Minimal change disease and treatment with steroids

Minimal change disease and treatment with steroids 7/24/2007 Zae Kim, MD Clinical Question • Why does MCD respond to steroid? • Why do they develop resistance? Introduction • Most common cause of the nephrotic syndrome in children • ~10-15% of nephrotic syndrome in adults, third most common after MN and FSGS – More common in Hispanics, Asians, Arabs and Caucasians • clinical and pathological entity defined by selective proteinuria and hypoalbuminemia that occurs in the absence of – cellular glomerular infiltrates or – immunoglobulin deposits Light microscopy of glomerulus in MCD Immunofluorescence Microscopy www.gamewood.net/rnet/renalpath/noimcx.jpg Electron Microscopy The glomerular capillary wall Normal MCD Van den Berg, Weening, Clinical Science (2004) 107, 125–136 What is the Pathogenesis? Pathogenesis - “Intrinsic factor” • Genetic basis for hereditary NS • NS of the Finnish type • Autosomal-recessive steroid-resistant NS • Familial forms of FSGS • Diffuse mesangila sclerosis associated with Denys-Drash syndrome and with Frasier syndrome • NS associated with nail-patella syndrome – Help elucidate molecular aspect of FSGS – Not clear for MCD Molecular anatomy of the podocyte foot process cytoskeleton Nature Genetics 24, 333 - 335 (2000) Pathogenesis – extrinsic factor, better explanation for MCD • Clinical Observations - Shalhoub’s hypothesis – MCD frequently remits with measles infection – Corticosteroids and alkylating drugs cause a remission – Association of MCD with Hodgkin disease • Experimental Observations – T cell hybridoma (Koyama KI 1991 (40): 453-460) – Removal of glomerular permeability factor leads to normal kidney (Ali Transplantation 1994 Oct 15;58(7):849-52) • “circulating factor” – possible link between T-cell response and glomerular disease How does steroid work in MCD? • Widely used in treatment but their mode of action is poorly understood • What is its effectiveness in MCD where there is no evident inflammation Steroid – quick overview • Inhibitory effects on both innate and acquired immunologic function • Innate Immune function – Reduced Inflammatory response: • inhibit transmigration of leukocytes • attenuate the generation of inflammatory exudates – Phospholipase A2 suppresion – COX-2 suppression • Acquired Immune function – Antigen presenting cells, B cell and T cells Overview of Intracellular Effects Could steroid have more direct effect in kidney? Direct effects of dexamethasone on human podocyte – Xing, Saleem, et al • Hypothesis: – Glucocorticoid exert direct protection of podocytes from injury and/or promotion of repair • Nephrin: podocyte specific protein – mutation of NPHS2 gene - cause congenital nephrotic syndrome of Finnish type – Studies show possible downregulation of nephrin in MCD Result – effects of dexamethasone on podocyte maturation at 37 C and expression of nephrin Immunofluorescent staining Quantificaton of nephrin Summary • Dexamethasone enhanced and accelerated podocyte maturation, with a particulary striking effect on expression of nephrin Other steroid response In disease state p21 Upregulated With dexamethasone downregulation allow podocyte to enter the cell cycle – enhance ability to repair Downregulated VEGF p52 a mitogen for vascular endotheila cells Induces apoptosis downregulated Overexpression of Interleukin-13 Induces Minimal-Change– Like Nephropathy in Rats • Background – MCD may be a T cell dependent disorder that results in glomerular podocyte dysfunction – Th2 cytokine bias in patients with MCD • MCD associated with atopy and allergy • Relapse MCD with elevated IL-4 and IL-13 – Association between MCD and Hodgkins’s disease • IL-13 known to be an autocrine growth factor for the ReedSternberg Hypothesis • IL-13 may play an important role in the development of proteinuria in MCNS by exerting a direct effect on podocytes, acting through the IL-13 receptors on the podocyte cell surface, initiating certain signaling pathways that eventually lead to changes in the expression of podocyte-related proteins (nephrin, podocin, and dystroglycan) • IL-13 transfected mouse was used as a model Mean 24-h urine albumin excretion (mg/24 h) Comparison of control, IL-13-transfected mouse at experiment end (day 70) Parameter Control Rats (n=17) 42.7 +/- 1.8 0.36 +/- 0.04 7.1 +/- 1.8 Group 1 (proteinuric rats), n=34 40.7 +/- 1.3 3.19 +/- 0.98 2.68 +/- 0.18 241.4 +/- 69.5 Grp 2: neprhrotic rats n=7 25.5 +/- 2.2 9.69 +/- 4.07 6.88 +/- 1.09 708.6 +/- 257.7 Serum albumin Urine albumin Serum IL-13 Serum cholesterol 1.72 +/- 0.05 Nephrin Podocin 0.16 +/- 0.03 0.25+/- 0.05 0.11 +/- 0.01 0.17 +/- 0.02 0.01 +/- 0.005 0.01 +/- 0.005 Yellow = p <0.001 vs control Red = p<0.001 vs control and Grp 1 Histopathologic features on day 70 at killing (A) Glomerulus of IL-13–transfected rat showing no significant histologic changes (periodic acid-Schiff stain). (B) Glomerulus of IL-13–transfected rat showing fusion of podocyte foot processes (arrows). (C) Glomerulus of control rat showing normal individual podocyte foot processes along the glomerular basement membrane (GBM; arrows). Control IL-13 infected nephrin Immunofluorescence staining of glomeruli for protein expression of nephrin, podocin, dystroglycan, and synaptopodin podocin dystroglycan synaptopodin Summary • IL-13-transfected rats – Developed minimal change like GN, as evidence by LM and EM changes – decrease in the expression of nephrin, podocin, and dystroglycan associated with increased urinary albumin excretion and podocyte foot process effacement • suggesting that these proteins are essential in maintaining the filtration barrier, thus controlling glomerular permeability • decrease was not due to loss of podocytes - What does it all mean… • There is more to steroid than I knew… • “circulating factor” – Prognostic indicator? • Why are some MCDs steroid responsive while others are resistant? The end