Clinical approach to Rapidly Progressive Renal failure and Rapidly Progressive Glomerulonephritis. Diagnosing crescentic Glomerulonephritis and Pauci immune vasculitis syndromes - churg strauss, wegeners and good pasture syndromes

1. 08.05.14
Clinical Approach
to
Rapid Progressive
Glomerulonephritis
Dr Garima Aggarwal
- DM Nephrology
- Amrita Institute of Medical Sciences,
- Kochi, India

2. 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.

3. CRESCENTIC GN
• 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

5. Normal Kidney
Crescent
Normal
glomerulus

6. TYPES OF RPGN —
Type 1: Anti-GBM antibody disease
Type 2: Immune complex —
• IgA nephropathy
• postinfectious glomerulonephritis
• lupus nephritis
• cryoglobulinemia.
Type 3: Pauci-immune
ANCA-positive- Wegener’s, microscopic polyangiitis or
Churg Straus
ANCA-negative, pauci-immune RPGN
Type 4: Double-antibody positive disease — Type 4 has
features of both types 1 and 3.
Idiopathic*

7. Rapid Progressive
Renal Failure?

8. Types of Renal Failure
(DURATION)
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.

9. • 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

10. RPRF
TUBULO
INTERSTITIAL
GLOMERULAR VASCULAR
ATIN
ATN
MYELOMA
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

11. Clinical Approach?

13. HISTORY
RPRF vs CKD vs AKI
History of hematuria, frothing of urine, HTN,
Oliguria/Anuria, progressive renal failure
SYSTEMIC FEATURES
hemoptysis, longstanding asthma or petechiae is
suggestive of vasculitis
arthralgia, 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

14. PHYSICAL EXAMINATION
Pallor – s/o CKD*,
Normal/ High BP. - TMA and renal artery stenosis.
Oral ulcer or butterfly rash is indicative of lupus
Skin petechiae may indicate lupus or vasculitis
Evidence of atheroembolic disease
Upper Respiratory tract involvement – sinuses*
RS – signs of asthma/alveolar hmghe
CNS- peripheral neuropathy

15. ROUTINE INVESTIGATIONS
CBC
Leucocytosis – Sepsis, vasculitis, TE dis
Eosinophilia – Churg Strauss
TCP – HUS/TTP, TMA
Peripheral smear – fragmented RBCs - TMA

16. URINE ANALYSIS
Dysmorphic RBCS, active sediments, Rbc casts,
Sub Nephrotic Proteinuria – Vasculitis, Lupus –
RPGN
Isomorphic RBCs , Eosinophiluria – AIN, TE dis
Nephrotic Range proteinuria – causes other
than RPGN

17. Hypercalcemia – Sarcoidosis, Myeloma
Raised LDH – TMA
Low complements – Lupus Nephritis,
Cryoglobulinemia, PSGN(C4 normal)
Raised ESR, CRP – Vasculitis, SLE
HBsAg – MPGN , Vasculitis
Hepatitis C – MPGN, Vasculitis
Chest X ray – cavities/nodules – ANCA ass
systemic vasculitis

18. SEROLOGICAL TESTS
ANA, APLA – Lupus Nephritis, APLA
ANCA – Pauci Immune GN
Anti GBM – Goodpasture’s Syndrome/Anti GBM dis
ASLO, Anti DNAse- PSGN
Cryoglobulins- Cryoglobulinemia
Anti Scl70 – Systemic sclerosis

19. Rapid progressive renal failure
Systemic features – Pulmonary renal/ rashes/
peripheral neuropathy/ flu like syndrome
Hematuria, sub nephrotic proteinuria, active
urinary sediment
Low complements
ANCA/ ANA/ Anti GBM/ ASLO – positive
Renal Biopsy

20. 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

21. IMMUNOFLUORESCENCE
RPGN I RPGN II RPGNIII
(Anti GBM) (IC mediated) (pauci immune)
Linear staining Granular mild or absent
IgG and C3 glomerular glomerular tuft
staining staining
Diff Igs +/or
complements

22. linear staining for IgG -
diffuse binding of anti-
GBM Ab
Granular staining on IF in
PSGN
Scanty Background
staining of puaci
immune

23. ELECTRON MICROSCOPY
• RPGN I and III – absence of electron dense
immune complex deposits
• RPGN II – Multiple electron dense deposits

24. 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

25. RPGN
Clinical/serology/Bx
Linear IF, IgG
Anti GBM +ve
Granular IF,
immune complex
Anti dsDNA, ANA/
Low C3-C4/ IgA/
ASLO, etc +ve
No IF,
ANCA +ve
Lung Hmrhge
YES
Goodpasture
syndrome
NO
Anti GBM
GN

26. RPGN
Clinical/serology/Bx
Granular IF,
immune complex
Anti dsDNA, ANA/
Low C3-C4/ IgA/
ASLO, etc +ve
No IF,
ANCA +ve
IgA Acute MPGN Others
Staph/strep
infection Mesangio DD Sub others
No Systemic Cap. Epithelial
Vasc. Vasculitis
IgA HSP PSGN MPGN I MPGN II MN SLE, etc

27. RPGN
Clinical/serology/Bx
No IF,
ANCA +ve
Sytemic vasculitis No Systemic
features
ANCA GN
Vasculitis with Granulomas Eosinophilia
No asthma or No asthma Granulomas
granulomas Asthma
Microscopic Wegeners Churg-Strauss
Polyangitis Garnulomatosis Granulomatosis

28. 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.

29. 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.

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

31. 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.

32. Wegener’s Granulomatosis

33. Microscopic Polyangitis

34. Churg- strauss Syndrome

35. Microscopic
polyangitis
Wegener’s
Granulom-atosis
Churg
Strauss
Kidney +++ ++ +
Skin ++ ++ +++
Lungs ++ +++ ++
Neurological + ++ +++
URT + +++ +

36. cANCA pANCA Negative
W.G 70 % 25 % 5%
Mic.polyan
gitis
40% 50 % 10 %
Churg Str. 10 % 60 % 30 %
Pauci
immune
GN
20 % 70 % 10 %

37. C-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 on ethanol fixed slide
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

38. THANK YOU..