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Minimal change
disease
Introduction
• Nephrotic syndrome is kidney disease with
proteinuria, hypoalbuminemia, and edema.
Nephrotic range proteinuria is 3 grams per
day or more
• Nephrotic syndrome may affect adults and
children, of both sexes and of any race
Nephrotic syndrome (NS)
Classification
• Nephrotic syndrome can be primary, being a
disease specific to the kidneys, or it can be
secondary, being a renal manifestation of a
systemic general illness
• In all cases, injury to glomeruli is an essential
feature
Primary causes of nephrotic
syndrome (NS)
Include, in approximate order of frequency :
• Minimal-change nephropathy
• Focal glomerulosclerosis
• Membranous nephropathy
• Hereditary nephropathies
Secondary causes of NS
Include, again in order of approximate frequency
:
• Diabetes mellitus
• Lupus erythematosus
• Amyloidosis and paraproteinemias
• Viral infections (eg, hepatitis B, hepatitis C,
human immunodeficiency virus [HIV] )
• Preeclampsia
Minimal change disease
• Most common cause of the nephrotic
syndrome (NS) in children
• ~10-15% of NS 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
NS in infancy and childhood is an
important entity
• A study from New Zealand found the
incidence of nephrotic syndrome to be almost
20 cases per million children under age 15
years 1
• In specific populations, such as those of
Finnish or Mennonite origin, congenital
nephrotic syndrome may occur in 1 in 10,000
or 1 in 500 births, respectively 2
•
•
1. J Paediatr Child Health. May 2007;43(5):337-41
2. Pediatr Nephrol. Dec 2004;19(12):1313-8
According to the International Study of
Kidney Diseases in Childhood (ISKDC)
• 84.5% of all children with primary nephrotic syndrome
have minimal-change nephrotic syndrome (MCNS)
• 9.5% have focal segmental glomerulosclerosis (FSGS)
• 2.5% have mesangial proliferation, and
• 3.5% have membranous nephropathy or another cause
of the disease 1,2
• MCNS remains the most important cause of chronic
renal disease in children
• 1. Kidney Int. Dec 1981;20(6):765-71
• 2. J Pediatr. Apr 1981;98(4):561-4
Pathophysiology
GBM = glomerular basement membrane;
Endo = fenestrated endothelial cells; ESL =
endothelial cell surface layer (often referred
to as the glycocalyx).
• Primary urine is formed
through the filtration of
plasma fluid across the
glomerular barrier; the
glomerular filtration rate
(GFR) is 125 mL/min
• The plasma flow rate
(Qp) is close to 700
mL/min, with the
filtration fraction being
20%
• The concentration of
albumin in serum is 40
g/L, while the estimated
concentration of albumin
in primary urine is 4
mg/L, or 0.1% of its
concentration in plasma
The barriers that keep protein and blood cells out of the
urine. These are the endothelial cell, basement
membrane and epithelial cell (podocyte). The epithelial
cell (podocyte) seems to be most important. Injury to
these barriers causes proteinuria and hematuria
Pathophysiology (contd.)
• The glomerular structural changes that may
cause proteinuria are
- (1) damage to the endothelial surface,
- (2) damage to the glomerular basement
membrane,
- and/or (3) damage of the podocytes
• In congenital nephrotic syndrome, the gene for
nephrin, a protein of the filtration slit, is
mutated, leading to nephrotic syndrome in
infancy
Pathophysiology (contd.)
• Albuminuria alone may occur, or, with greater
injury, leakage of all plasma proteins, (ie,
proteinuria) may take place
• Proteinuria that is more than 85% albumin is
selective proteinuria
• In minimal-change nephropathy, proteinuria is
selective
Minimal Change Disease Pathology
Pathogenesis of edema
• An increase in glomerular permeability leads to
albuminuria and eventually to hypoalbuminemia
• In turn, hypoalbuminemia lowers the plasma
colloid osmotic pressure, causing greater
transcapillary filtration of water throughout the
body and thus the development of edema
• A reduction in plasma volume, with a secondary
increase of sodium and water retention by the
kidneys
Metabolic consequences of
proteinuria
• levels of serum lipids are usually elevated
• The loss of antithrombin III and plasminogen
and increase in clotting factors, especially
factors I, VII, VIII, and X, increases the risk for
venous thrombosis and pulmonary embolism
• Hypovitaminosis D - malabsorption of Ca++
• Lower the patient's resistance to infections and
increase the risk of sepsis and peritonitis
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
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
MCD is a disorder of T cells
• T-cells release a cytokine that injures the
glomerular epithelial foot processes
• This leads to a decreased synthesis of
polyanions
• The polyanions constitute the normal charge
barrier to the filtration of macromolecules, such
as albumin
• When the polyanions are damaged, leakage of
albumin follows
• The identity of this circulating permeability
factor is uncertain, although it is postulated that
it may be hemopexin
• Some of the cytokines that have been studied in
MCD are interleukin-12 (IL-12) and interleukin-4
(IL-4)
• IL-12 levels have been found to be elevated in
peripheral blood monocytes during the active
phase and normalized during remission
• Interleukin-18 (IL-18) can synergize with IL-12
to selectively increase the production of
vascular permeability factor from T cells
• In addition, levels of IL-4 and CD23 (a receptor
for immunoglobulin E [IgE] 1 have been found to
be elevated in peripheral blood lymphocytes
• 1. Am J Med Sci. Oct 2009;338(4):264-7
• Synaptopodin is a proline-rich protein intimately
associated with actin microfilaments present in
the foot processes of podocytes
• Greater synaptopodin expression in podocytes
is associated with a significantly better
response to steroid therapy
• Interleukin-13 (IL-13) has been implicated in the
pathogenesis of MCD.
• IL-13 genetic polymorphisms correlate with the
long-term outcome of MCD.
• IL-13 overexpression can cause podocyte foot
process fusion and proteinuria 1
• 1. May 2007;18(5):1476-85
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
Reed-Sternberg
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-13transfected 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 -
• In patients who develop acute renal failure,
endothelin 1 expression is greater in the
glomeruli, vessels, and tubules than in the
nonacute renal failure group
• The glomerular epithelial cells (podocytes) and
the slit diaphragm connecting the podocyte foot
processes play a primary role in the
development of proteinuria
• Nephrin is a major component of the slit
diaphragm. The slit diaphragm is often missing
in MC nephrotic syndrome (MCD) kidneys
• The role of nephrin and the slit diaphragm in
MCD is not known. However, genetic variants of
a glomerular filter protein may play a role in
some patients with MCD
• Izzedine et al found a lack of glomerular
dysferlin expression associated with minimalchange nephropathy in a patient with limb-girdle
muscular dystrophy type 2B. 1
• In the same study, 2 of 3 other patients with
dysferlinopathy had microalbuminuria
• Although a multitude of studies have been
published, the mechanism by which T cells
increase glomerular permeability has remained
unproven
• 1. Am J Kidney Dis. Jul 2006;48(1):143-50
Frequency
• United States - In preadolescents, minimal-change
nephrotic syndrome (MCNS) makes up 85-95% of all
cases of nephrotic syndrome
• In adolescents and young adults, the prevalence is 50%,
while in adults, MCNS accounts for 10-15% of primary
nephrotic syndrome cases.
• The incidence of nephrotic syndrome is 2-7 new cases
annually per 100,000 children, and the prevalence is
15 cases per 100,000 children
 Asians may be at increased risk.
Incidence of important causes of nephrotic
syndrome, in number per million population
Clin J Am Soc Nephrol. May 2006;1(3):483-7
Nephrol Dial Transplant. 2007;22:1608-1618
• The left panel shows
systemic causes, and the
right panel lists primary
renal diseases that can
cause nephrotic
syndrome.
• fgs = focal
glomerulosclerosis,
• MN = membranous
nephropathy,
• min change = minimalchange nephropathy
Sex / Age
• It is found twice as frequently in boys than in
girls
• The frequency is the same between the sexes in
adults
• The incidence peaks in children aged 2 years,
with approximately 80% being younger than 6
years at the time of diagnosis
• In adults, the mean age of onset is 40 years.
A schema of the average patient ages associated with
various common forms of nephrotic syndrome
History
• Edema may be preceded by an upper respiratory tract
infection, an allergic reaction to a bee sting, or the use
of certain drugs or malignancies.
• Facial edema is noted first.
• Malaise and easy fatigability can occur.
• Weight gain often is an additional feature.
• The patient also may present with the following:
–
–
–
–
Hypovolemia
Hypertension
Thromboembolism
Infection
Physical
• BP - usually is normal in childrenbut may be elevated in
adults
• Dependent edema is the most prominent sign. The
retina has a wet appearance. Subungual edema with
horizontal lines (called Muehrcke lines) also may occur.
• Hernias may be found, and the elasticity of the ears may
be decreased.
• Heavy proteinuria - leads to a state of protein depletion
with muscle wasting, thinning of the skin, and growth
failure
• Pleural and ascitic fluid can accumulate. Rarely,
cellulitis, peritonitis, or pneumonia
• Children may have growth failure.
Causes
• Almost all cases are idiopathic, but a small percentage
of cases (approximately 10-20%) may have an
identifiable cause
• Causes may include the following: Secondary
– Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs),
rifampin, interferon, ampicillin/penicillin, trimethadione,
mercury-containing cosmetic skin cream
– Toxins - Mercury, lithium, bee stings, fire coral exposure
– Infection - Infectious mononucleosis, HIV, immunization
– Tumor - Hodgkin lymphoma (most commonly), carcinoma,
other lymphoproliferative diseases
– Posthematopoietic stem cell transplant
Laboratory Studies
• Urine analysis - profound proteinuria and oval fat bodies
observed.
– In children, the critical level for diagnosis is more than 40
mg/h/m2.
– In adults, the threshold is more than 3.5 g/d/1.73 m2.
• Albumin-to-creatinine concentration ratio is in excess of
5.
• Urine specific gravity is high because of proteinuria.
• A 24-hour urine is obtained for protein and creatinine
clearance.
• Hypoalbuminemia - Nephrotic syndrome in children is
defined by a serum albumin of less than 2.5 g/dL.
• Hyperlipidemia also is a feature of a nephrotic state.
• Renal function usually is normal except in cases of ARF
• Hyponatremia often is observed,
• Elevated hemoglobin and hematocrit
Imaging Studies Renal sonogram is normal.
• Procedures
• Because of the high prevalence of MCD in children with
nephrotic syndrome, an empiric trial of corticosteroids
commonly is the first step in therapy
• Renal biopsy typically is performed only in resistant
cases
• Generally, if proteinuria remains after 2 relapses or
courses of steroids, a tissue diagnosis should be made
before starting cytotoxic or immunosuppressive therapy
Medical Care
• Corticosteroids are the treatment of choice,
leading to complete remission of proteinuria in
most cases
• Approximately 90% of children respond within 2
weeks to prednisone at a dose of 60
mg/msq/d.
• The treatment is continued for another 6 weeks,
at lower doses of prednisone, after the
remission of proteinuria.
• In some children, proteinuria fails to clear by 68 weeks, and performing a renal biopsy may be
useful to determine if another process may be
present
Adults respond more slowly than children
• A response in up to 80-90% in adolescents and adults
• The time to remission is up to 16 weeks. If patients are
steroid-resistant or they relapse frequently, a trial of
immunosuppressants is given
• Immunosuppressants - cyclophosphamide and
chlorambucil
• Cyclosporine is considered to be an acceptable drug for
maintenance therapy in patients with frequent relapses
and steroid dependency. However, it is less efficacious
than cyclophosphamide at maintaining sustained
remission
Leg edema in MCD
before treatment
after treatment
Response of patients to steroids is used
to divide patients into various groups.
• Complete remission: This is defined as
complete resolution of proteinuria for at least 35 consecutive days.
• Partial remission: This is defined as a reduction
in the degree of proteinuria without complete
clearing.
• Relapse: This is defined as a reoccurrence of
proteinuria for at least 3-5 consecutive days.
• Because MCNS accounts for 90% of all cases of
idiopathic nephrotic syndrome in children, steroids are
started empirically. A biopsy is performed only in those
cases where no remission occurs
• In comparison, a biopsy is performed in all adults before
the initiation of treatment. Adults tend to respond more
slowly, with more than 25% taking as long as 12-16
weeks to undergo complete remission
• Initial regimen in adults consists of oral prednisone in a
daily dosage of 1 mg/kg of body weight for 8-16 weeks
(or for 1 wk after remission has been induced). The
patient is then placed on an alternate-day single-dose (1
mg/kg) regimen to minimize the incidence of adverse
effects.
• If proteinuria disappears or is reduced to a very low
level, high-dose alternate-day therapy is continued for
several weeks to 1 month and then slowly tapered over
several months in an attempt to reduce the likelihood of
relapse
To prevent relapse, steroids are
continued for several weeks after
remission.
• Steroid-sensitive patients: These patients have
complete remission within 8-12 weeks with infrequent
relapses. Children usually respond within 4-6 weeks,
whereas adults respond in up to 15 weeks. Treatment
usually is continued for another 6 weeks after complete
remission of proteinuria occurs.
• Steroid-dependent patients or frequent relapsers: If
remission is followed by recurrence, a second course of
steroids is given. Those patients who need steroids
repeatedly are categorized as frequent relapsers or
steroid-dependent patients. Relapse in these patients
can occur either during tapering of steroids or after
cessation of therapy.
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
Cytotoxic drugs
• Can be considered to either induce a remission
or decrease the adverse effects of continuous
steroid use.
• Cyclophosphamide 2 mg/kg/d for 8-12 weeks,
can be used in such patients
• Cyclosporine (4-6 mg/kg/d) also can be used in
patients who continue to relapse or who are
steroid-dependent.
• Because cyclophosphamide is cheaper and has
a better response rate, it is preferable over
cyclosporine in most patients with steroiddependent or frequently relapsing MCD
• Studies in adults and children have shown that
both cyclophosphamide and cyclosporine added
to steroid treatment may induce remission
• If these patients relapse at a later time, they
tend to become steroid-sensitive.
• Ref: Pediatr Nephrol. Nov 2009;24(11):2177-85
Pediatr Nephrol. Jun 2009;24(6):1187-92
• A study by Swartz et al of 55 children with
steroid-resistant or steroid-dependent MCD
determined that 23 of these patients also had
mesangial IgM that was visible through
immunofluorescence (one of the characteristics
of IgM nephropathy)
• The investigators also found that the children
with MCD and immunofluorescently-visible IgM
responded better to treatment with cyclosporine
than to therapy with cyclophosphamide
Kidney Int. Dec 2007;72(12):1429-47
• Adults are particularly prone to the adverse
effects of corticosteroids, but they do well on
cyclophosphamide.
Cyclosporine may be used as an alternative to
cyclophosphamide in order to avoid toxicities
associated with the latter
• Keeping the dosage of cyclosporine at a
minimum and carefully monitoring the drug’s
levels have been shown to be helpful in
avoiding cyclosporine-associated nephrotoxicity.
The treatment of MCD with
tacrolimus has produced varying
results
• Nephrol Dial
Transplant. Jun 2008;23(6):1919-25
• Nephrol Dial Transplant. Jul 2006;21(7):184854
• Clin Nephrol. Jun 2006;65(6):393-400
Mycophenolate mofetil (MMF)
• MMF may also be beneficial to patients with
frequent relapses. This was suggested by a
small study where 7 patients with MCD and
FSGS with multiple relapses were treated with
MMF (1 g bid). After 1 year, 5 of the 7 patients
were still in remission, and the steroid dose was
significantly decreased
• In addition, the immunomodulator levamisole
also has been used in children
Rituximab
• One case report describes long-term remission with
rituximab (an anti-CD20 antibody) 1
• Rituximab has been shown to be effective against
minimal-change disease.
• Relapse has been linked to the reappearance of B19
cells, which rituximab depletes
• Rituximab may therefore have a role in the treatment of
steroid-dependent and multirelapsing patients
•
1. Am J Kidney Dis. Jan 2007;49(1):158-61
Hypovolemia
– Immediate volume expansion with purified plasma
protein fraction and isotonic sodium chloride
solution
– Parenteral albumin infusion is not appropriate
long-term management for patients with
hypoalbuminemia because it has only a transient
effect. Such crises should be avoided with
recognition of the earlier signs of hypovolemia,
including abdominal pain, increase in hematocrit,
and response to contributing factors (eg, diarrhea,
septicemia, diuretic therapy).
Edema
– This condition should be controlled by dietary
sodium restriction.
– Small amounts of edema are not of much clinical
significance.
• The use of diuretics should be reserved for
patients with severe cases of edema,
particularly in the presence of respiratory or
gastrointestinal symptoms, and when the
condition restricts activity
Thrombotic episodes/ Infections
• Thrombotic episodes should be prevented by
mobilization and meticulous attention to venipuncture
and intravenous infusion sites. Established episodes
should be managed with heparinization.
• Infections
– These must be treated aggressively.
– Cellulitis, peritonitis, otitis, and pneumonia are common
infections.
• Susceptibility to pneumococcal infections warrants the
administration of penicillin prophylaxis to patients in
relapse; corticosteroids increase the problem of
infection
Diet
• An adequate dietary protein intake, in
accordance with the recommended daily
allowance (RDA) is necessary. No evidence
suggests that hepatic albumin synthesis is
elevated with protein intake that is higher than
the RDA.
• Dietary sodium restriction helps forestall the
progression of edema and also is prudent in the
management of hypertension
Activity
• Mobilization, rather than bed rest, is indicated
to avoid thromboembolic complications
Aidan has Minimal Change Disease
Thank You !