Diffuse Glomerulosclerosis Research Articles

MICROSCOPIC POLYANGIITIS PRESENTING WITH CARDIAC TAMPONADE

MICROSCOPIC POLYANGIITIS PRESENTING WITH CARDIAC TAMPONADE

Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice.

Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGFKD ) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS−/− ). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGFKD led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS−/−:VEGFKD mice. VEGFKD diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS−/−:VEGFKD (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS−/−:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGFKD -induced abnormal S-nitrosylation of specific proteins, including β3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure.

Renal post-mortem findings in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematological disorders presenting with an increased proliferation in one or several hematological cell lines. Renal manifestations of MPN have not been fully characterized so far. To morphologically assess the potential renal involvement in MPN patients, we analyzed histomorphological findings of a post-mortem cohort (n = 57) with a disease history of Philadelphia-negative MPN including polycythaemia vera, primary myelofibrosis, essential thrombocythemia, or chronic myelomonocytic leukemia (CMML). Seven (12.2%) patients presented with a pattern of diffuse glomerulosclerosis not attributable to diabetic or hypertensive nephropathy. Weak C4d staining suggestive for chronic thrombotic microangiopathy (TMA) was observed in 4/7 cases. Glomerulonephritis was excluded by light microscopy and immunohistochemistry. Patients with a pattern of diffuse glomerulosclerosis did not differ from the rest of the cohort regarding MPN subtype, disease duration, age, or sex. No significant proteinuria had been observed before death. Further findings attributed to MPNs were extramedullary hematopoiesis (n = 5; 8.8%) and tumor involvement in advanced disease (n = 4; 7.0%). Other common findings included arteriolosclerosis (n = 18; 31.6%) and signs of shock (n = 8; 14.0%). To our knowledge, this study is so far the largest investigating renal findings in MPN patients. There may be a causal relationship between idiopathic diffuse glomerular sclerosis and MPN, although its clinical significance and pathophysiology remain uncertain with TMA probably being relevant in a subgroup of cases. Our findings demonstrate the spectrum of renal findings in MPN from early to terminal disease of which hematologists should be aware of in daily clinical practice.

Anti-glomerular basement membrane disease

Background Anti-glomerular basement membrane (GBM) disease is an autoimmune disorder defined by the presence of autoantibody directed against α3 chain of type IV collagen. It is clinically characterized by rapidly progressive glomerulonephritis and lung hemorrhage. Patients and methods A retrospective study of 25 patients with anti-GBM disease, who were diagnosed and followed up at our institute from January 2011 to December 2017, was undertaken. Most patients presented with hypertension (76%), oliguria (80%), and dialysis-dependent renal failure (96%). Hemoptysis was seen in only one-third (28%) of patients. Diffuse glomerulosclerosis with crescents was the most common renal histopathology (60%) seen. Results Of all patients who were able to get adequate treatment in the form of plasmapheresis (56%) and immunosuppression (100%), only one (4%) patient recovered. Conclusion The majority of our patients with anti-GBM presented late in their clinical course of the disease, with advanced renal failure and irreversible lesion on kidney biopsy. High index of suspicion, early diagnosis, and aggressive management may improve the outcome of these patients.

Immunoglobulin light-chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease

AbstractLight chain (LC) deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin LC, leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse immunoglobulin κ locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no immunoglobulin heavy chain production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria, and finally kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor–based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function but also partially reversed kidney lesions. Finally, transcriptome analysis of presclerotic glomeruli revealed that proliferation and extracellular matrix remodeling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.

P0121KIDNEY BIOPSY FINDINGS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Abstract Background and Aims The aim of the study is to evaluate kidney biopsy findings other than renal diabetic changes in patients with type 2 diabetes mellitus. Method Diabetic patients with kidney biopsy between January 2003 and January 2020 were enrolled to the study. Kidney biopsy was performed to patients with suspicion of kidney disease other than diabetic nephropathy. The suspicious cases were patients without diabetic retinopathy, diabetes mellitus history less than 5 years, creatinine increase faster than expected course and hematuria. Demographic features, biopsy finding were all noted. Results Totally, 135 patients’ data were evaluated in which 54.1% was male. Demographic characteristics of the patients and laboratory data are given in Table 1. Mean age was 55.4±11 years and mean diabetes duration was 6.9±6.3 years. Mean duration of diabetes was 5.3±5.5 years in patients with nondiabetic nephropathy whereas it was 10.2±6.4 and 11.2±7.6 years in patients with diabetic and/or nondiabetic pathologies respectively (p<0.05). Serum creatinine and proteinuria level were lower, and hemoglobin levels were higher in patients with nondiabetic nephropathy (p <0.05).C3 was low in 3.7% of patients. ANA and ANCA positivity were seen in 8.1% and 3.7% of the patients, respectively. Patients without diabetic retinopathy was 81.7% of the total cohort. Biopsy indications were renal insufficiency (8.9%), nephrotic syndrome (24.4%), non-nephrotic proteinuria (16.4%), renal insufficiency with nephrotic range proteinuria (25.9%), renal insufficiency with non-nephrotic proteinuria (24.4%). Mean glomeruli number was 19.3±11.1. Ten patients had macroscopic hematuria in which all resolved with conservative care. Early diabetic changes, diffuse and/or nodular glomerulosclerosis were present in 3.1% and 96.9% of diabetic patients, respectively. Biopsies with diabetic changes with other nondiabetic pathologies were 3% of the biopsies. Isolated nondiabetic nephropathy was found in 23.7% of patients. Pathologic findings other then diabetic changes were as follows in patients without diabetic nephropathy: focal segmental glomerulosclerosis (FSGS) 49.5%, membranous glomerulonephritis 14,1%, Ig A nephropathy 12,1%, membranoproliferative glomerulonephritis 5 %, crescentic glomerulonephritis 4,1%, acute tubular necrosis 4,1%, amyloidosis 3%, tubulointerstitial damage 2%, others 6,1%. Conclusion Biopsy in diabetic patients is beneficial to show both diabetic nephropathy and other kidney pathologies. Kidney biopsy may be performed if there is suspicion of other glomerular pathologies. Focal segmental sclerosis was the most common pathology in our patients without diabetic nephropathy

Mechanisms of Scarring in Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS.

Evaluation of Type of Nephropathy in Patients of Type-2 Diabetes Mellitus

Background of the Study, Aims and Objectives: There are very few studies on histological patterns of diabetic nephropathy in our part of country. The aim of this study was to evaluate the renal involvement in patients with Type-2 diabetes mellitus (T2DM), assess the histopathological changes and establish a clinico-pathological correlation. Subjects, Method and Materials: Thirty two Type 2 DM patients with nephropathy, after screening consecutive hundred(100) Type 2 Diabetics admitted to the Medicine Department were evaluated for renal involvement by kidney biopsy and histopathological study. Statistical analysis was done by student’s t-test, chi-square and linear regression analysis. Results: Thirty two patients (32) with diabetic nephropathy (20 males and 12 females) formed the study group out of hundred (100) consecutive Type-2 diabetes mellitus patients (58 males and 42 females) admitted to Medicine Department of SCB Medical College Hospital, Cuttack. The frequency of occurrence of clinical diabetic nephropathy was 32%. Most of the patients were having duration of DM of 6-10 years (87.5%). Pedal edema was found in 96.87%, hypertension in 87.5% patients respectively. Regression analysis showed that durations of DM and HbA1c were the two significant risk factors (P Histopathologically, diffuse glomerulosclerosis was the most common form of renal abnormality found in 93.75% followed by nodular glomerulosclerosis in 62.50% with overlap in many patients, membranous nephropathy in 12.5% and focal necrotising glomerulonephritis in 6.25% respectively. There was no statistically significant clinicopathological correlation observed between clinical and biochemical parameters in patients harbouring the two predominant histological types of nephropathy i.e. diffuse and nodular glomerulosclerosis with respect to age, sex, duration of diabetes, body mass index, systolic blood pressure, HbA1c, 24 hour urinary protein, creatinine clearance, serum urea, serum creatinine or lipid profile. Conclusion: Durations of diabetes and HbA1c were found to be strongly associated with development of diabetic nephropathy. Diffuse glomerulosclerosis was the most common form of renal abnormality found in 93.75% followed by nodular glomerulosclerosis in 62.50% of patients.

Diabetic Kidney Disease: A New Concept for an Old Problem

Diabetes Mellitus (DM) is a growing worldwide epidemic. It was estimated that more than 366 million people would be affected. DM has spread its presence over the world due to lifestyle changes, increasing obesity and ethnicities, among others. Diabetic nephropathy (DN) is one of the most important DM complications. A changing concept has been introduced from the classical DN to diabetic chronic kidney disease (DCKD), taking into account that histological kidney lesions may vary from the nodular or diffuse glomerulosclerosis to tubulointerstitial and/or vascular lesions. Recent data showed how primary and secondary prevention were the key to reduce cardiovascular episodes and improve life expectancy in diabetic patients. A stabilization in the rate of end stage kidney disease has been observed in some countries, probably due to the increased awareness by primary care physicians about the prognostic importance of chronic kidney disease (CKD), better control of blood pressure and glycaemia and the implementation of protocols and clinical practice recommendations about the detection, prevention and treatment of CKD in a coordinated and multidisciplinary management of the DM patient. And also the new hypoglycemic agents, - DDP4 inhibitors, GLP1R agonists, SLGT2 inhibitors-, can facilitate the management of DM and its complications in the patients with renal function impairment. Early detection of DM and DCKD is crucial to reduce morbidity, mortality and the social and economic impact of DM burden in this population.

The Concept and the Epidemiology of Diabetic Nephropathy Have Changed in Recent Years.

Diabetes Mellitus (DM) is a growing worldwide epidemic. It was estimated that more than 366 million people would be affected. DM has spread its presence over the world due to lifestyle changes, increasing obesity and ethnicities, among others. Diabetic nephropathy (DN) is one of the most important DM complications. A changing concept has been introduced from the classical DN to diabetic chronic kidney disease (DCKD), taking into account that histological kidney lesions may vary from the nodular or diffuse glomerulosclerosis to tubulointerstitial and/or vascular lesions. Recent data showed how primary and secondary prevention were the key to reduce cardiovascular episodes and improve life expectancy in diabetic patients. A stabilization in the rate of end stage kidney disease has been observed in some countries, probably due to the increased awareness by primary care physicians about the prognostic importance of chronic kidney disease (CKD), better control of blood pressure and glycaemia and the implementation of protocols and clinical practice recommendations about the detection, prevention and treatment of CKD in a coordinated and multidisciplinary management of the DM patient. Early detection of DM and DCKD is crucial to reduce morbidity, mortality and the social and economic impact of DM burden in this population.

The Ameliorative Effect of Zingiber officinale in Diabetic Nephropathy.

Dear Editor, Diabetic nephropathy is a progressive kidney disease and is characterized by diffuse glomerulosclerosis and nephrotic syndrome. Diabetic nephropathy is due to angiopathy of capillaries in the kidney glomeruli and is a prime indication for dialysis. It might be seen in patients with diabetes mellitus (DM) after about five years in type 1 diabetes and affects 25% to 35% of patients under the age of 30 years. Diabetic nephropathy is a progressive complication of DM that may lead to death two or three years after the initial injury. It is the end-stage kidney disease and the most common cause of chronic kidney failure. The risk of diabetes nephropathy is higher if blood glucose level and blood pressure are poorly controlled. Furthermore, people with high blood cholesterol level have much higher risk than those with normal cholesterol level (1-4). Nowadays attention has been drawn toward the possible kidney protective properties of Zingiber officinale (ginger) in these patients. To figure out the ameliorative effect of ginger extract against tubular damage induced by gentamicin, we conducted an experimental study in 60 male Wistar rats (6 groups of 10 rats). We treated them as follows: group I, vehicle; group II, ginger for three days and then gentamicin for seven days; group III, ginger orally for three days and then ginger plus gentamicin for seven days; group IV, gentamicin for seven days; group V, gentamicin for ten days; and group VI, gentamicin for seven days and then ginger orally for ten days. At the end of the study, kidneys were removed for histological evaluation. In this study, we observed that ginger could prevent degeneration of the renal cells and reduce the severity of tubular damage caused by gentamicin. We concluded that ginger was effective as a prophylactic agent for renal tubular cells against the acts of injurious substances like gentamicin (5). In the study conducted by Tzeng et al. the ameliorative effects of ginger on renal damage in diabetic rats was investigated. In their study, diabetic rats were treated orally with ginger or metformin for eight weeks. They found that ginger displayed similar characteristics to those of metformin in reducing hyperglycemia and renal dysfunction in diabetic rats. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following the treatment with ginger. Furthermore, the protein expressions of renal nephrin and podocin in diabetic rats were significantly increased following the treatment with ginger. They suggested that the renoprotective effects of ginger might be similar to the action of metformin in the prevention of AMP-activated protein kinase protein phosphorylation (6). Metformin has been widely used in the patients with DM, especially in type 2 DM (7-10). Recently, the possible renoprotective role of metformin was noticed (7-10). In the study of Morales et al. ameliorative properties of metformin against gentamicin-induced renal tubular damage were shown (11). To find the potential efficacy of metformin in protecting kidney against gentamicin-induced acute kidney injury and to test whether delay treatment with metformin in acute kidney injury exerted similar efficacy on gentamicin-renal injury in rats, we conducted a study on Wistar rats. We found that metformin was able to prevent and ameliorate gentamicin-induced acute renal injury. Hence, it might have renoprotective efficacy (12). More recently, we observed the efficacy of coadministration of garlic extract and metformin in prevention of gentamicin–induced renal damage in 70 male Wistar rats (13-15). The result of these studies showed that metformin and ginger juice had ameliorative effects against gentamicin-induced nephrotoxicity. The protective effect of metformin on diabetic nephropathy was also recently published by Kari et al. (16). The incidence of DM and nephropathy of diabetes have risen rapidly (17-19). Therefore, the combination of metformin and ginger extract might be more effective to control of DM and might have additive protective efficacy on diabetic nephropathy. To better figure out the protective effect of ginger on kidney, particularly in combination with metformin, more researches are needed.

Evaluation of the effectiveness of diabetic nephropathy stage III in patients with type 2 diabetes mellitus therapy with sulodexide

Introduction. Diabetes mellitus (DM) - takes the main place in the structure of endocrine diseases, and the third after cardiovascular and cancer pathology. In Ukraine 1.2 million of people suffer from diabetes and type 2 diabetes occurs in 85-90% of them. In 2004, 3.4 million of people died from diabetes complications. Diabetic nephropathy (DN) is a serious chronic complication of diabetes that leads to the formation of nodular or diffuse glomerulosclerosis. It is the most frequent cause of terminal chronic renal failure (CRF) in the world, accounting for over 25% of all cases of CRF. The generally accepted classification is Moggensen`s classification (1983, WHO), according to which five stages of diabetic nephropathy are identified, the first two stages of them are preclinical. Leading role in the pathogenesis of DN takes hyperglycemia, which is implemented by the phenomenon of glucosetoxicity. A lot of facts underscore the importance of inflammatory mechanisms triggered by cytokines. There's immune and non-immune theory of DN. The basis of non-immune theory is a violation of the synthesis of glycosaminoglycans (GAGs) that are a major component of the glomerular basement membrane (GMB). GAGs create its negative charge, which prevents the passage through the renal filter small negatively charged molecules, including albumin. In hemodynamic regulation leading role belongs to the renin-angiotensin-aldosterone system (RAAS). The blockade of the RAAS system with ACE inhibitors is the basis of a treatment strategy of DN. All mentioned above became a reason for study of the possibility of a new direction in the treatment of DN using the drug sulodexid, which is a natural mixture of GAGs.Objective of the research. Evaluating the effectiveness of sulodexide therapy of DN stage III in patients with type 2 diabetes.Materials and methods. The patients were divided into 2 groups. Group I consisted of 24 patients aged 40 to 68 years. 5 of them were women and 19 were men. In 20 patients from the group alimentary-constitutional obesity was noted. II group consisted of 11 people: 4 women and 7 men, aged 48 to 68 years, 6 of which were suffering from alimentary-constitutional obesity. Patients received standard treatment of type 2 diabetes and hypertension. In group I, sulodexide (600 LPL units intramuscularly 1 time per day for 10 days) was further included. The research of microalbuminuria (MAU) was conducted on admission and on the 10th day of treatment.Results. The initial values of MAU in 1st group were 92,7 ± 25,2 mcg/min. In the dynamics of monitoring rates decreased to 44,4 ± 9,6 mcg/min. The degree of decrease was 47% (p <0.05). In 2nd Group MAU initial values were 46,7 ± 23,4 mcg/min. In the dynamics of monitoring MAU decreased to 29,5 ± 12,6 mcg/min. Degree of decrease was 27% (p <0.05)Conclusions. 1) In patients with stage III DN with diabetes type 2 by including in the basic therapy of sulodexide level MAU was reliable decreased on 47%, which is on 20% lower than in the comparison group (p <0.05).2) During the research reliable direct dependence of decreased MAU rates with its initial values and degree of obesity was found. It indicates the increase in the effectiveness of the drug at a higher initial level of MAU in people with overweight.

Integrin α1/Akita double-knockout mice on a Balb/c background develop advanced features of human diabetic nephropathy

Animal models that mimic human diabetic nephropathy are useful to identify key factors in pathogenesis of this disease as well as the development of new therapies. Several mouse models of diabetes have features of human diabetic nephropathy, yet none of these completely fulfill the Animal Models of Diabetes Complications Consortium criteria and completely reproduce pathological and functional features of the human disease. The Akita mouse carries a mutation in the insulin 2 gene and, to date, only survive as heterozygotes that develop spontaneous type 1 diabetes. Here we show that Akita mice with mutation of both insulin 2 alleles (Akita knockout (KO)) survive if crossed onto the Balb/c background. These mice develop hyperglycemia, more severe albuminuria and mesangial sclerosis compared to heterozygous mice on the same genetic background. Interestingly, crossing these AkitaKO mice with integrin α1KO mice, a model of exacerbated glomerulosclerosis after injury and also on the Balb/c background, resulted in a 16-fold increase in albuminuria, significant mesangial matrix expansion, nodular and diffuse glomerulosclerosis, and a 2-fold increase in glomerular basement membrane thickening when compared to non-diabetic mice. Moreover a significant decline in glomerular filtration was evident in the α1KOAkitaKO mice at 6 months of age. Thus, the integrin α1KOAkitaKO Balb/c mouse represents a promising model presenting with most features of human diabetic nephropathy.

DIABETES MELLITUS AND CHRONIC KIDENY DISEASE: MODERN DIAGNOSTICS AND TREATMENT

Diabetic nephropathy (DN)--is a leading cause of terminal renal failure in the developed countries. Kidney pathology development undergoes several stages--from preclinical structural changes in the first years of the disease to diffuse or nodular glomerulosclerosis 15-20 years after the diabetes onset. Microalbuminuria is an early marker of DN. Intensive treatment of DN at the stage of microalbuminuria leads to regress and remission of lab parameters of DN in 40 - 50% of patients after 2 years of treatment. Prognostic factors of DN remission are: tight glycaemia control, arterial hypertension control, especially while treated with renin-angiotensin blockers. Regress of structural changes of kidney tissue In a diabetic patient is possible only after a long-term (>10yrs) normoglycaemia maintenance.

Focal Segmental Glomerulosclerosis with Acute Renal Failure Associated with Eltrombopag Therapy

Eltrombopag, a small‐molecule nonpeptide agonist of the thrombopoietin receptor, is used for treatment of thrombocytopenia of various causes, including chronic idiopathic thrombocytopenic purpura (ITP) and hepatitis C‐related liver cirrhosis. During clinical trials, eltrombopag was discontinued in three patients due to ascites, neutropenia, and retinal exudates. Another recently reported major adverse event was reversible acute renal failure in a patient with antiphospholipid syndrome; nephrotoxicity caused by eltrombopag was highly suspected, but a kidney biopsy was not performed. We describe a 46‐year‐old woman with a history of mitral valve prolapse who had an incidental finding of an isolated low platelet count of 22 × 103/mm3. A tentative diagnosis of ITP was made, and oral prednisolone 25 mg twice/day was started. Despite prednisolone dosage adjustments over the next several weeks, her platelet count remained at 15–40 × 103/mm3, and oral eltrombopag 75 mg/day was begun. After seven doses, the patient came to the emergency department with persistent nausea and vomiting. Laboratory work‐up revealed renal failure, and eltrombopag was discontinued. The patient was hospitalized, and on day 2, her renal failure had progressed, and proteinuria was detected. On day 6, emergency hemodialysis was begun. A complete blood count on day 21 revealed progression of anemia and thrombocytopenia. Splenectomy was performed on day 35, which successfully reversed her thrombocytopenia. She was discharged on day 39, and hemodialysis was discontinued on day 44. At follow‐up on day 56, the patient's platelet count was within normal limits. On day 70, kidney biopsy results revealed a typical pattern of focal segmental and diffuse global glomerulosclerosis. By day 210, her ITP had resolved, and her renal function was stable. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the patient's development of acute renal failure and eltrombopag therapy. To our knowledge, this is the first case report of a patient who experienced acute renal failure and proteinuria concomitant with a pathology of focal segmental glomerulosclerosis after treatment with eltrombopag. This report of a serious case of reversible renal failure after treatment with eltrombopag may serve to inform clinicians about the possible severe renal adverse effects of eltrombopag before commencing with more extensive clinical use in the future.

Roasted licorice extracts dampen high glucose-induced mesangial hyperplasia and matrix deposition through blocking Akt activation and TGF-β signaling

Diabetic nephropathy (DN) characterized as nephrotic syndrome and diffuse glomerulosclerosis can cause renal failure and end-stage kidney disease. Expansion of mesangial matrix around capillaries in the kidney glomeruli is a prominent feature of DN. This study investigated whether licorice extracts inhibited mesangial cell (MC) proliferation and matrix accumulation induced by high glucose (HG). Human renal MC were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 d in the presence of water or ethanol extracts from raw licorice (LW, LE) or roasted licorice (RLW, RLE). Non-polar components including glycyrrhetic acid were elevated during licorice roasting, whereas polar components soluble in water extracts were diminished. Exposure of cells to HG caused significant increases in collagen IV secretion and connective tissue growth factor (CTGF) expression, which was appeased by RLW and RLE at transcriptional levels. The inhibitory potency was high in the order of RLE > or = RLW > or = LE > > LW. Non-polar glycyrrhetic acid but not glycyrrhizin retarded HG-stimulated mesangial matrix deposition through diminishing CTGF expression. In addition, RLW and RLE but not LW modulated membrane type matrix metalloproteinase-1 (MT-1 MMP) expression, MMP-2 activity and tissue inhibitor of MMP-2 (TIMP-2), which facilitated the degradation of mesangial matrix. Furthermore, the augmented expression of CTGF and TIMP-2 in HG-exposed cells was mediated by Akt activation and TGF-beta/Smad signaling through PKCbeta2-responsive signaling pathways. However, HG-down-regulated MT-1 MMP expression was independent of activation of ERK1/2 and Akt when using their inhibitors of DB98059 (ERK1/2) and LY294002 (Akt) alone or in combination. These results demonstrate that extracts from roasted licorice may be highly potent therapeutic agents for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetes nephropathy due to longstanding diabetes mellitus.

Factors of tubulointerstitial lesions in diabetic kidneys

As the number of cases with classical manifestations of diabetic nephropathy (DN), i.e. nodular or diffuse glomerulosclerosis, grows, an increasinglylarger number of DM patients especially those with DM2 present with renal pathology largely affecting interstitium and tubules (ischemic nephropathy,urinary infection, interstitial nephritis, etc.). The rate of renal filtration impairment in glomerular diseases (DN, glomerulonephritis) is also relatedto the severity of tubulointerstitial fibrosis (TIF). Intricate intercellular interactions activated by immune and non-immune factors have been shownto play an important role in the development of tubulointerstitial lesions. Studies of the most important factors contributing to remodeling tubulointerstitiumin DM patients may provide a deeper insight into the mechanisms of nephrosclerosis and extend possibilities for prognostication of renalfunction.

Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome

Podocin is a critical component of the glomerular slit diaphragm, and genetic mutations lead to both familial and sporadic forms of steroid-resistant nephrotic syndrome. In mice, constitutive absence of podocin leads to rapidly progressive renal disease characterized by mesangiolysis and/or mesangial sclerosis and nephrotic syndrome. Using established Cre-loxP technology, we inactivated podocin in the adult mouse kidney in a podocyte-specific manner. Progressive loss of podocin in the glomerulus recapitulated albuminuria, hypercholesterolemia, hypertension, and renal failure seen in nephrotic syndrome in humans. Lesions of FSGS appeared after 4 wk, with subsequent development of diffuse glomerulosclerosis and tubulointerstitial damage. Interestingly, conditional inactivation of podocin at birth resulted in a gradient of glomerular lesions, including mesangial proliferation, demonstrating a developmental stage dependence of renal histologic patterns of injury. The development of significant albuminuria in this model occurred only after early and focal foot process effacement had progressed to diffuse involvement, with complete absence of podocin immunolabeling at the slit diaphragm. Finally, we identified novel potential mediators and perturbed molecular pathways, including cellular proliferation, in the course of progression of renal disease leading to glomerulosclerosis, using global gene expression profiling.

The other end of spectrum in hypertension: ‘Idiopathic nodular glomerulosclerosis’

Dear Editor, Nodular glomerulosclerosis is observed in diabetes mellitus, dysproteinemias, lobular membranoproliferative glomerulonephritis, glomerular deposition disease, and chronic hypoxic states. Idiopathic nodular glomerulosclerosis (ING), which is a rare clinical entity, is diagnosed in the absence of these conditions. We report a case of ING in an elderly hypertensive lady. An 82-year-old woman was evaluated for chronic kidney disease. Her medical history included hypertension, permanent atrial fibrillation, and osteoarthritis. There was no personal or family history of diabetes mellitus, hepatitis, autoimmune, or connective tissue disease. She did not use any over-the-counter medications, herbal remedies, cigarettes, alcohol, or recreational drugs. On examination, her vitals revealed blood pressure of 140/93 mmHg, with an irregular heart rate of 74–86 beats/min. The rest of the physical examination was unremarkable. Laboratory parameters were significant for mild normocytic anemia with a hemoglobin level of 10.2 mg/dl, BUN of 65 mg/dl, and creatinine level of 1.7 mg/dl. Fasting blood glucose, 2-h glucose tolerance test, autoantibody screening, complements, hepatitis serology, and cryoglobulins were normal. Urinalysis was normal with random protein 18 mg/dl and creatinine 59.2 mg/dl. Serum protein electrophoresis confirmed by immunofixation revealed monoclonal IgM lambda quantitated at 0.11 g/dl; free kappa/lambda ratio was 1.17 (normal 0.26–1.65). Renal ultrasound demonstrated slightly asymmetric kidneys. Renal artery magnetic resonance angiography was normal. Light microscopy of left kidney biopsy showed 6 end-stage sclerotic glomeruli and 14 viable glomeruli. Nodular mesangial expansion, thickened peripheral capillary basement membranes, tubular atrophy, interstitial fibrosis, arteriolar intimal sclerosis, and patchy lymphoplasmacytic infiltrates were observed (Fig. 1). Congo red stain was negative. Immunofluorescence was positive for focal granular mesangial IgM deposits. Electron microscopy showed thickened glomerular basement membranes and expanded mesangial matrix, frequently forming mesangial matrix nodules. There were no electron dense deposits, and foot processes were fused in a patchy pattern. These findings were suggestive of diffuse and nodular glomerulosclerosis with moderate to severe arteriosclerosis. In the absence of other etiologies, it is possible that hypertension was responsible for nodular glomerulosclerosis in this patient. It is speculated that individuals with long standing hypertension have an increased or reset sensitivity to non-diabetic glycemic levels resulting in an exaggerated glomerulovascular response [1]. R. Kasmani (&) T. Thiyagarajan R. NarwalChadha K. Okoli F. Irani Department of Internal Medicine, St. Vincent Mercy Medical Center, Toledo, 2213, Cherry Street, Toledo, OH 43608, USA e-mail: rahilkasmani@hotmail.com

The Morphologic Patterns of Diabetic Nephropathy in Koreans

Background : Diabetic nephropathy is the most common cause of end-stage renal disease and it has various pathologic features. We investigated the clinicopathologic differences between the histologic classes of diabetic nephropathy. Methods : A total of 46 patients with diabetic nephropathy were evaluated. Morphologically, the renal lesions were divided into three categories: class 1, diffuse or nodular glomerulosclerosis: class 2, vascular change without evidence of glomerulosclerosis: and class 3, non-diabetic renal disease superimposed on diabetic glomerulosclerosis. We evaluated the laboratory findings and the histologic findings, including mesangial expansion, interstitial fibrosis and inflammation, arteriolar hyalinosis and tubular atrophy. Results : The proportion of each class was 32 cases (70%), 4 cases (9%) and 10 cases (21%), respectively. The clinical and laboratory data showed no significant difference among the classes. For the groups of class 1, the group with nodular sclerosis showed a higher serum creatinine level than did the diffuse group (p=0.003). IgA nephropathy was the most common nondiabetic renal disease superimposed on diabetic glomerulosclerosis in our study. Conclusions : The patients with nodular glomerulosclerosis presented with a more progressed clinicopathological features than did the patients with class 1 diffuse glomerulosclerosis. We also found 21% of all the patients with diabetic nephropathy had superimposed non-diabetic renal disease in a Korean population.