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

GEC: glomerular endotelial and epitelial cells

= „membrane attack

complex“)

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 GN1. 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)

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

Treatment of primary GN - conclusions

1. Patients with primary GN are threatened with:a. complications of NSb. 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)

Normal glomerulusMembranous GN

(MGN)

FSGS

Basement

membrane

Epitelial

cells=podocytes

Mesangial

cells

Endothelial

cells

Urinary

space

Capllary

lumenMinimal chenge nephropathy

(MCN)Nonproliferative GNNonproliferative GN

Fusion of

pedicels

Subepithelial

deposits

Sclerotisation of the loops

(here in perihilar region)

Glomerular permeability and proteinuria

Normal,,,, glomerulus

Basement

membrane

Epithelial cells =

podocytes

Mesangial

cells

Endothelial

cells

Urinary

space

Capillary

lumen 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)

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).

Interpedicellar space = slit diaphragma and the scheme showing possible anchoring of nephrin in this domain.

Slit diaphragma Nephrin

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

Lignt microscopy (LM): normal glomerulus or weak

mesangial hypercellularity (<5%),

Electrone microscopy (EM): fusion of

pedicels, microvilous changes

Fusion of pedicels Mikrovilous 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 TGF1 (expression of TGF1 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 patientsdo develop full remission of proteinuria during 8

– 12 weeks of treatment (in adults within 16 weeks)

2. Cortico (steroid) dependant patientsdo 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. 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.

2. Relapses should be treated in the same regime3. In patients suffering from frequent relapses or

corticosteroid-dependent patients to give the treatment:Cyclophosphamide 2 mg/kg/day for a period of 8 weeksor 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 commonTip lesion FSGS: more often

corticosensitive ?

Collapsing FSGS: rare variant, often

secondary (HIV)

Etiology of FSGS1. Primary FSGS

a. perihilar variantb. „tip“lesion

2. Secondary FSGSa. 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 FSGSimpairment of morphrology/function podocytar proteins (podocin, -actinin, CD2AP, and other)

2. Circulating permeabile factor/sa. immunoglobulin, or Ig-like moleculeb. 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 urineapolipoproteins 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 syndrome2. 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)

Korbet, NDT, 1999, 14 (Suppl. 3): 68 - 73

Cumulative renal survival in FSGS

Presence of NS Renal function Response to therapy

Therapy of FSGS

1. 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.

2. 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

3. Cytotoxic agents are drugs of 2nd line, evidence of their efficacy are not convincing

Membranous nephropathy (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

Notice: mesangial

(event.

subendothelial)

deposits are found in

secondary MGN

Event. We recognize stage V – reparation of epithel

Membranous GN– histological findings

Light microscopy (LM): thickened BM

Electrone microscopy (EM): demonstration of deposits, or event. „spikes“(BM)

GBM surrounds subepithelial

deposits (picture of „spikes“)

Subepithelial immunocomplexe

deposits (D)

Immunofluorescence (IF): diffuse granular positivity of

IgG, event. C3. (= sign of activity?).

GBM surrounds subepithelial

deposits (pictureof „spikes“)

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 frequent4. 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

Ponticelli et al., NEJM, 1992Torres et al., Kidney Int., 2002, 61: 219 - 227

Conservative versus IS therapyIS therapy: Prednisone vs Prednisone +

alkylating agents

Immunosupression

Conservative

treatment

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 monotherapy3. 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.

Guideline for the treatment of IMGN

Cattran, Kidney Int., 2001, 59: 1983 - 1994

Proliferative versus neproliferative GN (glomerular capillary loop – ultrastructural changes)

Normal glomerulus

Mesangioproliferative GN

Proliferative GNProliferative GN

Basal

membrane

Epitheliál

cells=podocytes

Mesangial

cells

Endotehelial

cells

Urinary

space

Capillary

lumen

neutrophils

Acute GN

Membranoproliferative GN

Increased number and

proliferation of mesangial

cells

Increaed number

and proliferation

of mesangial cells

to distal parts of

capillary loop

Subendothelial deposits

mesangial deposits of IgA

neutrophils

Subendothelial

deposits

Subepithelial deposits

Increased number and

proliferation of mesangial

cells