Post on 31-May-2015
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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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