Postinfectious glomerulonephritis

Ali Düzova

M.D., Professor of Pediatrics

Division of Pediatric Nephrology

Hacettepe University Faculty of Medicine, Ankara, Turkey

The 2nd IPNA-ESPN Master for Junior Classes,

01-02 September 2015, Leuven

Hacettepe University Ankara

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Outline

• Definition

• Epidemiology

• Pathogenesis

• Clinical features and pathology

• Management

– Evidence?

• Outcome

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Definition

• Postinfectious glomerulonephritis (GN) – “…. is an immune mediated glomerular injury that occurs as a result of

host response to an extrarenal infection”1

• Following terms are often, and incorrectly, used interchangeably 2 – Acute post-streptococcal GN (PSGN)

– Acute nephritic syndrome

– Acute glomerulonephritis

Kambham N. Adv Anat Pathol 2012;19:338–347.1

Rodriguez-Iturbe B, Mezzano S. Pediatric Nephrology, 6th edn.2

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Etiological Agents Associated with Acute Postinfectious Glomerulonephritis

Bacterial Viral Fungal Parasites

Streptococcus group A, C, G Streptococcus viridans Staphylococcus (aureus, albus) Pneumococcus Neisseria meningitidis Mycobacteria Salmonella typhosa Klebsiella pneumoniae Escherchia coli Yersinia enterocolitica Legionella Brucella melitensis Treponema pallidum Corynebacterium bovis Actinobacilli Cat-scratch bacillus

Coxsackievirus Echovirus Cytomegalovirus Epstein-Barr virus Hepatitis B, C HIV Rubella Measles Varicella Vaccinia Parvovirus Infl uenza Adenovirus Rickettsial scrub typhus

Coccidioides immitis Plasmodium malariae Plasmodfalciparum Schistosoma mansoniium Toxoplasma gondii Filariasis Trichinosis Trypanosomes

Tasic V. Acute Postinfectious GN. In: Comprehensive Pediatric Nephrology, 2009

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Epidemiology

• Sporadic, epidemic

• Poor communities, deficient hygienic conditions

• A decline in industrialized countries in the past three decades – Living conditions

– Fluorination of water

• Streptococcus pyogenes are reduced

– Access to health facilities

• Central Europe – Adult population; alcoholism, diabetes

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• Decreasing incidence – The Italian Biopsy Registry

• PSGN – Adult, > 60 year: 0.9 patients/million versus 0.4 patients/million – Children <15 year:

» 1987-1992: 2.6-3.7% of primary glomerulopathies » 1992-1994: only 9 cases

– Maracaibo, Venezuela – 1980-1985: 90-110 cases/year – 2001-2005: 15 cases/year

– Guadalajara, Mexico – Memphis, TN

• Communities with low socioeconomic status – Aboriginal communities – Valencia, Venezuela: 70% of admissions in a pediatric nephrology service – India: 73% of acute GNs in elderly

Epidemiology

Rodriguez-Iturbe B, Musser JM. The Current State of Poststreptococcal GN. JASN 2008; 19: 1855–1864.

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0

10

20

30

40

50

60

Hypoxic/ishemic injury Sepsis Acute gastroenteritis Acute glomerulonephritis Malignancy

1980s

2006-07

Acute kidney injury in children in Turkey

Gokalp et al. Ann Trop Paediatr 1991; 11: 119–121 Duzova et al. Pediatr Nephrol 2010; 25: 1453-1461

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Rodriguez-Iturbe B, Musser JM. The Current State of Poststreptococcal GN. JASN 2008; 19: 1855–1864.

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Carapetis JR et al. The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5: 685–694.

•95% less developed countries •Mortality rate: 1% •5,000 death/year

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Clinical features

• Age, gender – 4-14 years – Rare: < 2 years and >20 years – M/F : 2/1

• Antecedent infection, latent period – Skin 3-5 weeks – Upper resp. 1-2 weeks

• Clinical course – Subclinical – Acute nephritic syndrome – Nephrotic syndrome – Rapidly progressive (crescentic) GN (RPGN)

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Course Clinical features Remarks

Subclinical ↓Complement level Microscopic hematuria N, Blood pressure

• 4-5 x more common than symptomatic patients in household members

Acute nephritic syndrome

Typical picture Hematuria (1/3 gross) Hypertension (60-80%) Edema (90%) Moderate proteinuria Oliguria (<%50%)

Macroscopic hematuria: few days Edema and hypertension: 5-10 days

Nephrotic syndrome

2-4% Risk factor for progression to CKD

RPGN

<1% Risk factor for progression to CKD

Clinical features

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Pathogenesis

• Activation of the complement system and of the coagulation cascade

• Immune complexes: in circulation, in situ (cationic antigens, subepithelial)

– Antigen size, load

– Antigen/antibody ratio

– Duration of exposure

– Host’s capacity to remove the deposited complexes

• Location of immune complexes (granular, not linear) – Mesangium (speckled ) appearance

– Glomerular basement membrane (garland appearance)

– Both

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Pathogenesis: nephritogenic antigens

• Specific M proteins were considered first; but they are not – Rheumatogenic species

– Nephritogenic species (Group A strep: GAS) • Pyodermitis GAS M types 47, 49, 55

• Upper respiratory tract GAS M types 1, 2, 4, 12

• Other nephritogenic antigens

– S. zooepidemicus epidemic in Brazil

• SPEB/zSPEB: Streptococcal pyrogenic exotoxin (erythrotoxin) B and its zymogen precursor

• NAP1r : nephritis associated plasmin receptor

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Pathogenesis: nephritogenic antigens

• SPEB/zSPEB: Streptococcal pyrogenic exotoxin (erythrotoxin) B and its zymogen precursor

– Co-localized with complement and Ig deposits

– Localized within dense deposits

– Cationic nature (pk>8.0)

– Increased production of IL-6

• NAP1r : nephritis associated plasmin receptor

– Glyceraldehyde 3-phosphate dehydrogenase (GAPDH)

– Plasmin binding characteristics • Local inflammatory reactivity, penetration of nephritogenic Ag-Ab complexes

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Pathogenesis: other factors

• And cellular immunity – Infiltration of lymphocytes and macrophages

– Overexpression of ICAM-1 and LFA

– IL-8

– TGF-beta

– TNF-alpha

• Autoimmune reactivity – Anti –IgG Ab

– Anti-DNA antibodies

– ANCA

• Host factors?

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Laboratory findings

• Reduction in serum complement level (>90%)

• Activation of complement system

– Alternative (mainly): low C3; normal C1 and C4

– Classic

– Lectin

• IgG, IgM elevated (80%)

• Antistreptococcal antibody titers

– Anti-streptolysin O (ASO)

– Anti-DNase B

– Anti-zSPEB/SPEB

• Positive cultures (20-25%)

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Indications for renal biopsy Early Stage Recovery Phase

•Short latent period •Severe anuria •Rapid progressive course •Hypertension >2 weeks •Depressed GFR >2 weeks •Normal complement levels •Nonsignificant titres of antistreptococcal antibodies •Extrarenal manifestations

•Depressed GFR >4 weeks •Hypocomplementemia >12 weeks •Persistent proteinuria > 6 month •Persistent microhematuria > 18 months

• Atypical features that prompt a renal biopsy:

– RPGN

– Persistent gross hematuria

– Hypertension or nephrotic syndrome

– Extrarenal manifestations

– Short latency period to renal disease,

– Hypocomplementemia lasting >6 weeks

– Patient <2 years of age

– The threshold for performing a biopsy in an adult is generally lower

Kambham N. Adv Anat Pathol 2012;19:338–347.

Tasic V. Acute Postinfectious GN. In: Comprehensive Pediatric Nephrology, 2009.

•Normal complement level: r/o IgAN? •Low complement level after 1-2 months: r/o SLE, MPGN •Nephrotic range proteinuria •Rising proteinuria, RPGN •Age •Extrarenal manifestations

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Early Biopsy (<2 wk) Typical Features

Late Biopsy (>4-6 wk)

Clinical features Mild albuminuria and hematuria

Acute nephritic syndrome

Persistent microscopic hematuria and/or proteinuria

Light microscopy

Glomerular endocapillary proliferation may be focal and segmental

Diffuse global proliferation (“exudative” early on; lymphocytes, monocytes along with mesangial and endothelial proliferation predominate later)

Mesangial proliferation

IF microscopy

C3 and IgG; starry sky pattern

C3 and IgG; starry sky or garland pattern*

C3±IgG; mesangial pattern

Electron microscopy

Mesangial, subepithelial (humps), and± subendothelial deposits

Mesangial, subepithelial (humps), and±subendothelial deposits

Mesangial and±rare subepithelial humps in the mesangial “notch”

Kambham N. Adv Anat Pathol 2012;19:338–347. A.Duzova

By courtesy of Dr. D. Orhan, Hacettepe University.

By courtesy of Dr. D. Orhan, Hacettepe University.

Endocapillary proliferation and neutrophil infiltration

By courtesy of Dr. D. Orhan, Hacettepe University.

Crescent formation

C3

By courtesy of Dr. D. Orhan, Hacettepe University.

Kambham N. Adv Anat Pathol 2012;19:338–347.

Starry-sky pattern

Garland pattern

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Subepithelial dense deposit (hump)

By courtesy of Dr. D. Orhan, Hacettepe University.

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By courtesy of Dr. D. Orhan, Hacettepe University.

Subepithelial dense deposit (hump)

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Diagnosis, differential dignosis

• Clinical features

• Positive cultures

• Antibodies

– Anti NAP1r, SPEB

– ASO, Anti-DNase B

– Streptozyme test • ASO, Anti-DNase B, streptokinase, hyaluronidase

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Diagnosis, differential dignosis

• Complement level – Normal complement:

• IgAN, MPGN, HUS, HSP, vasculitis, anti-GBM

– Low

• C4↓↓; C3 N, ↓ cryoglobulinemia

• ↓ C4, C3, C1 SLE

• Nephrotic proteinuria: – r/o: SLE, MPGN, nepritis associated with visceral abscesses

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Kambham N. Adv Anat Pathol 2012;19:338–347. A.Duzova

Management • Antibiotic treatment

– Prevention • Skin infection • Throat infection • McIsaac (sensitivity 85 %; specificity 92%)

– Temperature 38°C – No cough, – Tender anterior cervical adenopathy – Tonsillar swelling or exudates – Age

» between 3 and 14 yr. 1 point » 15 to 44 no point » age > 44 yr gets 1 point. -1 point

• Rapid test: sensitivity low

– PSGN patients: treatment – Family members

McIsaac WJ et al. The validity of a sore throat score in family practice. CMAJ 2000; 163: 811–815. Edmonson MB, Farwell KR: Relationship between the clinical likelihood of group A streptococcal

pharyngitis and the sensitivity of a rapid antigen-detection test in a pediatric practice. Pediatrics 2005; 115: 280-285. A.Duzova

Management

• Edema, hypertension

– Loop diuretics

– Antihypertensives • Nifedipine

• Hydralazine

• ACE-i?

• …..

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Rodriguez-Iturbe B, Musser JM. The Current State of Poststreptococcal GN. JASN 2008; 19: 1855–1864.

Outcome

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Rodriguez-Iturbe B, Musser JM. The Current State of Poststreptococcal GN. JASN 2008; 19: 1855–1864.

Outcome

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Shunt nephritis

• Ventriculoatrial shunts (<2%)

• Ventriculoperitoneal shunts; rare

• S. epidermidis (75%)

• Less frequent

– S. aureus

– Propionibacterium acne, diphtheroids, Pseudomonas and Serratia

• C3 and C4 low

• The renal lesion

– Usually MPGN

– Deposits: complement and IgM; IgG in about two-third

– EM, dense deposits: subendothelial and mesangial

Haffner D, Schinderas F, Aschoff A. Nephrol Dial Transplant 1997;12:1143–1148. Fukada Y et al. Am J Nephrol 1993;13:78–82.

Rodriguez-Iturbe B, Mezzano S. Pediatric Nephrology, 6th edn.

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Infective endocarditis

• Microembolism (%30)

• Glomerulonephritis (%26)

• Tubulointerstitial nephritis

• Vasculitis

• Microorganisms – S. aureus, S. epidermidis, Streptococcus viridans and pyogenes,

Enterococcus fecalis

– E. coli, Proteus, Bartonella , Candida species.

Majumdar A et al. Renal pathological findings in infective endocarditis. Nephrol Dial Transplant 2000;15:1782–1787.

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Summary

• Changing epidemiology of PSGN

• Pathogenesis: nephritogenicity

• Biopsy: in specific cases, not pathognomonic

• Diagnosis: clinical, laboratory features

• Limited data for evidence based management

• Treatment and prevention for PSGN

• Prognosis is not always excellent

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