Minimal change disease

1
Minimal change disease
2
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

3
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

4
Primary causes of nephrotic syndrome (NS)

• Include, in approximate order of frequency
• Minimal-change nephropathy
• Focal glomerulosclerosis
• Membranous nephropathy
• Hereditary nephropathies

5
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

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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

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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 200743(5)337-41
  
• 2. Pediatr Nephrol. Dec 200419(12)1313-8

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 198120(6)765-71
• 2. J Pediatr. Apr 198198(4)561-4

9
Pathophysiology

• 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

GBM glomerular basement membrane Endo
fenestrated endothelial cells ESL endothelial
cell surface layer (often referred to as the
glycocalyx).
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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
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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

12
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

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Minimal Change Disease Pathology
14
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

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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

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Light microscopy of glomerulus in MCD
18
Immunofluorescence Microscopy
www.gamewood.net/rnet/renalpath/noimcx.jpg
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Electron Microscopy
20
The glomerular capillary wall
Normal
MCD
Van den Berg, Weening, Clinical Science (2004)
107, 125136
21
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)
23
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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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

25

• 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 2009338(4)264-7

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• 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 200718(5)1476-85

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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)
30
Comparison of control, IL-13-transfected mouse at
experiment end (day 70)
Parameter Control Rats (n17) Group 1 (proteinuric rats), n34 Grp 2 neprhrotic rats n7
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 lt0.001 vs control
Red plt0.001 vs control and Grp 1
31
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).
32
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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• 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

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• Izzedine et al found a lack of glomerular
  dysferlin expression associated with
  minimal-change 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 200648(1)143-50

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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.

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Incidence of important causes of nephrotic
syndrome, in number per million population

• 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 minimal-change nephropathy

Clin J Am Soc Nephrol. May 20061(3)483-7
Nephrol Dial Transplant. 2007221608-1618
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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.

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A schema of the average patient ages associated
with various common forms of nephrotic syndrome
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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

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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.

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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

44
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

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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

46
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
  6-8 weeks, and performing a renal biopsy may be
  useful to determine if another process may be
  present

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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

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Leg edema in MCDbefore treatment after
treatment
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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 3-5
  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.

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• 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

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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.

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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?
56
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
58
Summary

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

59
Other steroid response
In disease state With dexamethasone
p21 Upregulated downregulation allow podocyte to enter the cell cycle enhance ability to repair
VEGF a mitogen for vascular endotheila cells Downregulated
p52 Induces apoptosis downregulated
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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.

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• Because cyclophosphamide is cheaper and has a
  better response rate, it is preferable over
  cyclosporine in most patients with
  steroid-dependent 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 200924(11)2177-85

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Pediatr Nephrol. Jun 200924(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

63
Kidney Int. Dec 200772(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 drugs levels have
  been shown to be helpful in avoiding
  cyclosporine-associated nephrotoxicity.

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The treatment of MCD with tacrolimus has produced
varying results

• Nephrol Dial Transplant. Jun 200823(6)1919-25
• Nephrol Dial Transplant. Jul 200621(7)1848-54
•  Clin Nephrol. Jun 200665(6)393-400

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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

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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 200749(1)158-61

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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).

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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

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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

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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

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Activity

• Mobilization, rather than bed rest, is indicated
  to avoid thromboembolic complications

Aidan has Minimal Change Disease
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Thank You !