NEPHROTIC SYNDROME by EKE E.P.

1. NEPHROTIC SYNDROME BY DR. EKE EGHOSASERE PAUL DEPT. OF PAEDIATRICS FEDERAL MEDICAL CENTRE, KEFFI, NASARAWA STATE

2. OUTLINE Introduction/Definition Epidemiology Aetiology Pathophysiology Clinical Features Investigations Differentials Treatment Complications Prevention Prognosis Conclusion References 2

3. INTRODUCTION Nephrotic Syndrome (NS) has been described by physicians as far back as the 17 th 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 3

4. 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 4

5. DEFINITION Nephrotic Syndrome (NS) is a manifestation of glomerular disease characterized by Heavy proteinuria > 3.5g/day or > 40mg/m 2 / 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 5

6. 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 6

7. 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 7

8. AETIOLOGY There are 3 varieties of Nephrotic Syndrome: Primary (Idiopathic) Nephrotic Syndrome Secondary Nephrotic Syndrome Congenital Nephrotic Syndrome 8

9. A. PRIMARY NEPHROTIC SYNDROME Minimal change nephrotic syndrome Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis Membranous Nephropathy 9

10. 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% 10

11. 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

12. 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 12

13. 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 13

14. 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 ), filariasis 14

15. SECONDARY NS Contd. 2. Multisytemic and connective tissue diseases: SLE, Henoch Schonlein 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 15

16. SECONDARY NS Contd. 6. Heredo -familial disorders: SCD, Alport syndrome, Wegener vasculitides 7. Metabolic: Diabetes mellitus, hypothyroidism 8. Transplant rejection 16

17. C. CONGENITAL NEPHROTIC SYNDROME Presents during the 1 st 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

18. 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 - actinin 4) and MYH9 ( podocyte gene) Steroid resistant NS: mutations in NPHS2 ( podocin ) and WT1 genes 18

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21. 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) 21

22. CLINICAL FEATURES 1. 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 22

23. 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 23

24. 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 24

25. INVESTIGATIONS 1. 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 casts 25

26. INVESTIGATIONS Contd. 3. Serum electrolytes, urea and creatinine: Na + normal/low Ionized Ca 2+ normal, total Ca 2+ reduced Creatinine: normal/increased Cl - , K + , HCO 3 - , 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 26

27. 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 27

28. DIFFERENTIALS OF NEPHROTIC SYNDROME Acute glomerulonephritis PEM ( Kwashiokor ) CCF (Right heart failure) Chronic liver disease Beri-Beri 28

29. TREATMENT 1 st 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 29

30. 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/m 2 /day, maximum 60mg/day), divided into two to four doses per day for 4-6 weeks Then, tapered down to 40mg/m 2 /day given every other day as a single daily dose for at least 4 weeks 30

31. TREATMENT Contd. Remission: diuresis, urine trace or negative for protein for 3 consecutive days Relapse: 3-4+ proteinuria plus oedema ; prednisone 60mg/m 2 /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 31

32. 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 32

33. 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 33

34. TREATMENT ALGORITHM FOR NS 34

35. COMPLICATIONS 1. 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) 35

36. 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 36

37. PREVENTION General health education Specific protection Early diagnosis and treatment Limitation of disability Rehabilitation 37

38. 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 38

39. S.M. M 4yrs 2/12 39

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42. 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

43. REFERENCES Nelson Textbook of Paediatrics, 19 th Edition; Chapter 521: Nephrotic Syndrome Nelson Essentials of Paediatrics, 6 th Edition; Chapter 162: Nephrotic Syndrome and Proteinuria Current Paediatric Diagnosis and Treatment, 15 th Edition; Chapter 21, pg 616: Idiopathic Nephrotic Syndrome of Childhood Paediatric and Child Health in a Tropical Region by Azubuike and Nkanginieme , 2 nd 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 43

44. THANKS FOR LISTENING!!! 44