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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 842-850
Nondiabetic renal disease in patients with type 2 diabetes

1 Department of Medecine A, Charles Nicolle Hospital; Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
2 Faculty of Medicine, University of Tunis El Manar; Laboratory of Renal Pathology LR00SP01, Charles Nicolle Hospital, Tunis, Tunisia

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Date of Web Publication21-Jul-2017


Diabetic nephropathy (DN) is one of the major complications of type 2 diabetes mellitus (T2DM). The diagnosis of DN is mostly clinical. Kidney biopsy is indicated only if nondiabetic renal disease (NDRD) is suspected. This study is aimed to assess the prevalence of NDRD and to determine predictor and prognostic factors of DN, NDRD. It was a retrospective analytic study including T2DM patients in whom renal biopsies were performed at our department from 1988 to 2014. Seventy-five patients were included. Mean age was 52.7 years with sex ratio at 1.56. Renal biopsy findings were isolated NDRD in 33 cases, NDRD superimposed on DN in 24 cases, and isolated DN in 18 cases. Most common NDRD found were focal segmental glomerulosclerosis (21%) and membranous nephropathy (19%). Multivariate analysis showed that the absence of ischemic heart disease [odds ratio (OR) = 0.178, 95% confidence interval (CI) = 0.041–0.762], absence of peripheral vascular disease (OR = 0.173, 95% CI = 0.045–0.669), and presence of hematuria (OR = 7.200, 95%CI = 0.886–58.531) were independent predictors of NDRD. 24 patients reached end-stage renal disease 55% in DN group, 16% in DN associated to NDRD group, and 30% in NDRD group. The prevalence of NDRD found in our study confirmed usefulness of renal biopsy in patients with T2DM, especially in those without degenerative complications, hypertension, and insulin therapy.

How to cite this article:
Mami I, Harzallah A, Kaaroud H, Aoudia R, Hamida FB, Goucha R, Abdallah TB. Nondiabetic renal disease in patients with type 2 diabetes. Saudi J Kidney Dis Transpl 2017;28:842-50

How to cite this URL:
Mami I, Harzallah A, Kaaroud H, Aoudia R, Hamida FB, Goucha R, Abdallah TB. Nondiabetic renal disease in patients with type 2 diabetes. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Jun 1];28:842-50. Available from: http://www.sjkdt.org/text.asp?2017/28/4/842/211351

   Introduction Top

Diabetes is a global epidemic disease and the number of people with this disease is growing extremely fast. In 1985, only 30 million people worldwide had diabetes. Today, population of diabetic patients is estimated at 371 million people and the International diabetes federation predicts an increase thereof, up to half a billion people in 2030.[1] Tunisia is not excluded from this global tide. Indeed, the prevalence of diabetes in Tunisia is estimated at 10.9% of the population.[1]

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). It is the leading cause of end-stage renal disease (ESRD) worldwide. DN usually described is glomerulosclerosis. However, another renal disease known as nondiabetic renal disease (NDRD) can also occur, especially in type 2 DM (T2DM) patients. NDRD represent a heterogeneous group of renal disease. It can be isolated or associated to DN. The prevalence and the nature of this NDRD vary widely from a study to another.

Pathological changes of DN are almost always irreversible while some forms of NDRD are often treatable. That’s why, it is important to distinguish NDRD among T2DM patients.

The occurrence of NDRD has raised the issue of the contribution of renal biopsy in these patients. However, any renal biopsy in a diabetic must be justified by the presence of predictor factors of NDRD.

The purpose of this study was to evaluate the prevalence of NDRD in patients with DM and to determine predictors of DN and NDRD.

   Patients and Methods Top

We analyzed patients with type 2 diabetes who underwent renal biopsy at our department from January 1988 to May 2014. All patients were diagnosed as type 2 diabetes before performing renal biopsy. Indications for biopsy were uniform throughout the study period and were based on strong suspicion of NDRD clinically, and included one or more of the following factors: the presence of hematuria, short duration of diabetes, absence of retinopathy, rapid decrease of renal function, and presence of extrarenal signs.

Tissue samples were routinely processed by light microscopy and immunofluorescence. For light microscopy, tissue sections were stained with hematoxylin-eosin, Schiff'S periodic acid, methenamine silver, Masson trichrome, and Congo Red. Immunofluorescence examinations for immunoglobulin G, M, A, C3, C1q, and fibrinogen were performed. Electron microscopy was not performed in our study.

The following clinical data of each patient were analyzed: age at the time of biopsy, gender, duration and treatment of diabetes, history of hypertension, presence of diabetic retinopathy, diabetic neuropathy, coronary disease, peripheral vascular disease, carotid artery stenosis, blood pressure, and presence of hematuria.

The laboratory data collected at the time of biopsy were serum creatinine, estimated glomerular filtration rate (eGFR), 24-h urinary protein, hemoglobin, hemoglobin A1C, fasting blood glucose, serum albumin, and total serum cholesterol. Hemoglobin A1c results were not corrected to hemoglobin level.

Type 2 diabetes was defined according to the American Diabetes Association.[2] Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure >90 mm Hg; or antihypertensive medications being taken by the patient. Diabetic retinopathy was diagnosed by direct ophthalmoscopy and fluorescein angiography was performed by an ophthalmologist and was performed before renal biopsy in all cases.

Diabetic neuropathy was defined by the presence of sensitivity disorders and/or the abolition of tendon reflexes and/or orthostatic hypotension and/or signs of digestive, sexual, or urinary tract.

Coronary disease was defined by the presence of coronary history and/or disorders of repolarization on the electrocardiogram. Peripheral vascular disease was defined by the presence of history of peripheral arterial occlusive disease or clinical signs such as trophic disorders of arterial origin or imagery revealing arterial injury in the lower limbs. eGFR (mL/min/1.73 m2) was calculated by the modification of diet in renal disease equation.[3] Hematuria was defined as ≥2 ++, or >3 red blood cells/mm3 on phase contrast urine microscopy.

DN was diagnosed based on the presence at renal histology of mesangial expansion and diffuse intercapillary glomerulosclerosis with or without Kimmelstiel–Wilson nodules, basement membrane thickening and exudative lesions, such as fibrin caps, capsular drop or hyaline thrombi. ESRD was defined as creatinine clearance below 15 mL/min, the stage requiring initiation of maintenance dialysis.

   Statistical Analysis Top

Statistical analyses were performed using Statistical Package of Social Science (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA). The results were presented as means ± SD for continuous variables and percentage for categorical variables. Differences between groups were evaluated by Chi-square test for percentages and with Annova for averages.

Independent predictors of DN and NDRD were performed using logistic regression.

P <0.05 was considered statistically significant. A Kaplan–Meier method was used for comparison of survival.

   Results Top

Seventy-five patients with T2DM were included in this study. Mean age at biopsy was 52.7 years, 62% of patients were male. Median duration of diabetes was 69.5 months (0 month–30 years). Twenty-nine patients (38%) were insulin dependent. Hypertension was present at diagnosis in 43 cases (57%). Diabetic retinopathy was identified in 24 cases (32%). Thirty-five patients (47%) have nephrotic range proteinuria, and 19 patients (25%) have hematuria. Sixty patients have renal failure (80%), and eGFR was less than 60 mL/min/ 1.73 m2 in 53 cases (70%).

The most common indication for renal biopsy were the absence of diabetic retinopathy (41%) followed by short duration of diabetes (35%), [Table 1]. Renal histology revealed that 33 patients (44%) had isolated NDRD, 24 patients (32%) had mixed lesions of NDRD with DN, and 18 patients had isolated DN (24%). [Table 2] shows different types of NDRD detected. The most common NDRD was focal segmental glomerulosclerosis (FSGS) in 12 patients (21%), followed by membranous nephropathy in 11 patients (19%), and Ig A nephropathy in seven patients (12%) [Table 2]. Complications after renal biopsy were seen only in one case who had gross hematuria that resolved spontaneously without need for blood transfusion.
Table 1: Indications for renal biopsy.

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Table 2: Pathologic diagnosis of nondiabetic renal disease.

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The different NDRD corresponding for each indication of renal biopsy was summarized in [Table 3]. NDRD was related to other diseases in 15 cases. Membranous nephropathy was related to systemic lupus erythematosus in one case and Hashimoto thyroiditis in one other case. Ig A nephropathy was secondary to Henoch-Schonlein purpura in three cases. Membranoproliferative glomerulonephritis associated with mixed cryoglobulinemia that was related to hepatitis C was seen in one case.
Table 3: Indications of renal biopsy in nondiabetic nephropathy.

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The causes of crescentic glomerulonephritis in our study were Wegener granulomatosis in one case and microscopic polyangiitis into two cases. Vascular nephropathy was secondary to cholesterol crystal embolization in one case. The causes of chronic tubulointerstitial nephritis identified were multiple myeloma in three cases, primary Sjogren syndrome into two cases and sarcoidosis in one case.

Based on renal biopsy findings, we divided the patients into three basic groups group 1 including patients having isolated DN (18 cases); group 2 including patients having NDRD superimposed on DN (24 cases), and group 3 including patients having isolated NDRD (33 cases). [Table 4] summarizes the baseline patient demographics along with clinical and biochemical parameters.
Table 4: Clinical and laboratory parameters of patients.

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Comparison of clinical and laboratory data between the three groups, using univariate analysis, had demonstrated significant difference regarding age, insulin therapy, diabetic retinopathy, coronary disease, peripheral vascular disease, diastolic blood pressure, and hematuria [Table 4].

Predictor factors of diabetic nephropathy

Comparison between patients with DN and those without, using univariate analysis, showed significant difference regarding only insulin therapy and diabetic retinopathy [Table 5].
Table 5: Predictors of diabetic nephropathy by univariate analysis.

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Predictor factors of nondiabetic renal disease

Comparison between patients with NDRD and those without showed significant difference regarding masculine gender, presence of hematuria, coronary disease, peripheral vascular disease, lower mean arterial pressure, and lower diastolic blood pressure [Table 6].
Table 6: Predictors of nondiabetic renal disease by univariate analysis.

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We used multivariate logistic regression analysis to determine the risk factors associated with DN and NDRD. We studied variables found statistically significant in univariate analysis. Results are summarized in [Table 7].
Table 7: Multivariate logistic regression analysis of diabetic nephropathy and nondiabetic renal disease.

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After a median follow-up of 39.9 months (1.5–156 months), progression to ESRD was observed in 24 cases (32%) that was 10 patients in group 1 (55%), four patients in group 2 (16%), and 10 patients in group 3 (30%).

Risk factors of end-stage renal disease

To identify the risk factors of ESRD, we compared patients who progressed to ESRD (group ESRD) versus patients who did not progress to ESRD (group non-ESRD).

Comparison between two groups showed that diabetes duration over 60 months (P = 0.003), presence of diabetic retinopathy (P = 0.007), serum creatinine over 120 μmol/L (P = 0.05), and hemoglobin lower than 11 g/dL (P = 0.002) were statistically significant risk factors of ESRD by univariate analysis.

Kaplan–Meier analysis showed that time interval to ESRD was significantly shorter in patients having diabetes duration >60 months, diabetic retinopathy, serum creatinine >120 pmol/L, and hemoglobin <11 g/dL [Figure 1].
Figure 1: Kaplan–Meier plots for renal survival according to risk factors of end-stage renal disease.

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The presence of DN was not identified as significant risk factor for ESRD. Kaplan–Meier plots for renal survival according to DN are illustrated by [Figure 2].
Figure 2: Kaplan–Meier plots for renal survival according to diabetic nephropathy.

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By multivariate logistic regression analysis including these factors as variables, we found that diabetes duration >60 months, diabetic retinopathy, serum creatinine >120 μmol/L and hemoglobin <11 g/dL were all independent risk factors of ESRD [Table 8].
Table 8: Multivariate logistic regression analysis of end-stage renal disease.

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   Discussion Top

Currently DN is the leading cause of ESRD worldwide. The diagnosis of DN is often based on clinical criteria, and renal biopsy is practiced only if NDRD is suspected. In fact, NDRD is often seen in T2DM patients, but its real prevalence is still unknown. Among the 75 patients with T2DM who underwent renal biopsy, we found isolated NDRD in 44% of cases; NDRD associated to DN in 32% and isolated DN in 24%. Our findings are in accordance with studies showing NDRD prevalence rates of 12%–81%.

Meanwhile, this variability of the prevalence of NDRD reported is hard to explain. It may be related to small cohorts in some studies[4],[5] or to the geographical and ethnic factors in others.[6] The real prevalence of NDRD is difficult to define because renal biopsy is generally performed when clinical presentation is atypical. Consequently, NDRD prevalence in T2DM is often overestimated. Renal biopsy indications in our study did not differ from those reported in other studies and were based on strong clinical suspicion of NDRD.

The majority of NDRD found in our study were glomerulonephritis. Focal segmental glomerulosclerosis was the most common reported in our study in 21%, followed by membranous nephropathy in 19%, and IgA nephropathy in 12%. Our finding was also comparable to some reported studies[6],[7],[8] in contrast of those of ASIA where IgA nephropathy was the most common disease reported.[5],[9],[10]

The complete and correct diagnosis of glomerular diseases depends on the use of immunofluorescence and electron microscopy in the analysis of renal biopsy. Immunofluorescence microscopy is crucial in the diagnosis of IgA nephropathy and also in differentiation between types of crescentic glomerulonephritis. Electron microscopy is necessary to differentiate between primary and secondary focal segmental glomerulosclerosis, and in some cases, it can help diagnosing early DN (on the bases of thickened glomerular basement membranes).[11] In our study, immunofluorescence was performed in all cases, but electron microscopy was not available.

Glomerulonephritis is the most common NDRD reported in the literature.[7],[9],[12],[13] However, the mechanism involved in the development of NDRD in diabetic patients remains at present hypothetical. Due to the fact that there is still no general agreement on selection criteria for renal biopsy in T2DM patients, previous studies have revealed many clinical and laboratory findings that can be considered like predictors of NDRD. The results were not uniform.

Comparison of clinical and laboratory data between the three groups in our study, using univariate analysis, had shown significant difference regarding age, insulin therapy, diabetic retinopathy, coronary disease, peripheral vascular disease, diastolic blood pressure, and hematuria. By univariate and multivariate analysis, we identified insulin therapy and diabetic retinopathy as predictor factors of DN.

Independence of insulin therapy was investigated in a few studies and was found as a significant independent predictor of NDRD in the study of Horvatic et al and Wong et al.[11],[13]

Nephropathy and retinopathy are strongly related. Indeed, the presence of preexisting microvascular complications such us retinopathy is usually associated with the development of the other.[7] Some studies reported the absence of diabetic retinopathy as a significant predictor of NDRD.[7],[14] While in other reports, the presence of DN was predictor of DN.[15] However, it is important to know that 20–70%[16],[17] of patients with DN do not have diabetic retinopathy and 17.6% of patients with diabetic retinopathy do not have DN.[7] Thus, the absence of diabetic retinopathy is a predictor of NDRD but does not completely exclude the probability of having a DN.

Other predictor factors of NDRD in our study were hematuria, coronary disease, and peripheral vascular disease in multivariate analysis. Masculine gender, lower mean arterial pressure, and lower diastolic blood pressure were identified only in univariate analysis. Coronary disease was poorly studied in the literature, but hematuria was reported as significant predictor for NDRD in the majority of studies as well as in the recent meta-analysis of Liang et al.[14]

Zhou et al found that higher systolic blood pressure was a predictor factor of DN while Mou et al found that lower systolic blood pressure, lower mean arterial pressure, and lower diastolic blood pressure were predictor factors of NDRD in univariate analysis.[10],[12].

However, analysis of proteinuria differs from study to another. In fact, Sharma et al[18] found, in a large series of 620 diabetics, that nephrotic proteinuria was inversely associated with an isolated NDRD (odds ratio = 1.02; 95% confidence interval: 0.98–1.05; P = 0, 04).[18]

Similarly, Mak et al found that low proteinuria <3.5 g/24 was predictive of NDRD (P = 0.009).[5] However, Haddiya et al noted that abundant proteinuria was predictive of NDRD.[19] These conflicting results can be due varying definitions of proteinuria.

The influence of NDRD on renal outcomes in type 2 diabetic patients has not been well established, and only few studies have compared renal survival between DN, DN+NDRD and NDRD groups.[7],[8],[20] The meta-analysis of Liang et al have found that patients with NDRD had a better prognosis than those with DN but without significant difference (P = 0.07).[14]

In our study, the DN+NDRD group had a lower risk to develop ESRD than the DN group which can be explained by lower mean baseline creatinine in this group.

Few reports have studied the prognostic factors for renal survival in diabetic patients; however, definition of ESRD differs between the studies. Indeed, some authors hold a higher serum creatinine 500 μmol/L and other serum creatinine greater than 700 μmol/L or requiring maintenance dialysis.[7],[8],[13]

In our study, we defined ESRD by renal creatinine clearance below 15 mL/min and requiring maintenance dialysis.

Our results were in accordance with those reported by Chang et al and Wong et al, who found also that diabetic retinopathy was predictor of ESRD in multivariate analysis.[7],[13]. However, Kim et al found that the absence of diabetic retinopathy was associated with favorable renal outcome in the intensive treatment 8 group.

DN was founded as risk factor of ESRD in many reports.[7],[12],[21] This is explained by ireversible histological lesions leading to ESRD at macroalbuminuria stage. However, in our study, we did not find that DN is a prognostic factor for renal survival. Hypertension is an escalator of several renal diseases, including DN.[22] Chang et al found that hypertension is prognostic factor in multivariate analysis.

Some limitations of our study should be mentioned. The study was retrospective and most of our studied patients were selected for renal biopsy because of a higher suspicion of NDRD. This may overestimate real prevalence of NDRD. In addition, hematuria or diabetic retinopathy cannot be considered as independent predictor factors since they are related to selection bias from the beginning of the study for performing renal biopsy.

   Conclusion Top

Several NDRD are unknown and are mostly considered as DN. Most of them can be treatable with etiopathogenic treatment. Thus, it would be desirable to expand renal biopsy indications, which is considered today as an invasive procedure. For this purpose, we recommend to practice renal biopsy in patients with type 2 diabetes and chronic kidney disease, mainly in the absence of degenerative complications and especially diabetic retinopathy, diabetes with shorter duration, or presence of hematuria or independence of insulin therapy.

Conflict of interest: None declared.

   References Top

International Diabetes Federation. IDF Diabetes Atlas 5th edition. 2012 update. Last accessed September 2013.  Back to cited text no. 1
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9.  Back to cited text no. 2
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70.  Back to cited text no. 3
Richards NT, Greaves I, Lee SJ, Howie AJ, Adu D, Michael J. Increased prevalence of renal biopsy findings other than diabetic glomerulopathy in type II diabetes mellitus. Nephrol Dial Transplant 1992;7:397-9.  Back to cited text no. 4
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.  Back to cited text no. 5
Mazzucco G, Bertani T, Fortunato M, et al. Different patterns of renal damage in type 2 diabetes mellitus: A multicentric study on 393 biopsies. Am J Kidney Dis 2002;39:713-20.  Back to cited text no. 6
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.  Back to cited text no. 7
Kim YJ, Kim YH, Kim KD, et al. Non diabetic kidney disease in type 2 diabetic patients. Kidney Res Clin Pract 2013;32:115-20.  Back to cited text no. 8
Zhuo L, Ren W, Li W, Zou G, Lu J. Evaluation of renal biopsies in type 2 diabetic patients with kidney disease: A clinicopathological study of 216 cases. Int Urol Nephrol 2013;45: 173-9.  Back to cited text no. 9
Zhou J, Chen X, Xie Y, Li J, Yamanaka N, Tong X. A differential diagnostic model of diabetic nephropathy and non-diabetic renal diseases. Nephrol Dial Transplant 2008;23: 1940-5.  Back to cited text no. 10
Horvatic I, Tisljar M, Kacinari P, et al. Non-diabetic renal disease in Croatian patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2014;104:443-50.  Back to cited text no. 11
Mou S, Wang Q, Liu J, et al. Prevalence of non-diabetic renal disease in patients with type 2 diabetes. Diabetes Res Clin Pract 2010;87: 354-9.  Back to cited text no. 12
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.  Back to cited text no. 13
Liang S, Zhang XG, Cai GY, et al. Identifying parameters to distinguish non-diabetic renal diseases from diabetic nephropathy in patients with type 2 diabetes mellitus: A meta-analysis. PLoS One 2013;8:e64184.  Back to cited text no. 14
Ockrim Z, Yorston D. Managing diabetic retinopathy. BMJ 2010;341:c5400.  Back to cited text no. 15
Parving HH, Gall MA, Skøtt P, et al. Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 1992;41:758-62.  Back to cited text no. 16
Christensen PK, Larsen S, Horn T, Olsen S, Parving HH. Causes of albuminuria in patients with type 2 diabetes without diabetic retinopathy. Kidney Int 2000;58:1719-31.  Back to cited text no. 17
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.  Back to cited text no. 18
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.  Back to cited text no. 19
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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.  Back to cited text no. 20
Hironaka K, Makino H, Ikeda S, Haramoto T, Ota Z. Nondiabetic renal disease complicating diabetic nephropathy. J Diabetes Complications 1991;5:148-9.  Back to cited text no. 21
Shahbazian H, Rezaii I. Diabetic kidney disease; review of the current knowledge. J Renal Inj Prev 2013;2:73-80.  Back to cited text no. 22

Correspondence Address:
Amel Harzallah
Department of Medicine A, Charles Nicolle Hospital, Tunis
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PMID: 28748887

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]


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