ANCA-negative Pauci-Immune Glomerulonephritis

Supervisor: VS 楊松昇

Speaker: PGY 陳恩揆

Clerk 陳昱臻

Clinical manifestations of GN

• Hematuria

• Proteinuria

• Renal insufficiency

• Hypertension

• Edema

• Hypercoagulability

• Systemic findings

months

6 weeks

days

Acute GN

RPGN

Chronic GN

Progression

Evaluation of glomerulonephritis

• modest proteinuria (1-4 g/d)

• microscopic hematuria

• RBC and WBC casts.

• Serum C3 and C4

• ANCA(proteinase-3 and myeloperoxidase)

• Anti-GBM Ab

• ANA

• Anti-dsDNA Ab

• HBV, HCV and HIV

• Serum free light chains

Hematuria Proteinuria

• RBC casts or dysmorphic red blood cells

• exclude anatomic lesions, such as BPH or malignancy of the urinary tract, particularly in older men.

• Sustained proteinuria >1–2 g/24 h

• Exclude functional or transient proteinuria(nonsustained, generally <1 g/24 h).

• Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure

Primary/Idiopathic RPGN

• Type 1 (anti-glomerular basement membrane disease)

• Type 2 (immune-complex mediated)

• Type 3 (pauci-immune)

• Type 4 (combinations of types 1 and 3)

• Type 5 (ANCA-negative, pauci-immune renal vasculitis)

Secondary RPGN

• Infectious process

• Secondary to systemic illness

• Drugs use

• Antithyroid agents

• Superimposed on another primary glomerular disease

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The role of neutrophils

• Immunohistochemical staining for neutrophil markers(CD15, myeloperoxidase) was much more prominent in active lesions than in inactive lesions

• the degree of neutrophil infiltration in the glomeruli and interstitium: ANCA(-) > ANCA(+)

• Neutrophil-gelatinase-associated lipocalin and lactoferrin.

• Lipocalin: a specific marker of neutrophil degranulation

• Lactoferrin: a biomarker of neutrophil activation and degranulation

• serum levels of neutrophil-gelatinase-associated lipocalin and lactoferrin: ANCA-negative > ANCA-positive

Neutrophil activation

• Anti-endothelial cell antibodies (AECA) are presented in over 50% of patients (10 of 19) with ANCA-negative pauci-immune crescenti glomerulonephritis. AECA bind to endothelial cells, which could facilitate the interaction of neutrophils with these cells via Fc and C3b receptors on neutrophils.

• Autoantibodies to human lysosomal membrane protein 2 (LAMP2) are present in over 90% of individuals with active pauci-immune focal necrotizing glomerulonephritis. These antibodies can activate neutrophils and cause apoptosis of endothelial cells in vitro.

http://www.ijpmonline.org/article.asp?issn=0377-4929;year=2012;volume=55;issue=1;spage=28;epage=32;aulast=Minz#ref8

https://jasn.asnjournals.org/content/21/10/1628.long

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• Clinical and pathologic characteristics were compared between patients with and without ANCA.

https://jasn.asnjournals.org/content/18/2/599#T3

Compared with ANCA(+) PIGN:

• The level of urinary protein and the prevalence of nephrotic syndrome were significantly higher

• the prevalence of extrarenal involvement was significantly lower in ANCA-negative patients.

• Among all the ANCA(-) PIGN, all of them had hematuria and proteinuria. The level of urinary protein was 5.47 ± 3.32 g/24 h.

Compared with ANCA(+) PIGN:

• the ANCA-negative patients were much younger

• Patients with negative ANCA had a significantly lower percentage of normal glomeruli.

• Among glomeruli with crescent formation, the percentage of cellular crescent tended to be higher in patients with negative ANCA than that in patients with positive ANCA

Treatment

Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014

Induction therapy

• Gold standard: corticosteroids + cyclophosphamide

• Corticosteroids: 1. IV pulse of methylprednisolone(7mg/kg BW/day) for 3 consecutive

days, followed by oral prednisone(1mg/kg BW/day) for the first 4 weeks

2. reduced gradually over the next 3-5 months.

• Cyclophosphamide: 1. Monthly, IV with starting dose of 0.5g/m2 of BSA

2. Oral with initial dose of 2mg/kg BW/day

3. The duration of cyclophosphamide therapy is usually 6-12 months

Indications of plasma exchange

• Pulmonary hemorrhage

• Severe renal dysfunction(serum Cr > 5.66mg/dL or >500 umol/L)

Maintenance therapy

• Azathioprine at a dose of 2 mg/kg of body weight/day

• More patients with AAV had sustained remission at 28 months with rituximab than with azathioprine while the frequencies of severe adverse events were similar in the two groups

Reference

• Clinical journal of American Society: ANCA Glomerulonephritis and Vasculitis

• Nature: ANCA-negative pauci-immune crescentic glomerulonephritis

• Clinical and experimental Nephrology: Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014

• KDIGO Clinical Practice Guideline for Glomerulonephritis(2012)

• Evidence-based clinical practice guidelines for rapidly progressive glomerulonephritis 2014

• Kidney diseases: The Prevalence and Management of Pauci-Immune Glomerulonephritis and Vasculitis in Western Countries

• International journal of Rheumatic disease: Pauci-immune glomerulonephritis: does negativity of anti-neutrophilic cytoplasmic antibodies matters?

• International journal of Rheumatic disease: Pauci-immune glomerulonephritis: the ANCA-negative side of the coin

• Journal of the American Society of Nephrology: Histopathologic Classification of ANCA-Associated Glomerulonephritis

• StatPearls: Crescentric Glomerulonephritis

• UptoDate: Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis

• UptoDate: Glomerular disease: Evaluation and differential diagnosis in adults

Thank you