Transcript Primary glomerulonephritides

Primary glomerulonephritides (GN)
Miroslav Merta
Klinika nefrologie 1. LF a VFN
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…)
Mechanisms of glomerular lesions
= „membrane
attack complex“)
GEC: glomerular endotelial and epitelial cells
PMNs: polymorphonuclears
Pattern of GN - immunofluorescency
• Immune complexe – 85%
• Pauci – immune 14%
• Anti- GBM 1-2%
Inflammatory affection of
glomeruli
is characterized by:
•
Exsudation of neutrophils/macrophages
•
Proliferation of mesangial/endothelial cells
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)
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
Treatment of primary GN
1. Treatment and treatment tactics
with well defined indications, good
clinical experience
•
corticosteroids
•
•
•
•
cytotoxic agents (CPA, chlorambucil)
azathioprine
cyklosporine
symptomatic treatment:
– ACEI či AT2 receptors blockers,
– Hypolipidemics (statins)
Treatment of primary GN
2. Drugs with limited clinical experience
•
mycophenolate
tacrolimus
rapamycine
intravenous immunoglobulins
monoclonal antibodies
•
•
•
•
–
–
•
•
anti-TNF=infliximab, adalimumab
anti-CD20=rituximab
solubile cytokine receptors (TNF rec.=etanercept)
plasmaexchange
Treatment of primary GN conclusions
1. Patients with primary GN are threatened
with:
a. complications of NS
b. progression of the disease to ESRF
2. Urinary findings important, however renal
biopsy essential for dg., treatment and
prognosis.
3. Primary GN are treatable diseases.
Patients should be treated according to
available clinical evidence.
Proliferative versus nonproliferative GN
(glomerular capillary wall – ultrastructural changes)
Epitelial
cells=podocytes
Urinary
space
Fusion of
pedicels
Basement
membran
e
Capllary
lumen
Subepithelial
deposits
Minimal chenge nephropathy
(MCN)
Endothelial
cells
Mesangial
cells
Nonproliferative GN
Membranous GN
(MGN)
Normal glomerulus
FSGS
Sclerotisation of the
loops (here in perihilar
region)
Glomerular permeability and proteinuria
Epithelial cells =
podocytes
Urinary
space
Mesangial
cells
Basement
membran
e
Capillar
Endothelial
y lumen
cells
Normal,,,,
glomerulus
Fusion of pedicels (= lesion of
podocytes) is important for
initiation of proteinuria
(=probably not only consequence
of pru)
Role of nephrin, podocin, actinin in the structure
and function of podocytes and interpedicellar
space (=„slit diaphragma“)
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 the„slit
diaphragma“, and podocytes).
Slit diaphragma
Nephrin
Interpedicellar space = slit diaphragma and the scheme showing possible anchoring of nephrin in this domain.
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
Relative frequency of primary GN in causes of
nephrotic syndrome (NS)
Korbet et al., Am. J. Kidney Dis., 1996, 27: 647 - 651
Minimal changes of glomeruli
(minimal change disease – MCD,
minimal change nephropathy – MCN)
Fůze pedicel
Normal glomerulus
Minimal changes of glomeruli
Minimal changes of glomeruli
- histological findings
Fusion of pedicels
Lignt microscopy (LM): normal glomerulus or weak
mesangial hypercellularity (<5%),
Mikrovilous
changes
Electrone microscopy (EM): fusion
of pedicels, microvilous changes
Immunofluorescence (IF): weak positivity of IgM, event. IgA,IgG, C3
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)
Minimal changes of glomeruli
– basic characteristics
1. Full blown nephrotic syndrome with
selective proteinuria
2. Rarely presence of hematuria,
hypertension a decrease of kidney
function
3. Absence of glomerular abnormits in the
histological (LM, IF) picture.
4. Typical picture of damage of epithelial
cells (fusion of pedicels) in EM
Minimal changes of glomeruli
- prevalence in patients with NS
(dependence on age)
Children
- 85 – 95%
Adults < 40 y
- 50%
Adults > 40 y
- 20 – 25%
Classification of patients with MCN in
dependance on the answer to the treatment with
corticosteroids (KS) – cortico-sensitivity
1. 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
Therapy of MCD in adults
1.
2.
3.
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
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
Bowman´s.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..
FSGS – basic histological types
Perihilar FSGS: most common
Tip lesion FSGS: more
often corticosensitive ?
Collapsing FSGS: rare variant,
often secondary (HIV)
Etiology of FSGS
1. Primary FSGS
a. perihilar variant
b. „tip“lesion
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
Patogenesis of primary FSGS
1. Late manifestation of inborn FSGS
impairment of morphrology/function podocytar
proteins
(podocin, -actinin, CD2AP, and other)
2. 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)
Mutations of podocytar proteins in FSGS
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
Odstranění cirkulujícího permeabilního faktoru
(plasmaferézou, plasmaadsorbcí) u FSGS snižuje
vylučování bílkovin do moči
Dantal et al., NEJM, 1994
Mitwalli et al., NDT, 1998
Focal segmental glomerulosclerosis
- basic characteristics
1. Asymptomatic proteinuria or full blown
nephrotic syndrome
2. Commonly presence of hematuria,
hypertension and decrease of renal
functions
3. Slow decrease of renal functions
- 10y renal survival in 50%
4. Typical histological finding is focal and
segmental sclerosis of glomerular tuft
Factors influencing prognosis in primary FSGS
(presence of NS, renal function, response to therapy)
Cumulative renal survival in FSGS
Presence of NS
Renal function Response to therapy
Korbet, NDT, 1999, 14 (Suppl. 3): 68 - 73
Therapy of FSGS
1.
2.
3.
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
Membranous nephropathy (MGN)
Notice: mesangial
(event.
subendothelial)
deposits are found
in secondary MGN
Subepithelial immunocomplexe
deposits (arrows)
GBM surrounds subepithelial
deposits (picture of „spikes“)
Subepithelial deposits loose in EM
electrolucent appearance (they
are“wash-out“), thickened BM
„Intramembranous„ rather
than subetelial deposits
Event. We recognize stage V – reparation of
epithel
Membranous GN
– histological findings
Light microscopy (LM): thickened BM
Immunofluorescence (IF): diffuse granular
positivity of IgG, event. C3. (= sign of activity?).
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)
Etiology of membranous GN
1. Idiopathic MGN
2.
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
Idiopathic membranous GN
- basic characteristics
1. Membranous GN accounts for 15-25% cases
of NS in adults
2. Proteinuria of nephrotic range is present
approxiomately in 80% of patients, in the
remaining subgroup the proteinuria is less
pronounced
3. Microscopic hematuria is frequent
4. Hypertension and ESRD are not initial
symptoms, but may develop during the
further course of the disease.
5. Histology – subepithelial deposit leading to
thickening of GBM
(Untreated) Idiopatic MGN
- high frequency of spontaneous remissions
Mosconi et al., NEJM, 1993
Idiopatic membranous GN
- natural course of the disease
1. Spontaneous remission develops
approximately in 1/3 of patients
2. Nephrotic syndrome outlasts in other
1/3 of patients
3. Approximately 20-30% of patients do
progress to ESRD during 20-30 y of
follow-up
Idiopatic MGN
– efficacy of immunosupressive (IS) therapy
Conservative versus IS therapy
IS therapy: Prednisone vs
Prednisone + alkylating agents
Immunosupression
Conservative
treatment
Torres et al., Kidney Int., 2002, 61: 219 - 227
Ponticelli et al., NEJM, 1992
Treatment of idiopatic MGN
1.
2.
3.
4.
Before starting IS therapy do consider its necessity, do
exploit the profit of conzervative treatment (ACEi, ABR)
Cortikosteroids only partially efficient in monotherapy
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
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.
Guideline for the treatment of IMGN
Cattran, Kidney Int., 2001, 59: 1983 - 1994
Proliferative versus neproliferative GN
(glomerular capillary loop – ultrastructural changes)
Epitheliál
cells=podocytes
Urinary
space
Basal
membran
e
Capillar
y lumen
Subendothelial
deposits
Acute GN
Increased number and
proliferation of
mesangial cells
neutrophils
Proliferative GN
Subepithelial deposits
Endotehelial
cells
Mesangial
cells
Increaed
number and
proliferation of
mesangial cells
to distal parts
of capillary loop
Normal glomerulus
Increased number and
proliferation of
mesangial cells
mesangial deposits of IgA
Mesangioproliferative
GN
Subendothelial deposits
neutrophils
Membranoproliferative
GN