C, Puapairoj A. Clinical and pathological characteristics of non-diabetic renal disease in type 2 diabetes patients. Clin Kidney J 2018; 11:342-7.
Lee EY, Chung CH, Choi SO. Non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Yonsei Med J 1999;40:321-6.
Matias P, Viana H, Carvalho F, Santos JR. Diabetes mellitus and renal disease: when to perform a renal biopsy? Port J Nephrol Hypert 2009;23:167-73.
Yaqub S, Kashif W, Hussain SA. Non-diabetic renal disease in patients with type-2 diabetes mellitus. Saudi J Kidney Dis Transpl 2012;23: 1000-7. [Full text]
He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: A meta-analysis. Diabetologia 2013;56:457-66.
Prakash J, Lodha M, Singh SK, Vohra R, Raja R, Usha. Diabetic retinopathy is a poor predictor of type of nephropathy in proteinuric type 2 diabetic patients. J Assoc Physicians India 2007;55:412-6.
Lin YL, Peng SJ, Ferng SH, Tzen CY, Yang CS. Clinical indicators which necessitate renal biopsy in type 2 diabetes mellitus patients with renal disease. Int J Clin Pract 2009;63:1167- 76.
Simó-Servat O, Hernández C, Simó R. Genetics in diabetic retinopathy: Current concepts and new insights. Curr Genomics 2013;14:289-99.
Manzoor Ahmad Parry
Department of Nephrology, Gauhati Medical College and Hospital, Bhanghagarh, Kamrup (M), Assam
[Table 1], [Table 2], [Table 3], [Table 4]