Rash

ADULT ONSET
MINIMAL CHANGE DISEASE
Nephrology Grand Rounds
Aditya Mattoo, MD
October 20th, 2009
Outline
 Background
 Pathophysiology
 Etiologies
 IgA and MCD
 Clinical Findings
 Treatment
 Prognosis
BACKGROUND
Background

 Minimal change disease (MCD) is also known as

nil disease.

 Minimal change disease is defined by nephrotic

syndrome with normal appearing light microscopy
with foot process effacement on electron microscopy
in the absence of cellular infiltrates or immune
deposits.
Background

 Low levels of mesangial IgM and/or C3 without

ultrastructural evidence for electron dense deposits is
acceptable for a diagnosis of minimal change
glomerulopathy.

 IgA mesangial deposition is a rare occurrence and

whether or not it represents a pathological or a
coincidental finding is uncertain.
Electron Microscopy

A. Normal podocyte foot processes

B. MCD with podocyte foot process effacement
Background
 Most common form of nephrotic syndrome in
children.

 In children younger than 10 years, MCD makes up

to 90% of all cases of nephrotic syndrome.

 In adolescents above the age of 10, MCD accounts

for 50% of nephrotic cases.

 While in adults, MCD accounts for 10-15% of

primary nephrotic syndrome cases.
 Background
 In children, MCD is found twice as frequently in
boys than in girls.
 The frequency is the approximately the same

between the sexes in adults.

 The incidence peaks in children at age with
approximately 80% being younger than 6 years at the
time of diagnosis.
 In adults, the mean age of onset is 40 years.

 The percentage of nephrotic patients with MCD is

highest in Asian and Caucasian populations.
Waldman et al. CJASN 2: p445, 2007.
PATHOPHYSIOLOGY
Pathophysiology
 The underlying cause of MCD is still uncertain, however,
evidence points to T-cell dysfunction as a major player.

 First postulated by Shalhoub in 1974, this theory (also

known as the Shalhoub hypothesis) is supported by the
following observations:

- Remissions of MCD occur in the setting of a measles

infection where viral associated immunosuppression
occurs.
- MCD occurs more frequently in patient’s with lymphoma.
- MCD is responsive to steroids and alkylating drugs.
- Atopic individuals who have exaggerated Th2 responses to
common allergens are at a higher risk of developing MCD.
Pathophysiology
 The following observations support the possibility of a
circulating “permeability factor” of immune origin which
alters glomerular podocyte permeability causing
proteinuria:
- A T-cell hybridoma made from patient with MCD
released a substance that when injected into rats,
induced proteinuria and foot process effacement.
- Two kidneys of a young donor with presumptive MCD
(never biopsied) were transplanted into two recipients
without baseline proteinuria. Proteinuria diminished
rapidly in both recipients and was absent by week six.
Koyama A et al. KI 40: p453, 1991.
Ali AA et al. Transplantation 58: p849, 1994.
Permeability Factor – IL-13
 One of the leading permeability factor suspects is
IL-13.
 IL-13 is known to be an autocrine growth factor for
the Reed-Sternberg cell in Hodgkin’s lymphoma.
 IL-13 expression was upregulated in T cells in
children with steroid sensitive nephrotic syndrome
who were in relapse.
 Receptors of IL-13 have been demonstrated on
podocytes and stimulation of cultured monolayers of
podocytes with IL-13 lead to decreased transepithelial
electrical resistance.
Skinnider BF et al. Int Arch Allergy Immunol 126: p 267, 2001.
Yap HK et al. JASN 10: p 529, 1999.
Van den Berg JG et al. JASN 11: p413, 2000.
Permeability Factor – IL-13
 Rats were transfected
with the IL-13 gene, which
resulted in the
overexpression of IL-13.

 Transfected rats
demonstrated significant
albuminuria,
hypoalbuminemia and
hypercholesterolemia when
compared to controls.
Kin-Wai L et al. JASN 18: p 1476, 2007.
Permeability Factor – IL-13

 At day 70, light microscopy was

indistinguishable from control
rats, however, the EM of
transfected rats demonstrated up
to 80% foot process effacement.
 Permeability Factor – IL-13

 Glomerular gene expression

was significantly down-
regulated for nephrin,
podocin and dystroglycan,
proteins found on the
podocyte and thought to be
essential in maintaining the
filtration barrier.

 This decrease was not due to

loss of podocytes as
glomerular expression of
WT-1 (a podocyte specific
cell marker) showed no
difference in IL-13 and
control rats.
 Pathophysiology – Role of B-cells
- It was serendipitously noted in a few cases of patients with
lymphoproliferative disorders and nephrotic syndrome that
when treated with rituximab the nephrotic syndrome
unexpectedly remitted.
- Recent case reports have demonstrated complete remission in
patients with steroid dependent/resistant minimal change
disease when treated with rituximab.
- One case report, noted that a patient remained in remission for 9
months while B-cells counts were undetectable, but relapse
occurred when B-cells returned.
- Could the permeability factor be produced by B-cells or by T-
cells through pathways regulated or stimulated by B-cells?
Gilbert R et al. Pediatric Nephrology 21: p1698, 2006.
Yang T et al. NDT 23:p377, 2008.
ETIOLOGIES
Etiologies
 Idiopathic (80-90% of cases)

 Secondary
 Drugs – NSAIDs, gold, rifampin, penicillins,
trimethadione
 Toxins - mercury, lead
 Atopic agents - bee stings, poison ivy, pollen
 Infection – Syphilis, Infectious mononucleosis, HIV
 Tumor - Hodgkin lymphoma (most commonly), other
lymphoproliferative diseases, carcinomas
 Other glomerular diseases – IgA nephropathy, Lupus,
PKD.
Glassock R. NDT 18:p vi52, 2003.
IgA and MCD
 Albeit an uncommon occurrence, mesangial IgA
deposition in MCD has been reported since the 1980s
in a few case series.

 Typically the IgA deposition is mild and questions

have been raised if IgA plays a pathogenic role
constituting an overlapping syndrome, whether the
finding is coincidental, or is this variant of MCD.

 All patients responded to corticoidsteroid treatment

with remission of nephrotic syndrome, which is
atypical for IgA nephropathy.
IgA and MCD
 Choi et al in published the findings of 60 patients (43
adults and 17 children) with MCD and mesangial IgA
deposition.

- 363 cases of MCD were seen at a single center in

Seoul, Korea over a 6 year period of which mesangial
IgA deposits were noted in 60 patients (16.8%)

- Hematuria occurred in 69% of the adults and 88% of

the children of which seven patients presented with
macroscopic hematuria.
Choi J et al. Yonsei Medical Journal 31:p258, 1990.
IgA and MCD
 Tsukada et al published a single center case series
out of Tokyo, Japan.

- Of the 63 patient’s diagnosed with MCD over a 6

year period, 15 had mesangial IgA deposition
(23.8%).
- There were no differences in creatinine clearance
or amount of proteinuria.
- Hematuria resolved after treatment with steroids in
all 15 patients.
Tsukada M et al. Nephrology 6:pA18, 2001.
IgA and MCD
 A case report of two patients with MCD and mesangial
IgA deposition who remitted with glucocorticoid
treatments was published in 1989.

 The two patients were rebiopsied, which demonstrated

that the previous mesangial expansion and mesangial IgA
deposits disappeared.

 As it is unusual for IgA deposits to disappear in serial

renal biopsies in patients with IgA nephropathy, the
authors proposed that this finding represents a distinct
clinical syndrome and is not merely coincidental.
Ignatius KP et al. AJKD 16:p361, 1989.
CLINICAL FINDINGS
 Clinical Findings
 Although there is an abundance of data regarding the
course, response to treatment and outcomes in pediatric
patients, much less is known about adults with MCD.

 Typically MCD is characterized by sudden onset

(days to weeks) of the signs and symptoms of the
nephrotic syndrome (edema, proteinuria,
hypoalbuminemia and hyperlipidemia).

 Hypertension, hematuria and renal dysfunction are

seen in a minority of cases in both children and adults
with MCD.
Clinical Findings
 Some proposed mechanisms for acute kidney injury
include ischemic tubular injury and interstitial
edema or nephrosarca leading to tubular collapse.

 Susceptibility to bacterial infections is a

considerable source of morbidity, proposed
mechanisms include:
 hypogammaglobulinemia from urinary losses
 impaired production of antibodies
 decreased levels of alternative complement factor D
Clinical Findings on Presentation

Korbet Nolasco Fujimoto Nakayama Waldman

Study et al et al Mak et al et al et al et al ISKDC

Number of Patients 40 89 51 33 62 95 401

Age 41 42 37 28 57 45 12wk-16yr

Male 48% 56% 70% 67% 52% 39% 66%

Proteinuria (g/d) 8.7 10.2 16.4 12.4 13.5 9.9

Serum albumin (g/dl) 2.1 1.9 1.7 1.8 1.8 2.2

Hypertension 21% 30% 55% 9% 32% 42% 14%

Microscopic hematuria 21% 28% 33% 15% 43% 29% 22%

Renal insufficiency (SCr > 1.3mg/dl) 18% 61% 55% 15% 33% 18% 29%
Clinical Findings – MCD Patients with AKI

Waldman et al. CJASN 2: p445, 2007.

TREATMENT
Treatment - Glucocorticoids
 Glucocorticoid therapy remains the mainstay of treatment
with complete remission in 75-97% of adults with MCD.
 There is only one randomized control treatment trial in
adults with MCD that compared prednisone with no therapy
(n=31).
- 75 % of prednisone treated patients had remission to
<1g/day of proteinuria within 6 months.
- In the untreated group, 50% were in remission at 18 months
and approximately 70% at three years.
 There are no randomized control trials comparing
prednisone to other agents for the initial therapy in adults with
MCD.

Black DA et al. BMJ 3:p421, 1970.

Treatment - Glucocorticoids
Initial response to steroids (1-1.5mg/kg/day) in adult onset minimal change disease.
Complete remission defined as < 0.3 g/d of proteinuria.
Partial remission defined as >50% reduction of proteinuria from baseline.

Study Korbet et al Nolasco et al Mak et al Fujimoto et al Nakayama et al Waldman et al ISKDC

Number of
Patients 40 89 51 33 62 95 401

Remission 98% 91% 92% 97% 98% 92% 95%

Complete 91% 78% 76% 97% 93% 75% 95%

Partial 7% 13% 16% 5% 17%

Steroid
Resistance 2% 9% 8% 3% 2% 8% 5%
Glucocorticoid Treatment Response
 There were no features at presentation that predicted a
response (or lack thereof) to steroids.
 Responders tended to have a slightly lower serum
creatinine at presentation compared with nonresponders
but this was not statistically significant (1.3 vs 1.6mg/dl).
 Of note, seven steroid resistant patients underwent
repeat biopsy in the Waldman study, FSGS was identified
in six cases. (whether the diagnosis of FSGS was missed
on initial biopsy or there was progression to FSGS is
uncertain).

Waldman et al. CJASN 2: p445, 2007.

Glucocorticoid Time to Remission

 Compared to children, time to complete remission is

prolonged with 50% responding in 4 weeks and 10-25%
requiring more than 4 months of therapy.
Relapses

Relapse defined as resumption of nephrotic range proteinuria (>3.5 g/d).

Frequent relapsers defined as >3 relapses in 1 year period.
Steroid dependent defined as relapse upon tapering steroid therapy or within 4 weeks
of discontinuation of steroids.

Nakayama et
Study Korbet et al Nolasco et al Mak et al Fujimoto et al al Waldman et al ISKDC

Number of
Patients 40 89 51 33 62 95 401
Total Relapses

65% 76% 70% 37% 62% 73% 71%

Frequent-
relapsers
16% 26% 27% 44%
Steroid-
dependent
40% 14% 50% 10% 18%
 Second Line Treatment
 For frequent relapsers and steroid-dependent patients.

 No prospective treatment trials, all retrospective

observational reports.

 Both cyclophosphamide and cyclosporine reported to

induce and maintain remission in up to 60% of MCD
patients, less so in steroid resistant cases (10%).

 Cyclosporine tends to achieve a more rapid remission, but

between 60-90% of patients relapse after discontinuation
making cyclosporine dependence a major issue.
Meyrier A et al. NDT 18:p vi79, 2003.
Ponticelli et al. KI 43:p1377, 1993.
Second Line Treatment
 Although small retrospective case series have used
azathioprine, mycophenolate mofetil, and tacrolimus,
the data is very limited.

 Lemivasole
- An immunomodulator which enhances antibody
production and phagocytic activity of PMNs and
monocytes, has been used in children with frequent
relapses and steroid-dependence with increasing rates
of steroid free remissions.
- A few case reports in adults suggesting possible role in
the treatment of MCD.
 Rituximab
PROGNOSIS
Prognosis

 Complications of
nephrotic syndrome have
been reported in 21% of Study
Korbet et
al
Nolasco
et al Mak et al
Fujimoto
et al
adults in long term follow up Number of
including: Patients 40 89 51 33
Follow up 54 91 169 46
- Thrombotic events 13% (mo)
- Life threatening
Nephrotic 20% 6% 2% 3%
infections 11%
- Myocardial infarction 9% ESRD 5% 1% 2%

Death 8% 17% 2% 3%
 Mortality rate is higher in
adults as compared to
children which is
approximately 3%.
THANK YOU