BY

DR. EKE EGHOSASERE PAUL

DEPT. OF PAEDIATRICS

FEDERAL MEDICAL CENTRE, KEFFI, NASARAWA STATE

OUTLINE Introduction/Definition

Epidemiology

Aetiology

Pathophysiology

Clinical Features

Investigations

Differentials

Treatment

Complications

Prevention

Prognosis

Conclusion

References 2

INTRODUCTION Nephrotic Syndrome (NS) has been described by

physicians as far back as the 17th century

Theodore Zwinger III of Basel (1658-1724) described the oedema of NS at length

Domenuco Cotugno (1736-1820) in Naples described the proteinuria associated with the oedema

Leiter first introduced the term “Nephrotic Syndrome” in 1931

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INTRODUCTION Contd. Nephrotic Syndrome (NS) is primarily a paediatric

disorder

It is the most common chronic renal disease of childhood

Long term and day-to-day management of a child with NS should be a collaboratory effort between the primary care physician and paediatric nephrologist

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DEFINITIONNephrotic Syndrome (NS) is a manifestation of glomerular disease characterized by

Heavy proteinuria > 3.5g/day or > 40mg/m2/hr or 3+ or 4+ (albustix) or early morning spot urine Protein:Creatinine of > 2-3:1

Hypoalbuminaemia < 2.5g/dL

Massive generalized oedema

Hyperlipidaemia: cholesterol level > 250mg/dL or > 6mMol/L

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EPIDEMIOLOGY Among Caucasians, idiopathic NS constitutes about

90% of their cases, with minimal change disease being responsible for 85% of these

In Africa, membranoproliferative and focal segmental glormerulosclerosis (FSGS) are common

FSGS is currently the most common glomerular disorder resulting in end stage kidney disease in children and young adults in US and many parts of the world

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EPIDEMIOLOGY Contd. 31% of 2266 Nigerian children treated for renal disease

were found to have Nephrotic Syndrome (Okoro and Okafor, 1998)

Incidence: 2-4 new cases/100,000 population per year

Peak age incidence in most Nigerian centres occurs in the school age as against pre-school age reported in Caucasian series

Commoner in males, M:F = 2:1

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AETIOLOGYThere are 3 varieties of Nephrotic Syndrome:

Primary (Idiopathic) Nephrotic Syndrome

Secondary Nephrotic Syndrome

Congenital Nephrotic Syndrome

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A. PRIMARY NEPHROTIC SYNDROME Minimal change nephrotic syndrome

Focal segmental glomerulosclerosis

Membranoproliferative glomerulonephritis

Membranous Nephropathy

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MINIMAL CHANGE NEPHROTIC SYNDROME (MCNS) Most common histologic form of primary NS in children

More than 80% of children under 7 years of age with NS have MCNS

Children 7 to 16 years old with NS have a 50% chance of having MCNS

M:F = 2:1

Response to steroids= 90%

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FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) Accounts for approximately 10-20% of children with primary

NS

May present like MCNS, or with less impressive proteinuria

FSGS may develop from MCNS or present as a separate entity

A circulating factor that increases glomerular permeability is found in some patients with FSGS

Over 1/3 of children with FSGS progress to renal failure

Response to steroids: 15-20%11

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) Characterized by hypocomplementaemia with signs of

glomerular renal disease

Present in 5-15% of children with primary NS

Typically persistent

Has a high likelihood of progression to renal failure over time

Response to steroids: not established

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MEMBRANOUS NEPHROPATHY Occurs in less than 5% of children with primary NS

Seen most commonly in adolescents and children with systemic infections like hepatitis B, syphilis, malaria and toxoplasmosis

Also seen in those receiving drug therapy (gold salts, penicillamine)

Response to steroids: may be slow progression

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B. SECONDARY NEPHROTIC SYNDROME

1. Post infectious:

a. Protozoal:

Plasmodium malariae: very important here, in late 1960’s said to have accounted for 80% of patients with NS in Ibadan, ¼ of cases seen in Zaria

P. falciparum: rarely

Toxoplasmosis

b. Bacterial: post streptococcal AGN, syphillis (rarely)

c. Viral: HBV, CMV, Varicella, HIV

d. Parasitic: S. mansoni (sometimes haematobium), filariasis14

SECONDARY NS Contd.2. Multisytemic and connective tissue diseases: SLE, HenochSchonlein purpura, Sarcoidosis, Amyloidosis

3. Allergic disorders: bee sting, serum sickness, poison ivy, pollens

4. Drugs and heavy metals: mercury, lead, gold, penicillamine, trimethadione

5. Neoplastic: lymphomas, leukaemias, Wilms tumour

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SECONDARY NS Contd.6. Heredo-familial disorders: SCD, Alport syndrome, Wegener vasculitides

7. Metabolic: Diabetes mellitus, hypothyroidism

8. Transplant rejection

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C. CONGENITAL NEPHROTIC SYNDROME

Presents during the 1st 2 months of life, 2 common types

The Finnish type: autosomal recessive, more common in persons of Scandinavian descent, due to a mutation in the nephrin protein component in the glomerular filtration slit

Second type: heterogenous group of abnormalities including diffuse mesangial sclerosis and conditions associated with drugs or infections; prenatal onset is supported by elevated levels of maternal alpha-fetoprotein 17

PATHOPHYSIOLOGY Underlying abnormality: increased permeability of

glomerular capillary wall

On biopsy: extensive effacement of podocyte foot processes, normal negative charge which restricts filtration of serum proteins is lost

Idiopathic NS: Complex disturbances in T-cell mediated immunity

FSGS: mutations in podocyte proteins (podocin, α-actinin4) and MYH9 (podocyte gene)

Steroid resistant NS: mutations in NPHS2 (podocin) and WT1 genes

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PATHOPHYSIOLOGY Contd. Massive proteinuria results in decline of serum

proteins (albumin)

Reduced plasma oncotic pressure leads to fluid shift from vascular to interstitial compartment, and plasma volume contraction

Oedema enhanced by activation of renin-angiotensin-aldosterone system

Liver lipoprotein synthesis is increased, leading to elevated serum lipids (cholesterol, triglycerides)

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CLINICAL FEATURES1. Oedema:

Usually starts from the face (periorbital swelling), limbs, abdomen, genitalia

Subsides with ambulation

Weight increase in spite of poor appetite

Patients present late (sometimes about 1-2 months) after onset of symptoms

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CLINICAL FEATURES Contd.

2. Abdominal swelling, abdominal pain

3. Diarrhoea

4. Anorexia

5. Frothy urine, decreased urinary output

6. Change in quality of hair: related to protein deficiency

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CLINICAL FEATURES Contd.7. Pallor and shiny skin

8. Ascites

9. Blood Pressure: usually normal in early stage, could be raised in MPGN

10. Respiratory difficulty from pleural effusion

11. Features of infection: pneumonia, UTI

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INVESTIGATIONS1. Urinalysis:

Dip stick: 3+ or 4+ proteinuria

Microscopic haematuria (20% of children)

Other tests of proteinuria:

24 hour urinary protein excretion = >2g/day

Spot urine Protein : Creatinine > 2-3: 1

2. Urine microscopy: RBC, WBC casts25

INVESTIGATIONS Contd.3. Serum electrolytes, urea and creatinine: Na+ normal/low Ionized Ca2+ normal, total Ca2+ reduced Creatinine: normal/increased Cl-, K+, HCO3

-, urea: usually normal

4. Serum albumin ↓, < 2.5g/dL

5. Cholesterol ↑, > 250mg/dL

6. Stool: S. mansoni ova

7. Others: FBC, Hepatitis B and C testing, HIV, serum complement

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INVESTIGATIONS Contd.8. Renal biopsy; indications include:

Age of onset < 1 year or > 8 years

Steroid resistance

Frequent relapses or steroid dependency

Significant chronic nephritic manifestations: haematuria, hypertension, renal insufficiency, hypocomplementaemia

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DIFFERENTIALS OF NEPHROTIC SYNDROME Acute glomerulonephritis

PEM (Kwashiokor)

CCF (Right heart failure)

Chronic liver disease

Beri-Beri28

TREATMENT 1st episode of NS with mild/moderate oedema may be

managed as outpatients

Indications for admission:

Generalized oedema severe enough to cause respiratory distress

Tense scrotal or labial oedema

Complications: sepsis, peritonitis, pneumonia, thromboembolic phenomenon, FTT

Patient or family compliance with treatment is in doubt

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TREATMENT Contd. Children 1-8 years with uncomplicated NS most likely

steroid responsive, steroids can be commenced without renal biopsy

Prednisone 2mg/kg/day (60mg/m2/day, maximum 60mg/day), divided into two to four doses per day for 4-6 weeks

Then, tapered down to 40mg/m2/day given every other day as a single daily dose for at least 4 weeks

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TREATMENT Contd. Remission: diuresis, urine trace or negative for protein for 3

consecutive days

Relapse: 3-4+ proteinuria plus oedema; prednisone 60mg/m2/day in a single AM dose until remission, then switched to alternate day dosing, tapered over 4-8weeks

Steroid dependent: relapse while on alternate day steroid therapy, or within 28 days of completing therapy

Frequent relapsers: respond well to prednisone therapy but relapse > 4 times in a 12 month period

Steroid resistant: proteinuria (2+ or greater) after 8 weeks of steroid therapy

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TREATMENT Contd. For steroid resistant NS: cyclophosphamide (2mg/kg over

8-12 weeks), chlorambucil, cyclosporine A, levamisole

Oedema:

Restriction of salt intake

Loop diuretics eg. Frusemide, with spironolactone

If severe: cautious administration of 25% albumin (0.5-1.0g/kg IV over 1-2 hours) with an IV loop diuretic

Albumin is rapidly excreted, salt restriction and diuretics should be continued

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TREATMENT Contd. Acute hypertension is treated with β-blockers or

calcium channel blockers

Persistent hypertension usually responds to angiotensin-converting enzyme (ACE) inhibitors

ACE inhibitors and angiotensin II blockers also helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients

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TREATMENT ALGORITHM FOR NS

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COMPLICATIONS1. Increased susceptibility to infections (peritonitis: S. pneumoniae, E. coli, Klebsiella)

Reduced immunoglobulins

Oedema fluid acting as a culture medium

Reduced bactericidal activity of leococytes

Immunosuppressive therapy

Reduced perfusion of the spleen due to hypovolaemia

Loss in urine of factor B (alternative pathway particularly significant in opsonization of encapsulated organisms)

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COMPLICATIONS Contd.2. Hypovolaemia: diarrhoea, diuretics

3. Hypercoagulative state, thromboembolism: increased prothrombotic factors (fibrinogen) and loss of fibrinolytic factors (antithrombin III, proteins C and S)

4. Hyperlipidaemia: increased risk of atherosclerotic vascular disease

5. Chronic renal insufficiency, failure

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PREVENTION General health education

Specific protection

Early diagnosis and treatment

Limitation of disability

Rehabilitation

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PROGNOSIS Nearly 80% of children with MCNS experience relapse

(heavy proteinuria that persists for 3 or more consecutive days)

Steroid responsive patients have little risk of chronic renal failure

FSGS: may initially respond to steroids, later not respond, may progress to end stage renal failure

Recurrence of FSGS occurs in 30% of children who undergo renal transplantation

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S.M.M4yrs 2/12

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CONCLUSION Nephrotic Syndrome is a manifestation of glomerular

disease characterized by heavy proteinuria, hypoalbuminaemia, hypercholesterolaemia and oedema

Most children with NS have a form of primary or idiopathic NS

Children between 1 and 8 years with uncomplicated NS are likely to have steroid responsive MCNS, steroid therapy may be commenced without renal biopsy

Nearly 80% of them will experience relapse 42

REFERENCES Nelson Textbook of Paediatrics, 19th Edition; Chapter 521: Nephrotic

Syndrome

Nelson Essentials of Paediatrics, 6th Edition; Chapter 162: Nephrotic Syndrome and Proteinuria

Current Paediatric Diagnosis and Treatment, 15th Edition; Chapter 21, pg 616: Idiopathic Nephrotic Syndrome of Childhood

Paediatric and Child Health in a Tropical Region by Azubuike and Nkanginieme, 2nd Edition; Chapter 59: Nephrotic Syndrome and Acute Glomerulonephritis

Renal Medicine; History of Nephrotic Syndrome: http://www.renalmed.co.uk/history-of/nephrotic-syndrome

Wikipedia; Nephrotic Syndrome: http://en.wikipedia.org/wiki/Nephrotic_syndrome

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THANKSFORLISTENING!!!

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