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
VEGF
a mitogen for
vascular endotheila
cells
p52
Induces apoptosis
With dexamethasone
downregulation allow
podocyte to enter the cell
cycle – enhance ability to
repair
Downregulated
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)
Group 1
(proteinuric rats),
n=34
Grp 2: neprhrotic
rats n=7
Serum albumin
42.7 +/- 1.8
40.7 +/- 1.3
25.5 +/- 2.2
Urine albumin
0.36 +/- 0.04
3.19 +/- 0.98
9.69 +/- 4.07
Serum cholesterol 1.72 +/- 0.05
2.68 +/- 0.18
6.88 +/- 1.09
Serum IL-13
7.1 +/- 1.8
241.4 +/- 69.5
708.6 +/- 257.7
Nephrin
0.16 +/- 0.03
0.11 +/- 0.01
0.01 +/- 0.005
Podocin
0.25+/- 0.05
0.17 +/- 0.02
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
podocin
dystroglycan
synaptopodin
Immunofluorescence staining
of glomeruli for protein
expression of nephrin, podocin,
dystroglycan, and 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