Non-Diabetic Renal Disease in Type 2 Diabetic Patients with Nephropathy

1. Assistant Professor, Department of Nephrology, Enam Medical College & Hospital, Savar, Dhaka 2. Classified Eye Specialist, Combined Military Hospital, Savar Cantonment, Dhaka 3. Assistant Professor, Department of Medicine, Shaheed Monsur Ali Medical College,Uttara, Dhaka 4. Professor, Department of Nephrology, Dhaka Medical College & Hospital, Dhaka 5. Associate Professor, Department of Nephrology, Dhaka Medical College & Hospital, Dhaka Correspondence Jubaida Khanam Chowdhury, Email:drtuli_111@ymail.com Abstract


Introduction
Diabetes mellitus (DM) represents one of the most important health problems worldwide. Over the last years, the global prevalence of type 2 diabetes mellitus (T2DM) has reached epidemic proportions fuelled by the global rise in the prevalence of obesity and unhealthy lifestyles. The natural history of the renal involvement in diabetes is better characterized in patients with type 1 diabetes mellitus (T1DM) since the beginning of diabetes is precisely known, but the natural history of diabetic nephropathy is less well-established in type 2 DM because alterations of glucose metabolism are indolent and the diagnosis of diabetes is usually established many years afterwards. A significant part of nephrology practice today consists of diabetic kidney disease (DKD). 1 Diabetic nephropathy is not the sole renal disease in diabetic patients. Nephropathy in a patient suffering from DM may not be related directly to diabetic disease. Nondiabetic renal disorder (NDRD) and other diabetic renal diseases may be present in the same patient. 2 Kidney disease other than diabetic nephropathy can occur in type 2 diabetic patients and such kidney diseases are known as non-diabetic renal diseases, either isolated or superimposed on diabetic nephropathy (DN). 3 The majority of diabetic patients with renal involvement are not biopsied. Patients with T2DM selected for renal biopsy are typically those with a presentation that is out of keeping with 'classical' DN. These indications can be grouped broadly into either acute presentations, with a rapid loss of renal function over a short period [acute kidney injury (AKI)] or non-acute presentations in which there are atypical clinical features. Therefore, the correct diagnosis of such patients would be crucial for disease specific therapy. 4 DN is hard to reverse. However, certain NDRDs, such as membranous nephropathy, mesangial proliferative glomerulonephritis, IgA nephropathy are often treatable, even remittable. 5,6 Correct diagnosis is important for the patient since prognosis and treatment may vary according to the underlying cause. Biopsy proven DN has been reported to occur in proteinuric type 2 diabetic patients in the absence of retinopathy (RP). It means that absence of retinopathy cannot exclude the presence of DN because 50-70% patients with DN do not have retinopathy. Clearly DN can occur in absence of RP in type 2 proteinuric diabetic patients.
The presence of retinopathy suggests the occurrence of DN but does not exclude nondiabetic nephropathy. The renal-retinal relationship in type 2 diabetic patient may not be helpful for clinical diagnosis of DN and lack of RP is a poor predictor of nondiabetic kidney diseases. Therefore, presence or absence of diabetic retinopathy did not prove to be significant enough in excluding nondiabetic renal diseases.
Renal biopsy remains an integral part of clinical nephrology practice because the information it provides is pivotal for making a specific diagnosis, for planning patient management and for evaluating disease activity and prognosis. 7 This study was undertaken to describe the histological pattern of nondiabetic renal disease (NDRD) in type 2 diabetic patients who underwent renal biopsy for their atypical presentation.

Materials and Methods
This cross-sectional study was conducted in Department of Nephrology, Dhaka Medical College & Hospital, Dhaka from August 2015 to October 2016. Total 37 type 2 diabetic patients were selected. An informed written consent was taken from each patient. Every patient went through detailed history taking and physical examination. A standardized questionnaire was used to collect demographic data, age at diagnosis of DM, clinical presentation and findings. Previous investigation reports were recorded where necessary. Ophthalmological examination of eye was done in every patient for evidence of diabetic retinopathy (DR) which was confirmed by an ophthalmologist.
Renal biopsy was done in all type 2 diabetic patients with following criteria: a) Presence of microscopic hematuria or active urinary sediment b) Nephrotic range proteinuria without retinopathy

Results
In this study renal biopsy were done in 37 cases. Among them NDRD were found in 19 (57.6%) cases, NDRD plus DN in 7 (21.2% ) cases and isolated DN in 7 ( 21.2%) subjects. Table I shows distribution of patients according to baseline characteristics. Mean age at biopsy was nearly similar in Group I and Group II patients but it was less in Group III. Hypertension was more in Group II patients compared to other two Groups. Duration of diabetes was significantly less in the isolated NDRD group compared with the other groups. Most of the Group I patients (63.2%) had history of DM for less than 5 years, 57.1% Group II patients had history of DM for 5-10 years and 57.1% Group III patients had history of DM for >10 years. p value was significant (0.038).  Table III shows distribution of patients according to ophthalmoscopic findings. In Group A (patients with DR) NDRD, DN and mixed lesion were present in 7 (41.2%), 5 (29.4%) and 5 (29.4%) cases. In Group B (patients without DR) NDRD, DN and mixed lesion were present in 12 (75%), 2 (12.5%) and 2 (12.5%) cases respectively. p value (0.189) was not significant. Fisher exact test was done to measure the level of significance. Table IV shows biochemical parameters of different groups of patients. Serum creatinine levels were significantly higher in patients with DN (isolated as well as with superimposed disease) compared with those with NDRD, but p value was not significant (p >0.654). Nephrotic range proteinuria was more in NDRD plus DN compared to NDRD and DN, and p value (0.054) was not significant. Microscopic hematuria was more in NDRD group patients (79%) than in other two groups.

Discussion
The prognostic importance of kidney biopsy and its usefulness in identifying NDKD is an important issue that must be taken into consideration in T2DM patients. Isolated DKD patients tend to have a worse prognosis compared to NDKD patients. [8][9][10] DN is one of the most frequent and clinically important complications of diabetes mellitus. It affects approximately 40% of the patients who have diabetes for more than 20 years and has become the leading cause of end stage renal disease (ESRD) worldwide. 11,12 In this study it was observed that mean age (years) at biopsy was nearly similar in Group I (Isolated NDRD) and Group II (NDRD superimposed on DN), 48.21 ± 9.45 and 49.29±7.39 years respectively, but in Group III (Isolated DN ) mean age was 44 ± 12.88 years which was lower than in other two groups. Unnikrishnan et al 13  Absence of diabetic retinopathy is said to be one of the important predictors of NDRD. In people with type 1 diabetes, the association is stronger than in those with type 2 diabetes. This correlation has been reported by Lee et al 18 who showed that absence of retinopathy was one of the significant factors that  19 reported that absence of retinopathy showed the highest sensitivity (87%) and specificity (93%) for the prediction of NDRD. In our study patients without DR, NDRD, DN and mixed lesion were found in 12 (75%), 2 (12.5%) and 2 (12.5%) cases respectively.
In patients with short duration of DM, heavy proteinuria, active urinary sediment or rapid deterioration of renal function renal biopsy showed NDRD in 57.6% cases, DN in 21.2% and mixed lesion in 21.2% cases. Therefore, renal biopsy should be recommended in type 2 diabetic patients with risk factors of NDRD for accurate diagnosis, prompt initiation of disease-specific treatment and ultimately better renal outcome.