Clinical and pathological characteristics of non-diabetic renal disease in type 2 diabetes patients

Clinical and pathological characteristics of non-diabetic renal disease in type 2 diabetes patients Background: Renal involvement in type 2 diabetes is mainly due to diabetic nephropathy (DN). Nevertheless, a sizable proportion of diabetic patients could actually have nondiabetic renal diseases (NDRDs) or DN plus NDRDs. This study aimed to explore the pathological features of NDRD in diabetic patients and to assess the predictability of diagnosing NDRD (6DN) versus isolated DN on the basis of clinical parameters. Methods: Medical records of type 2 diabetes patients who underwent renal biopsy under suspicion of NDRD from January 2011 through November 2015 were analyzed retrospectively. Results: A total of 101 patients were enrolled in this study. The most frequent indication for renal biopsy was recent onset of nephrotic syndrome (41%), followed by rapidly progressive renal failure (29%) and active urinary sediment (21%). On renal biopsy, 51% of patients had isolated DN, 20% had isolated NDRD and 29% had DN plus NDRD. IgA nephropathy was the most common cause of isolated NDRD, whereas acute tubular necrosis (39%) and acute interstitial nephritis (33%) were the main causes of NDRD superimposed on DN. Male gender, short-duration diabetes (<8 years), lower glycated hemoglobin and active urinary sediment (10 red and white blood cells per high-power field) were independent predictors of NDRD according to multiple logistic regression analysis. Conclusions: Judicious use of renal biopsy revealed NDRD (6DN) in nearly half of type 2 diabetes patients with atypical renal presentation, especially in male patients with well-controlled diabetes, those who have had diabetes for a short duration and those with active urinary sediment. Key words: diabetic nephropathy, nondiabetic renal disease, renal biopsy, type 2 diabetes Introduction patients on maintenance dialysis is lower than in nondiabetic Diabetic nephropathy (DN) is a devastating complication of dia- patients with ESRD due to the presence of other renal diseases betes mellitus and is a leading cause of end-stage renal disease [2, 3]. There is a wide variation in the prevalence of nondiabetic (ESRD) worldwide [1]. Moreover, patient survival in diabetic renal disease (NDRD) due to variable selection criteria for renal Received: April 30, 2017. Editorial decision: August 17, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 NDRD study in type 2 diabetes patients | 343 biopsy, and geographical differences. Previous studies evaluat- difference test for equal variances and the Dunnett test for ing histological findings in renal biopsies performed in diabetic unequal variances. The homogeneity of variance was clarified patients have shown that approximately one-third of the cases using the Levene test. Categorical data were compared by the exhibit pure diabetic nephropathy, one-third a nondiabetic con- chi-squared and Fisher’s exact test. Univariate and multivari- dition and another third diabetic nephropathy with a superim- able analyses of variables considered as potential predictors of posed disease [4, 5]. The atypical clinical features that have NDRD superimposed on DN versus isolated DN were performed previously been shown to predict renal involvement by NDRD using logistic regression. P-values<0.05 were considered statis- in diabetic patients are sudden onset of proteinuria, proteinuria tically significant. All statistical analysis was performed using in the absence of diabetic retinopathy, active urinary sediment, SPSS for Windows version 17.0 and STATA version 14.0. rapidly decreasing renal function and short duration of diabetes The study was approved by Khon Kaen University Faculty of [6–9]. However, due to the variability of clinical courses and the Medicine Ethics Committee. frequency of confounding medical comorbidities in this popula- tion, differentiating between DN and NDRD in individual Results patients without the assistance of renal biopsy remains prob- lematic. The aim of this study is to explore the etiology of A total of 101 patients with type 2 diabetes who were suspected biopsy-proven NDRD in the Thai population and to determine of having NDRD underwent renal biopsy from January 2011 the predictability of diagnosing NDRD with or without DN ver- through November 2015. The mean age of the cohort at biopsy sus isolated DN in patients with type 2 diabetes, based on clini- was 516 12 years. Approximately 57% of the patients were men. cal and laboratory data. The mean duration of diabetes was 6.76 4.2 years. Our study showed that most patients had notable renal dysfunction, with a mean serum creatinine of 2.86 2.2 mg/dL and estimated glo- Materials and methods merular filtration rate (eGFR) 40.46 29.4 mL/min/1.73 m . Mean The demographic, clinical and biochemical data of patients proteinuria for the entire cohort was within the nephrotic range with type 2 diabetes who underwent native renal biopsy in (5.86 3.4 g/day). Fifty-two patients (51%) had isolated DN, 20 Srinagarind hospital from January 2011 through November 2015 patients (20%) had isolated NDRD and 29 patients (29%) had DN were analyzed retrospectively. Data were collected from histo- plus NDRD. Clinical and laboratory parameters of the three pathological reports, requisition forms and discharge summa- groups are summarized in Table 1. Patients with isolated DN ries. Post-transplant patients and patients with a lack of had significantly longer duration of diabetes than patients with adequate clinical data or inadequate renal biopsies were isolated NDRD (8.16 4.8 versus 3.86 1.5 years, P< 0.05). The excluded. The indications for renal biopsy in this cohort prevalence of diabetic retinopathy was significantly higher in included the following characteristics: active urinary sediment, patients with isolated DN (84.6%) than patients with isolated hematuria with dysmorphic red blood cells6 red blood cell NDRD (15%) and patients with DN plus NDRD (65.5%). Patients casts; recent onset of nephrotic syndrome, sudden appearance with DN plus NDRD had significantly higher serum creatinine of proteinuria>3.5 g/day with edema and/or hypoalbuminemia than patients with isolated DN or isolated NDRD. Patients with (serum albumin<3.0 g/dL); renal failure without significant pro- isolated DN had significantly higher fasting plasma glucose, gly- teinuria; acute kidney injury, increase in serum creatinine cated hemoglobin and serum total cholesterol than patients by0.3 mg/dL within 48 h or1.5 times baseline that is pre- with isolated NDRD. Patients with isolated DN had significantly sumed to have occurred within the prior 7 days; and rapidly higher proteinuria than patients with isolated NDRD (6.96 3.2 progressive renal failure, renal failure over weeks or months in versus 3.56 2.1 g/day, P< 0.05). More importantly, patients with patients with previously stable renal function. The pathologic NDRD (6DN) had significantly more active urinary sediment criteria for DN included diffuse mesangial sclerosis and glomer- than patients with isolated DN. Neither mean systolic blood ular basement membrane thickening at the light microscopic pressure, diastolic blood pressure, hemoglobin nor serum albu- and ultrastructural levels, with or without mesangial nodularity min appeared to differ among patients with isolated DN, those (Kimmelstiel–Wilson nodule). Supportive histologic features of with isolated NDRD and those with DN plus NDRD. DN included: thickening of the tubular basement membrane of Indications for renal biopsy (Figure 1) included recent onset nonatrophic tubules; diffuse linear staining of glomerular and of nephrotic syndrome in 41 patients (40.6%), rapidly progres- tubular basement membrane for albumin and IgG; and hyalino- sive renal failure in 29 patients (28.7%), active urinary sediment sis of glomeruli and vessels producing fibrin caps, capsular in 21 patients (20.8%), acute kidney injury in 9 patients (8.9%) drops and arteriolar hyalinosis. Because some degree of intersti- and renal failure without significant proteinuria in 1 patient tial inflammation is commonly seen in DN, a diagnosis of acute (1.0%). Upon renal biopsy, most of the patients presenting with interstitial nephritis was made only if interstitial inflammatory recent onset of nephrotic syndrome (85.4%) and rapidly progres- cell infiltrates included eosinophils-involved areas without tub- sive renal failure (44.8%) turned out to have isolated DN and DN ular atrophy/interstitial fibrosis. A diagnosis of acute tubular plus NDRD, respectively. Moreover, about three-quarters of necrosis was made if nonatrophic tubules displayed diffuse patients presenting with active urinary sediment were found to acute tubular injury, including epithelial simplification, loss of have NDRD (6DN) on renal biopsy. brush border and focal cytoplasmic shedding. Based on the kid- The frequency of NDRD in renal biopsies on patients with ney biopsy findings, patients were categorized as isolated DN, type 2 diabetes was 49%. Most of these patients (29%) had NDRD isolated NDRD or DN plus NDRD. concurrent with DN while the remainder (20%) had isolated Statistical analysis included computing (i) the frequency NDRD. The renal histological lesions identified in patients with counts and percentages for the categorical variables and (ii) the NDRD superimposed on DN and those with isolated NDRD are means and standard deviations for the continuous variables. presented in Table 2. The most common NDRDs with concomi- One-way analysis of variance (ANOVA) and post hoc multiple tant DN were acute tubular necrosis (38.9%), acute interstitial comparisons were used to determine the significance among nephritis (33.3%) and crescentic glomerulonephritis (8.3%). the means of multiple groups with the least-significant Glomerular diseases such as IgA nephropathy, membranous Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 344 | K. Kritmetapak et al. Table 1. Demographic and clinical characteristics of the study patients at the time of renal biopsy Characteristics Isolated DN (N¼ 52) Isolated NDRD (N¼ 20) DN plus NDRD (N¼ 29) P-value Male sex, n (%) 23 (44.2) 13 (65) 22 (75.9) 0.017 Age (years) 516 13 5067536 12 0.72 b c Duration of diabetes (years) 8.16 4.8 3.86 1.5 6.46 3.1 <0.001 b a,c Presence of diabetic retinopathy, n (%) 44 (84.6) 3 (15) 19 (65.5) <0.001 Systolic blood pressure (mmHg) 1496 17 1416 10 1496 20 0.17 Diastolic blood pressure (mmHg) 81688064836 9 0.27 Hemoglobin (g/dL) 9.76 1.5 10.46 1.1 9.66 1.5 0.16 Fasting plasma glucose (mg/dL) 1836 5.7 1406 6.7 1646 5.3 0.002 b c HbA1c (%) 8.56 1.0 7.36 0.1 8.16 1.1 <0.001 b c Serum creatinine (mg/dL) 2.696 2.05 1.456 0.50 3.906 2.06 <0.001 d 2 b c eGFR (mL/min/1.73 m ) 38.26 27.6 58.76 23.9 31.86 31.5 0.004 b a Serum total cholesterol (mg/dL) 3006 89 2266 42 2496 82 0.001 Serum albumin (g/dL) 2.86 0.6 3.06 0.4 2.76 0.5 0.14 b a Proteinuria (g/24 h) 6.96 3.2 3.56 2.1 5.36 3.5 <0.001 b a Urinary red blood cells/HPF 264126 9 76 8 <0.001 b a Urinary white blood cells/HPF 16186 6 66 11 <0.001 HPF, high-power field. Isolated DN versus DN plus NDRD (P< 0.05). Isolated DN versus isolated NDRD (P< 0.05). Isolated NDRD versus DN plus NDRD (P< 0.05). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation. Table 2. Renal pathology of NDRD, with and without DN, in type 2 diabetes patients NDRD Isolated superimposed NDRD Histology on DN (N¼ 29) (N¼ 20) P-value Acute tubular necrosis 14 (38.9) 0 (0) <0.001 Acute interstitial nephritis 12 (33.3) 1 (5.0) 0.007 IgA nephropathy 1 (2.8) 7 (35.0) 0.005 Membranous nephropathy 0 (0) 5 (25.0) 0.008 Lupus nephritis 2 (5.6) 4 (20.0) 0.21 Crescentic glomerulonephritis 3 (8.2) 1 (5.0) 0.64 Membranoproliferative 0 (0) 1 (5.0) 0.22 glomerulonephritis Focal segmental 1 (2.8) 0 (0) 0.41 glomerulosclerosis IgM nephropathy 2 (5.6) 1 (5.0) 1.00 Fig. 1. Indications for renal biopsy in the study patients. Chronic interstitial nephritis 1 (2.8) 0 (0) 1.00 nephropathy and lupus nephritis were more likely to be present Values are presented as n (%). in the absence of, rather than superimposed on, DN. Some patients have more than one renal pathology. The results of univariate analysis indicated that male gen- der, short duration of diabetes, absence of diabetic retinopathy, active urinary sediment, lower cholesterol levels, glycated patients with type 2 diabetes who have undergone renal biopsy, hemoglobin and proteinuria were significantly associated with the prevalence of NDRD varies widely from 12% to 79%, depend- NDRD (6DN). However, in a multivariate logistic regression ing on the selection criteria and the population being studied model (Table 3), male gender [odds ratio (OR) 4.43, 95% confi- [4, 7, 12–15]. Various predictive factors for NDRD have been dence interval (CI) 1.39–14.15, P¼ 0.01] and active urinary sedi- identified in diabetic patients, including absence of diabetic ment (OR 4.75, 95% CI 1.46–15.43, P¼ 0.01) were significantly retinopathy, rapid decline of renal function, abrupt onset of associated with NDRD (6DN). Moreover, diabetes of long dura- nephrotic syndrome and presence of active urinary sediment tion (>8 years) and higher glycated hemoglobin levels were sig- [7, 15, 16]. nificantly inversely associated with NDRD (6DN). We found that the mean duration of diabetes was signifi- cantly longer in patients with isolated DN (8.16 4.5 years) than in patients with NDRD with or without DN (5.36 2.9 years). Discussion Similarly, Chang et al. reported a mean diabetes duration of 5.9 years in patients with NDRD versus 10.6 years in patients DN is one of the most frequent and clinically significant compli- with DN alone (P< 0.001 for comparison) [17]. Furthermore, cations of diabetes mellitus. It affects approximately 40% of short duration of diabetes (<8 years) had a high likelihood of patients who have had diabetes for >20 years and has become a predicting NDRD versus isolated DN. Our results supported major cause of ESRD worldwide [10, 11]. Interestingly, among Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 NDRD study in type 2 diabetes patients | 345 Table 3. Multivariate analysis of clinical parameters in patients with previous study by Dai et al., which showed that acute interstitial NDRD with or without DN nephritis was more common in cases of DN compared with other glomerulopathies [22]. The presence of interstitial eosino- Variables OR 95% CI P-value philic infiltration is the hallmark of drug-induced tubulointer- stitial nephritis. However, this finding can also be seen in other Male gender 4.43 1.39–14.15 0.01 conditions, including autoimmune diseases, tubulointerstitial Duration of diabetes (>8 years) 0.15 0.04–0.49 0.002 nephritis with uveitis, eosinophilic granulomatosis with poly- Glycated hemoglobin (HbA1c) 0.16 0.05–0.47 0.001 angiitis (Churg-Strauss syndrome) and parasitic infections [23– Active urinary sediment 4.75 1.46–15.43 0.01 25]. Furthermore, it is not uncommon to identify eosinophilic Active urinary sediment is defined as 10 or more red and white blood cells per infiltration adjacent to disrupted tubules or chronic tubulointer- high-power field. stitial injury in DN. These tubulointerstitial changes in DN are thought to be related to the renal microvasculature alterations those of the majority of previous reports suggesting that a characteristic of longstanding diabetes, and it is generally held higher degree of proteinuria is found in patients with DN than that they are due to chronic ischemia [26]. Among all cases of in those with isolated NDRD [7, 8, 12, 16, 18]. The prevalence of nondiabetic glomerulopathies in this cohort, IgA nephropathy hypertension was similar in all three groups in our study, which was the most common biopsy finding. The most common non- is consistent with the findings from previous reports [7]. Recent diabetic glomerular diseases previously reported in patients onset of nephrotic syndrome, rapidly progressive renal failure with type 2 diabetes are IgA nephropathy [8, 27, 28], focal seg- and active urinary sediment were the most frequent indications mental glomerulosclerosis [15, 16] and membranous neph- for renal biopsy in our study. It is interesting that most of our ropathy [16, 29]. Interestingly, we observed three human patients presenting with rapidly increasing proteinuria actually immunodeficiency virus -negative patients (3.7% DN cases) who had isolated DN on renal biopsy. A plausible explanation for presented with rapidly progressive renal failure and had cres- this finding is that the majority of our patients had longstand- centic formation superimposed on DN in renal biopsy. The etio- ing poorly controlled diabetes with established microvascular logical linkage between diabetic glomerulosclerosis and the complications (e.g. diabetic retinopathy). These patients may, development of crescents has been scarcely mentioned in pre- thus, develop progressively increasing albuminuria faster than vious literature. Recently, Salvatore et al. also reported 26 dia- other patients. It is worth mentioning here that about 10% of betic patients (5% DN cases) with aggressive clinical courses of our patients with isolated DN had active urinary sediment. renal involvement whose renal biopsies showed collapsing glo- Okada et al. found an association between the presence of arte- merulopathy (pseudocrescent formation) presumed to be the riolar hyalinosis in renal biopsy and persistent microscopic result of extensive microvascular sclerosis/hyalinosis [30]. One hematuria in type 2 diabetes patients [19]. Moreover, critical gap in our knowledge is whether crescentic and pseu- Matsumura et al. reported that diabetic patients with glomerular docrescent formation is associated with different outcomes in hematuria exhibited histologically advanced diffuse lesions, patients with type 2 diabetes. In our series, IgM nephropathy nodular lesions, microaneurysms, crescent formation, capsular and lupus nephritis were the most common finding in nondia- adhesion and interstitial lesions more often than those without betic glomerular diseases superimposed on DN, excluding cres- hematuria [20]. centic glomerulonephritis. These results demonstrate that the Our study revealed that 49% of type 2 diabetes patients who prevalence of various types of biopsy-proven renal diseases in underwent renal biopsy had NDRD, either isolated or superim- diabetic patients may be related to the local prevalence of renal posed on underlying DN. Our cohort also demonstrated that disease in the total population of a given geographical area with acute tubular necrosis was the most common nondiabetic renal similar ethnic characteristics, and the presence of NDRD in pathology superimposed on DN in type 2 diabetes patients pre- cases of type 2 diabetes may only be a coincidence. Recently, senting with acute kidney injury. The etiologies of acute tubular Fiorentino et al. [31] conducted a meta-analysis, combining 48 necrosis are classified as ischemic processes, nephrotoxic studies and 4876 participants, and it showed that the preva- agents and sepsis. Diabetic patients are prone to have normo- lence of DN, NDRD, and DN plus NDRD ranged from 6.5% to 94%, tensive ischemic acute kidney injury due to atherosclerotic vas- 3% to 82.9% and 4% to 45.5% of the overall diagnoses, respec- culature and impaired renal autoregulation [21]. Moreover, tively. Moreover, IgA nephropathy was the most common NDRD infectious complications are common in immunocompromised (3–59%). Our study complements the findings of earlier meta- diabetic patients and are the leading cause of hospitalization. analysis. We found that NDRDs are highly prevalent in patients Various drugs, especially nonsteroidal anti-inflammatory drugs, with diabetes and clinical judgment alone can miss the correct and herbal remedies are also prevalent causes of nephrotoxic diagnosis. acute tubular necrosis and acute interstitial nephritis in diabetic In our study, diabetic retinopathy had a close correlation patients. Taken together, this means that diabetic patients are with the presence of DN (6NDRD), but it was not an independ- at risk of developing acute tubular necrosis attributable to mul- ent predictor by multivariate analysis. Sensitivity of diabetic ret- tifactorial factors. Recently, Sharma et al. also reported a high inopathy for DN (6NDRD) was 78% with a specificity of 85%, and incidence of acute tubular necrosis as a superimposed disease a positive predictive value of 95% with a negative predictive on DN in a large cohort of type 2 diabetes patients [4]. The high value of 49%. Recently, He et al. performed a meta-analysis that prevalence of acute tubular necrosis supports the number of demonstrated that the sensitivity and specificity of diabetic ret- epidemiologic cohorts in which acute kidney injury episodes inopathy in predicting diabetic nephropathy were 65% (95% CI are associated with a cumulative risk for progression to ESRD, 0.62–0.68) and 75% (95% CI 0.73–0.78), respectively. In addition, particularly in patients with diabetes. Soni et al. reported acute the pooled positive and negative predictive values of diabetic interstitial nephritis to be the most common concurrent non- retinopathy to predict diabetic nephropathy were 72% (95% CI diabetic pathology in clinical renal biopsies from type 2 diabetes 0.68–0.75) and 69% (95% CI 0.67–0.72), respectively [32]. A meta- patients [7]. However, it was slightly less common than acute analysis by Liang et al.[33] also showed that the absence of dia- tubular necrosis in our study. Our results support those of a betic retinopathy predicted NDRD (OR 0.15, 95% CI 0.09–0.26, Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 346 | K. Kritmetapak et al. 7. Soni SS, Gowrishankar S, Kishan AG et al. Non diabetic renal P 0.00001). However, discordance in the occurrence of the two complications has been reported and dissimilar genetic predis- disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; positions have been suggested [34]. The results of our study fur- 11: 533–537 ther support the American Diabetes Association Standards of 8. Tone A, Shikata K, Matsuda M et al. Clinical features of non- Medical Care in Diabetes 2017 that patients with an active uri- diabetic renal diseases in patients with type 2 diabetes. nary sediment, or rapidly decreasing renal function, should be Diabetes Res Clin Pract 2005; 69: 237–242. 9. Huang F, Yang Q, Chen L et al. Renal pathological change in referred to a nephrologist for further diagnosis, including the possibility of kidney biopsy [35]. patients with type 2 diabetes is not always diabetic nephrop- Our study has a number of limitations. First, biopsy-based athy: a report of 52 cases. Clin Nephrol 2007; 67: 293–297 clinicopathologic studies suffer from selection bias. As a result, 10. Gross JL, de Azevedo MJ, Silveiro SP et al. Diabetic nephrop- athy: diagnosis, prevention, and treatment. Diabetes Care our data can only be applied to those patients who have a high pre-test probability of NDRD. A second limitation is that we lack 2005; 28: 164–176 long-term follow-up data on our patients and, thus, cannot con- 11. Collins AJ, Foley RN, Gilbertson DT et al. United States Renal clude whether different types of renal pathology affect future Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl (2011) renal outcomes. In conclusion, our data show that almost half of patients 2015; 5: 2–7 12. Gambara V, Mecca G, Remuzzi G et al. Heterogeneous nature with type 2 diabetes presenting with atypical features of DN are found to have NDRD (6DN) upon renal biopsy. Male gender, of renal lesions in type II diabetes. J Am Soc Nephrol 1993; 3: short duration of diabetes (<8 years), lower glycated hemoglobin 1458–1466 and active urinary sediment were independent predictors of 13. Mak SK, Gwi E, Chan KW et al. Clinical predictors of non- diabetic renal disease in patients with non-insulin depend- NDRD (6DN). Moreover, absence of diabetic retinopathy is a good indicator of isolated NDRD. Acute tubular necrosis is the ent diabetes mellitus. Nephrol Dial Transplant 1997; 12: most common NDRD superimposed on DN, whereas IgA nephr- 2588–2591 opathy is the most prevalent renal pathology in type 2 diabetes 14. Ruggenenti P, Gambara V, Perna A et al. The nephropathy of non-insulin-dependent diabetes: predictors of outcome rel- patients with isolated NDRD. Early diagnosis of renal disease by renal biopsy in diabetic patients is indispensable to preserving ative to diverse patterns of renal injury. J Am Soc Nephrol renal function in those patients with renal diseases for which 1998; 9: 2336–2343 the natural history can be modified by proper treatment. This is 15. Pham TT, Sim JJ, Kujubu DA et al. Prevalence of nondiabetic renal disease in diabetic patients. 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Clinical and pathological characteristics of non-diabetic renal disease in type 2 diabetes patients

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Abstract

Background: Renal involvement in type 2 diabetes is mainly due to diabetic nephropathy (DN). Nevertheless, a sizable proportion of diabetic patients could actually have nondiabetic renal diseases (NDRDs) or DN plus NDRDs. This study aimed to explore the pathological features of NDRD in diabetic patients and to assess the predictability of diagnosing NDRD (6DN) versus isolated DN on the basis of clinical parameters. Methods: Medical records of type 2 diabetes patients who underwent renal biopsy under suspicion of NDRD from January 2011 through November 2015 were analyzed retrospectively. Results: A total of 101 patients were enrolled in this study. The most frequent indication for renal biopsy was recent onset of nephrotic syndrome (41%), followed by rapidly progressive renal failure (29%) and active urinary sediment (21%). On renal biopsy, 51% of patients had isolated DN, 20% had isolated NDRD and 29% had DN plus NDRD. IgA nephropathy was the most common cause of isolated NDRD, whereas acute tubular necrosis (39%) and acute interstitial nephritis (33%) were the main causes of NDRD superimposed on DN. Male gender, short-duration diabetes (<8 years), lower glycated hemoglobin and active urinary sediment (10 red and white blood cells per high-power field) were independent predictors of NDRD according to multiple logistic regression analysis. Conclusions: Judicious use of renal biopsy revealed NDRD (6DN) in nearly half of type 2 diabetes patients with atypical renal presentation, especially in male patients with well-controlled diabetes, those who have had diabetes for a short duration and those with active urinary sediment. Key words: diabetic nephropathy, nondiabetic renal disease, renal biopsy, type 2 diabetes Introduction patients on maintenance dialysis is lower than in nondiabetic Diabetic nephropathy (DN) is a devastating complication of dia- patients with ESRD due to the presence of other renal diseases betes mellitus and is a leading cause of end-stage renal disease [2, 3]. There is a wide variation in the prevalence of nondiabetic (ESRD) worldwide [1]. Moreover, patient survival in diabetic renal disease (NDRD) due to variable selection criteria for renal Received: April 30, 2017. Editorial decision: August 17, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 NDRD study in type 2 diabetes patients | 343 biopsy, and geographical differences. Previous studies evaluat- difference test for equal variances and the Dunnett test for ing histological findings in renal biopsies performed in diabetic unequal variances. The homogeneity of variance was clarified patients have shown that approximately one-third of the cases using the Levene test. Categorical data were compared by the exhibit pure diabetic nephropathy, one-third a nondiabetic con- chi-squared and Fisher’s exact test. Univariate and multivari- dition and another third diabetic nephropathy with a superim- able analyses of variables considered as potential predictors of posed disease [4, 5]. The atypical clinical features that have NDRD superimposed on DN versus isolated DN were performed previously been shown to predict renal involvement by NDRD using logistic regression. P-values<0.05 were considered statis- in diabetic patients are sudden onset of proteinuria, proteinuria tically significant. All statistical analysis was performed using in the absence of diabetic retinopathy, active urinary sediment, SPSS for Windows version 17.0 and STATA version 14.0. rapidly decreasing renal function and short duration of diabetes The study was approved by Khon Kaen University Faculty of [6–9]. However, due to the variability of clinical courses and the Medicine Ethics Committee. frequency of confounding medical comorbidities in this popula- tion, differentiating between DN and NDRD in individual Results patients without the assistance of renal biopsy remains prob- lematic. The aim of this study is to explore the etiology of A total of 101 patients with type 2 diabetes who were suspected biopsy-proven NDRD in the Thai population and to determine of having NDRD underwent renal biopsy from January 2011 the predictability of diagnosing NDRD with or without DN ver- through November 2015. The mean age of the cohort at biopsy sus isolated DN in patients with type 2 diabetes, based on clini- was 516 12 years. Approximately 57% of the patients were men. cal and laboratory data. The mean duration of diabetes was 6.76 4.2 years. Our study showed that most patients had notable renal dysfunction, with a mean serum creatinine of 2.86 2.2 mg/dL and estimated glo- Materials and methods merular filtration rate (eGFR) 40.46 29.4 mL/min/1.73 m . Mean The demographic, clinical and biochemical data of patients proteinuria for the entire cohort was within the nephrotic range with type 2 diabetes who underwent native renal biopsy in (5.86 3.4 g/day). Fifty-two patients (51%) had isolated DN, 20 Srinagarind hospital from January 2011 through November 2015 patients (20%) had isolated NDRD and 29 patients (29%) had DN were analyzed retrospectively. Data were collected from histo- plus NDRD. Clinical and laboratory parameters of the three pathological reports, requisition forms and discharge summa- groups are summarized in Table 1. Patients with isolated DN ries. Post-transplant patients and patients with a lack of had significantly longer duration of diabetes than patients with adequate clinical data or inadequate renal biopsies were isolated NDRD (8.16 4.8 versus 3.86 1.5 years, P< 0.05). The excluded. The indications for renal biopsy in this cohort prevalence of diabetic retinopathy was significantly higher in included the following characteristics: active urinary sediment, patients with isolated DN (84.6%) than patients with isolated hematuria with dysmorphic red blood cells6 red blood cell NDRD (15%) and patients with DN plus NDRD (65.5%). Patients casts; recent onset of nephrotic syndrome, sudden appearance with DN plus NDRD had significantly higher serum creatinine of proteinuria>3.5 g/day with edema and/or hypoalbuminemia than patients with isolated DN or isolated NDRD. Patients with (serum albumin<3.0 g/dL); renal failure without significant pro- isolated DN had significantly higher fasting plasma glucose, gly- teinuria; acute kidney injury, increase in serum creatinine cated hemoglobin and serum total cholesterol than patients by0.3 mg/dL within 48 h or1.5 times baseline that is pre- with isolated NDRD. Patients with isolated DN had significantly sumed to have occurred within the prior 7 days; and rapidly higher proteinuria than patients with isolated NDRD (6.96 3.2 progressive renal failure, renal failure over weeks or months in versus 3.56 2.1 g/day, P< 0.05). More importantly, patients with patients with previously stable renal function. The pathologic NDRD (6DN) had significantly more active urinary sediment criteria for DN included diffuse mesangial sclerosis and glomer- than patients with isolated DN. Neither mean systolic blood ular basement membrane thickening at the light microscopic pressure, diastolic blood pressure, hemoglobin nor serum albu- and ultrastructural levels, with or without mesangial nodularity min appeared to differ among patients with isolated DN, those (Kimmelstiel–Wilson nodule). Supportive histologic features of with isolated NDRD and those with DN plus NDRD. DN included: thickening of the tubular basement membrane of Indications for renal biopsy (Figure 1) included recent onset nonatrophic tubules; diffuse linear staining of glomerular and of nephrotic syndrome in 41 patients (40.6%), rapidly progres- tubular basement membrane for albumin and IgG; and hyalino- sive renal failure in 29 patients (28.7%), active urinary sediment sis of glomeruli and vessels producing fibrin caps, capsular in 21 patients (20.8%), acute kidney injury in 9 patients (8.9%) drops and arteriolar hyalinosis. Because some degree of intersti- and renal failure without significant proteinuria in 1 patient tial inflammation is commonly seen in DN, a diagnosis of acute (1.0%). Upon renal biopsy, most of the patients presenting with interstitial nephritis was made only if interstitial inflammatory recent onset of nephrotic syndrome (85.4%) and rapidly progres- cell infiltrates included eosinophils-involved areas without tub- sive renal failure (44.8%) turned out to have isolated DN and DN ular atrophy/interstitial fibrosis. A diagnosis of acute tubular plus NDRD, respectively. Moreover, about three-quarters of necrosis was made if nonatrophic tubules displayed diffuse patients presenting with active urinary sediment were found to acute tubular injury, including epithelial simplification, loss of have NDRD (6DN) on renal biopsy. brush border and focal cytoplasmic shedding. Based on the kid- The frequency of NDRD in renal biopsies on patients with ney biopsy findings, patients were categorized as isolated DN, type 2 diabetes was 49%. Most of these patients (29%) had NDRD isolated NDRD or DN plus NDRD. concurrent with DN while the remainder (20%) had isolated Statistical analysis included computing (i) the frequency NDRD. The renal histological lesions identified in patients with counts and percentages for the categorical variables and (ii) the NDRD superimposed on DN and those with isolated NDRD are means and standard deviations for the continuous variables. presented in Table 2. The most common NDRDs with concomi- One-way analysis of variance (ANOVA) and post hoc multiple tant DN were acute tubular necrosis (38.9%), acute interstitial comparisons were used to determine the significance among nephritis (33.3%) and crescentic glomerulonephritis (8.3%). the means of multiple groups with the least-significant Glomerular diseases such as IgA nephropathy, membranous Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 344 | K. Kritmetapak et al. Table 1. Demographic and clinical characteristics of the study patients at the time of renal biopsy Characteristics Isolated DN (N¼ 52) Isolated NDRD (N¼ 20) DN plus NDRD (N¼ 29) P-value Male sex, n (%) 23 (44.2) 13 (65) 22 (75.9) 0.017 Age (years) 516 13 5067536 12 0.72 b c Duration of diabetes (years) 8.16 4.8 3.86 1.5 6.46 3.1 <0.001 b a,c Presence of diabetic retinopathy, n (%) 44 (84.6) 3 (15) 19 (65.5) <0.001 Systolic blood pressure (mmHg) 1496 17 1416 10 1496 20 0.17 Diastolic blood pressure (mmHg) 81688064836 9 0.27 Hemoglobin (g/dL) 9.76 1.5 10.46 1.1 9.66 1.5 0.16 Fasting plasma glucose (mg/dL) 1836 5.7 1406 6.7 1646 5.3 0.002 b c HbA1c (%) 8.56 1.0 7.36 0.1 8.16 1.1 <0.001 b c Serum creatinine (mg/dL) 2.696 2.05 1.456 0.50 3.906 2.06 <0.001 d 2 b c eGFR (mL/min/1.73 m ) 38.26 27.6 58.76 23.9 31.86 31.5 0.004 b a Serum total cholesterol (mg/dL) 3006 89 2266 42 2496 82 0.001 Serum albumin (g/dL) 2.86 0.6 3.06 0.4 2.76 0.5 0.14 b a Proteinuria (g/24 h) 6.96 3.2 3.56 2.1 5.36 3.5 <0.001 b a Urinary red blood cells/HPF 264126 9 76 8 <0.001 b a Urinary white blood cells/HPF 16186 6 66 11 <0.001 HPF, high-power field. Isolated DN versus DN plus NDRD (P< 0.05). Isolated DN versus isolated NDRD (P< 0.05). Isolated NDRD versus DN plus NDRD (P< 0.05). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation. Table 2. Renal pathology of NDRD, with and without DN, in type 2 diabetes patients NDRD Isolated superimposed NDRD Histology on DN (N¼ 29) (N¼ 20) P-value Acute tubular necrosis 14 (38.9) 0 (0) <0.001 Acute interstitial nephritis 12 (33.3) 1 (5.0) 0.007 IgA nephropathy 1 (2.8) 7 (35.0) 0.005 Membranous nephropathy 0 (0) 5 (25.0) 0.008 Lupus nephritis 2 (5.6) 4 (20.0) 0.21 Crescentic glomerulonephritis 3 (8.2) 1 (5.0) 0.64 Membranoproliferative 0 (0) 1 (5.0) 0.22 glomerulonephritis Focal segmental 1 (2.8) 0 (0) 0.41 glomerulosclerosis IgM nephropathy 2 (5.6) 1 (5.0) 1.00 Fig. 1. Indications for renal biopsy in the study patients. Chronic interstitial nephritis 1 (2.8) 0 (0) 1.00 nephropathy and lupus nephritis were more likely to be present Values are presented as n (%). in the absence of, rather than superimposed on, DN. Some patients have more than one renal pathology. The results of univariate analysis indicated that male gen- der, short duration of diabetes, absence of diabetic retinopathy, active urinary sediment, lower cholesterol levels, glycated patients with type 2 diabetes who have undergone renal biopsy, hemoglobin and proteinuria were significantly associated with the prevalence of NDRD varies widely from 12% to 79%, depend- NDRD (6DN). However, in a multivariate logistic regression ing on the selection criteria and the population being studied model (Table 3), male gender [odds ratio (OR) 4.43, 95% confi- [4, 7, 12–15]. Various predictive factors for NDRD have been dence interval (CI) 1.39–14.15, P¼ 0.01] and active urinary sedi- identified in diabetic patients, including absence of diabetic ment (OR 4.75, 95% CI 1.46–15.43, P¼ 0.01) were significantly retinopathy, rapid decline of renal function, abrupt onset of associated with NDRD (6DN). Moreover, diabetes of long dura- nephrotic syndrome and presence of active urinary sediment tion (>8 years) and higher glycated hemoglobin levels were sig- [7, 15, 16]. nificantly inversely associated with NDRD (6DN). We found that the mean duration of diabetes was signifi- cantly longer in patients with isolated DN (8.16 4.5 years) than in patients with NDRD with or without DN (5.36 2.9 years). Discussion Similarly, Chang et al. reported a mean diabetes duration of 5.9 years in patients with NDRD versus 10.6 years in patients DN is one of the most frequent and clinically significant compli- with DN alone (P< 0.001 for comparison) [17]. Furthermore, cations of diabetes mellitus. It affects approximately 40% of short duration of diabetes (<8 years) had a high likelihood of patients who have had diabetes for >20 years and has become a predicting NDRD versus isolated DN. Our results supported major cause of ESRD worldwide [10, 11]. Interestingly, among Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 NDRD study in type 2 diabetes patients | 345 Table 3. Multivariate analysis of clinical parameters in patients with previous study by Dai et al., which showed that acute interstitial NDRD with or without DN nephritis was more common in cases of DN compared with other glomerulopathies [22]. The presence of interstitial eosino- Variables OR 95% CI P-value philic infiltration is the hallmark of drug-induced tubulointer- stitial nephritis. However, this finding can also be seen in other Male gender 4.43 1.39–14.15 0.01 conditions, including autoimmune diseases, tubulointerstitial Duration of diabetes (>8 years) 0.15 0.04–0.49 0.002 nephritis with uveitis, eosinophilic granulomatosis with poly- Glycated hemoglobin (HbA1c) 0.16 0.05–0.47 0.001 angiitis (Churg-Strauss syndrome) and parasitic infections [23– Active urinary sediment 4.75 1.46–15.43 0.01 25]. Furthermore, it is not uncommon to identify eosinophilic Active urinary sediment is defined as 10 or more red and white blood cells per infiltration adjacent to disrupted tubules or chronic tubulointer- high-power field. stitial injury in DN. These tubulointerstitial changes in DN are thought to be related to the renal microvasculature alterations those of the majority of previous reports suggesting that a characteristic of longstanding diabetes, and it is generally held higher degree of proteinuria is found in patients with DN than that they are due to chronic ischemia [26]. Among all cases of in those with isolated NDRD [7, 8, 12, 16, 18]. The prevalence of nondiabetic glomerulopathies in this cohort, IgA nephropathy hypertension was similar in all three groups in our study, which was the most common biopsy finding. The most common non- is consistent with the findings from previous reports [7]. Recent diabetic glomerular diseases previously reported in patients onset of nephrotic syndrome, rapidly progressive renal failure with type 2 diabetes are IgA nephropathy [8, 27, 28], focal seg- and active urinary sediment were the most frequent indications mental glomerulosclerosis [15, 16] and membranous neph- for renal biopsy in our study. It is interesting that most of our ropathy [16, 29]. Interestingly, we observed three human patients presenting with rapidly increasing proteinuria actually immunodeficiency virus -negative patients (3.7% DN cases) who had isolated DN on renal biopsy. A plausible explanation for presented with rapidly progressive renal failure and had cres- this finding is that the majority of our patients had longstand- centic formation superimposed on DN in renal biopsy. The etio- ing poorly controlled diabetes with established microvascular logical linkage between diabetic glomerulosclerosis and the complications (e.g. diabetic retinopathy). These patients may, development of crescents has been scarcely mentioned in pre- thus, develop progressively increasing albuminuria faster than vious literature. Recently, Salvatore et al. also reported 26 dia- other patients. It is worth mentioning here that about 10% of betic patients (5% DN cases) with aggressive clinical courses of our patients with isolated DN had active urinary sediment. renal involvement whose renal biopsies showed collapsing glo- Okada et al. found an association between the presence of arte- merulopathy (pseudocrescent formation) presumed to be the riolar hyalinosis in renal biopsy and persistent microscopic result of extensive microvascular sclerosis/hyalinosis [30]. One hematuria in type 2 diabetes patients [19]. Moreover, critical gap in our knowledge is whether crescentic and pseu- Matsumura et al. reported that diabetic patients with glomerular docrescent formation is associated with different outcomes in hematuria exhibited histologically advanced diffuse lesions, patients with type 2 diabetes. In our series, IgM nephropathy nodular lesions, microaneurysms, crescent formation, capsular and lupus nephritis were the most common finding in nondia- adhesion and interstitial lesions more often than those without betic glomerular diseases superimposed on DN, excluding cres- hematuria [20]. centic glomerulonephritis. These results demonstrate that the Our study revealed that 49% of type 2 diabetes patients who prevalence of various types of biopsy-proven renal diseases in underwent renal biopsy had NDRD, either isolated or superim- diabetic patients may be related to the local prevalence of renal posed on underlying DN. Our cohort also demonstrated that disease in the total population of a given geographical area with acute tubular necrosis was the most common nondiabetic renal similar ethnic characteristics, and the presence of NDRD in pathology superimposed on DN in type 2 diabetes patients pre- cases of type 2 diabetes may only be a coincidence. Recently, senting with acute kidney injury. The etiologies of acute tubular Fiorentino et al. [31] conducted a meta-analysis, combining 48 necrosis are classified as ischemic processes, nephrotoxic studies and 4876 participants, and it showed that the preva- agents and sepsis. Diabetic patients are prone to have normo- lence of DN, NDRD, and DN plus NDRD ranged from 6.5% to 94%, tensive ischemic acute kidney injury due to atherosclerotic vas- 3% to 82.9% and 4% to 45.5% of the overall diagnoses, respec- culature and impaired renal autoregulation [21]. Moreover, tively. Moreover, IgA nephropathy was the most common NDRD infectious complications are common in immunocompromised (3–59%). Our study complements the findings of earlier meta- diabetic patients and are the leading cause of hospitalization. analysis. We found that NDRDs are highly prevalent in patients Various drugs, especially nonsteroidal anti-inflammatory drugs, with diabetes and clinical judgment alone can miss the correct and herbal remedies are also prevalent causes of nephrotoxic diagnosis. acute tubular necrosis and acute interstitial nephritis in diabetic In our study, diabetic retinopathy had a close correlation patients. Taken together, this means that diabetic patients are with the presence of DN (6NDRD), but it was not an independ- at risk of developing acute tubular necrosis attributable to mul- ent predictor by multivariate analysis. Sensitivity of diabetic ret- tifactorial factors. Recently, Sharma et al. also reported a high inopathy for DN (6NDRD) was 78% with a specificity of 85%, and incidence of acute tubular necrosis as a superimposed disease a positive predictive value of 95% with a negative predictive on DN in a large cohort of type 2 diabetes patients [4]. The high value of 49%. Recently, He et al. performed a meta-analysis that prevalence of acute tubular necrosis supports the number of demonstrated that the sensitivity and specificity of diabetic ret- epidemiologic cohorts in which acute kidney injury episodes inopathy in predicting diabetic nephropathy were 65% (95% CI are associated with a cumulative risk for progression to ESRD, 0.62–0.68) and 75% (95% CI 0.73–0.78), respectively. In addition, particularly in patients with diabetes. Soni et al. reported acute the pooled positive and negative predictive values of diabetic interstitial nephritis to be the most common concurrent non- retinopathy to predict diabetic nephropathy were 72% (95% CI diabetic pathology in clinical renal biopsies from type 2 diabetes 0.68–0.75) and 69% (95% CI 0.67–0.72), respectively [32]. A meta- patients [7]. However, it was slightly less common than acute analysis by Liang et al.[33] also showed that the absence of dia- tubular necrosis in our study. Our results support those of a betic retinopathy predicted NDRD (OR 0.15, 95% CI 0.09–0.26, Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/342/4161463 by Ed 'DeepDyve' Gillespie user on 20 June 2018 346 | K. Kritmetapak et al. 7. Soni SS, Gowrishankar S, Kishan AG et al. Non diabetic renal P 0.00001). However, discordance in the occurrence of the two complications has been reported and dissimilar genetic predis- disease in type 2 diabetes mellitus. Nephrology (Carlton) 2006; positions have been suggested [34]. The results of our study fur- 11: 533–537 ther support the American Diabetes Association Standards of 8. Tone A, Shikata K, Matsuda M et al. Clinical features of non- Medical Care in Diabetes 2017 that patients with an active uri- diabetic renal diseases in patients with type 2 diabetes. nary sediment, or rapidly decreasing renal function, should be Diabetes Res Clin Pract 2005; 69: 237–242. 9. Huang F, Yang Q, Chen L et al. Renal pathological change in referred to a nephrologist for further diagnosis, including the possibility of kidney biopsy [35]. patients with type 2 diabetes is not always diabetic nephrop- Our study has a number of limitations. First, biopsy-based athy: a report of 52 cases. Clin Nephrol 2007; 67: 293–297 clinicopathologic studies suffer from selection bias. As a result, 10. Gross JL, de Azevedo MJ, Silveiro SP et al. Diabetic nephrop- athy: diagnosis, prevention, and treatment. Diabetes Care our data can only be applied to those patients who have a high pre-test probability of NDRD. A second limitation is that we lack 2005; 28: 164–176 long-term follow-up data on our patients and, thus, cannot con- 11. Collins AJ, Foley RN, Gilbertson DT et al. United States Renal clude whether different types of renal pathology affect future Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl (2011) renal outcomes. In conclusion, our data show that almost half of patients 2015; 5: 2–7 12. Gambara V, Mecca G, Remuzzi G et al. Heterogeneous nature with type 2 diabetes presenting with atypical features of DN are found to have NDRD (6DN) upon renal biopsy. Male gender, of renal lesions in type II diabetes. J Am Soc Nephrol 1993; 3: short duration of diabetes (<8 years), lower glycated hemoglobin 1458–1466 and active urinary sediment were independent predictors of 13. Mak SK, Gwi E, Chan KW et al. 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Clinical Kidney JournalOxford University Press

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