NEPHROTIC SYNDROME

THE SWOLLEN CHILD

DEFINITION
It is a clinical syndrome of: 1. 2. Heavy proteinuria >1 g/m2/day Hypoproteinemia serum albumin < 2.5 g/dL Protein:Creatinine > 200mg/mmol Oedema Hypercholestrolnemia > 250 mg/dL

3. 4.

EPIDEMIOLOGY
West Uncommon: 3 new cases per 100,000 child population Asian Higher incidence: 16 new cases per 100,000 child population Malaysia No available data, it is thought to have higher incidence than in the west

CLASSIFICATION
Primary or Idiopathic no known aetiology Minimal change disease (MCD) Focal Segmental Glomerulosclerosis (FSGS) Membranous nephropathy congenital nephrotic syndrome Secondary Systemic disease - SLE - HSP - DM Infections - Post-infectious GN - Hepatitis B - Syphilis - Malaria Drugs Toxins and allergen - bee sting - food allergy

Minimal Change Disease most common (70-80%) M:F = 2:1 < 7 years old steroid-sensitive nephrotic syndrome do not progress to renal failure often precipitated by respiratory infections Features:
age between 1 and 10 years no macroscopic haematuria normal blood pressure normal complement levels normal renal function.

FSGS 10% of NS in childhood progress from MCD / separate entity circulating factor that increases glomerular permeability to albumin

Membranous nephropathy 1% of NS in childhood common in adolescent and children with - systemic infection - hep B - syphilis - malaria - toxoplasmosis - drug therapy heamaturia present

Congenital NS clinical Ns presents during the first 3 months of life 2 types - Finish - heterogeneous group of abnormalities

PATHOPHYSIOLOGY
Primary disorder:
Loss of glomerular BM sialoprotein Decrease serum protein

Loss of normal negative charge

Decrease plasma oncotic pres.

Increase glomerular permeability

Fluid shift from vascular to interstitial

Massive proteinuria

Contraction of plasma volume

 Edema:

- under fill theory: hypoalbuminemia - over fill theory: tubular NaCl reabsorption secondary to RAAS intravascular expansion fluid shift following pressure gradient
Hypercholesterolemia

- hypopratenemia hepatic lipoprotein synthesis serum lipid (cholesterol, lipoprotein) lipid metabolism

COMPLICATION

Infection Spontaneous bacterial peritonitis, cellulitis, bacteriemia (S.pneumoniae, E.coli) Steroid and immunosuppressant toxicity Hypovolaemia abdominal pain and may feel faint, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. A low urinary sodium (<20mmol/L) and a high packed cell volume Thromboembolism hypercoagulable state due to urinary losses of antithrombin, thrombocytosis exacerbated by steroid therapy increased synthesis of clotting factors increased blood viscosity from the raised haematocrit, This is usually arterial and may affect the brain, limbs and splanchnic circulation Hypercholesteroleamia Acute renal failure (rare)

CLINICAL MANIFESTATION
Sudden onset of dependent pitting oedema

- periorbital - scrotal or vulva - ankle or leg Weight gain Ascites - abdominal pain - malaise Diarrhea (dt intestinal oedema) Respiratory distress (dt pulm. oedema)

HISTORY TAKING
First time or relapse??? History of edema noted on awakening in the morning or sudden swelling?? Distribution Colour changes Initiating factor? (bee sting) Painful?? Weight gain (edema) Respiratory distress Breathlessness

Diarrhea
Urine: frothy Pass medical and drug history: recent illness, allergies, asthma Family history

PHYSICAL EXAMINATION
Assessment of hydration status identifies fluid imbalances (dehydration,

overhydration)

Blood pressure: hypertension Henoch-Schnlein purpura (purpura) Systemic lupus erythematosus (malar rash) Rales heard on lung auscultation suggest extravascular fluid from overload or

hypoalbuminemia

Palpation and percussion of the abdomen may reveal ascites or masses Liver enlargement is present in several multisystem diseases (systemic lupus

erythematosus, infections, polycystic disease) and in glomerulosclerosis

DIFFERENTIAL DIAGNOSIS
Main ddx: 1.

2.
3. 4.

5.

Anaphylaxis Cellulitis (orbital,periorbital) Angioedema Nephrotic synd. Other causes of hypoalbuminaemia

Transient proteinuria Postural orthostatic proteinuria Glomerular abnormalities

INVESTIGATIONS
Diagnostic studies: 1.

2.
3. 4.

Proteinuria +1> on 2/3 random urine sample (Dipstick) P:C (> 200mg/mmol) (early morning) Serum lipid C3 level ( sensitive n specific if other than MCD)

Full blood count: HCT, WBC

Renal profile: normal in MCD Serum albumin: <25g/dL Urinalysis and quantification for urinary protein excretion

abundant hyaline cast Haematuria (other thn MCD) Na+ <10mmol/L in hypovolaemia

 Other investigations

complement levels: decrease suggest other thn MCD Antistreptolysin O titre and throat swab Hepatitis B antigen

DEFINITION FOR DX & TX OF IDIOPATHIC NS

REMISSION: Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3 consecutive days. RELAPSE: Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3 consecutive days. FREQUENT RELAPSES: Two or more relapses within 6 months of initial response or four or more relapses within any 12 month period. STEROID DEPENDENCE: Two consecutive relapses occurring during the period of steroid taper or within 14 days of its cessation. STEROID SENTITIVE: Normalization of proteinuria within 4 weeks after start of standard initial therapy with daily oral predinisolone STEROID RESISTANCE: Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy.

MANAGEMENT
STEROID SENSITIVE Prednisolone regime for initial dx:

60 mg/m2/day (max 80mg/day) for 4 weeks 40 mg/m2/48 hr (max 60mg/dose) for further 4 weeks

Prednisolone regime for relapses: 60 mg/m2/day (max 80mg/day) until remission 40 mg/m2/48 hr for 4 weeks

Frequent relapse or steroid dependent: Long term low dose prednisolone for 3-6 months

SCHEMA OF TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME 1. Nephrotic Syndrome Initial Diagnosis Prednisolone 60 mg/m2/day (max 80/day) for 4 week

Prednisolone 40

mg/m2/48

Response hours for 4 weeks

No Response

Renal Biopsy *Discontinue *Steroid taper at 25% monthly over 4 months

2. Relapse Prednisolone 60 mg/m2/day (max 80 mg/day) till remission, then 40 mg/m2/48 hours for 4 weeks and discontinue. 3. Frequent Relapses Reinduce as for (2) above, then taper and keep low dose alternate day prednisolone at 0.1 - 0.5 mg/kg/dose for 6 months. 4. Relapse on prednisolone As for (3) if not steroid toxic, consider cyclophosphamide (cumulative dose 168 mg/kg) if steroid toxic. 5. Relapses post cyclophosphamide As for (2) and (3) if not steroid toxic. If steroid toxic, refer paediatric nephrologist to consider a). second course cyclophosphamide or b). cyclosporine therapy.

STEROID RESISTANT
Symptomatic therapy: diuretic blood pressure control : ACEi (captopril, enalapril), angiotensin II receptor antagonist hyperlipidaemia Immunosuppressive therapy: Steroids cyclophosphamide Cyclosporin, tacrolimus, mycophenolate mofetil Indications for renal biopsy A renal biopsy is also NOT required prior to cytotoxic therapy Steroid resistant nephrotic syndrome Secondary NS Congenital NS

Steroid toxicity
Stunting of growth Cataracts Striae

Severe cushingoid features obehavioural changes, a rounded face, central obesity and the tendency to bruise more easily, hirsutism
Osteoporosis Proximal myopathy Recurrent infection dt low immunity

MANAGEMENT
Mx of oedematous state Bed rest to be avoided as there is a tendency of hrpercoagulability Dietary advice: no added salt, normal protein with adequate calories Prophylactic antibiotics: oral penicillin particularly in during relapse with gross oedema Hypovolaemia: infuse salt poor albumin or 5% albumin, plasma protein derivatives or human plasma Diuretics

 Mx complication: Infection: parenteral penicillin and a third generation cephalosporin (in primary peritonitis) If exposed to chickenpox and measles varicella-zoster immunoglobulin (VZIG) should be given within 72 hours after exposure to chickenpox / single dose of intravenous immunoglobulin. Thrombosis : Warfarin, low-dose aspirin, and dipyridamole all have been used to minimize the risk of clots.

URINE ALBUMIN MONITORING

It is advocated that monitoring of urine albumin

excretion be done regularly either at home with urinary dipstix or at the nearest health centre.

EDUCATION
Education: Parents and school teachers should be provided with information regarding the disease which includes: 1. Advice and precaution of infection 2. Danger of sudden steroid withdrawal (adrenal crisis) 3. Immunisation: While the child is on corticosteroid treatment and within 6 weeks after its cessation, only killed vaccines may be safely be administered to the child. Live vaccines can be administered 6 weeks after cessation of corticosteroid therapy

PROGNOSIS
Idiopathic NS

Steroid sensitive (90%)

Steroid resistant (10%)

Frequent relapses/S.dependent (50%)

ESRF

Infrequent relapses (33%)

No relapses (25%)

NUR AMIRA BINTI MOHD ASRI

CASE SCENARIO
A 7 year old Malay boy was admitted 3 days ago with the chief complaints of facial puffiness and passing smokey and frothy urine for 1 week. The facial puffiness initially started off as periorbital oedema which then progressed to involve the entire face within a week. Urinary output was also decreased. He also complaint of fever for one week which was of low grade, intermittent with no chills and rigor. There is also presence of an erythematous itchy skin lesion on his right elbow which was first noticed 2 weeks back. There is no history of sore throat, flu, blood transfusion, nausea, and vomiting, rashes, dyspnoea and chest pain. General examinations revealed pallor, high blood pressure of 139/96 mmHg, and an erythmatous scaly circular skin lesion on his right elbow. Urine biochemistry revealed protein 3+, RBC 4+. Blood urea was raised to 500 umol/L.

NEPHRITIC SYNDROME
It is a clinical complex, usually acute onset,

characterized by:
oedema eg facial puffiness Microscopic/macroscopic haematuria (teacoloured urine) hypertensi on Oligouria (decreased urine output) Azotemia/uremia (excess urea in urine)

 The lesions that cause nephritic syndrome have in

common proliferation of cells within in glomeruli, accompanied by a leukocytic infiltration. This inflammatory reaction injures the capillary walls, permitting escape of RBC into the urine(hematuria) , and induced hemodynamics changes that lead to a reduction in GFR which are manifested clinically by oligouria, reciprocal fluid retention and azotemia Hypertension is the result of the fluid retention by kidney secretion of renin.

NEPHROTIC SYNDROME

GLOMERULONEPHR ITIS

Acute poststreptococcal GN
lgA nephropathy

NEPHRITIC SYNDROME

Henoch-schnlein purpura
SLE

POSTSTREPTOCOCCAL AGN
The commonest cause of nephritic syndrome Usually followed a nephritogenic streptococcal

pharyngitis or impetigo with a strain of group A beta-hemolytic streptococci Immune-mediated inflammation Occurs most frequently in children 2 to 12 years old Boys are frequently affected This is diagnosed by evidence of a recent streptococcal infection (culture of the organism, raised ASOT) and low complement C3 levels, that return to normal after 6-8 weeks Long term prognosis is good

Epidemiology of post acute strep GN

121 of the 124 nephritis patients had

poststreptococcal infection.
(Department of paediatrics, HUSM, July 1987-June 1988)

Globally-incidence has decreased in the past 3

decades Most commonly-sporadic Despite that,epidemic cases in some poor and rural communities

pathogenesis
Throat/skin infection by gp A beta hemolytic streptococci (serotype 12, 4 and 1)

Antibodies to streptococcus (antistreptolysin O) are formed in the circulation Antigen-antibody circulating immune complexes are subsequently deposited along the glomerular basement membrane (GBM)

Streptococcal infection

Immune complex formation +deposited in GBM Complement system activated Immune injuries
Cellular proliferation

Low serum complement

GBM fracture

Capillary lumen narrowed

Glomerular blood flow decreased

hematuri a

proteinuria

oligouria

GFR low

Distal sodium reabsorption

Retention of water and sodium Blood volume increased Edema and hypertension

HENOCH-SCHNLEIN PURPURA
It is a systemic syndrome involving

the skin (purpuric rash), gastrointestinal tract (abdominal pain, joints (athritis), and kidney
The combination of

Skin rashes(symmetrical distributed over the buttocks,extensor surface of arms and legs and the ankles. Athralgia (knees and ankles) Periarticular oedema Colicky abdominal pain, GI petechiae,hematemesis, melaena, intussusception Glomerulonephritis

Usually occurs between the ages of 3-10 years olds Twice as common in boys peaks during winter months Is often preceded by an upper respiratory infection Unknown cause however it is postulated that genetic predisposition and antigen exposure increase circulating lgA levels. By immunofluorescence and electron microscopy the findings may be similar to those of IgAN

Systemic lupus erythematosus (SLE)

Is an autoimmune disease that presents mainly in

adolescent girls and young women(5% in childhood girl, rare in children younger than 9 yo, equal gender distribution in children) Multisystem disorder of unknown etiology characterized by the production of large amounts of circulating antibodies due to loss of T lymphocytes control on B lymphocytes which leads to autoantibody production Presence of multiple antibodies including antibodies to double-stranded DNA .

Criteria for diagnosis of SLE

signs
Malar rash (butterfly

Investigation data

rash) Photosensitivity Oral and nasopharyngeal ulcers Pleuritis and pericarditis Non erosive arthritis ( more than 2 joints with effusion and tenderness.

Protenuria(>500mg/2

4 hrs) or RBC cellular cast in urine Positive anti-dsDNA Evidence of presence of antiphospholipid antibodies

lgA NEPHROPATHY
Affects children and young adults Begins as an episode of gross hematuria that occurs within 1 or 2

days of a nonspecific upper respiratory tract infection. Is one the most common causes of recurrent microscopic or gross hematuria and is the most common glomerular disease revealed by renal biopsy The pathology hallmark is the deposition of lgA in the mesangium Prognosis is good in children

immunofluorescence with anti-IgA antibodies deposited in the mesangium

Familial nephritis
The commonest familial nephritis is Alports

syndrome X-linked recessive disorder Is associated with nerve deafness and ocular defect The mother may have hematuria Can progress to end-stage renal failure by early adult life in males.

Basic workup of a child with hematuria

History-age,gender,sosioeconomic status,family

history,drug history Physical examination-height,weight,blood pressure,funduscopy,presence or absence of abdominal mass,skin appearance,genitalia,edema,complete physical examination. Laboratory-urinalysis (includingmicroscopic examination and RBC morphology), urine culture, complete blood count (including platelets), serum electrolytes, creatinine,calcium, serum complement, random urine for total protein, creatinine, renal imaging studies.
Nelson p758

DALLIANA ADIA BTE ABD LATIF 2008402292

History
Antedencent hx of streptococcal throat of skin

infection- post-streptococcal GN Ask about symptoms of swelling-facial, perioral,pedal edema, or ascites Symptom of pulmonary edema/ CHF (eg dyspnoea with exertion, orthopnoea, SOB) Gross hematuria (eg dark, rust, coke, tea coloured) Family hx, other family member with nephritis or renal failure- Alport syndrome

 Epistaxis, headache, encephalopathy- severe

hypertension Oligouria Nonspecific symptoms eg malaise, fever, anorexia, weakness For tubulointestinal nephritis- try to obtain a history of a known etiology (eg bacterial, viral, drug related, metabolic, other) TIN, usually hx of polyuria than oliguria

Investigation
Laboratory FBC- anemia, leucocytosis

Urinalysis and culture- hematuria, proteinuria,

RBCs cast,other cellular masts, pyuria? Bacteriological an serology- Anti streptolysin-O titer (>200IU/mL), Anti-DNAse B, throat swab/skin swab, lupus serology, serum IgA Measure complement level- C3 RFT- blood urea, serum creatinine, electrolytes, BUN

 Acute poststreptococcal GGN- low C3, positive ASOT

and anti DNAase B TIN- hematuria, eosinophilia, sterile pyuria, low grade proteinuria, eosinophiluria, urinary WBc casts

Imaging
Renal ultrasonography- usually to exclude other

causes of hypertension and hematuria but usually not conducted in real cut nephritic sydrome

Histology
light microscopy: lymphocytes, PMN leukocytes

Immunofluoroscene- IgG, IgA, IgM, or complement

Electron- deposit in mesangial, subendothelial, or

subepithelial

Post-streptococcal nephritis
Urinalysis

ASOT
Low complement C3 levels- return to normal after 3-

4 weeks

Management
Treat the primary pathology- immunosuppressive

med eg steroids or cyclophosphamide in lupus Supportive care- Fluid and electrolyte balance, diuretics, Ca channel blocker, ACEi, monitor rapid deterioration in renal function Diet- fluid restriction, sodium, potassium restriction, Ca supplement Dialysis

Complication
Complication of severe hypertension (e.g. cerebral

haemorrhage, seizure, enchepalopathy,stroke, end organ damage) Complication of renal failure (e.g. hyperkalemia, fluid overload, electrolyte abnormality, uremic symtoms, anemia, abnormal bone mineralization, sexual dysfunction, poor growth, anorexia) Complication of primary disease (eg SLE)

Nephrotic and nephritic

Nephrotic noninflammatory Started from infancy Glomerular basement changes: decrease charge selectivity, size selctivity, or increase permeability Nephritic inflammatory More in the school age group Capillary changes

Sudden onset of hematuria (brown urine), RBC , RBC casts, and WBC, and granular casts present Massive proteinuria, mainly albuminuria (>1g/m2/24 hrs) Hypoalbuminemia (serum albumin <2.5g/dL) mild proteinuria Hypoalbuminemia

Nephrotic Edema (dt hypoalbuminemia) Hyperlipidemia (>250 mg/dL) dt increase lipoprotein Lipiduria Piss it all away and get fat (edema and hyperlipidemia)

Nephritic Edema (salt and water retention)

No lipid in the urine Immune, inflammation, I cant pee, I cant see (HTN)