????? Nephrotic Syndrome

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?????Nephrotic Syndrome

• ?????????? ???

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Definition

• Nephrotic syndrome (NS) is defined by the
  presence of following
• Heavy proteinuria (gt3.5g/d)
• Hypoalbuminemia (serum albumin lt30g/L)
• Peripheral edema
• Hyperlipidemia / hypercholesterolemia

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Major causes of NS (primary or idiopathic)

• Minimal change disease (?????)
• Mesangial proliferative glomerulonephritis
  (??????????)
• Focal segmental glomerulonephritis (????????????)
  
• Membranous glomerulonephritis (????)
• Membranoproliferative glomerulonephritis
  (?????????/????????????)

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Major causes of NS (secondary or systemic)

• Antoimmune systemic lupus erythematosus (SLE)
• Endocrine diabetic nephropathy
• Infections Hepatitis B, C, HIV
• Allergenic Henoch-Schonlen purpura
• Neoplastic Hodgkins and non-Hodgkins
  lymphomas, multiple myeloma
• Others Amyloidosis, Hereditary nephritis,
  medications

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Pathophysiology

• Heavy protinuria
• Hypoalbuminemia
• Edema
• Hyperlipidemia

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Heavy proteinuria

• Damage to the charge-selective barrier of GMB
  ?ultrafiltration of negatively charged albumin
• Damage to the size-selective barrier of GMB
  ?passsage of lager molecular proteins
• Protein filtration gt reabsorption capacity of
  tubules
• Heperperfusion/Hyperfiltration factors
  (hypertension, protein-rich diet) ?proteinuria
  increase

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Consequence of urinary loss of plasma proteins

• Serum protein ?or hypoalbuminemia
• IgG/Complement ??infection
• Coagulation component alternation (anticoagulants
  ?)?thrombosis
• Hormone-binding proteins ?/metal-binding proteins
  ??endocrine or metabolic abnormalities
• Lager proteins may increase

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Hypoalbuminemia

• Urinary loss
• albumin catabolism ? by tubules
• Malnutrition due to GI changes

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Edema

• Reduced plasma oncotic pressure (colloid osmotic
  pressure)
• Hypovolemia ?renin-angiotensin-aldosteron ?
  Sympathetic nervouse and vasopression systems ?
• Primary renal Na retension (non-plasma Hormone
  effects on the kidney)

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Hyperlipidemia

• One of the sentinel features of NS with numerous
  alterations in lipids profiles (hypercholesterolem
  ia, hypertriglyceridemia, LDL and VLDL ?)
• Overproduction by the liver of lipoproteins
• Decreased catabolism of lipoproteins and
  triglyceride

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Minimal changes nephropathy(MCD, ???????)

• Overview and Terminology
• First described in 1913 by Monk as lipoid
  nephrosis
• other terms nil disease and idiopathic
  nephrotic syndrome

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Pathogenesis

• Unclear
• Most likely a consequence of T cell abnormalities
  (glomerular permembility factor)
• Other potential mechanisms (circulating immune
  complexes)

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Histopathology

• Light microscope (LM)
• Lack alteration in glomerular structure
• Some lipid droplets in tubule cells
• Immunoflurescent microscopy( IM)
• No change
• Electron microscopy (EM)
• Fusion of epithelial foot processes

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Clinical presentation

• Most common in children accouting for 10-15 of
  NS in adults with male predominance
• Typical feature of NS
• Uncommon with nephritic features (hematuria,
  hypertension)
• Renal function (normal or dereasesd transiterily)

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Diagonosis

• Children and prealdolescent children presenting
  with NS will have MCD (about 80-85)
• Children with NS sensitive to steroid treatment
• Secondary MCD kept in mind when adult or old
  patients presents with MCD
• Renal biopsy

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Treatment (1)

• Corticosteroid therapy
• Exquisitely sensitive
• Dose of prednisone
• Caution with the side-effects of steroid

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Dose of prednisone

• Initial
• (full)
• Tapering(slowly)
• Maintainece
• (longer)

• Adult
• 1 mg/kg/d8-12w
• 10reduction/1-2w
• Effetively minimal dose(10mg/d)6-12m

• Children
• 2mg/kg/dlt60mg/d8-12w
• 10reduction/1-2w
• Effetively minimal dose(10mg/d)6-12m

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Treatment (2)

• Cytotoxic therapy
• For patients with more relapses,
  steroid-dependant or steroid-resistant
• Cyclophosphamide
• 2mg.kg-1.d-1 total dose 6-8g side-effects
• Chlorambucil (?????)
• 0.1-0.2mg/kg/d for 8 weeks

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Treatment(3)

• Cyclosporine
• Selectively inhibits Th, Tc
• As the second line medication to treat patients
  with steroid-resistant, frequently
  relapsing/steroid-dependent MCD
• 5 mg .kg-1.d-1 for 8-12 weeks, then tapering
• Side effects

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Treatment (4)

• Other medications MMF
• General therapy
• Symptomatic treatment
• Chinese medicine

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Mesangial proliferative glomerulonephritis(MsPGN,
??????????)
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Overview and Terminology

• MsPGN is a morphlogic entity and characterized by
  glomerular mesangial hypercellularity
• This morphologic definition includes many
  well-characterized GNs (IgA nephropathy,
  Henoch-Schonlein purpura nephritis, lupus
  nephritis and others)
• When these well-defined entities are diagnosed
  and excluded, the resuliting are known as MsPGN
  or non-IgA MsPGN

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Pathogenesis

• Unclear
• Possibly due to immune complex depositon and
  complement fixation
• Altered mesangial function may play an active role

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Clinic presentation

• More in adolescents and young adults, more male
  patients
• 50 of patients with a pre-episode of upper
  respiratory tract infection
• 70 of patients with hematuria
• Some patients with mild hypertension, azotemia
• Accounting for 20-25 of renal biopsed patients
  and 30 of primary NS

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Histopathology

• LM
• Varying degrees of mesangial hypercellularity
  with an increase in mesangial matrix
• IM
• IgG, IgM, C3 deposition in mesangial region
  and/or in capillary wall in granular pattern
• EM
• Elctron-dense deposits in the mesangium

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Differential diagnosis

• Clinical presentation
• Renal biopsy
• Exclusion of the secondary GN and other primary
  glomerulopathies (IgA nephropathy)

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Treatment

• Therapy for MsPGN not-defined
• Efficacy of steroid or cytotoxic therapy depends
  on the degree of pathologic injury
• Other medications (ACEI /ARB /Chinese medicine)

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Membranous Nephropathy(MN, ????)

• Overview and Terminology
• Most common pattern of idiopathic NS in adults,
  less common than MCD in children
• 15-25 of MN adult patients with no associated
  systemic illnesses
• Up to 30 of MN patients with associated systemic
  illnesses(SLE,HBV,tumors)

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Pathogenesis

• Immune complex formation in situ at the
  subepithelial capillary wall
• Deposition of circulating immune complexes
• Complement activation ?proteinuria

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Clinical presentation

• Heavy proteinuria in more than 80 of patients
  with full expression of NS
• 30 of patients with microscopic hematuria
• More male patients and more severe
• 80-90 of patients old than 30 years at
  diagnosis
• The older the patients, the greater possibility
  of malignancy
• Most common pattern of NS associated with venous
  thromboses

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Histopathology

• Usually classified as four stages
• LM capillary walls thickened with
  subepithelial projections (Spikes)
• IM strong granular capillary wall
  staining for IgG, C3
• EM subepithelial electron-dense
  deposits all along the capillary walls

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Diagnosis(1)

• Based on histological findings in patients whose
  history, physical examination and appropriated
  laboratory tests exclue the likelihood of a
  secondary cause

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Diagnosis(2)

• Following lab tests negtive or normal
• Antinuclear Ab
• Anti-DNA Ab
• Rheumatoid factor
• Glycosylated HB
• Hepatitis Ag or Ab
• Carcinoembryonic Ag
• cryoglobulins

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Treatment (1)

• Treatment of idiopathic MN remains
  controversial and should be individualized
• SteroidsCytotoxic (ponticelli protocol)

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Ponticelli protocol

• Months 1, 3, 5 methylprednisone 1.0 iv qd3d

• Months 2, 4, 6 chlorambucil 0.2mg/kg/d

• then methylprednisone 0.4mg/kg/d27d

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Treatment (2)

• Immune inhibition agents(MMF,??)
• ACEI/ARB
• Other therapies (anticoagulation)

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Focal segmental glomerulosclerosis(FSGS,
??????????)
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Terminology

• Focal vs diffuse
• Some glomeruli involved (focal)
• All glomoruli involved (diffuse)
• Segmental vs global (dealing with individual
  glomerulus)
• Only part of the glomerulus involved (segmental)
• Whole golmerulus involved (global)

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Overview

• Accounting for less than 15 of cases of
  idiopathic NS in children, but more in adults
• Hematuria,hypertension and GFR?often found in
  patients at presentation

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Pathogenesis

• Loss of renal mass( compensatory theory)
• GEC injury
• RAS activation
• Cytokine overproduction(TGF-ß)

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Clinical presentaion

• Most patients with idiopathic FSGS present with
  asymptomatic proteinuria or full NS
• Detection of asympotomatic cases occurs often at
  physicals
• Patients with NS present with edema

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Histopathology

• LM focal segmental distribution of sclerosis
  (mesangial matrix ?,capillary lumen obliteration,
  adhesion to Bowmans capsule)
• IM IgM and C3 deposition in focal areas(?????)
• EM some or extensive effacement of foot process

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Diagnosis

• Renal biopsy required
• Few glomerular sampling may not find the
  sclerotic glomerulus
• Finding of tubular fibrosis in such biopsy may
  suggest the possibility of unobserved sclerosis
  glomeruli
• Patients thought to have MCD with a poor response
  to steroids or cytotoxic may have FSGS

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Treatment

• FSGS with normal renal function
• More intensive and more prolonged
  immunosuppressive therapy(6-12months, steroid,
  cytotoxic, cyclosporine, MMF)
• ACEI/ARB
• FSGS with GFR decrease
• Follow the therapies for chronic renal failure

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Membranoproliferative glomerulonephritis(MPGN,???
??????)
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Overview and Terminology

• Other terms as mesangiocapillary
  GN(????????????)Lobular GN(????????)Hypocmplem
  entemic GN(??????)
• Secondary conditions are more common than the
  idiopathic forms

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Pathogenesis

• Immune complex deposition in the mesangial and
  capillary wall ?C activation(for MPGN type ?)
• MPGN type ?does not appear to involve immune
  complex, but rather utilize some other mechanism
  for C activation

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Clinical presentation

• Less common entity of NS, but if it occurs, most
  in children and young adults
• Patients present with Nephrotic (type ?, 2/3 slow
  progression), Nephritic(type ?, 5, aggressive)
  or in combination features
• Preceding upper respiratory infection and
  persistent proteinuria, hematuria,
  hypocomplementemic, anemia indicate an incidence
  of MPGN

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Histopathology

• LM marked mesangial proliferation and
  thickening of GBM, glomrular lobularity, double
  contours(tram-tracks)
• IM IgG and C3 granular deposits in mesangium
  and capillary walls
• EM subendothelial and mesangial electron-dense
  deposits

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Diagnosis

• Clinical features
• Persistent hypocomplementemia, anemia not
  compatible with renal damage, nephrotic with
  hemoturia, early hypertension and GFR?
• Renal biopsy with exclusion of secondary MPGN

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Treatment and prognosis

• Effective therapy needed
• Steroid and cytotoxic maybe effective on some
  younger age patients
• Symptomatic therapies( anticoagulation)
• Renal function protecting therapies
• Poor prognosis, 50of patients following 10 year
  course progress to ESRD

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? ?

• ?????????
• ???gt3.5g/d
• ???????30g/L
• ??
• ????
• 1,2???NS???

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?????????

• ???
• ???????(MCD)
• ??????????(MsPGN)
• ????(MN)
• ??????????(FSGS)
• ?????????(MPGN)

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• ????????,?????,????
• ????LM??,IM(-),EM???????
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????

• ???????????,????,????????,???????
• ????LM ???????,GBM?? IM IgG,C3?????? EM
  GBM????????,????
• ????????????????????? (ponticelli??)
  ??????,?20-35???????????

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• ???????????????????????GFR?
• ????LM ??????IM IgM,C3??????,EM
  ?????????
• ?????????????????,???????

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• ????LM ?????????,??????,???IM
  IgG,C3??????????????EM ?????????????
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• ????????????,??????(???????),???
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??

• ?????
• ?????
• CTX
• MMF
• CsA?FK506
• ????(???)
• ?????

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Questions

• This 5-year-old boy has 4 protein in his urine
  on stick testing. His serum albumin is 21g/L.
  What is the most likely diagnosis?

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• These picture are from the renal biopsy of a
  60-year-old man who presented with nephrotic
  syndrome. What is the diagnosis?

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• How to treat minimal change disease patients with
  steroid?

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Thank You!