Idiopathic Nephrotic Syndrome

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Idiopathic Nephrotic Syndrome

• Dr.Fahad Gadi, MD
• Pediatrics Demonstrator
• King Abdulaziz University
• Rabigh Medical School

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Nephrotic Syndrome

• Generally has a glomerular cause
• Types primary and secondary
• Secondary NS anaphylactoid purpura, systemic
  lupus erythematosus, diabetes mellitus, sickle
  cell disease, syphilis,

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NS Types

• Minimal change nephrotic syndrome (MCNS)
• Focal segmental glomerulosclerosis (FSGS)
• Congenital nephrosis
• Membranoproliferative glomerulonephritis (MPGN)
• Membranous glomerulonephritis (MGN).

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FSGS

• Second most common histologic subtype
• FSGS is always a histopathologic diagnosis
• FSGS may manifest in a fashion that is
  indistinguishable from MCNS, but it may also be
  found only after years of clinical nephrotic
  syndrome when earlier biopsies have been
  interpreted as MCNS.
• FSGS is a known consequence of hyperfiltration
  and is regularly seen in patients with reflux
  nephropathy and in some patients with a single
  kidney whose other has been lost because of
  conditions such as multicystic dysplastic kidney
  disease

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Congenital NS

• Congenital nephrotic syndrome becomes a
  consideration when nephrosis appears during the
  first year of life and particularly in those
  instances in which the clinical syndrome starts
  in the first few months

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MPGN

• In older children and adolescents.
• Clinical picture is more closely associated with
  a nephritic picture, but on occasion it may
  appear similar to MCNS or FSGS.
• Membranous glomerulonephritis (MGN) accounts for
  less than 1 of the cases of NS in childhood and
  adolescence
• Often associated with hepatitis or other viral
  disease.

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Mortality

• MCNS reported cumulative mortality rate (at 20 y
  postonset) of less than 15 (range in various
  studies, 5-15).
• FSGS cumulative mortality rate is greater than
  50

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Morbidity

• Hospitalization, in some instances
• A prolonged period of treatment
• Frequent monitoring both by parents and by
  physician
• Administration of medications associated with
  significant adverse events
• A high rate of recurrence (ie, relapses in gt60
  of patients)
• The potential for progression to chronic renal
  failure (CRF)

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Definitions

• Nephrotic Syndrome (NS)- Edema, Albumin lt 2.5
  mg/dL, proteinuria gt 40 mg/m2hr
• Remission- Urinary protein lt 4 mg/ m2hr or
  Albustix 0/Trace for 3 consecutive days
• Steroid Responsive- Remission with steroids alone

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Definitions

• Relapse- Urinary protein gt 40 mg/m2hr or
  Albustix gt 2 for 3 consecutive days
• Frequent Relapses- Two or more relapses within 6
  months of initial response or 4 or more relapses
  within any 12 month period

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Definitions

• Steroid Dependence- Two consecutive relapses
  occurring during corticosteroid treatment or
  within 14 days of its cessation
• Steroid Resistance- Failure to achieve response
  in spite of 4 weeks of prednisone 60 mg/m2day

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Pathogenesis not clear

• Believed to have an immune pathogenesis
• Despite the regular finding of elevated levels of
  IgE and an association with atopy in
  steroid-responsive NS, current data merely
  suggest a common immune activation rather than a
  direct association
• Glomerular capillary permeability to albumin is
  selectively increased

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Epidemiology

• Incidence
• Incidence 2-7 new cases per 10,000
• Prevalence 15.7 cases per 10,000
• Age
• MCD 2.5 years median age
• FSGS 6 years median age
• Sex
• 32 Boys Girls in children lt6 yo
• Equal ratio in those older

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Epidemiology

• Familial incidence
• European survey 63 of 1877 nephrotic children had
  affected siblings
• Familial NS similar with respect to
  histopathology and steroid response

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Epidemiology

• Bonilla-Felix has noted a lower incidence of MCD
  and higher incidence of FSGS than previously
  reported
• Gulati in 1999 reported a doubling of the
  incidence of FSGS over historical controls

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Associated Disorders

• Atopy has been found in 34-60 of children with
  MCD
• Meadow reported plasma IgE levels elevated in 10
  of 84 with MCD
• Malignancy
• Hodgkins disease
• T cell lymphomas
• Thymoma/ myasthenia gravis
• Diabetes Mellitus

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Clinical Features- Edema

• Physical exam
• Accumulates in gravity dependent tissues
• Puffiness around eyes
• Genital edema is generally painful

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Clinical Features- Edema

• Pathogenesis
• 80 of oncotic pressure due to albumin
• Below 2 g/dL edema accumulates
• Intravascular volume depletion
• Renin-aldosterone activation
• Plasma volume (PV) has not always been found to
  be decreased and, in fact, in most adults,
  measurements of PV have shown it to be increased.
  Only in young children with MCNS have most (but
  not all) studies demonstrated a reduced PV.
  Additionally, most studies have failed to
  document elevated levels of renin, angiotensin,
  or aldosterone, even during times of avid sodium
  retention. Active sodium reabsorption also
  continues despite actions that should suppress
  renin effects

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Hematuria

• Frequency of macrohematuria depends on the
  histologic subtype of NS.
• More common in those patients with MPGN
• In MCNS has been reported to be as high as 3-4
  of cases.
• Higher percentage of patients with FSGS have
  microhematuria than those with MCNS, but this is
  not helpful in differentiating between types of
  NS in the individual patient.

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Hematuria microscopic

• Microscopic hematuria is present at the onset of
  the disease in 20-30 of patients with MCNS, but
  it disappears thereafter. By contrast,
  microscopic hematuria is consistently present in
  80-100 of patients with MPGN and in 60 of
  patients with MN.
• Patients with FSGS have hematuria more often than
  patients with MCNS, but the presence of hematuria
  cannot be used to distinguish between the 2
  conditions.

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Clinical Features- Edema

• Evidence against
• Analbuminemia
• Steroid induced diuresis
• Increased intravascular volume
• Low renin/aldosterone levels

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Clinical Features- Hypovolemia

• Classic teaching
• Not all patients are hypovolemic

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Clinical Features- Infection

• Bacterial infections
• Prone to bacterial sepsis
• Cellulitis
• IgG levels low
• Lymphocyte function impaired
• Viral Infections
• Measles may induce remission in NS
• Relapse preceded by viral infection

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Clinical Features- Thrombosis

• Serious risk of thrombosis
• Increased fibrinogen concentration
• Antithrombin III concentration reduced
• NS patients resistant to heparin
• Platelets hyperaggregable
• Increased blood viscosity

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Laboratory Features

• Hct may be elevated
• Hyponatremia is common
• Plasma creatinine is elevated in 33 of patients

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Laboratory- Plasma Protein

• Albumin
• Hypoalbuminemia due to loss via the kidney
• Immunoglobulins
• IgG levels reduced
• IgM levels elevated
• IgM-IgG-Switching

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Laboratory- Hyperlipidemia

• Increased synthesis of cholesterol, triglycerides
  and lipoproteins
• Decreased catabolism of lipoproteins
• Decreased activity of lipoprotein lipase
• Decreased LDL receptor activity
• Increased urinary loss of HDL

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Laboratory- Urinalysis

• Broad, waxy casts
• Lipid droplets
• Hematuria 22.7 of MCNS
• Low urine sodium
• High osomolality

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Laboratory- Proteinuria

• gt 40 mg/hour m2
• Urine protein/creatinine ratio gt 2
• Unusual to see tubular proteinuria

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Selectivity Index

• Clearance of IgG/ Clearance of Transferrin
• MCD
• 53 lt 0.10
• 13 gt 0.20
• FSGS
• 15 lt 0.10
• 57 gt 0.20

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Indications for Biopsy

• Pretreatment
• Recommended
• Onset age lt 6 months
• Macroscopic hematuria
• Microscopic hematuria and HTN
• Low C3
• Renal failure
• Discretionary
• Onset between 6-12 months or gt 12 years
• Persistent HTN or hematuria

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Indications for Biopsy

• Post treatment
• Steroid resistance
• Frequent relapsers

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Steroid Sensitive Nephrotic Syndrome- SSNS

• Natural history
• 1 year mortality 2.5
• Late outcome of 152 patients followed 14-19 years
  7.2 mortality
• 1/4 of patients have a single relapse
• 1/3 relapse occasionally
• 1/2 become steroid dependent
• Most remit at puberty
• 2-7 will continue to relapse
• Renal survival near 100

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Diuretic Therapy

• loop diuretics (furosemide) given orally in usual
  amounts (1-2 mg/kg/d) are safe and moderately
  effective
• If the edema is sufficiently intense that
  intravenous diuretic therapy seems indicated,
  then salt-poor albumin should be infused (usually
  at 1 gram/kg body weight given IV over 2-4 hours)
• Diuretics other than loop diuretics (eg,
  thiazides, spironolactone, metolazone) are
  generally not potent enough alone
• diuresis but may give an added effect when
  combined with furosemide. Metolazone (with or
  without spironolactone) may be beneficial in
  combination with furosemide for resistant edema.

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Treatment- Diet

• Low protein
• Decreases albuminuria
• Malnutrition
• Salt restriction
• During edema

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Treatment- Antibiotics/ Immunizations

• Prophylactic Penicillin with ascites
• Gram negative coverage for peritonitis
• Streptococcal immunization
• Varicella
• VZIG if exposed
• Immunizations
• No live viruses while on daily steroids
• No oral polio for siblings

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Treatment- Albumin

• Controversial
• Indication- Hypovolemia
• Abdominal pain
• Hypotension
• Oliguria
• Renal insufficiency

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Complications

• Mortality
• 1940s- 40 1 year mortality
• Now 1-2
• Main cause of death
• Infection
• Thrombosis

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Steroid Initial therapy

• Higher dosages or longer courses of daily
  steroids do not significantly change the response
  rate in MCNS
• 90 of patients with MCNS respond to this therapy
  with complete clearing of proteinuria, but only
  about 20 of children with FSGS and lt5 of those
  with MPGN experience a clinical remission
  (defined as a diuresis without complete clearing
  of proteinuria).
• The majority of children with MCNS will respond
  between the 10th and 14th days of such therapy,
  but a full course of at least 4 weeks of daily
  therapy is still recommended.
• Children who do not respond (ie, complete
  clearing of proteinuria) should be referred to a
  pediatric nephrologistfor percutaneous renal
  biopsy and consideration be given to an
  alternative plan of treatment.

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Corticosteroids Initiation

• High dose steroids
• 2 mg/kg/day (max 80 mg)
• 60 mg/m2 (max 80 mg)
• 3 accepted protocols
• 80 respond within 2 weeks

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Corticosteroids Initiation
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Corticosteroids Initiation

• Higher dosages or longer courses of daily
  steroids do not significantly change the response
  rate in MCNS
• The intensity and duration of the initial
  corticosteroid regime influences the rate of
  relapse of NS

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Cochrane metaanlysis steroid

• In children in their first episode of SSNS,
  treatment with prednisone for at least three
  months results in fewer children relapsing by 12
  to 24 months with an increase in benefit being
  demonstrated for up to seven months of treatment
  compared with two months therapy. In a population
  with a baseline risk for relapse of 60 with two
  months of prednisone, daily prednisone for four
  weeks followed by alternate-day therapy for six
  months would be expected to reduce the number of
  children experiencing a relapse by about 33.
• In comparison with three months of therapy, six
  months of therapy results in a reduced risk for
  relapse without increase in adverse effects.
• The reduction in risk for relapse is associated
  with both an increase in duration and an increase
  in dose.
• During daily therapy, prednisone is as effective
  when administered as a single daily dose compared
  with divided doses.
• Alternate-day therapy is more effective than
  intermittent therapy (three consecutive days of
  seven days) in maintaining remission.
• In relapsing SSNS, long duration of alternate-day
  prednisone is more effective than the standard
  duration therapy for relapse originally
  recommended by the ISKDC

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Corticosteroids- Maintenance

• Individualized for each patient
• Usually tapered over 6 months- 1 year

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Steroid

• 4 weeks intensive (daily) treatment
• 8 weeks 1.5 mg/kg/d (one dose every other
  morning)
• 8 weeks 1.0 mg/kg/d (one dose every other
  morning)
• 8 weeks 0.5 mg/kg/d (one dose every other
  morning)

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Relapse

• No predictors of relapse
• Relapses as responsive
• 25 spontaneously remit
• Treatment deferred 5 days
• Intensification of relapse treatment has little
  effect on subsequent relapse rate

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Corticosteroids- Relapse

• 60 mg/m2/day until remission
• Change to alternate day
• Taper over 1-3 months

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Steroid Toxicity

• Cushingoid habitus
• Obesity
• Striae
• Hirsutism
• Acne
• Growth failure
• Avascular necrosis
• Osteoporosis

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Steroid Toxicity

• Peptic ulceration
• Pancreatitis
• Posterior lens opacities
• Myopathy
• Increased ICP
• Susceptibility to infection

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Indications for Alternative Therapy-SSNS

• Relapse on Prednisone Dosage gt0.5 mg/kg/alt day
  plus
• Severe steroid side effects
• High risk of toxicity- diabetes
• Unusually severe relapses
• Relapses on Prednisone Dosage gt1.0 mg/kg/alt day

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Options for Alternative Therapy- SSNS

• Alkylating Agents
• Nitrogen mustard
• Cyclophosphamide
• Chlorambucil
• Levamisole
• Cyclosporine

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Cyclophosphamide- SSNS

• 8 weeks of 3 mg/kg/day
• 69 of children with SRNS remain in remission for
  1 year
• 44 for 5 years
• Younger children do worse
• Steroid dependent children do worse
• 2 mg/kg/day may or may not have any benefit

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Chlorambucil- SSNS

• 0.2 mg/kg/day for 8 weeks
• Jones 1988 5 patients with SSNS
• 1 course induced remission for 7.4 months
• 2 course induced remission for 22 months
• Bailey 1989 5 patients with SSNS
• All remitted with 1 course
• Elzouki 1990 16 patients with SSNS
• 56 complete remission (39 month follow)
• Relapse rate cut in half

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Levamisole- SSNS

• Antihelmithic with immunomodulating properties
• 2.5 mg/kg/qOD for 2 months
• Tenbrock 1998
• 5 patients SSNS
• 5/5 complete remission
• 24 month followup

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Levamisole- SSNS

• British association for Pediatric Nephrology
• 1991 61 children
• Levamisole vs placebo same dose
• Steroids stopped at 56 days
• 14/31 in levmisole group in complete remission at
  112 days
• 4/30 in placebo group in complete remission

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Cyclosporine- SSNS

• 5 mg/kg/day
• Used with steroids
• Patients usually respond well
• Cyclosporine dependence is common
• Long term side effects unknown

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Steroid Resistant Nephrotic Syndrome (SRNS)

• Natural history
• 40 ESRD by 5 years ISKDC
• Tejani 70 ESRD by 2 years
• 12 of all transplants are performed for the
  diagnosis FSGS
• 12-24 of pediatric ESRD patients have FSGS as
  diagnosis
• Heavy proteinuria, hypertension and interstitial
  fibrosis are risk factors for rapid loss of renal
  function
• Progression to ESRD in 2 years

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SRNS- Mendoza Protocol

• Alkylating agent added if complete or partial
  remission not achieved by 2 weeks, or if Urine
  protein/creatinine ratio gt 2 at 10 weeks
• Cyclophosphamide 2-2.5 mg/kg/day for 8-12 weeks
• Chlorambucil 0.18-0.22 mg/kg/day for 8-12 weeks

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SRNS- Mendoza Protocol
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SRNS- Cyclophosphamide

• ISKDC Trial of SRNS (FSGS)
• Prednisone 40 mg/m2 qOD x 12 months
• Cyclophosphamide 2.5 mg/kg/day x 3 months plus
  the same prednisone dose
• Control 28 complete remission
• Treatment group 25 complete remission
• Geary- 12/29 patients full or partial response
• Tejani reported 0/10 responded

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SRNS- ACE Inhibition

• Milliner reported a 50 decrease in proteinuria
  without a decrease in GFR in patients with SRNS
  treated with ACE I