1 / 28

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

detchison
Télécharger la présentation

Minimal change disease and treatment with steroids

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Minimal change disease and treatment with steroids 7/24/2007 Zae Kim, MD

  2. Clinical Question • Why does MCD respond to steroid? • Why do they develop resistance?

  3. 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 pathologicalentity defined by selective proteinuria and hypoalbuminemiathat occurs in the absence of • cellular glomerular infiltratesor • immunoglobulin deposits

  4. Light microscopy of glomerulus in MCD

  5. Immunofluorescence Microscopy www.gamewood.net/rnet/renalpath/noimcx.jpg

  6. Electron Microscopy

  7. The glomerular capillary wall Normal MCD Van den Berg, Weening, Clinical Science (2004) 107, 125–136

  8. What is the Pathogenesis?

  9. 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

  10. Molecular anatomy of the podocyte foot process cytoskeleton Nature Genetics24, 333 - 335 (2000)

  11. 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

  12. 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

  13. 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

  14. Overview of Intracellular Effects

  15. Could steroid have more direct effect in kidney?

  16. 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

  17. Result – effects of dexamethasone on podocyte maturation at 37 C and expression of nephrin Immunofluorescent staining Quantificaton of nephrin

  18. Summary • Dexamethasone enhanced and accelerated podocyte maturation, with a particulary striking effect on expression of nephrin

  19. Other steroid response

  20. 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 factorfor the Reed-Sternberg

  21. Hypothesis • IL-13 may play an important role in the development ofproteinuria 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 tochanges in the expression of podocyte-related proteins (nephrin, podocin, and dystroglycan) • IL-13 transfected mouse was used as a model

  22. Mean 24-h urine albumin excretion (mg/24 h)

  23. Comparison of control, IL-13-transfected mouse at experiment end (day 70) Yellow = p <0.001 vs control Red = p<0.001 vs control and Grp 1

  24. 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).

  25. Control IL-13 infected Immunofluorescence staining of glomeruli for protein expression of nephrin, podocin, dystroglycan, and synaptopodin nephrin podocin dystroglycan synaptopodin

  26. 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 podocytefoot process effacement • suggesting that these proteins areessential in maintaining the filtration barrier, thus controllingglomerular permeability • decrease was not due to loss ofpodocytes -

  27. 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?

  28. The end

More Related