(GLOMERULOPATHY)Syafruddin HarisDivision NephrologyChild Health Department Faculty of Medicine – University of Syiah Kuala

GLOMERULOPATHY

MAIN CAUSE OF KIDNEY FAILURE IN CHILDREN

DEFINITION: INFLAMATORY CHANGES IN GLOMERULUS

DUE TO IMMUNOLOGIC MECHANISM

CLINICAL MANIFESTATIONS# ISOLATED PROTEINURIA# PROTEINURIA + OEDEMA (i.e.nephrotic syndrome)# ISOLATED HAEMATURIA# HYPERTENSION +/- proteinuria/haematuria# RENAL FAILURE

CLASSIFICATION

1. CONGENITAL• Alport syndrome• Congenital nephrotic syndrome

2. ACQUIRED – PRIMARY / IDIOPATHIC

3. SECONDARY• POST INFECTION – POSTSTREPTOCOCCAL GLOMERULONEPHRITIS• MULTISYSTEM DISEASES : Lupus erythematosus, haemolytic uraemic synd• INTOXICATION: drugs, metal• NEOPLASMS• Etc

1. Minimal change2. Focal segmental glomerulosclerosis3. Mesangial proliferative glomerulonephritis4. Membrano-proliferative glomerunephritis5. Membranous glomerulonephritis6. IgA Nephropathy7. Glomerulonephritis others

DEFINITIONNEPHROTIC SYNDROME is defined as

A clinical state characterized by the combination of - heavy proteinuria- hypoproteinaemia- oedema- hyperlipidaemia

Heavy proteinuria : > 50 mg/kg BW/day or >40mg/m2/hcreatinine/protein ratio > 2 mg/mgselective proteinuria

Hypoalbuminaemia : < 2.5 g/dl

Hyperlipidaemia : variable degreeinvariably present

Epidemiology

• Incidence– Incidence 2-7 new cases per 10,000– Prevalence 15.7 cases per 10,000

• Age– MCD 2.5 years median age– FSGS 6 years median age

• Sex– 3:2 Boys; Girls in children <6 yo– Equal ratio in those older

CLASSIFICATION

1. CONGENITAL NEPHROTIC SYNDROME

2. IDIOPATHIC NEPHROTIC SYNDROME

3. SECONDARY NEPHROTIC SYNDROME

CONGENITAL NEPHROTIC SYNDROME

clinical onset in the first 3 months of life proteinuria in utero or at birth elevated amniotic fluid level of alpha-fetoprotein before 20 weeks’ gestation Classification :

Primary Finnish type Diffuse mesangial sclerosis Minimal changes NS Focal segmental glomerulosclerosis

Secondary congenital syphilis, toxoplasmosis, cytomegalovirus XY gonadal dysgenesis and Wilms tumour nephroblastoma etc

CONGENITAL NEPHROTIC SYNDROME

2 autosomal recessive inheritance2 incidence in Finland: 12 cases/100 000 births2 born prematurely 35-38 weeks2 small for gestational age2 placenta weighing > 25% birth weight2 breech presentation, fetal asphyxia2 widened cranial sutures, large fontanelles, pliable

cartilagenous tissue2 small nose, wide-set eyes, low-set ears

the majority of cases

Prognosis : infaust

SECONDARY NEPHROTIC SYNDROME

Causes of secondary nephrotic syndrome

1. Extrinsic antigens, drugs, and toxins

2. Infections

3. Intrinsic antigens

4. Neoplasms

5. Associations, possibly doubtful

• Penicillamine •Gold• Mercury •Trimethadione• Probenecid •Volatile hydrocarbon• Bee’s sting •snake venom

• Hepatitis B •Syphilis• Malaria •Filariasis• Leprosy •Schistosomiasis

• Lupus erythematosus •Syorgen’s syndrome• Sarcoidosis •Renal tubular antigen• Transplantation •vasculitis syndrome

• Carcinoma •Lymphoma• Leukemia

• Diabetes mellitus •Renal vein thrombosis• Rheumatoid arthriris •Sickle cell disease• Guillan Barre synd.

PATHOPHYSIOLOGY

1. PROTEINURIA2. PERMEABILITY IMPAIRMENT

• MOLECULE IONIC CHARGE• MOLECULE SIZE

Glomerular Capillary Membranes Mechanism of Proteinuria

A SIZE-SPECIFIC BARRIER

A CHARGE-SPECIFIC BARRIER

CD2 associated protein

Podocin

Nephrin

PodocyteSlit Diaphragm Podocyte

The action is at the slit diaphragm

PROTEINURIA

- Transferine - Glob.Thyroxin - Glob. Vit. D - Coagulation factors F VII, IX, XII

IgG IgE IgA IgM Fibrinogen

HYPOALBUMINAEMIA

B-lipoprot hyperlipidaemia

ONCOTIC PRESSURE

OEDEMAHYPOVOLAEMIA

Lipiduria

Aldosteron Na and H2O retention

Hb Packed cell vol Viscocity Vein thrombosis

Peripheral circulation collaps

Death

Renal perfusion

renin plasma Ureum + K

CLINICAL MANIFESTATIONS

Oedema (uptill 40% BW), ascites, hydrothorax,scrotal oedema

Secondary infections : skin, peritonitisAnaemiaGrowth disturbancesTetany (hypocalcaemia)Hypovolemic shockVein thrombosisAcute renal failure: oliguria/anuria, metabolic acidosis,

potassium

Nephrotic syndrome

Generelised edema(anasarca)

Older child with nephrotic syndrome

Pitting peripheral

oedema

Nephrotic Syndrome

Ascites

Nephrotic syndrome

SCROTAL EDEMA LABIAL EDEMA

LABORATORY FINDINGS

Urinary analysis:specific gravity , pH proteinuria massive

(selective - albumin 85-95%)qualitative/semiquantitative > 2+quantitative : Esbach

leukocyturiahaematuriadouble refractile lipoid bodieshyaline cast

Plasma :Hb , Hthypoalbuminaemia, reverse ratio alb/globhypercholesterolaemianormal: ureum, creatinine

IDIOPATHIC NEPHROTIC SYNDROME

The Morphologic Spectrum of primary nephrotic syndrome (Churg, Habib & White, 1970) 1. Minimal change2. Focal segmental glomerulosclerosis3. Proliferative glomerulonephritis

MesangialWith crescent formationFocalDiffuse exudative Mesangiocapillary (membrano-proliferative)

4. Membranous glomerulonephritis5. Advance chronic glomerulonephritis

EPIDEMIOLOGY

MINIMAL DISEASE

PROLIFERATIVE DISEASE

MEMBRANOUS DISEASE

TREATMENT1. Medication

1. STEROID2. DIURETICS3. IMMUNOSUPRESSIVE AGENTS

2.Dietary (nephrotic diet)

LOW SALT (1-2 g/day)high PROTEIN 2-3 g/kg/day

3. OPTIMIZING CONDITION

(physic,psychology,social)- Activity : not limited- Immunization: as scheduled- Psychological support : the child +

parents

FOLLOW UP OUT PATIENT CLINIC:

- Symptomatic : weekly - monthly- Asymptomatic : every 3-6 months (renal

function evaluation) ADMISSION :

generelized oedema, severe hypertension,severe infection, shock, acute renal

failure

STANDARD TREATMENTCORTICOSTEROID (PREDNISON)

4 MINGGU

IMMUNOSUPRESSIVE AGENTS

Prednison FD: 60 mg/m2/day Prednison AD: 40 mg/m2/day

REMISSION (-) REMISSION (+)

STEROID RESISTANT

STEROIDSENSITIVE

4 MINGGU

FULL DOSE ALTERNATING

INITIAL TREATMENT

THE INTERNATIONAL COMMITTEE OF KIDNEY DISEASE IN CHILDREN (1967)

RECOMMENDED DOSAGESPREDNISON

DAILY : 60 mg/m2/day in 3 divided dose

Intermittent : 40 mg/m2/day in 3 divided dose,

3 executive days in a week

Alternatively : 35 mg/m2/day single dose

CICLOPHOPHAMIDE2-3 mg/kg/day for 8 – 12 weeks in combination with steroid intermittent

CHLORAMBUCILE

0,1-0,2 mg/kg/day in divided dose with steroid AD

Classification

Idiopathic nephrotic syndrome• Steroid sensitive nephrotic

syndrome– SSNS

• Steroid resistant nephrotic syndrome– SRNS

Definitions• Remission-

– Urinary protein < 4 mg/ m2*hr or Albustix = 0/Trace for 3 consecutive days

• Steroid Responsive – Remission with steroids alone

• Relapse – Urinary protein > 40 mg/m2*hr or

Albustix > 2+ for 3 consecutive days • Frequent Relapses

– Two or more relapses within 6 months of initial response or 4 or more relapses within any 12 month period

Definitions

• Steroid Dependence – Two consecutive relapses occurring

during corticosteroid treatment or within 14 days of its cessation

• Steroid Resistance– Failure to achieve response in spite of

4 weeks of prednisone 60 mg/m2*day

THE CLINICAL RESPONS OF MINIMAL CHANGES PATIENTS TO STEROID (ISKDC)

Minimal Change 100%

Responsive 93% Early Non responsive 7%

No-relaps36%

InfrequentRelapser 18%

FrequentRelapser 39% Non responsive 5%

Late responsive 5%

Non-responsive 2%

(Kidney Int. 13-43, 1978)

PROGNOSIS

RENAL FUNCTION graduallyfailure

rapid, about 5 – 10 years

SECONDARY

DEFINITION

ACUTE POST INFECTION GLOMERULONEPHRITIS

IMMUNOLOGICAL REACTIONS IN KIDNEYUPON EXTRA RENAL INFECTION CAUSED BY AGENTS

The most common :

Extra renal infection with group A beta-hemolytic streptococci

ACUTE POST STREPTOCOCCAL GLOMERULONEPHRITIS

EPIDEMIOLOGIC CHARACTERISTICS

Actual incidence hard to ascertainlarge % of cases : subclinical in nature

Developing countries : a common form of GN in childrenthe disease is self-limited in most

Advent of antibiotics and better public health influence incidence

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

ACUTE POSTSTREPTOCOCCAL GLOMERULONEPHRITIS (APSGN)

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

Upper Respiratory

• Sore Throat • Tonsillar exudate• Fever• Chills• 20% school

children carriers

Skin

• Impetigo– Lesions on

extremities– Commonly on face– Pustular and

crusty

INFECTIONS PRECEDING ACUTE GN

BACTERIAL   Group A, Beta-hemolityc streptococci   Streptococcus viridans   Streptococcus pneumoniae   Streptococcus grup C (Streptococcus zooepidermicus) Staphylococcus aureus   Staphylococcus epidermidis   Salmonella typhosa Gonococcus Mycoplasma   Staphylococcus albus   Treponema pallidum Corynebacterium bovis Klebsiella pneumoniae Diplococcus pneumonia Brucella suis Meningococcus Leptospira Propionibacterium acnes Mycobacterium leprae Actinobacillus

-

INFECTIONS PRECEDING ACUTE GN

VIRAL§       Varicella-zantu - Coxsackie B§       Rubella - Echovirus§       Cytomegalovirus - Enterovirus§       Epstein-Barr - Picornavirus§       Hepatitis B - Onconavirus§       Measles - Influenza§       Mumps - HIV

PARASITIC§       Plasmodium falsiparum - leishmanias§       Plasmodium malariae - tripanosomes§       Toxoplasma gondii - trichinosis§       Schistosoma mansoni - filaria FUNGAL RICKETSIAL§       Coccidiodes immitus - Scrub typhus

ASSOCIATION BETWEEN

AGN – STREPTOCOCCI INFECTION

1. Following scarlet fever

2. Group A, -streptococcus hemolytic has been isolated

3. ASTO • Latent period

# pharyngitis associated : 10 d

# impetigo associated : 21 d

PATHOGENESIS

HYPOTHESIS:• CIRCULATING IMMUNE COMPLEX

FORMATION • IN SITU IMMUNE COMPLEX FORMATION• AUTOIMMUNE PROCESS

Neuraminidase produced by streptococci alters endogenous IgG and makes it autoantigenic altered IgG form circulating complexes deposited in kidney

CLINICAL MANIFESTATIONS

A. ACUTEB. SUB ACUTE (RAPIDLY PROGRESSIVE)C. CHRONIC

CLINICAL MANIFESTATIONS - Various (subclinical – mild - severe)- Sudden onset of painless gross hematuria

(coke- or tea-colored urine)- Oedema (puffy eyes - generalized)- Oliguria / anuria- Acute renal failure- Hipertension

hypertensive encephalopathy : headache,vomiting, lethargy, confusion, seizures

- Congestive heart failure or pulmonary edema- Anaemia

FREQUENCY OF CLINICAL MANIFESTATIONS IN APSGN

Gross hematuria 25 – 33 %Volume overload

oedema 85 %hipertension 60 – 80 %circulatory congestion 20 %

CNS symptoms 10 %

LABORATORY FEATURES

URINALYSIS :

proteinuria 1 - 4+

hematuria

abnormal sediment:

dysmorphic RBCs, WBCs, cellular casts,

granular casts, RBC casts

SERUM :

- BUN/ureum , creatinine

- K , acidosis, hyperphosphatemia, Ca - Hypocomplementemia

in first week, normal in 8 –10 wks

- Properdin level - Evidence of a recent streptococcal infection

antistreptozyme, ASO, antihyaluronidase, anti-DNase B

PATHOLOGY ANATOMY

Light microscopyDIFFUSE ENDOCAPILLARY PROLIFERATIVE GLOMERULONEPHRITIS

- diffuse mesangial cell and matrix proliferation- endothelial cell proliferation- infiltration polymorphonuclear cells and monocytes - occlusion capillary lumens

Electron microscopy - electron-dense deposits in mesangium- HUMPS (large deposits in subepithelial location)

pathognomonic

Immunofluorescence microscopyirregular fine – coarse granular staining in mesangiumand along capillary loop for IgG, C3, IgM, IgA,

DIAGNOSIS

Sudden onset of gross hematuria, oedema, hypertensionand acute renal failure following a recent streptococcal infection

Urinalysis findings characteristic of GN

Laboratory evidence of a recent streptococcal infection

Low serum complement

DIFFERENTIAL DIAGNOSIS IgA Nephropathy synpharyngetic hematuria Associated with systemic disease Chronic glomerulonephritis

TREATMENT (1)

1. Bed rest2. Antibiotic for eradicating streptococci

- Procain 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

TREATMENT (2)

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

6. Symptomatic treatmenthypertensionhypertensive encephalopathycongestive heart failureacute renal failure

TREATMENT (3)

Treatment of hypertension associated with APSGN

Mild Severe

Diuretics furosemide furosemide i.v. i.v. or p.o.

Vasodilators hydralazine diazoxide i.v.Na-nitroprusside i.v.

Ca-channel blockernifedipine p.o. Nifedipin sublingual

ACE inhibitor captopril p.o.

Evaluation to Document Likelihood of TypicalAPSGN (1)

1 . Typical of presentation with no findings suggestive of other systemic disease

2. Evidence of prior streptococcal infectiona. Throat or skin lession culture positive for streptococcib. Elevated antibody titers

3. Complement abnormalities typicala. Decreased CH50 and C3 during acute phaseb. C4 usually normalc. Levels rise toward normal by 6-8 wks

Evaluation to Document Likelihood of TypicalAPSGN (2)

4. Beginning recovery in 1 weeka. Diuresisb. Blood pressure normalizec. BUN, creatinine begin to fall

5. Normalization of urine sedimentd. Resolution of gross hematuria by 2-3 weekse. Resolution of proteinuria by 3-6 monthsf. Resolution of microscopic hematuria by 1 year

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

A clinicopathologic entity

Rapidly deteriorating renal function PA : diffuse glomerular epithelial crescent formation

(crescentic glomerulonephritis)

Clinical manifestations:similar to APSGN severerapidly deteriorating

Management:steroid / immunosupressive agents : controversial

CHRONIC GLOMERULONEPHRITIS (1)

Haematological abnormalitiesProteinuria persist

Acute exacerbation of chronic glomerulonephritis

Evidence of chronicity of diseaseanaemia, abnormal growth pattern,exacerbation of acute nephritic syndrome

CHRONIC GLOMERULONEPHRITIS (2)

Mightbe asymptomatic renal failureMild oedema , subfebrile temperature

NEPHROTIC STAGE OF GLOMERULONEPHRITIS

a predominant picture of nephrotic syndrome- clear oedema- reverse ratio of albumin/globulin- hypercholesterolemia

Renal function progressively

CHRONIC GLOMERULONEPHRITIS (3)

Laboratory findings

Urine : isostenuriaproteinuriahematurialeukocyturia

Serum: ureum , creatinine K, Ca , P

anaemia : normochrom normocytic

CHRONIC GLOMERULONEPHRITIS (4)

PATHOLOGY ANATOMY

MACROSCOPICALLY- SHRINKED KIDNEY- CONTRACTED KIDNEY

MICROSCOPICALLY- HYALINE DEGENERATION- TUBULUS ATROPHY- NEPHRON REPLACED WITH FIBROID TISSUE

+ LYMPHOCYTE INFILTRATION

TREATMENT STRATEGY FOR ACUTE GLOMERULONEPHRITIS

1. Bed rest as necessary2. Fluid and salt restriction3. Specific intervention for

a. Hypertension and other sign of volume overloadb. Hyperkalemiac. Acidemiad. Hyperphosphatemia

4. Confirm likelihood of poststreptococcal disease5. Watch for onset of recovery within 7 days6. Keep high index of suspicion for diseases other

than APSGN

NEPHRITIC OEDEMA NEPHROTIC OEDEMA

Renal and water retention

Expansion of circulatory volume

Alteration of Starling forces(capillary hydraulic pressure )

Oedema formation

Oedema formation

Renal and water retention

Alteration of Starling forces(capillary osmotic pressure )

Volume contraction

EFFECTIVE CIRCULATORY VOLUME

Renal perfusion

PRA

Angiotensin II

Aldosterone

Distal Nareabsorption

Sodium and water retention

ANP ?

Volume receptors

AVP

Water reabsorption

Internalfactors

Sympathetic activity

Alterations ofperitubular Starling

forces

Renal nerve activity

Proximal Na reabsorption

PRA =plasma renin activity; AVP = arginine vasopressin; ANP=atrial natriuretic peptide

Clinical and laboratory evaluation in acute GN

History (sore throat, impetigo)Physical examination (blood pressure, fluid overload)Urinalysis, 24-h urine for protein and creatinineThroat culture, skin lesion cultureBlood chemistry : serum electrolytes, ureum, creatinine,

Ca, P, total proteins, albumin, cholesterolSerum complement (CH50, C3, C4)Serum for anti streptococcal antibodies

Antinuclear antibody testAntiglomerular basement membrane and antineutrophil

cytoplasmic antibodies in patient presenting with rapidly progressive GN

Renal biopsy (if unresolved)