| Abstract|| |
Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM), leading to chronic kidney disease/end-stage renal disease. Wide spectrum of nondiabetic renal diseases (NDRD) is reported in type-2 diabetes (type-2 DM). We carried out this single-center study to find clinical, laboratory, and histological features of NDRD in type-2 DM patients and to assess the prevalence of NDRD in India. A single-center retrospective study which included analysis of renal biopsies from patients with type-2 DM, performed between January 2008 and September 2016. Biopsy findings were categorized into three groups, Group-I (isolated NDRD); Group-II (NDRD superimposed on underlying DN); and Group-III (isolated DN). Out of 152 diabetic patients (111 males and 41 females), 35 (23.03%) patients were of Group-I (isolated NDRD), 35 (23.03%) of Group-II (NDRD superimposed on underlying DN), and 82 (53.95%) of Group-III (isolated DN). The mean age (in years) was 55.08 ± 10.71, 55.65 ± 8.71, and 54.45 ± 9.01 respectively in Group-I, II, and III. Nephrotic syndrome (NS) was the most common clinical presentation in all groups. Duration of DM was significantly shorter in Group-I than in Group-II. Diabetic retinopathy was absent in Group-I. Proteinuria was more in Group-III than Group-I. Low serum C3 and/or C4 levels was observed in five (14.29%) cases of Group-I and Group-II each and two (2.43%) cases of Group-III. Nearly, 70 (46.05%) patients were found to have NDRD either in isolated form or as combined lesions. The most common histological types of NDRD were acute tubulointerstitial nephritis (38.57%) followed by benign nephrosclerosis (15.72%), membranous nephropathy (10%), IgA nephropathy (7.14%), and membranoproliferative glomerulonephritis (7.14%). The incidence of NDRD (with/without DN) in type-2 DM is very high. Shorter duration of diabetes, hematuria, absence of retinopathy, low serum complement levels, and nephrotic range proteinuria are predictors of NDRD.
|How to cite this article:|
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
|How to cite this URL:|
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 [serial online] 2017 [cited 2019 Sep 21];28:1330-7. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1330/220877
| Introduction|| |
The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide. The World Health Organization has recognized DM as a global epidemic, and about 20%–40% of diabetic patients develop diabetic renal disease on follow-up.,
In addition, patients with type-2 DM are prone to develop renal diseases other than DN.,, The precise diagnosis of these nondiabetic renal diseases (NDRD) have prognostic and therapeutic implications, and it can be difficult to clinical difference between NDRD and diabetic nephropathy (DN).,
In type-1 DM, NDRD is rare and accounts for only 2%–3% of unselected cases with proteinuria. The clinical criteria for suspecting NDRD in patients with type-1 DM to suspect NDRD are microhematuria, absence of diabetic retinonephropathy, uncharacteristic change in renal function, and immunological abnormalities., The prevalence of NDRD in type-2 DM varies from 12%–80% depending on selection criteria and the study population.,,,,,,,,,,,,,,,,,, The prevalence of NDRD in Asian and European patients was reported to be 26.7% and 22% respectively from various studies.,,,,,,,,,,,, It is important to differentiate DN and NDRD because their therapy and prognosis are different. We carried out this single-center retrospective study to find the clinical, laboratory, and histological features of NDRD in type-2 DM patients and to assess the prevalence of NDRD.
| Materials and Methods|| |
We analyzed renal biopsies from patients diagnosed with type-2 DM from January 2008 to September 2016. Postrenal transplant recipients and inadequate renal biopsies were excluded. The indication of renal biopsies in patients with NDRD included persistent hematuria, active urinary sediments, rapidly progressive renal failure (RPRF), sudden onset of nephrotic syndrome (NS), proteinuria in the absence of diabetic retinopathy (DR), and short duration of diabetes. All biopsies were performed by Nephrologists under ultrasonographic guidance using 18 gauge renal biopsy needle. Two cores of renal tissue were obtained, one was submitted for light microscopy (LM) and other for immunofluorescence (IF) studies. Electron microscopy (EM) was not performed due to its nonavailability. For LM, 3 μm thick paraffin sections were stained with hematoxylin and eosin (H&E), Periodic acid–Schiff, Jone's methenamine silver, and Gomori's trichrome stains. IF sections were stained using anti-human IgG, IgA, IgM, C3, and C1q antisera (MP bio-medical, USA), antihuman kappa and lambda light chain anti-sera, fibrinogen antiserum as indicated in selected cases of acute nephritis/rapidly progressive renal failure or suspected vasculitis. Diabetic glomerulosclerosis was diagnosed by mesangial expansion, diffuse intercapillary glomerulosclerosis with or without Kimmelstiel-Wilson nodule formation, basement membrane thickening and fibrin cap or capsular drop lesions with hyaline arteriosclerosis. Based on biopsy findings, patients were categorized into three groups; Group-I: isolated NDRD, Group-II: NDRD superimposed on underlying DN, and Group-III: isolated DN. Clinical parameters included age, gender, duration of diabetes, presence or absence of hypertension (HTN) and retinopathy. Laboratory parameters studied included serum creatinine (SCr) (mg/dL), serum urea (mg/dL), fasting and postmeal sugar (mg/dL), urine examination, and 24-h urine protein estimation. Serological studies for antinuclear antibody (ANA), anti-double stranded DNA (dsDNA) and complement C3 and C4 levels were performed in selected cases. Funduscopic examination was performed in all patients by ophthalmologist.
NS was defined as proteinuria of >3.5 g/day/1.73 m2 body surface area with edema and/or hypoalbuminemia (serum albumin <3.5 g/dL). Acute kidney injury (AKI) was defined as abrupt loss of renal function with increase in SCr by ≥0.3 mg/dL within 48 h; or increase in SCr by ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days or urine volume of <0.5 mL/kg/h for 6 h. Hematuria was defined as ≥3 erythrocytes/high power field on urine microscopic examination. Chronic renal failure (CRF) was defined as abnormalities of kidney structure or function present for >3 months with glomerular filtration rate <60 mL/min/1.73 m2 and elevated SCr (>1.5 mg/dL). RPRF was defined as renal failure over days/weeks with proteinuria usually <3 g/day, hematuria and red cell casts. Hypertension was defined when blood pressure was ≥140/90 mm Hg.
| Statistical Analysis|| |
Collected data were analyzed using IBM Statistical Package for the Social Sciences for Windows version 21.0 (SPSS Inc., Chicago, IL, USA). Continuous data were expressed as mean ± SD and noncontinuous data in percentage and numerical values. Differences between groups were assessed using the univariate Chi-square test for categorical variables. ANOVA and Kruskal–Wallis tests were used for continuous variables. P <0.05 was considered statistically significant.
| Results|| |
Out of 152 diabetic patients, 111 were males and 41 were females, 35 (23.03%) patients belonged to Group-I (isolated NDRD), 35 (23.03%) to Group-II (NDRD superimposed on underlying DN) and 82 (53.95 %) to Group-III (isolated DN). The mean age was 55.08 ± 10.71 years, 55.65 ± 8.71 years and 54.45 ± 9.01 years in Group-I, II, and III, respectively [Table 1].
The indications of renal biopsy included NS in 65 (42.76%), AKI in 34 (22.36%), RPRF in 19 (12.5%), CRF in 18 (11.84%), and HTN in 16 (10.52%) patients. The most common clinical presentation in Group-I was NS in 17 (48.57%) followed by AKI in 12 (34.28%) patients. In Group-II, AKI was observed in 10 (28.57%), NS in nine (25.71%), and RPRF in nine (25.71%) patients. In Group-III, the most common presentation was NS 39 (47.56%) followed by CRF in 13 (15.85%) and HTN in 12 (14.63%) patients [Table 2].
The duration of DM was significantly shorter in Group-I (5.59 ± 4.96 years) than in Group-III (10.45 ± 6.62 years) (P = <0.01). SCr was also significantly higher in Group-II than in Group-I and Group-III (P = <0.01). DR was absent in all patients of Group-I. Blood pressure was comparable in all the groups. Hematuria was observed in 34.28% cases of Group-I and 25.6% of cases in Group-III. Proteinuria was higher in Group-III when compared to Group-I and II.
Serological evaluation was done in 98 (64.5%) cases. Out of these, low serum C3 and/or C4 level was reported in five (14.29%) patients of Group-I and Group-III each and in two (2.43%) patients of Group-III [Table 3]. However, out of 12 cases of low serum complement level, only four (25%) were associated with hypocomplementemic glomerulonephritis (lupus nephritis, membranoproliferative glomerulonephritis, and postinfectious glomerulonephritis). Remaining eight cases had secondary FSGS or hypertensive nephropathy.
The histological lesions observed in Group-I and Group-II are presented in [Table 4]. The most common histological lesion was membranous nephropathy (MN) (17.14%) followed by IgA nephropathy (IgAN) (11.42%) and mesangial proliferative glomerulonephritis (MePGN) (8.57%) in Group-I and acute tubulointerstitial nephritis (ATIN) (57.14%) followed by benign nephrosclerosis (25.71%) in Group-II.
Nearly, 70 (66%) patients had NDRD either in isolated form or as combined lesion. The most common type of NDRD was ATIN (38.57%) followed by benign nephrosclerosis (15.72%), MN (10%), IgAN (7.14%), MPGN (7.14%), and MePGN (4.2%) [Figure 1].
|Figure 1. Frequency of histological lesions in NDRD and NDRD superimposed on underlying DN patients|
NDRD: Nondiabetic renal diseases, DN: Diabetic nephropathy.
Click here to view
The prevalence of total NDRD (isolated and combined disease) in our study was 66% and ATIN was most common histological lesion. In other regions of the world, the prevalence was also reported more than 60% [Table 5].
| Discussion|| |
The prevalence of total NDRD (isolated and combined disease) in our study was 66% which was comparable to that reported in India, and other regions of the world where the prevalence observed was more than 60%. Lower prevalence reported in some part of the world may be due to small cohort of study or geographic and ethnic factors.
Males were more commonly affected than females in all the three groups, but more males were in each group. Similar results were reported in other studies.,, Age was comparable in all three groups.
In this study, the duration of diabetes was significantly less in the isolated NDRD group compared with the other studies.,,,,,,,,,, However, Mak et al and Bertani et al found no significant difference in the duration of diabetes among the different groups.,
We found SCr was significantly high in combined disease than in patients with isolated NDRD and DN. Yaqub et al have also reported that SCr levels were significantly higher in patients with DN than NDRD. Similar results were also reported by Matias et al.
In this study, proteinuria was higher in patients with DN than those with NDRD. The previous study also reported that proteinuria was comparatively higher and favored DN than NDRD.,, Sharma et al has also mentioned that shorter duration of DM and subnephrotic proteinuria suggest NDRD alone.
In our study, blood pressure was comparable in all groups. Similar reports were noted in previous studies. Zhou et al have also reported that the mean systolic blood pressure in patients of DN group was higher than in NDRD group.
Hematuria is observed more with patients having NDRD and combined disease than in patients with DN in our study. There is a strong correlation between NDRD and microscopic hematuria which has been reported in various studies.,,, However, we did not find a statistically significant difference in hematuria between both groups.
DR is more frequently seen in DN and absence of DR is a predictor of NDRD. In type-1 DM, nearly, 90% of the patients develop DR but in type-2 DM, the incidence varies from 40% to 75%. DR was absent in all patients with NDRD in our study. Several other studies also showed that absence of DR is an important predictor of NDRD.,,,
We have reported low serum complement (C3 and/or C4) levels in patients with isolated NDRD and combined disease rather than DN alone. Hypocomplementemic glomerulonephritis was reported in 25% of cases. Serum ANA/dsDNA levels were also comparatively more in patients of Group-I as compared to patients of Group-II and Group-III.
Wong et al reported that absence of retinopathy, with hematuria and/or proteinuria ≥2 g/day constitute the strongest indication of NDRD. Thus, combination of indicators constitute a more sensitive predictor of NDRD than any one of them alone.
We reported 70 (46.05%) patients with NDRD either in isolated form or as combined lesions. The most common NDRD were ATIN (38.57%), benign nephrosclerosis (15.71%) followed by IgAN (7.14%), and MPGN (7.14 %). The other Indian studies also reported ATIN, MN, and MCD as the common histological lesions of NDRD., However, FSGS was the most common NDRD reported in American and IgAN in Korean population.,,
| Limitations of study|| |
EM was not performed due to its nonavailability. EM study would be helpful for further confirmation of NDRD and DN. The sample size was small as compared to few other studies. Bigger sample size may be helpful for further defining of the prevalence of NDRD and common histological lesion.
| Conclusion|| |
The incidence of NDRD (isolated/combined with DN) in type-2 DM is very high in our study population. Shorter duration of diabetes, hematuria, absence of retinopathy, nephrotic range proteinuria with low serum complement levels strongly predict NDRD. Renal biopsy should be considered in diabetics in the absence of retinopathy, with hematuria and/or proteinuria ≥2 g/day constitute the strongest indication of NDRD to determine the underlying cause of proteinuria.
Conflict of interest: None declared.
| References|| |
Kikkawa R, Koya D, Haneda M. Progression of diabetic nephropathy. Am J Kidney Dis 2003;41:S19-21.
Ritz E, Rychlík I, Locatelli F, Halimi S. Endstage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am J Kidney Dis 1999;34:795-808.
Prakash J. Non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (type 2 DM). J Assoc Physicians India 2013;61:194-9.
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.
John GT, Date A, Korula A, et al. Nondiabetic renal disease in noninsulin-dependent diabetics in a South Indian hospital. Nephron 1994;67: 441-3.
Kleinknecht D, Bennis D, Altman JJ. Increased prevalence of non-diabetic renal pathology in type II diabetes mellitus. Nephrol Dial Transplant 1992;7:1258-9.
Prakash J, Sen D, Usha, Kumar NS. Non-diabetic renal disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2001;49:415-20.
Olsen S. Identification of non-diabetic glomerular disease in renal biopsies from diabetics – A dilemma. Nephrol Dial Transplant 1999;14:1846-9.
Serra A, Romero R, Bayés B, Lopez D, Bonet J. Is there a need for changes in renal biopsy criteria in proteinuria in type 2 diabetes? Diabetes Res Clin Pract 2002;58:149-53.
Soleymanian T, Hamid G, Arefi M, et al. Non-diabetic renal disease with or without diabetic nephropathy in type 2 diabetes: Clinical predictors and outcome. Ren Fail 2015;37:572-5.
Wilfred DC, Mysorekar VV, Venkataramana RS, Eshwarappa M, Subramanyan R. Nondiabetic renal disease in type 2 diabetes mellitus patients: A Clinicopathological study. J Lab Physicians 2013;5:94-9.
] [Full text]
Soni SS, Gowrishankar S, Kishan AG, Raman A. Non diabetic renal disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; 11:533-7.
Liu S, Guo Q, Han H, et al. Clinico-pathological 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. Int Urol Nephrol 2016;48:1691-8.
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.
Haddiya I, Hamzaoui H, Al Hamany Z, et al. Isolated non diabetic renal disease in diabetic patients: A Moroccan report. Saudi J Kidney Dis Transpl 2010;21:555-8.
] [Full text]
Zhou J, Chen X, Xie Y, et al. A differential diagnostic model of diabetic nephropathy and non-diabetic renal diseases. Nephrol Dial Transplant 2008;23:1940-5.
Ghani AA, Al Waheeb S, Al Sahow A, Hussain N. Renal biopsy in patients with type 2 diabetes mellitus: Indications and nature of the lesions. Ann Saudi Med 2009;29:450-3.
] [Full text]
Byun JM, Lee CH, Lee SR, et al. Renal outcomes and clinical course of nondiabetic renal diseases in patients with type 2 diabetes. Korean J Intern Med 2013;28:565-72.
Zukowska-Szczechowska E, Tomaszewski M. Renal affection in patients with diabetes mellitus is not always caused by diabetic nephropathy. Rocz Akad Med Bialymst 2004; 49:185-9.
Wong TY, Choi PC, Szeto CC, et al. Renal outcome in type 2 diabetic patients with or without coexisting nondiabetic nephropathies. Diabetes Care 2002;25:900-5.
Olsen S, Mogensen CE. How often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature. Diabetologia 1996;39:1638-45.
Tone A, Shikata K, Matsuda M, et al. Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. Diabetes Res Clin Pract 2005;69:237-42.
Huang F, Yang Q, Chen L, et al. Renal pathological change in patients with type 2 diabetes is not always diabetic nephropathy: A report of 52 cases. Clin Nephrol 2007;67:293-7.
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]
Mak SK, Gwi E, Chan KW, et al. Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Nephrol Dial Transplant 1997;12:2588-91.
Bertani T, Mecca G, Sacchi G, Remuzzi G. Superimposed nephritis: A separate entity among glomerular diseases? Am J Kidney Dis 1986;7:205-12.
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.
Agius E, Attard G, Shakespeare L, et al. Familial factors in diabetic nephropathy: An offspring study. Diabet Med 2006;23:331-4.
Matias P, Viana H, Carvalho F. Diabetes mellitus and renal disease: When to perform a renal biopsy? Port J Nephrol Hypert 2009;23:167-73.
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.
Das U, Dakshinamurty KV, Prayaga A, Uppin MS. Nondiabetic kidney disease in type 2 diabetic patients: A single center experience. Indian J Nephrol 2012;22:358-62.
] [Full text]
Kamal V Kanodia
Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K.M. Mehta Institute of Kidney Diseases and Research Center and Dr. H. L. Trivedi Institute of Transplantation Sciences, Civil Hospital Campus, Asarwa, Ahmedabad
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]