Non-diabetic Glomerular Disease Research Articles

Potential Role of Mineralocorticoid Receptor Antagonists in Nondiabetic Chronic Kidney Disease and Glomerular Disease.

Glomerular disease is a leading cause of CKD and ESKD. Although diabetic kidney disease is the most common cause of glomerular disease, nondiabetic causes include malignancy, systemic autoimmune conditions, drug effects, or genetic conditions. Nondiabetic glomerular diseases are rare diseases, with a paucity of high-quality clinical trials in this area. Furthermore, late referral can result in poor patient outcomes. This article reviews the current management of nondiabetic glomerular disease and explores the latest developments in drug treatment in this area. Current treatment of nondiabetic glomerular disease aims to manage complications (edema, hypertension, proteinuria, hyperlipidemia, hypercoagulability, and thrombosis) as well as target the underlying cause of glomerular disease. Treatment options include renin-angiotensin-aldosterone system inhibitors, statins/nonstatin alternatives, loop diuretics, anticoagulation agents, immunosuppressives, and lifestyle and dietary modifications. Effective treatment of nondiabetic glomerular disease is limited by heterogeneity and a lack of understanding of the disease pathogenesis. Sodium-glucose cotransporter-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs, such as finerenone), with their broad anti-inflammatory and antifibrotic effects, have emerged as valuable therapeutic options for a range of cardiorenal conditions, including CKD. ns-MRAs are an evolving drug class of particular interest for the future treatment of nondiabetic glomerular disease, and there is evidence that these agents may improve kidney prognosis in various subgroups of patients with CKD. The benefits offered by ns-MRAs may present an opportunity to reduce the progression of CKD from a spectrum of glomerular disease. Several novel ns-MRA are in clinical development for both diabetic and nondiabetic CKD.

#6467 DETERMINANTS OF NON-DIABETIC KIDNEY DISEASES IN DIABETIC PATIENTS

Abstract Background and Aims While diabetic nephropathy is the main kidney disease in patients with type 2 diabetes mellitus, a variety of non-diabetic kidney diseases (NDKD) may also occur. The decision to order a biopsy in diabetic patients is not an easy one as diabetic kidney disease is itself a proteinuric condition. The main objective of this study is to define factors that may differentiate isolated diabetic nephropathy and non-diabetic kidney disease in diabetic patients. In addition, we also aimed to analyze the effects of treatment choices on renal and overall survival. Method The study was conducted at a university hospital, which served as a tertiary healthcare center. One hundred and three diabetic patients who underwent kidney biopsy were involved in the study. Demographic characteristics, physical examination findings, laboratory tests and kidney biopsy findings were retrospectively evaluated. Results According to kidney biopsy findings 30 patients (29,1%) had isolated diabetic nephropathy. NDKDs were present in 73 (70,9%) of the patients. 78,1% of the patients with NDKDs had non-diabetic glomerular diseases. Among glomerular diseases, focal segmental glomerulosclerosis (36,9%), IgA nephropathy (17,8%) and membranous nephropathy (13,7%) were the leading three diseases. The duration of diabetes (p=0,00), HBA1C level (p=0,00) and the amount of proteinuria (p=0,02) were higher in patients who had isolated diabetic nephropathy. Presence of diabetic retinopathy (p=0,00), concomitant vascular diseases (p=0,02) and the use of insulin treatment were also more often in patients with isolated diabetic nephropathy. Multivariate analysis revealed that patients with higher HBA1C levels and longer diabetes duration had more tendencies to have isolated diabetic nephropathy. Immunosuppressive treatments for glomerular diseases were administered in around 50% of the patients. However, renal and overall survivals were not different between patients who received immunosuppressive treatments and those who didn't. Conclusion A renal biopsy in diabetic patients might be preserved for those with shorter diabetes duration and lower HBA1C levels. As poor glycemic control and susceptibility to infections pose additional risks, immunosuppressive treatments might not always be beneficial.

In situ assessment of Mindin as a biomarker of podocyte lesions in diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal failure worldwide. Several mechanisms are involved in the pathogenesis of this disease, which culminate in morphological changes such as podocyte injury. Despite the complex diagnosis and pathogenesis, limited attempts have been made to establish new biomarkers for DN. The higher concentration of Mindin protein in the urine of patients with type 2 diabetes mellitus suggests that it plays a role in DN. Therefore, this study investigated whether in situ protein expression of Mindin can be considered a potential DN biomarker. Fifty renal biopsies from patients diagnosed with DN, 57 with nondiabetic glomerular diseases, including 17 with focal segmental glomerulosclerosis (FSGS), 14 with minimal lesion disease (MLD) and 27 with immunoglobulin A nephropathy (IgAN), and 23 adult kidney samples from autopsies (control group) were evaluated for Mindin expression by immunohistochemistry. Podocyte density was inferred by Wilms' tumor 1 (WT1) immunostaining, while foot process effacement was assessed by transmission electron microscopy. Receiver operative characteristic (ROC) analysis was performed to determine the biomarker sensitivity/specificity. Low podocyte density and increased Mindin expression were observed in all cases of DN, regardless of their class. In the DN group, Mindin expression was significantly higher than that in the FSGS, MCD, IgAN and control groups. Higher Mindin expression was significantly positively correlated with foot process effacement only in class III DN cases. Furthermore, Mindin protein presented high specificity in the biopsies of patients with DN (p < 0.0001). Our data suggest that Mindin may play a role in DN pathogenesis and is a promising biomarker of podocyte lesions.

Prevalence of Nondiabetic Glomerular Diseases in Patients with Type 2 Diabetes Mellitus

Prevalence of Nondiabetic Glomerular Diseases in Patients with Type 2 Diabetes Mellitus

Remission of Proteinuria in a Patient Affected by Crescentic IgA Nephropathy with Rapidly Progressive Glomerulonephritis Treated by Sodium-Glucose Cotransporter-2 Inhibitors: Casual or Causal Relationship?

Crescentic IgA nephropathy (IgAN) with rapidly progressive glomerulonephritis (RPGN) is often associated with rapidly declining kidney function. Up to this date, specific therapy for crescentic IgAN is still unknown. Accumulating evidence suggests that sodium-glucose co-transporter-2 inhibitors (SGLT-2i) may have a role in standard therapy of glomerular diseases. However, it is unclear at what point in the natural history of specific glomerular diseases SGLT-2i can be beneficial. We report the clinical and histological features of a patient with crescentic IgAN that presented as an RPGN, who received intensive immunosuppression and renal replacement therapeutic (RRT). At the third month, the patient presented with significant improvement in his kidney function. At that point, we decided to start dapagliflozin in addition to his renin-angiotensin system (RAS) blocker, basing our decision on its proven renal benefits such as slowing the rate of decline in kidney function and reducing albuminuria. At the eighth month, the patient’s renal function gradually improved from serum Cr of 6.07 to 2.1 mg/dL; and urine albumin to creatinine ratio (UACR) declined from 5655 mg/g to 200 mg/g. The use of SGLT-2i in primary and secondary nondiabetic glomerular disease appears promising. It is crucial and necessary to accumulate more evidence for a more complete understanding of the mechanisms of the actions of SGLT-2i in non-diabetic glomerular disease.

SGLT2 Inhibitors for Nephrologists

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are the mainstay of therapy for the prevention of progressive renal damage in diabetic and non-diabetic kidney diseases, especially glomerulonephritides. Sodium-glucose co-transporter-2 inhibitors are a relatively new class of oral antidiabetic drugs. Early evidence suggests that there are renal and cardiovascular benefits of this class of drugs that extend beyond glycaemic control for patients both with and without diabetes. With each and every trial, the limit for the glomerular filtration rate has been set lower, making the drugs more suitable from the perspective of nephrologists. This drug class has the potential to become the mainstay of reno-protective strategies used by nephrologists, in addition to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. This article reviews the evidence and reports that are already published regarding the use of sodium-glucose co-transporter-2 inhibitors to treat non-diabetic glomerular disease.

Kidney biopsy in very elderly patients: indications, therapeutic impact and complications

BackgroundFew data is available on the risk/benefit balance of native kidney biopsy (KB) in very elderly patients.MethodsMulticenter retrospective cohort study in the Aix-Marseille area: the results of KB and medical charts of all patients over 85 years biopsied between January 2010 and December 2018 were reviewed.Results104 patients were included. Median age was 87 years. Indications for KB were: acute kidney injury (AKI) in 69.2% of patients, nephrotic syndrome (NS) with AKI in 13.5%, NS without AKI in 12.5%, and proteinuria in 4.8%. Median serum creatinine was 262 μmol/L, 21% of patients required dialysis at the time of KB. Significant bleeding occurred in 7 (6.7%) patients, requiring blood cell transfusion in 4 (3.8%), and radiological embolization in 1 (1%). The most frequent pathological diagnoses were: non-diabetic glomerular diseases (29.8%, including pauci-immune crescentic glomerulonephritis in 9.6%), hypertensive nephropathy (27.9%), acute interstitial nephritis (16.3%), renal involvement of hematological malignancy (8.7%), and acute tubular necrosis (6.7%). After KB, 51 (49%) patients received a specific treatment: corticosteroids (41.3%), cyclophosphamide (6.7%), rituximab (6.7%), bortezomib (3.8%), other chemotherapies (3.8%). Median overall survival was 31 months.ConclusionsKB can reveal a diagnosis with therapeutic impact even in very elderly patients. Severe bleeding was not frequent in this cohort, but KB may have not been performed in more vulnerable patients.

Metformin ameliorates the severity of experimental Alport syndrome

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin also ameliorates tumor progression, inflammatory disease, and fibrosis. However, the ability of metformin to improve non-diabetic glomerular disease and chronic kidney disease (CKD) has not been explored. To investigate the effect of metformin on non-diabetic glomerular disease, we used a mouse model of Alport syndrome (Col4a5 G5X) which were treated with metformin or losartan, used as a control treatment. We also investigated the effect of metformin on adriamycin-induced glomerulosclerosis model. Pathological and biochemical analysis showed that metformin or losartan suppressed proteinuria, renal inflammation, fibrosis, and glomerular injury and extended the lifespan in Alport syndrome mice. Transcriptome analysis showed that metformin and losartan influenced molecular pathways-related to metabolism and inflammation. Metformin altered multiple genes including metabolic genes not affected by losartan. Metformin also suppressed proteinuria and glomerular injury in the adriamycin-induced glomerulosclerosis mouse model. Our results showed that metformin ameliorates the glomerular sclerosis and CKD phenotype in non-diabetic chronic glomerular diseases. Metformin may have therapeutic potential for not only diabetic nephropathy but also non-diabetic glomerular disease including Alport syndrome.

Nuclear receptors in podocyte biology and glomerular disease.

Nuclear receptors have a broad spectrum of biological functions in normal physiology and in the pathology of various diseases, including glomerular disease. The primary therapies formany glomerular diseases are glucocorticoids, which exert their immunosuppressive and direct podocyte protective effects via the glucocorticoid receptor (GR). As glucocorticoids are associated with important adverse effects and a substantial proportion of patients show resistance to these therapies, the beneficial effects of selective GR modulators are now being explored. Peroxisome proliferator-activated receptor-γ (PPARγ) agonism using thiazolidinediones has potent podocyte cytoprotective and nephroprotective effects. Repurposing of thiazolidinediones or identification of novel PPARγ modulators are potential strategies to treat non-diabetic glomerular disease. Retinoic acid receptor-α is the key mediator of the renal protective effects of retinoic acid, and repair of the endogenous retinoic acid pathway offers another potential therapeutic strategy for glomerular disease. Vitamin D receptor, oestrogen receptor and mineralocorticoid receptor modulators regulate podocyte injury in experimental models. Further studies are needed to better understand the mechanisms of these nuclear receptors, evaluate their synergistic pathways and identify their novel modulators. Here, we focus on the role of nuclear receptors in podocyte biology and non-diabetic glomerular disease.

A role for NPY-NPY2R signaling in albuminuric kidney disease

Albuminuria is an independent risk factor for the progression to end-stage kidney failure, cardiovascular morbidity, and premature death. As such, discovering signaling pathways that modulate albuminuria is desirable. Here, we studied the transcriptomes of podocytes, key cells in the prevention of albuminuria, under diabetic conditions. We found that Neuropeptide Y (NPY) was significantly down-regulated in insulin-resistant vs. insulin-sensitive mouse podocytes and in human glomeruli of patients with early and late-stage diabetic nephropathy, as well as other nondiabetic glomerular diseases. This contrasts with the increased plasma and urinary levels of NPY that are observed in such conditions. Studying NPY-knockout mice, we found that NPY deficiency in vivo surprisingly reduced the level of albuminuria and podocyte injury in models of both diabetic and nondiabetic kidney disease. In vitro, podocyte NPY signaling occurred via the NPY2 receptor (NPY2R), stimulating PI3K, MAPK, and NFAT activation. Additional unbiased proteomic analysis revealed that glomerular NPY-NPY2R signaling predicted nephrotoxicity, modulated RNA processing, and inhibited cell migration. Furthermore, pharmacologically inhibiting the NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. Our findings suggest a pathogenic role of excessive NPY-NPY2R signaling in the glomerulus and that inhibiting NPY-NPY2R signaling in albuminuric kidney disease has therapeutic potential.

SAT-168 RAPIDLY PROGRESSIVE RENAL FAILURE IN A DIABETIC: AN INTERESTING CASE REPORT

The prevalence of non-diabetic nephropathy in patients with diabetes has been reported to vary widely between 12% to 79%. Various studies have reported Minimal change disease, Focal segmental glomerulosclerosis and IgA nephropathy as the commonest non-diabetic glomerular disease in patients with diabetes. Here we are reporting an interesting case of rapidly progressive glomerulonephritis in a patient with type 2 diabetes. Case report:A 55 year old male presented with Oliguria and Dyspnea since 1 week, with history of multiple pustules over body since 3 days. There was no history of cough, hemoptysis, fever, loin pain or dysuria. He had a past history of Hypertension and Diabetes since 15 yrs. He had history of NSAID intake since 1yr. On examination he was dyspneic, he had pallor, edema and pustules all over the body. His systemic examination was within normal limits. Blood Investigations:Urine routine-3+ proteinuria, 6-8 WBCs and no RBCs, Urine protein creatinine ratio- 6.5, Blood urea- 123mg/dL, and Serum creatinine- 8.4mg/dL. He was suspected to have RPRF and serum complements were sent. His C3 was 57(low) and C4 was 19 (normal), ANA and ANCA were negative. A provisional diagnosis of Infection related Glomerulo Nephritis(IRGN). However, in view of symptoms pre-dating appearance of skin lesions, renal biopsy was done. Light microscopy showed 8 glomeruli, of which one was globally sclerotic.4 glomeruli show cellular crescents. Endocapillary proliferation with hypercellularity and lobular accentuation was seen. Mesangial nodules which were weakly PAS and silver positive and blue on trichrome are seen in all the glomeruli. The nodules were almost of uniform size and distributed evenly within and between glomeruli. Tubular epithelial cell injury noted, Tubular basement membrane appeared prominent. Tubules showed 20% atrophy. Interstitium showed 30% fibrosis with lymphocyte infiltration. Blood vessel showed medial wall thickening. Congo red stain negative. Immunoflorescence showed IgG (+3) linear positivity over the tubular basement membranes, Bowmans capsule, and also positive over the mesangial nodules. Kappa and lambda light chains were negative. IgM, IgA, C3 and C1q were negative. Electron microscopy showed punctate deposits along the inner aspects of the Glomerular basement membrane, prominent mesangial nodular expansion and mild to moderate foot process effacement. Tubular Basement Membrane showed similar punctate deposits. He was hence diagnosed as having Gamma heavy chain deposition disease. He was treated with Bortezomib in view of logistic reasons. He had partial renal recovery with creatinine stabilised at 4 mg/dl and dialysis independent. Nodular lesions in Diabetes mellitus isn’t always diabetic nephropathy. HCDD( Heavy chain deposition disease) is a differential to consider in case of nodular glomerular lesions. Immunofluorescence is an important tool for diagnosis. In our case, preliminary investigations were suggestive of a IRGN, however biopsy gave the diagnosis. Hence, there must be low threshold for biopsy in doubtful cases. Also, HCDD presenting as rapidly progressive glomerulonephritis is extremely rare with very few cases reported. Treatment should be considered in view of nephrotoxicity of the Heavy chains, even in absence of a hematological disorder.

Diabetic Kidney Disease: Past and Present.

Diabetes mellitus (DM) afflicting humans has been recognized as a disease for >3000 years. However, very little was known about its etiology and pathogenesis until about a century ago when increasing knowledge about anatomy and physiology of the human body gradually led to our understanding that the hormone insulin produced by the Islets of Langerhans in the pancreas plays a crucial role in the metabolism of glucose and maintaining the blood sugar level within a normal range. DM is caused by inadequate insulin production (type 1) or insulin resistance (type 2). For thousands of years, DM has been considered as a disease of the kidney; however, with the understanding of the pathogenesis of DM, it became clear that diabetic kidney disease (DKD) is a complication and not a cause of DM. DKD is associated with increased matrix expansion that manifests morphologically as a diffuse or nodular expansion of the mesangium and diffuse thickening of the glomerular and tubular basement membranes. Hyperglycemia plays a crucial role in the development of pathologic changes within the kidney. Once established, DKD usually undergoes a slow but relentless progression to end-stage renal disease. However, recent studies have shown that its progression can be slowed or even reversed by strict control of hyperglycemia. Morphologically, DKD may resemble several other glomerular diseases that must be ruled out before a definitive diagnosis. Patients with DM may also develop nondiabetic glomerular or interstitial diseases with or without DKD. The findings in nephrectomy specimens and the differential diagnoses are presented in detail.

Epidemiology of Glomerular Disease in Southern Arizona: Review of 10-Year Renal Biopsy Data.

Glomerulonephritis stands third in terms of the etiologies for end-stage kidney disease in the USA. The aim of this study was to look at the patterns of biopsy-proven glomerulonephritis based on data from a single center.Kidney biopsy specimens of all patients above the age of 18 years, over a 10-year period, who had diagnosis of nondiabetic glomerular disease, were selected for the study.The most common histopathological diagnosis was focal and segmental glomerulosclerosis (FSGS) (22.25%, 158/710) followed by membranous nephropathy (20.28%, 144/710) and immunoglobulin (Ig)A nephropathy (19.71%, 140/710). There was male preponderance in all histological variants except IgA nephropathy, lupus nephritis, and pauci-immune glomerulonephritis. The race distribution was uneven, and all histological variants, except minimal change disease and lupus nephritis, were more commonly seen in whites. In a separate analysis of the histological pattern in Hispanics, lupus nephritis was the most common pathology (28.70%, 62/216) followed by FSGS (18.05%, 39/216). In American Indian population, the most common pathology was IgA nephropathy (33.33%, 8/24) followed by FSGS (16.67%, 4/24).This study highlights the histopathological patterns of glomerular disease in southern Arizona. The data suggest regional and ethnic variations in glomerular disease that may point towards genetic or environmental influence in the pathogenesis of glomerular diseases.

Effects of Therapy on Urine Neutrophil Gelatinase-Associated Lipocalin in Nondiabetic Glomerular Diseases with Proteinuria.

Urine neutrophil gelatinase-associated lipocalin (NGAL) is widely used as a biomarker for acute kidney injury. Cross-sectional studies have shown that NGAL may be elevated in glomerular diseases, but there is limited information on the value of NGAL in predicting treatment response or on the changes of NGAL levels after therapy. We prospectively evaluated the effects of therapy on NGAL in nondiabetic glomerular diseases. Urine NGAL was collected at biopsy and follow-up at 12 months. At baseline, NGAL in glomerular disease patients (n = 43) correlated with proteinuria, but not with glomerular filtration rate (GFR). After therapy with renin-angiotensin blockers and/or immune modulating agents, change of NGAL correlated with change of proteinuria, but not with change of GFR. NGAL at baseline was not different between patients in complete remission (CR) at follow-up compared to those not in remission (NR). Compared to baseline, NGAL at follow-up decreased in CR (n = 10), but not in NR. Change of NGAL was greater in CR than NR. In conclusion, the change of urine NGAL correlated with the change of proteinuria. Baseline NGAL was not a predictor of complete remission. Future studies will be necessary to determine the role of NGAL as a predictor of long term outcome in proteinuric glomerular diseases.

Vitamin D receptor activator and dietary sodium restriction to reduce residual urinary albumin excretion in chronic kidney disease (ViRTUE study): rationale and study protocol.

Optimal albuminuria reduction is considered essential to halting chronic kidney disease (CKD) progression. Both vitamin D receptor activator (VDRA) treatment and dietary sodium restriction potentiate the efficacy of renin-angiotensin-aldosterone-system (RAAS) blockade to reduce albuminuria. The ViRTUE study addresses whether a VDRA in combination with dietary sodium restriction provides further albuminuria reduction in non-diabetic CKD patients on top of RAAS blockade. The ViRTUE study is an investigator-initiated, prospective, multi-centre, randomized, double-blind (paricalcitol versus placebo), placebo-controlled trial targeting stage 1-3 CKD patients with residual albuminuria of >300 mg/day due to non-diabetic glomerular disease, despite angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. During run-in, all subjects switched to standardized RAAS blockade (ramipril 10 mg/day) and blood pressure titrated to <140/90 mmHg according to a standardized protocol. Eligible patients are subsequently enrolled and undergo four consecutive study periods in random order of 8 weeks each: (i) paricalcitol (2 µg/day) combined with a liberal sodium diet (∼200 mmol Na(+)/day, i.e. mean sodium intake in the general population), (ii) paricalcitol (2 µg/day) combined with dietary sodium restriction (target: 50 mmol Na(+)/day), (iii) placebo combined with a liberal sodium diet and (iv) placebo combined with dietary sodium restriction. Data are collected at the end of each study period. The primary outcome is 24-h urinary albumin excretion. Secondary study outcomes are blood pressure, renal function (estimated glomerular filtration rate), plasma renin activity and, in a sub-population (N = 9), renal haemodynamics (measured glomerular filtration rate and effective renal plasma flow). A sample size of 50 patients provides 90% power to detect a 23% reduction in albuminuria, assuming a 25% dropout rate. Further reduction of residual albuminuria by combination of VDRA treatment and sodium restriction during single-agent RAAS-blockade will justify long-term studies on cardiorenal outcomes and safety. NTR2898 (Dutch trial register).

A New Mechanism for Albuminuria-Induced Podocyte Injury

A large body of evidence describes the relationship between albuminuria and progressive renal damage.[1][1]–[3][2] Podocyte injury contributes to progressive albuminuria in diabetic and nondiabetic glomerular diseases, with antiproteinuric regimens providing a renoprotective effect.[4][3]–[6][4

Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease

Compelling experimental evidence exists for the role of oxidants and iron in glomerular disease. In preliminary studies, we confirmed increased urinary catalytic iron in patients with glomerulonephritis and diabetic nephropathy. We conducted two separate single-center, prospective, single-armed, open-labeled, proof-of-concept studies to evaluate the safety and efficacy of an oral iron chelator in patients with glomerulonephritis and diabetic nephropathy. Study 1 comprised 15 patients with biopsy-proven glomerulonephritis who had persistent proteinuria despite treatment with steroids and/or cyclophosphamides. Study 2 comprised 38 adult patients with diabetic nephropathy. Patients in Study 1 were treated with deferiprone (50 mg/kg/day) in three divided doses for 6 months and Study 2 patients were treated for 9 months. In Study 1, two patients had severe gastrointestinal intolerance and withdrew from the study after one dose and are not included in the results. There was a significant reduction (47 ± 9% mean) in 24-h urinary protein (4.01 ± 1.61 to 2.21 ± 1.62 [p = 0.009]), with no significant changes in serum creatinine. In Study 2, treatment with deferiprone resulted in a marked, persistent drop in the mean albumin/creatinine ratio (187 ± 47 at baseline to 25 ± 7 mg/g, [p = 0.01]) and stable renal function over a 9-month period. No clinically significant adverse events were observed in either study. Although these are small, open-labeled, and non-randomized studies, our results suggest that future randomized, double-blind trials examining the utility of deferiprone to treat glomerular diseases appear warranted.

Non-diabetic renal diseases in diabetics

Abstract Diabetic nephropathy (DN) is a specific condition with a well-defined clinical course especially in type I diabetes. This is usually progressive and irreversible and does not have any specific treatment. But ‘diabetic nephropathy’ is not the only renal ailment found in diabetes. Renal conditions other than DN which are found in diabetics are collectively called non-diabetic renal disease. This is a heterogeneous mixture of glomerular and non-glomerular conditions. Although, some glomerulapathies were supposed to be more common in diabetics previously, a close review of various studies based on kidney biopsy, across the globe, suggests that the type and frequency of non-diabetic glomerular disease is dictated by indication of biopsy (proteinurea, hematurea, renal failure) and the underlying population studied. For example, in USA commonest lesion was focal and segmental glomerular sclerosis (FSGS), in Korea immunoglobulin A, in Iraq membranoproliferative glomerulonephritis (MPGN) and in India post infectious glomerulonephritis and interstitial nephritis. Ischemic nephropathy due to macrovascular diabetic complication, infections, chronic pyelonephritis, bladder dysfunction, obstructive uropathy, electrolyte abnormalities are common. Due to co-morbidities and various medications, episodes of acute kidney injury are also frequent. Many patients of primary renal diseases may develop drug-induced diabetes such as post transplant diabetes mellitus. Various conditions may co-exist with underlying DN. During evaluation of diabetic patients by nephrologist, a meticulous identification of all these non-diabetic renal conditions gives an opportunity to treat reversible conditions with specific therapy, help in renoprotection and helps in proper prognostication. A detailed classification of non-diabetic renal disease has been proposed for the benefit of clinicians.

Endothelin-1 and Endothelin A Receptor Immunoreactivity Is Increased in Patients with Diabetic Nephropathy

Background: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. Materials and methods: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. Results: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. Conclusion: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.

Protein kinase C ß inhibition ameliorates experimental mesangial proliferative glomerulonephritis

Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy where therapy targeting the β isoform of this enzyme has been examined. However, PKC-β is also increased in various forms of human glomerulonephritis, including IgA nephropathy. Accordingly, we sought to examine the effects of PKC-β inhibition in the Thy1.1 model of mesangial proliferative glomerulonephritis. Following administration of monoclonal OX-7, anti-rat Thy-1.1 antibody, Male Wistar rats were randomized to receive either the PKC-β inhibitor, ruboxistaurin (10 mg/kg per day in chow) or vehicle. Animals were then examined 6 days later. PKC-β inhibition was associated with reductions in mesangial cellularity and extracellular matrix deposition. Proteinuria was, however, unaffected. In vitro, PKC-β inhibition showed modest, dose-dependent reductions in mesangial cell (3) H-thymidine and (3) H-proline incorporations, indices of cell proliferation and collagen synthesis, respectively. The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by PKC-β inhibition suggests the potential clinical utility of this approach as a therapeutic strategy in non-diabetic glomerular disease.