Successful treatment of a rare variant of mesangioproliferative glomerulonephritis with IgM deposits with Cyclosporin A

We present a case with a rare variant of glomerulonephritis, IgM nephropathy, which occurs mainly with nephrotic syndrome. The clinical features of this variant of kidney damage are characterized; the pathogenetic and the transformation of this form of nephritis into focal segmental glomerulosclerosis are discussed. The development of severe nephrotic syndrome at the beginning of the disease, the formation of secondary steroid resistance have confirmed this hypothesis and have justified the treatment with cyclosporin A aimed at the recovery of the function of the podocyte with remission of nephritis.

P0348THE DUAL ENDOTHELIN ETA AND ANGIOTENSIN AT1 RECEPTOR BLOCKER SPARSENTAN PROTECTS AGAINST THE DEVELOPMENT OF ALBUMINURIA AND GLOMERULOSCLEROSIS IN THE GDDY MOUSE MODEL OF IGA

Background and Aims gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG, and C3 deposits and progressive mesangioproliferative glomerulonephritis. A previous study in the ddY mouse model, the more genetically heterogeneous predecessor of gddY mice, using the endothelin type A receptor (ETAR) antagonist FR139317 resulted in amelioration of proteinuria and preservation of kidney function. Treatment of ddY mice with the angiotensin II type 1 receptor (AT1R) blocker valsartan resulted in significant protection from glomerulosclerosis (GS) without a significant prevention in proteinuria. Here we examined the effect of sparsentan (SP), a dual ETAR and AT1R blocker, currently in phase 3 trials for focal segmental glomerulosclerosis and IgAN, on the development of albuminuria and GS in gddY mice. Method gddY mice at 4 wks of age were fed with control (C) chow (n=5) or chow containing 900 ppm (n=10) or 1800 ppm (n=10) SP (approximately 180 and 360 mg/kg/day) for 8 wks. Albuminuria (U-Alb) was assessed at 4, 6, 8, and 12 wks of age and plasma levels of SP were determined at 8 am and 4 pm at wks 6, 8, and 12. Kidney biopsies were taken at the end of the study at 12 wks of age for processing and 30 glomeruli per animal were scored for the percentage of GS. Results gddY mice fed SP in the diet for 8 wks from 4 wks of age demonstrated significantly (*P<0.05) decreased U-Alb compared to mice fed the C diet in a dose-dependent manner (Figure 1). The development of GS in mice fed the diet containing 1800 ppm SP was significantly (*P<0.05) attenuated compared to C diet (Figure 2). Plasma levels of SP taken at 8 am and 4 pm after 8 wks of treatment were (mean±SD) 281±107 and 105±62 ng/ml for 900 ppm SP respectively, and 774±674 and 304±176 ng/ml for 1800 ppm SP, respectively. Weight gain in mice fed SP was not different from mice that received C diet. Conclusion Eight weeks of treatment with SP attenuated increases in albuminuria and GS associated with the development of IgAN in gddY mice. If translated to the clinic, these data support SP as a new approach to the treatment of IgAN.

Analysis of the effect of immunosuppressive therapy on the progression of chronic kidney disease with mesangioproliferative nephritis

Aim. To assess the effect of immunosuppressive cyclophosphamide therapy and its regimens on the rate of progression of chronic kidney disease in mesangioproliferative glomerulonephritis. Methods. 72 patients with mesangioproliferative glomerulonephritis and indications for immunosuppressive therapy with disease activation were included in the comparative analysis: 56 patients received cyclophosphan in conventional doses (26 patients with daily or every other day, 30 patients with in pulse mode 1 time per month), and 16 patients did not receive cyclophosphan. Duration of the disease before observation ranged from 0 to 33.58 years, a median follow-up was 6.00 (interquartile range 1.6313.17) years, and after observation from 0 to 5 years with the median follow-up was 2.00 (1.003.50) years. The examination included nephrobiopsia with a morphological diagnosis, activity index/sclerosis, and glomerulonephritis progression rate for decreased glomerular filtration rate (ml/min/1.73 m per year). Results. The progression rate of chronic kidney disease was higher in the group of patients not receiving immunosuppressive therapy, 5.57 (3.277.95) ml/min/1.73 m2 per year compared with of the treated patients group, 3.05 (2.046.78) ml/min/1.73 m2 per year (p=0.040). There were no differences in the rate of decrease in glomerular filtration rate between groups depending on the treatment regimen: 4.86 (2.126.77) ml/min/1.73 m2 per year with regular and 3.67 (2.04 6.91) ml/min/1.73 m2 per year with a pulse mode (p=0.720). The rate of glomerulonephritis also did not differ significantly: 1.0 (1.02.0) and 2.0 (1.02.0) relapses over 5 years, respectively (p=0.691) in both treatment regimens. Conclusion. The treatment of patients with mesangioproliferative glomerulonephritis with cyclophosphane, in combination with prednisone or without it, regardless of the treatment regimen induces a slowdown in the progression of chronic kidney disease, improving the long-term prognosis and without affecting the frequency of relapses of the disease.

TAFRO syndrome with skin manifestations treated with bortezomib and tocilizumab; a case report

TAFRO syndrome is a new presentation of idiopathic multicentric Castleman disease which is termed as thrombocytopenia, anasarca, myelofibrosis, renal failure and organomegaly (TAFRO). The exact pathophysiology of TAFRO syndrome is unclear and management is mostly based on case reports and expert opinion. In this report, a 37 years old male patient with TAFRO syndrome is discussed. The patient was referred with fever, sweating, anorexia, abdominal distension and generalized edema which has been hospitalized multiple times for such complaints. The patient also developed skin lesions dispersed in red nodules, which was reported as "granuloid hemangioma". Renal biopsy suggested mesangioproliferative glomerulonephritis and bone marrow specimen showed hypercellular active marrow with reticulin fibrosis. The lymph node biopsies were reported as Castleman disease. This report demonstrates that different manifestations of TAFRO syndrome may overlap with other syndromes and can be managed by Bortezomib and Tocilizumab.

Expression of the Alpha8 Integrin Chain Facilitates Phagocytosis by Renal Mesangial Cells

Background/Aims: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC. Methods: MC were isolated from wild type (WT) and Itga8-/- mice. Latex beads were coated with matrix components. Apoptosis was induced by cisplatin in macrophages and in DiI-stained MC. After coincubation of latex beads or apoptotic cells with MC, the phagocytosis rate was detected in WT and Itga8-/- MC via fluorescence microscopy and FACS analysis. Results: Itga8-/- MC showed reduced phagocytosis of matrix-coated beads and apoptotic cells compared to WT MC. Reduction of stress fibers was observed in Itga8-/- compared to WT MC. Inhibition of cytoskeletal reorganization by inhibition of Rac1 or ROCK during phagocytosis significantly decreased the rate of phagocytosis by WT MC but not by Itga8-/- MC. Conclusion: The expression of Itga8 facilitates phagocytosis in MC, likely mediated by Itga8-cytoskeleton interactions. An impairment of MC phagocytosis might thus contribute to a delayed glomerular regeneration in Itga8-/- mice.

Henoch-Schönlein purpura associated with Strongyloides stercoralis infection

Introduction. Henoch-Sch?nlein purpura (HSP) is a small blood vessel vasculitis, which usually manifests during childhood. The exact cause of the disease is unknown. Case report. We reported a 14-year-old girl who had been admitted to our clinic due to the appearance of red macules on her extremities and face, vomiting, and pain in the abdomen and joints. The patient was initially diagnosed with Henoch- Sch?nlein purpura. At the end of the fourth week of illness, larvae of Strongyloides stercoralis were detected in stool samples. The patient was therefore treated with mebendazole, after which all symptoms permanently withdrew. About a month later laboratory examinations were repeated demonstrating increasing signs of renal damage. Kidney biopsy was performed, showing mesangioproliferative glomerulonephritis with crescents and IgA and C3 positive staining in the mesangium. Upon reviewing the clinical presentation, biochemically demonstrated progressive renal damage and biopsy results, the patient was diagnosed with HSP nephritis. Conclusion. The time course of the disease and present knowledge concerning the pathogenic mechanisms of HSP suggest that Strongyloides stercoralis infection could have caused HSP in the presented patient, which was complicated by nephritis.