Sudung O. Pardede

Department of Child Health Faculty of Medicine University of Indonesia –Cipto Mangunkusomo

HospitalJakarta

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Glomerular capillary membranes mechanism of proteinuria

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A SIZE-SPECIFIC BARRIER

A CHARGE-SPECIFIC BARRIER

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GlomerulonephritisSynonyms:

GlomerulonephropathyGlomerular diseases

Definition:A group of conditions in which inflammation in the

glomerulus occurs The mechanisms for glomerular injury are complex

more often are inisiated by an immune response

Classification of glomerulonephritis

1. Congenital or inherited:a. Alport syndromeb. Congenital NSc. Familial hematuria

2. Acquired a. Primary or idiopathic:b. Secondary:

1. infection-related2. associated with a multisystem disease3. drugs4. neoplasia5. miscellaneous

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a. Primary or idiopathic:

Minimal changesMesangial proliferative GNFocal segmental glomerulosclerosisMembranoproliferative GNMembranous glomerulonephropathyIgA nephropathyRapidly progressive GNFocal proliferative GNDiffuse proliferative GN proliferative GN

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b. Secondary:1. Infection related:

Poststreptococcal GN Subacute bacterial endocarditis Postpneumococcal GN Shunt nephritis Hepatitis B, C, HIV Malaria, leprosy, schistosomiasis, etc

2. Associated with multisystem disease Henoch-Schoenlein purpura Systemic lupus erythematosus Hemolytic uremic syndrome Collagen vascular disease: polyarteritis nodosa,

vasculitis Goodpasture syndrome, etc

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b. Secondary…………….:3. Drugs:

Penicillamine, NSAID Captopril, gold salts, Trimethadione, lithium, mercury, etc

4. Neoplasia Leukemia Lymphoma Carcinoma

5. Miscellaneous Renal transplant rejection Sickle cell disease Reflux nephropathy 9

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Classification of glomerulonephritis

Etiology: congenital x primary x secondary

According time period: acute x subacute x chronic

According renal biopsy: focal x segmental x diffuse

According number of cells: non-proliferative x proliferative

According immunofluorescence:

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EtiologyCongenital:

Intra uterinePrognosis: infaust

Primary glomerular disease:Disorders in which the glomeruli are the sole or

predominant tissue involved. Usually : idiopathic.

Secondary glomerular disease:

Glomerular injury is a feature of a systemic disease, vascular, metabolic or genetic disorders involving multiple organs or systems.

Time periode or chronology

Acute : days to weeks

Subacute/rapidly progressive:over weeks to few months

Chronic : many months to years

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Location of lesion One kidney;focal : <50% of all glomerulidiffuse : ≥50% of all glomeruli

One glomerulus:segmental : part of individual glomerulusglobal : entire glomerulus

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A B C

Fig. Penampang dalam pemeriksaan mikroskop cahaya yang memperlihatkan kelainan glomerulus yang: A. Difus; B. Fokal; C. segmental

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Pathology features

Proliferative: increased glomerular cellIntracapillary/endocapillary:

endothelial or mesangial cellsExtracapillary:

cells in Bowman’s spaceCrescent: half-moon-shaped collection of

cells in Bowman’s space

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Pathology features……

Membranous:expansion of glomerular basement membrane

as a dominant feature

Sclerosis:increased amount of homogenous non-fibrillar

extracellular material similar to GBM and mesangeal matrix

Fibrosis:deposition of type I and III collagen commonly as a consequence of healing of

crescents or tubulointerstitial inflammation

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Acute glomerulonephritis:

constellation of clinical manifestations caused by

glomerular injury and inflammation

that leads to decline in glomerular filtration rate

Etiology

InfectionsBacteria: Streptococci, pneumococci,

staphylococci, Treponema pallidum, Salmonella typhi

Virus: Hepatitis B, Echovirus, Ebstein B virus, HIV.

Protozoa: MalariaVascular-colagen disease:

Purpura Henoch Schönlein, SLE,Genetic

Alport’s syndromeDrugs

Methicillin19

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Symptoms and Signs

Hematuria (with RBC casts)ProteinuriaHypertension Renal function impairment

Oliguria Elevated plasma creatinine/Reduction in GFR

Acute fluid overload Peripheral oedema Pulmonary oedema Congestive cardiac failure

Smith JM, Faizan MK, Addy AA. Clinical Paediatric Nephrology, 3 rd ed.,Oxford, Toronto, 2003,p.367-80. Bagga A. Pediatric Nephrology, 6th ed.,Wlsevier, 2009,p.815-28

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EpidemiologyActual incidence is not known, because the

majority of APSGN cases are sub clinical in nature

APSGN: schooll-aged children 5 – 15 years < 2 years : < 5% Male > female

APSGN: skin infection younger than pharingeal infection10-15% of nephritogenic infection APSGN

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Alatas A, et al. Maj Kedok Indones 1983Kazzi AA, et al. http://www.emedicine.com/emerg/topic219.htm. 2006

Parmar MS. http://www.emedicine.com/med/topic879.htm. 2006Smith JM, et al. Clinical paediatric nephrology. 2003

Etiology

Post infection of group A Streptococcus hemoliticus

Specific serotype of APSGN: Type 12: pharyngitis : onset : 10 (7-14) days

Type 49: skin infection (impetigo): onset: 21 days ( 3-6

weeks)

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Nephritogenic strains of Streptococci

Group ABeta-hemolytic Respiratory tract – M 1,2,4,12,18,25 Skin – M 49, 55, 57, 60

Group CStreptococciStreptococcus zooepidermicus

Site of infection:upper respiratory tract: pharynx, tonsilles, middle earskin

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a. Host factors: Age 5 -15 years Sex : boys > girls Genetic Nutrition Socio-economic conditions

b. Bacterial factors: M Protein

Endostreptozine Cationic protein) Streptococcal pyrogenic exotoxin B Nephritis associated plasmin receptor Streptokinase Streptolysin O Streptodornase Hyaluronidase acid Neuraminidase DNA-ase Nicotinamide adenine dinucleotidase

Pathogenesis

Hypothesis:• Circulating immune complex formation • In situ immune complex formation• Autoimmune process

Neuraminidase produced by streptococci removes sialic acid from Ig, alters endogenous IgG and

makes it autoantigenic altered IgG form circulating complexes deposited in kidney

Streptokinase:Plasminogen plasmin

Activate complement casacade

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Clinical manifestations 5 - 15 years

After pharingytis or impetigo:

-pharingytis: 7-14 days

-skin infection: 3-6 weeks

Acute nephritic syndrome: Hematuria Oedema Hypertension : headache, seizures, vision abnormality Proteinuria Oliguria/anuria

28Smith JM, Faizan MK, Eddy AA. Clinical Pediatric Nephrology, 3rd ed., Oxford, 2003;h.3-79

Fluid overloadgeneralized oedema: 85%acute pulmonary oedema: 14%heart failure: 2%

Hematuria: microscopic: + 100%macroscopic

Hypertension: 60-80%: encephalopathy hypertension: rareNephrotic proteinuria: < 5%Hypoalbuminemia: mild, intravascular dilutionAnaemiaAnaemia GFR: 45%Normal: 1-2 weeks

29Smith JM, Faizan MK, Eddy AA. Clinical Pediatric Nephrology, 3rd ed., Oxford, 2003;h.3-79

LaboratoryUrinalysis:

Hematuria Proteinuria Erythrocyte casts Leucocyturia Leucocyte casts Dysmorphic erythrocyte Normal

Streptococcus infections: Antibody for streptococcus antigen :

Titer ASO: pharingytis (80-90%), skin infection (<50%), Normal: 16-18%

Streptozyme assay: (ASO, streptokinase, hyaluronidase, DNA-se B, NADase) : pharingytis: 95%, skin infection: 80%

Serologi negative: maybe not APSGN Throat swab (normal: + 20%)

30Smith JM, Faizan MK, Eddy AA. Clinical Pediatric Nephrology, 3rd ed., Oxford, 2003;h.3-79

Laboratory ………

Immunology: Complement:

C3 C4 normal

renal function: Creatinine and ureum Hyperkalemia Hyperphosphatemia Acidosis Calcium and phosphate

Hematology: Mild anemia Mild thrombositopenia

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Smith JM, Faizan MK, Eddy AA. Clinical Pediatric Nephrology, 3rd ed., Oxford, 2003;h.3-79

Complications

Encephalopathy hypertension Acute renal failure Pulmonary oedema Congestive heart failure

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Treatment

1. Bed rest2. Antibiotic for eradicating streptococci

- Penicillin 10 days- Erythromicyn

3. Dietetic (fluid & salt restriction)- low protein 1 g/kgBW/day - low salt 1 g/day- IVFD as necesarry

4. Prolonged anuria dialysis- peritoneal dialysis- haemodialysis

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Treatment ……..

5. DiureticsFurosemide 1 mg/kgbw/dose 2x/ day

6. Symptomatic treatmenthypertensionhypertensive encephalopathycongestive heart failureacute renal failure

Indications for in-patient management of APSGN

HypertensionOedemaOliguriaMacroscopic hematuriaElevated plasma creatinineElectrolyte abnormalities

35Smith JM, Faizan MK, Addy AA. Clinical Paediatric Nephrology, 3 rd ed.,Oxford, Toronto, 2003,p.367-80.

Prognosis 95 – 98% : complete resolution

: self limited disease: 1 – 2 weeks

< 3% : died in the acute phase < 1% : RPGN

Hematuria-proteinuria until 12 months: CGN

Ad vitam/for life : goodAd sanationum/for cure : goodAd fungsionum/for function : good

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Clinical course of APSGN symptoms

Oedema : subside day 3 (4,3 + 1,8)

Macroscopic hematuria : subside day 2 (5,1 + 4,2)

Hypertension : subside day 3 (4,6 + 2,4)

Oliguria : subside day 3 (3,8 + 2,6)

C3 complement normal : 6-8 weeks

ASO normal : 1-6 months

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2 weeks 4 weeks 2 months 6 months 1 year 2 years

Gross haematuria, Oliguria, azotaemia

Hypertension

Depression of C3

Persistent proteinuria

Microscopic haematuria or intermittent Orthostatic proteinuria

Fig. Natural history of APSGN

Smith JM, Faizan MK, Addy AA. Clinical Paediatric Nephrology, 3 rd ed.,Oxford, Toronto, 2003,p.367-80.

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Acute non post streptococcal GN

symptoms are not similar with APSGNfamily history of glomerular diseaseunder 4 years or over 15 yearsprevious history of similar symptomsevidence of extra-renal disease

evidence of acute or chronic non streptococcal infection

evidence of chronic renal disease

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Shunt nephritis 4% of infected shunt

Hydrocephalus with VP shunt

Coagulase-negative Staphylococcus

Fever, lethargy, arthralgia, hepatomegali, purpura,

adenopathy, BW ,

Kidney: hematuria, proteinuria (30% nephrotic), azotemia,

hypertension

Lab: anemia,lecocytosis, ESR , C3 dan C4 (90%)

Therapy: - AB

- removal shunt

- supportive41

Infective endocarditis - nephritis

RareStaphylococcus aureusRenal manifestations:

Hematuria Proteinuria Hypertension Renal function

GSFS, diffuse proliferative GN, rapid progressive GN

Hypocomplementemia: 60-90%

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Hepatitis B - nephritisMembranous nephropathy, MPGN, minimal

changes, IgA nefrophaty, FSGS, diffuse proliferative GN, cresentic GN

Age: 2- 12 yearsBoy: 75-80%Renal manifestations:

oedema, Proteinuria (nephrotic) Hypertension: 25% Hematuria Hypocomplementemia: 15-64%

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Hepatitis C - nephritis

MPGN, acite proliferative GN, mebranous nephropathy

RareRenal manifestations:

proteinuria renal function C3 and C4

Therapy: Antiviral: ribavarine -interferon: proteinuria

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HIV Nephritis

Urinalysis: routineFSGS, minimal changes, IgA nephropathyRenal manifestations:

Proteinuria nephrotic Hematuria: not significant Normotension Hypocomplementemia

Therapy: antiviral ACE inhibitor: proteinuric effect

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Others glomerulonephritis

Henoch Schoenlein purpura nephritisIgA nephritisMembranoproliferative

glomerulonephritisLupus nephritisANCA positive nephritis

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APSGN Henoch-SchönleinPurpura

IgANephropathy

MPGN SLE ANCA-positive vasculitis

Mean age (years)Antecedent infectionGross haematuriaNephrotic syndrome*Serum C3Serum C4Diagnostic serologyExtrarenal disease

5-15

Yes

30%

5%

LowNormal***ASOT; streptozymeRare

4-14

35%

20%

5-10%

NormalNormalNo

Yes

10-20

Concurrent common50-80%

<10%

NormalNormalNo

Rare

8-12

Common

20-50%

30-50%

LowNormal/lowNo

Rare

15-20

Rare

<10%

0-50%**

LowLowANA, anti- dsDNACommon

12-20

Flu-like prodrome common30%

< 10%

NormalNormalANCA

Common

Table: presenting clinical features of paediatric glomerular diseases that may mimic APSGN

* Some of these values are estimates, as good epidemiological data are not published** Incidence depends upon the histological class of lupus nephritis*** A small number of cases presenting early in the clinical course of the disease may have very transiently depressed C4 levels.