Minimal change disease and treatment with steroids

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Minimal change disease and treatment with
steroids
7/24/2007 Zae Kim, MD
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Clinical Question

• Why does MCD respond to steroid?
• Why do they develop resistance?

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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

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Light microscopy of glomerulus in MCD
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Immunofluorescence Microscopy
www.gamewood.net/rnet/renalpath/noimcx.jpg
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Electron Microscopy
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The glomerular capillary wall
Normal
MCD
Van den Berg, Weening, Clinical Science (2004)
107, 125136
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What is the Pathogenesis?
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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

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Molecular anatomy of the podocyte foot process
cytoskeleton
Nature Genetics  24, 333 - 335 (2000)
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Pathogenesis extrinsic factor, better
explanation for MCD

• Clinical Observations - Shalhoubs 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
  1558(7)849-52)
• circulating factor
• possible link between T-cell response and
  glomerular disease

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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

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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

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Overview of Intracellular Effects
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Could steroid have more direct effect in kidney?
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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

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

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

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Other steroid response
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Overexpression of Interleukin-13 Induces
Minimal-ChangeLike 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 Hodgkinss disease
• IL-13 known to be an autocrine growth factor for
  the Reed-Sternberg

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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

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Mean 24-h urine albumin excretion (mg/24 h)
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Comparison of control, IL-13-transfected mouse at
experiment end (day 70)
Yellow p lt0.001 vs control
Red plt0.001 vs control and Grp 1
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Histopathologic features on day 70 at
killing(A) Glomerulus of IL-13transfected rat
showing no significant histologic changes
(periodic acid-Schiff stain). (B) Glomerulus of
IL-13transfected 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).
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Immunofluorescence staining of glomeruli for
protein expression of nephrin, podocin,
dystroglycan, and synaptopodin
Control
IL-13 infected
nephrin
podocin
dystroglycan
synaptopodin
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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 -

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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?

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The end