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(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)