Approach to Rapidly Progressive Glomerulonephritis RPGN

Clinical Approach to Rapid Progressive Glomerulonephritis

Dr Garima Aggarwal- DM Nephrology

- Amrita Institute of Medical Sciences,- Kochi, India

08.05.14

Rapidly Progressive Glomerulonephritis (RPGN) Refers to a clinical syndrome characterized by a Rapid loss of renal function, Oliguria or anuria, Features of glomerulonephritis

dysmorphic erythrocyturia, erythrocyte cylindruria, glomerular proteinuria.

• RPGN – morphologically - extensive crescent formation.

• The severity of the disease -degree of crescent formation.

• nonspecific response to severe injury to the glomerular capillary wall .

• Rents are induced in the glomerular capillary wall- movement of plasma products, including fibrinogen, into Bowman's space with subsequent • fibrin formation, • the influx of macrophages and T cells,• release of proinflammatory cytokines-IL-1 and TNF a

CRESCENTIC GN

Normal Kidney

Crescent

Normal glomerulus

TYPES OF RPGN — Type 1: Anti-GBM antibody disease Type 2: Immune complex —

• IgA nephropathy• postinfectious glomerulonephritis• lupus nephritis• cryoglobulinemia.

Type 3: Pauci-immuneANCA-positive- Wegener’s, microscopic polyangiitis or

Churg StrausANCA-negative, pauci-immune RPGN

Type 4: Double-antibody positive disease — Type 4 has features of both types 1 and 3. Idiopathic*

Rapid Progressive Renal Failure?

Acute – HOURS TO DAYS ; <2 weeks●An increase in serum creatinine of ≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours;●An increase in serum creatinine of ≥1.5 times baseline, which is known or presumed to have occurred within the prior seven days; or●Urine volume <0.5 mL/kg per hour for more than six hours

Chronic - WEEKS TO MONTHS ; >3months• Glomerular filtration rate (GFR) <60 mL/min per 1.73 m2 or• evidence of kidney damage - albuminuria or abnormal findings

on renal imaging have been present for three months or more.

Types of Renal Failure (DURATION)

• The clinical diagnosis of these cases may be called Rapidly Progressive Renal Failure (RPRF), which may be defined as progressive renal impairment over a period of DAYS TO FEW WEEKS.

• ~ 2weeks to 3 months• heterogeneous group of clinical syndromes• ‘Renal Emergency’• may progress to irreversible end-stage renal

disease (ESRD) needing life-long renal replacement therapy

RPRF

TUBULO INTERSTITIAL

GLOMERULAR

VASCULAR

ATINATNMYELOMA

KIDNEY

RPGN Atheroembolic renovascular dis.

B/L Renal Vein thrombosis

TMA – HUS/TTP Mal. HTN Sys. Sclerosis

APLA

RARELY – Occult viscera sepsis, Sarcoidosis, Obstructive Nephropathy

Clinical Approach?

HISTORYRPRF vs CKD vs AKIHistory of hematuria, frothing of urine, HTN,

Oliguria/Anuria, progressive renal failure SYSTEMIC FEATUREShemoptysis, longstanding asthma or petechiae is

suggestive of vasculitisarthralgia, oral ulcers or photosensitivity indicates

presence of lupus. Backache, fractures or bone pains - multiple

myeloma. Recent Drug history, fluid loss, sepsis Long-standing history of DM/ HTN

PHYSICAL EXAMINATIONPallor – s/o CKD*, Normal/ High BP. - TMA and renal artery stenosis. Oral ulcer or butterfly rash is indicative of lupusSkin petechiae may indicate lupus or vasculitisEvidence of atheroembolic disease Upper Respiratory tract involvement – sinuses*RS – signs of asthma/alveolar hmgheCNS- peripheral neuropathy

ROUTINE INVESTIGATIONS

CBCLeucocytosis – Sepsis, vasculitis, TE disEosinophilia – Churg StraussTCP – HUS/TTP, TMAPeripheral smear – fragmented RBCs - TMA

URINE ANALYSISDysmorphic RBCS, active sediments, Rbc casts,

Sub Nephrotic Proteinuria – Vasculitis, Lupus – RPGN

Isomorphic RBCs , Eosinophiluria – AIN, TE disNephrotic Range proteinuria – causes other

than RPGN

Hypercalcemia – Sarcoidosis, MyelomaRaised LDH – TMALow complements – Lupus Nephritis,

Cryoglobulinemia, PSGN(C4 normal)Raised ESR, CRP – Vasculitis, SLEHBsAg – MPGN , Vasculitis Hepatitis C – MPGN, VasculitisChest X ray – cavities/nodules – ANCA ass

systemic vasculitis

SEROLOGICAL TESTSANA, APLA – Lupus Nephritis, APLAANCA – Pauci Immune GNAnti GBM – Goodpasture’s Syndrome/Anti GBM disASLO, Anti DNAse- PSGNCryoglobulins- CryoglobulinemiaAnti Scl70 – Systemic sclerosis

Rapid progressive renal failureSystemic features – Pulmonary renal/ rashes/

peripheral neuropathy/ flu like syndromeHematuria, sub nephrotic proteinuria, active

urinary sedimentLow complementsANCA/ ANA/ Anti GBM/ ASLO – positive

Renal Biopsy

Renal Biopsy findings

LIGHT MICROSCOPY• Hallmark lesions – Crescents• Cellular, fibro cellular, fibrous• Lesions usually in various

stages of activity/ resolution• Necrotising inflammation-10%• Fibrinoid necrosis, peri

glomerular granulomas • (RPGN III) Anti-GBM glomerulonephritis

with a large cellular crescent forming a cap over the glomerular tuft

IMMUNOFLUORESCENCERPGN I RPGN II RPGNIII(Anti GBM) (IC mediated) (pauci immune)

Linear staining Granular mild or absentIgG and C3 glomerular glomerular tuft staining staining

Diff Igs +/orcomplements

linear staining for IgG - diffuse binding of anti-GBM Ab

Granular staining on IF in PSGN

Scanty Background staining of puaci immune

ELECTRON MICROSCOPY

• RPGN I and III – absence of electron dense immune complex deposits

• RPGN II – Multiple electron dense deposits

Anti GBM Disease EM – Absence of electron dense IC deposits with distinct breaks in the GBM – triggering crescent formation

MPGN showing several electron dense IC deposits subepithelial and sub endothelial

RPGNClinical/serology/Bx

Linear IF, IgGAnti GBM +ve

Granular IF, immune complexAnti dsDNA, ANA/ Low C3-C4/ IgA/ ASLO, etc +ve

No IF,ANCA +ve

Lung Hmrhge

YES

Goodpasturesyndrome

Anti GBM GN

NO

RPGNClinical/serology/Bx

Granular IF, immune complexAnti dsDNA, ANA/ Low C3-C4/ IgA/ ASLO, etc +ve

No IF,ANCA +ve

IgA Acute MPGN OthersStaph/strepinfection Mesangio DD Sub others

No Systemic Cap. EpithelialVasc. VasculitisIgA HSP PSGN MPGN I MPGN II MN SLE, etc

RPGNClinical/serology/Bx

No IF,ANCA +ve

Sytemic vasculitis No Systemic features

ANCA GNVasculitis with Granulomas EosinophiliaNo asthma or No asthma Granulomasgranulomas AsthmaMicroscopic Wegeners Churg-StraussPolyangitis Garnulomatosis Granulomatosis

RPGN Type I: Anti GBM Disease

• Cells accumulate in Bowman’s space, form crescents.

• Peptides within the noncollagenous portion of the α3-chain of collagen type IV.

• What triggers the formation of these antibodies is unclear in most patients.

• There is linear deposition of antibodies and complement components along the GBM.

RPGN Type I: Goodpasture’s Syndrome

• The anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated with renal failure.

•Patchy parenchymal consolidations are present, which usually are •bilateral, symmetric perihilar, and bibasilar. •The apices and costophrenic angles usually are spared

Pauci immune vasculitis• A group of small vessel vasculitis related to

ANCA.• Can be renal limited/systemic.• Systemic –microscopic polyangitis,Wegener’s

granulomatosis,Churg Strauss syndrome.• Wegener’s-Granulomatous inflammation +

necrotizing vasculitis.• Churg Strauss-Eosinophil-rich and

granulonatous inflammation + necrotizing vasculitis.

• Microscopic polyangitis-necrotizing vasculitis.

Wegener’s Granulomatosis

Microscopic Polyangitis

Churg- strauss Syndrome

Microscopic polyangitis

Wegener’sGranulom-atosis

Churg Strauss

Kidney +++ ++ +

Skin ++ ++ +++

Lungs ++ +++ ++

Neurological + ++ +++

URT + +++ +

cANCA pANCA Negative

W.G 70 % 25 % 5%

Mic.polyangitis

40% 50 % 10 %

Churg Str. 10 % 60 % 30 %

Pauci immune GN

20 % 70 % 10 %

C-ANCA on ethanol fixed slide

P-ANCA on ethanol fixed slide

C-ANCA is identified as a positive result when there is intense positive granular staining of the cytoplasm that extends to the border of the human granulocyte substrate displaying a 1+ or greater fluorescence and there is absence of nuclear staining

P-ANCA exhibits intense positive perinuclear staining of the multi-lobed nucleus with a poorly defined cell border. A 1+ or greater fluorescence is considered a positive result

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