Primary glomerulonephritides (GN)

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Primary glomerulonephritides (GN)

• Miroslav Merta
• Klinika nefrologie 1. LF a VFN

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Definition of GN, definition of primary GN

• In GN (generally) we find
• an immunological process
• an inflammatory character of glomerular affection
• In primary GN we find
• an isolated affection of kidneys
• Some GN can manifest as well as primary or as
  secondary GN (MGN, MPGN)

3
Mechanisms of glomerular lesions
membrane attack complex)
GEC glomerular endotelial and epitelial cells
PMNs polymorphonuclears
4
Pattern of GN - immunofluorescency

• Immune complexe 85
• Pauci immune 14
• Anti- GBM 1-2

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Inflammatory affection of glomeruliis
characterized by

• Exsudation of neutrophils/macrophages
• Proliferation of mesangial/endothelial cells

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Classification of primary GN

• 1. Non-proliferative GN
• - minimal change nephropathy-disease (MCN)
• - focal segmental glomerular sclerosis
  (FSGS)
• - membranous GN (MGN)
• 2. Proliferative GN
• - Acute GN
• - IgA nefropathy (IGAN)
• - membranoproliferative GN (MPGN)

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Role of renal biopsy in glomerular disease

• 1. Diagnosis of GN
• 2. Assessment of activity of the disease
  important for the decision to treat (intention to
  treat)
• 3. Assessment of chronicity important for the
  prognosis of the disease

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Treatment of primary GN

• Treatment and treatment tactics with well defined
  indications, good clinical experience
• corticosteroids
• cytotoxic agents (CPA, chlorambucil)
• azathioprine
• cyklosporine
• symptomatic treatment
• ACEI ci AT2 receptors blockers,
• Hypolipidemics (statins)

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Treatment of primary GN

• 2. Drugs with limited clinical experience
• mycophenolate
• tacrolimus
• rapamycine
• intravenous immunoglobulins
• monoclonal antibodies
• anti-TNF?infliximab, adalimumab
• anti-CD20rituximab
• solubile cytokine receptors (TNF
  rec.etanercept)
• plasmaexchange

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Treatment of primary GN - conclusions

• Patients with primary GN are threatened with
• a. complications of NS
• b. progression of the disease to ESRF
• Urinary findings important, however renal biopsy
  essential for dg., treatment and prognosis.
• Primary GN are treatable diseases. Patients
  should be treated according to available clinical
  evidence.

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Proliferative versus nonproliferative GN
(glomerular capillary wall ultrastructural
changes)
Urinary space
Fusion of pedicels
Epitelial cellspodocytes
Basement membrane
Subepithelial deposits
Capllary lumen
Minimal chenge nephropathy (MCN)
Endothelial cells
Mesangial cells
Nonproliferative GN
Membranous GN (MGN)
Normal glomerulus
FSGS
Sclerotisation of the loops (here in perihilar
region)
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Glomerular permeability and proteinuria
Urinary space
Epithelial cells podocytes
Mesangial cells
Basement membrane
Capillary lumen
Endothelial cells
Role of nephrin, podocin, actinin in the
structure and function of podocytes and
interpedicellar space (slit diaphragma)
Fusion of pedicels ( lesion of podocytes) is
important for initiation of proteinuria
(probably not only consequence of pru)
Normal,,,, glomerulus
Glomerulární permeabilita a proteinurie
Filtration barrier is formed by endothel
(pores), GBM and interpedicellar processes.
Permeability of proteins through glomerular wall
is influenced by charge (repelling of negatively
charged proteins as albumine by the negative
charge of GEC) a also by the selective
permeability of capillary wall of the glomerulus
in dependence on the size of the particules
sieved (modulated particularly by theslit
diaphragma, and podocytes).
Slit diaphragma
Nephrin
Interpedicellar space slit diaphragma and the
scheme showing possible anchoring of nephrin in
this domain.
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Nonproliferative GN- selectivity of proteinuria

• Impairment of glomerular capillary wall leads to
  
• 1. Selective proteinuria nefrotic range
  minimal change nephropathy (MCN)
• 2. Non-selective proteinuria (associated event.
  with microscopic hematuria)
• - FSGS
• - idiopatic membranous GN

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Relative frequency of primary GN in causes of
nephrotic syndrome (NS) Korbet et al., Am. J.
Kidney Dis., 1996, 27 647 - 651
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Minimal changes of glomeruli (minimal change
disease MCD, minimal change nephropathy MCN)
Fuze pedicel
Minimal changes of glomeruli
Normal glomerulus
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Minimal changes of glomeruli- histological
findings
Fusion of pedicels
Mikrovilous changes
Lignt microscopy (LM) normal glomerulus or weak
mesangial hypercellularity (lt5),
Electrone microscopy (EM) fusion of pedicels,
microvilous changes
Immunofluorescence (IF) weak positivity of IgM,
event. IgA,IgG, C3
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Patogenetic factors involved in the process of
development of minimal changes of glomeruli

1. Circulating soluble permeable factor
   (hemopexin?)
2. Decreased synthesis of glomerular polyanionts
   (heparan sulfate) by podocytes
3. Impairment of adhesion of podocytes on GBM (?
   -dystroglycan, ?1-integrins?)
4. Impairment of expression of TGF?1 (expression of
   TGF?1 observed only in steroid-resistant MCD and
   FSGS)

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Minimal changes of glomeruli basic
characteristics

• Full blown nephrotic syndrome with selective
  proteinuria
• Rarely presence of hematuria, hypertension a
  decrease of kidney function
• Absence of glomerular abnormits in the
  histological (LM, IF) picture.
• Typical picture of damage of epithelial cells
  (fusion of pedicels) in EM

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Minimal changes of glomeruli- prevalence in
patients with NS (dependence on age)

• Children - 85 95
• Adults lt 40 y - 50
• Adults gt 40 y - 20 25

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Classification of patients with MCN in dependance
on the answer to the treatment with
corticosteroids (KS) cortico-sensitivity

• Cortico-sensitive patients
• do develop full remission of proteinuria during
  8 12 weeks of treatment (in adults within 16
  weeks)
• 2. Cortico (steroid) dependant patients
• do develop relapse during the period of
  tapering the dosis of CS or shortly (2 weeks)
  after termination of CS treatment
• 3. Cortico (steroid) resistant
• do not respond to the treatment with CS

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Therapy of MCD in adults

• Initial treatment with prednisone 1mg/kg for a
  period of 8-16 weeks or at least 1 week after
  achievement of remission, thereafter several
  weeks (4) a treatment with dosis of 1 mg/kg in
  alterning interval, thereafter slow withdravel of
  CS (tapering) during a period of several
  months.
• Relapses should be treated in the same regime
• In patients suffering from frequent relapses or
  corticosteroid-dependent patients to give the
  treatment
• Cyclophosphamide 2 mg/kg/day for a period of 8
  weeks
• or CyA 5 mg/kg/day for a period of 6-12 months
• Treatment of CS-resistant patients is not
  usually successful

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FSGS basic histological features (LM)
Light microscopy (LM) only focally (in some
glomeruli especially juxtamedullar ones) a
segmentally (only in some segments of glomeruli)
presence and sclerotisation of glomerular loops,
caused by accumulation of acelular matrix with
adhesions to Bowmans.capsule (hyalinosis). Mild
mesangial hypercelularity may be present,Further
development of FSGS is followed by global
sclerotisation of glomeruli and tubular atrophy
and fibrosis interstitium..
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FSGS basic histological types
Tip lesion FSGS more often corticosensitive ?
Collapsing FSGS rare variant, often secondary
(HIV)
Perihilar FSGS most common
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Etiology of FSGS

• Primary FSGS
• a. perihilar variant
• b. tiplesion
• 2. Secondary FSGS
• a. foci of healing
• b. hyperfiltration in residual nephrones
• - agenesis of kieny
• - vesico-ureteral reflux
• - morbid obesity
• c. injury of epithelial cells
• - HIV nephropathy (collapsing FSGS)
• - heroin nephropathy

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Patogenesis of primary FSGS

• Late manifestation of inborn FSGS
• impairment of morphrology/function podocytar
  proteins
• (podocin, ?-actinin, CD2AP, and other)
• Circulating permeabile factor/s
• a. immunoglobulin, or Ig-like molecule
• b. protein with MW of 30-50 kDa
• c. faktor inhibating NO inducible
  synthasis in mesangial cells (hemopexin)
• 3. Deficit of inhibitors of permeabile factors
  by loss into urine
• apolipoproteins of HDL complexe
• (e.g. apo J, apo E2 and apo E4)

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Mutations of podocytar proteins in FSGS
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Mutations of podocytar genes and their gene
products/proteins
Disease Gene Locus Inheritance Gene Protein
CNF (MIM 256300) 19q13.1 AR NPHS1 Nephrin
SRN1 (MIM 600995) 1q25-q31 AR NPHS2 Podocin
FSGS1 (MIM 603278) 19q13 AD ACTN4 ?-actinin
FSGS2 (MIM 603965) 11q21-22 AD FSGS2 ?
FSGS3 (mouse) (MIM 607832) 6q AD FSGS3 CD2 AP
CNF congenital NS of Finnish type SRN(S)
steroid resistant NS
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Odstranení cirkulujícího permeabilního faktoru
(plasmaferézou, plasmaadsorbcí) u FSGS snižuje
vylucování bílkovin do moci
Dantal et al., NEJM, 1994
Mitwalli et al., NDT, 1998
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Focal segmental glomerulosclerosis - basic
characteristics

• Asymptomatic proteinuria or full blown nephrotic
  syndrome
• Commonly presence of hematuria, hypertension and
  decrease of renal functions
• Slow decrease of renal functions
• - 10y renal survival in 50
• 4. Typical histological finding is focal and
  segmental sclerosis of glomerular tuft

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Factors influencing prognosis in primary FSGS
(presence of NS, renal function, response to
therapy)
Cumulative renal survival in FSGS
Response to therapy
Presence of NS
Renal function
Korbet, NDT, 1999, 14 (Suppl. 3) 68 - 73
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Therapy of FSGS

• Response to CS may increase from 10-30 to 60 by
  prolongation of therapy by higher doses (60
  mg/m2) for a period minimum of 3 months, patients
  should be considered steroid resistant after 6
  mo.
• Cyclosporine may cause a decrease of proteinuria
  and decrease the risk of progression to ESRD
  even in steroid-rezistant patients, the therapy
  should be prolonged (at least 6 mo), relapses
  after withdravel of CyA are frequent
• Cytotoxic agents are drugs of 2nd line, evidence
  of their efficacy are not convincing

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Membranous nephropathy (MGN)
Notice mesangial (event. subendothelial)
deposits are found in secondary MGN
GBM surrounds subepithelial deposits (picture of
spikes)
Subepithelial immunocomplexe deposits (arrows)
Subepithelial deposits loose in EM electrolucent
appearance (they arewash-out), thickened BM
Intramembranous rather than subetelial deposits
Event. We recognize stage V reparation of
epithel
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Membranous GN histological findings
Immunofluorescence (IF) diffuse granular
positivity of IgG, event. C3. ( sign of
activity?).
Light microscopy (LM) thickened BM
GBM surrounds subepithelial deposits (pictureof
spikes)
Subepithelial immunocomplexe deposits (D)
GBM surrounds subepithelial deposits (picture of
spikes)
Electrone microscopy (EM) demonstration of
deposits, or event. spikes(BM)
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Etiology of membranous GN

• Idiopathic MGN
• Secondary MGN (therapy different from therapy of
  idiopthic MGN)
• - infection (hepatitis B, syphilis, malaria)
• - drugs (organic gold, penicillamine, NSAID)
• - tumors (carcinomas, for ex. Ca of coli, lung
  Ca, or gastric Ca, also lymphomas)
• - systemic lupus erythematosus

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Idiopathic membranous GN - basic characteristics

• Membranous GN accounts for 15-25 cases of NS in
  adults
• Proteinuria of nephrotic range is present
  approxiomately in 80 of patients, in the
  remaining subgroup the proteinuria is less
  pronounced
• Microscopic hematuria is frequent
• Hypertension and ESRD are not initial symptoms,
  but may develop during the further course of the
  disease.
• Histology subepithelial deposit leading to
  thickening of GBM

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(Untreated) Idiopatic MGN - high frequency of
spontaneous remissions
Mosconi et al., NEJM, 1993
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Idiopatic membranous GN - natural course of the
disease

• Spontaneous remission develops approximately in
  1/3 of patients
• Nephrotic syndrome outlasts in other 1/3 of
  patients
• Approximately 20-30 of patients do progress to
  ESRD during 20-30 y of follow-up

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Prognosis of IMGN with respect to the
presence/absence of NS
B-renal survival and death
A- renal survival
Bez NS
Bez NS
NS
NS
Yoshimoto et al., Kidney Int., 2004, 65 148 - 153
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Idiopatic MGN efficacy of immunosupressive
(IS) therapy
IS therapy Prednisone vs Prednisone alkylating
agents
Conservative versus IS therapy
Immunosupression
Conservative treatment
Ponticelli et al., NEJM, 1992
Torres et al., Kidney Int., 2002, 61 219 - 227
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Treatment of idiopatic MGN

1. Before starting IS therapy do consider its
   necessity, do exploit the profit of conzervative
   treatment (ACEi, ABR)
2. Cortikosteroids only partially efficient in
   monotherapy
3. Cytotoxic agents (cyclophosphamide, leukerane)
   bring about long-term remission of NS and
   ameliorate renal survival. With regard to serious
   side-effects these agents should be reserved to
   patients with serious involvement/resp. with
   progressing form of MGN
4. Cyklosporine seems to be satisfactory alternative
   to cytotoxic therapy. The impact on proteinuria
   is clear, however the effect on stabilisation of
   disease is questionable. There is concern about
   relapse after withdraval.

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Guideline for the treatment of IMGN
Cattran, Kidney Int., 2001, 59 1983 - 1994
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Proliferative versus neproliferative GN
(glomerular capillary loop ultrastructural
changes)
Subendothelial deposits
Urinary space
Acute GN
Epitheliál cellspodocytes
Basal membrane
Increased number and proliferation of mesangial
cells
neutrophils
Capillary lumen
Proliferative GN
Subepithelial deposits
Endotehelial cells
Mesangial cells
Subendothelial deposits
Increaed number and proliferation of mesangial
cells to distal parts of capillary loop
Normal glomerulus
neutrophils
Increased number and proliferation of mesangial
cells
mesangial deposits of IgA
Mesangioproliferative GN
Membranoproliferative GN