Idiopathic Nephrotic Syndrome

1. Idiopathic Nephrotic Syndrome Dr.Fahad Gadi, MD Pediatrics Demonstrator King Abdulaziz University Rabigh Medical School

2. Nephrotic Syndrome • Generally has a glomerular cause • Types: primary and secondary • Secondary NS : anaphylactoid purpura, systemic lupus erythematosus, diabetes mellitus, sickle cell disease, syphilis,

3. NS: Types • Minimal change nephrotic syndrome (MCNS) • Focal segmental glomerulosclerosis (FSGS) • Congenital nephrosis • Membranoproliferative glomerulonephritis (MPGN) • Membranous glomerulonephritis (MGN).

4. FSGS • Second most common histologic subtype • FSGS is always a histopathologic diagnosis • FSGS may manifest in a fashion that is indistinguishable from MCNS, but it may also be found only after years of clinical nephrotic syndrome when earlier biopsies have been interpreted as MCNS. • FSGS is a known consequence of hyperfiltration and is regularly seen in patients with reflux nephropathy and in some patients with a single kidney whose other has been lost because of conditions such as multicystic dysplastic kidney disease

5. Congenital NS • Congenital nephrotic syndrome becomes a consideration when nephrosis appears during the first year of life and particularly in those instances in which the clinical syndrome starts in the first few months

6. MPGN • In older children and adolescents. • Clinical picture is more closely associated with a nephritic picture, but on occasion it may appear similar to MCNS or FSGS. • Membranous glomerulonephritis (MGN) accounts for less than 1% of the cases of NS in childhood and adolescence • Often associated with hepatitis or other viral disease.

7. Mortality • MCNS: reported cumulative mortality rate (at 20 y postonset) of less than 15% (range in various studies, 5-15%). • FSGS: cumulative mortality rate is greater than 50%

8. Morbidity • Hospitalization, in some instances • A prolonged period of treatment • Frequent monitoring both by parents and by physician • Administration of medications associated with significant adverse events • A high rate of recurrence (ie, relapses in >60% of patients) • The potential for progression to chronic renal failure (CRF)

9. Definitions • Nephrotic Syndrome (NS)- Edema, Albumin < 2.5 mg/dL, proteinuria > 40 mg/m2*hr • Remission- Urinary protein < 4 mg/ m2*hr or Albustix = 0/Trace for 3 consecutive days • Steroid Responsive- Remission with steroids alone

10. Definitions • 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

11. 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

12. Pathogenesis: not clear • Believed to have an immune pathogenesis • Despite the regular finding of elevated levels of IgE and an association with atopy in steroid-responsive NS, current data merely suggest a common immune activation rather than a direct association • Glomerular capillary permeability to albumin is selectively increased

13. 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

14. Epidemiology • Familial incidence • European survey 63 of 1877 nephrotic children had affected siblings • Familial NS similar with respect to histopathology and steroid response

15. Epidemiology • Bonilla-Felix has noted a lower incidence of MCD and higher incidence of FSGS than previously reported • Gulati in 1999 reported a doubling of the incidence of FSGS over historical controls

16. Associated Disorders • Atopy has been found in 34-60% of children with MCD • Meadow reported plasma IgE levels elevated in 10 of 84 with MCD • Malignancy • Hodgkin’s disease • T cell lymphomas • Thymoma/ myasthenia gravis • Diabetes Mellitus

17. Clinical Features- Edema • Physical exam • Accumulates in gravity dependent tissues • Puffiness around eyes • Genital edema is generally painful

18. Clinical Features- Edema • Pathogenesis • 80% of oncotic pressure due to albumin • Below 2 g/dL edema accumulates • Intravascular volume depletion • Renin-aldosterone activation • Plasma volume (PV) has not always been found to be decreased and, in fact, in most adults, measurements of PV have shown it to be increased. Only in young children with MCNS have most (but not all) studies demonstrated a reduced PV. Additionally, most studies have failed to document elevated levels of renin, angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium reabsorption also continues despite actions that should suppress renin effects

19. Hematuria • Frequency of macrohematuria depends on the histologic subtype of NS. • More common in those patients with MPGN • In MCNS has been reported to be as high as 3-4% of cases. • Higher percentage of patients with FSGS have microhematuria than those with MCNS, but this is not helpful in differentiating between types of NS in the individual patient.

20. Hematuria: microscopic • Microscopic hematuria is present at the onset of the disease in 20-30% of patients with MCNS, but it disappears thereafter. By contrast, microscopic hematuria is consistently present in 80-100% of patients with MPGN and in 60% of patients with MN. • Patients with FSGS have hematuria more often than patients with MCNS, but the presence of hematuria cannot be used to distinguish between the 2 conditions.

21. Clinical Features- Edema • Evidence against • Analbuminemia • Steroid induced diuresis • Increased intravascular volume • Low renin/aldosterone levels

22. Clinical Features- Hypovolemia • Classic teaching • Not all patients are hypovolemic

23. Clinical Features- Infection • Bacterial infections • Prone to bacterial sepsis • Cellulitis • IgG levels low • Lymphocyte function impaired • Viral Infections • Measles may induce remission in NS • Relapse preceded by viral infection

24. Clinical Features- Thrombosis • Serious risk of thrombosis • Increased fibrinogen concentration • Antithrombin III concentration reduced • NS patients resistant to heparin • Platelets hyperaggregable • Increased blood viscosity

25. Laboratory Features • Hct may be elevated • Hyponatremia is common • Plasma creatinine is elevated in 33% of patients

26. Laboratory- Plasma Protein • Albumin • Hypoalbuminemia due to loss via the kidney • Immunoglobulins • IgG levels reduced • IgM levels elevated • IgM-IgG-Switching

27. Laboratory- Hyperlipidemia • Increased synthesis of cholesterol, triglycerides and lipoproteins • Decreased catabolism of lipoproteins • Decreased activity of lipoprotein lipase • Decreased LDL receptor activity • Increased urinary loss of HDL

28. Laboratory- Urinalysis • Broad, waxy casts • Lipid droplets • Hematuria 22.7% of MCNS • Low urine sodium • High osomolality

29. Laboratory- Proteinuria • > 40 mg/hour * m2 • Urine protein/creatinine ratio > 2 • Unusual to see tubular proteinuria

30. Selectivity Index • Clearance of IgG/ Clearance of Transferrin • MCD • 53% < 0.10 • 13 % > 0.20 • FSGS • 15% < 0.10 • 57% > 0.20

31. Indications for Biopsy • Pretreatment • Recommended • Onset age < 6 months • Macroscopic hematuria • Microscopic hematuria and HTN • Low C3 • Renal failure • Discretionary • Onset between 6-12 months or > 12 years • Persistent HTN or hematuria

32. Indications for Biopsy • Post treatment • Steroid resistance • Frequent relapsers

33. Steroid Sensitive Nephrotic Syndrome- SSNS • Natural history • 1 year mortality 2.5% • Late outcome of 152 patients followed 14-19 years 7.2% mortality • 1/4 of patients have a single relapse • 1/3 relapse occasionally • 1/2 become steroid dependent • Most remit at puberty • 2-7% will continue to relapse • Renal survival near 100%

34. Diuretic Therapy • loop diuretics (furosemide) given orally in usual amounts (~1-2 mg/kg/d) are safe and moderately effective • If the edema is sufficiently intense that intravenous diuretic therapy seems indicated, then salt-poor albumin should be infused (usually at 1 gram/kg body weight given IV over 2-4 hours) • Diuretics other than loop diuretics (eg, thiazides, spironolactone, metolazone) are generally not potent enough alone • diuresis but may give an added effect when combined with furosemide. Metolazone (with or without spironolactone) may be beneficial in combination with furosemide for resistant edema.

35. Treatment- Diet • Low protein • Decreases albuminuria • Malnutrition • Salt restriction • During edema

36. Treatment- Antibiotics/ Immunizations • Prophylactic Penicillin with ascites • Gram negative coverage for peritonitis • Streptococcal immunization • Varicella • VZIG if exposed • Immunizations • No live viruses while on daily steroids • No oral polio for siblings

37. Treatment- Albumin • Controversial • Indication- Hypovolemia • Abdominal pain • Hypotension • Oliguria • Renal insufficiency

38. Complications • Mortality • 1940’s- 40% 1 year mortality • Now 1-2% • Main cause of death • Infection • Thrombosis

39. Steroid: Initial therapy • Higher dosages or longer courses of daily steroids do not significantly change the response rate in MCNS • 90% of patients with MCNS respond to this therapy with complete clearing of proteinuria, but only about 20% of children with FSGS and <5% of those with MPGN experience a clinical remission (defined as a diuresis without complete clearing of proteinuria). • The majority of children with MCNS will respond between the 10th and 14th days of such therapy, but a full course of at least 4 weeks of daily therapy is still recommended. • Children who do not respond (ie, complete clearing of proteinuria) should be referred to a pediatric nephrologistfor percutaneous renal biopsy and consideration be given to an alternative plan of treatment.

40. Corticosteroids Initiation • High dose steroids • 2 mg/kg/day (max 80 mg) • 60 mg/m2 (max 80 mg) • 3 accepted protocols • 80% respond within 2 weeks

41. Corticosteroids Initiation

42. Corticosteroids Initiation • Higher dosages or longer courses of daily steroids do not significantly change the response rate in MCNS • The intensity and duration of the initial corticosteroid regime influences the rate of relapse of NS

43. Cochrane metaanlysis: steroid • In children in their first episode of SSNS, treatment with prednisone for at least three months results in fewer children relapsing by 12 to 24 months with an increase in benefit being demonstrated for up to seven months of treatment compared with two months therapy. In a population with a baseline risk for relapse of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate-day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. • In comparison with three months of therapy, six months of therapy results in a reduced risk for relapse without increase in adverse effects. • The reduction in risk for relapse is associated with both an increase in duration and an increase in dose. • During daily therapy, prednisone is as effective when administered as a single daily dose compared with divided doses. • Alternate-day therapy is more effective than intermittent therapy (three consecutive days of seven days) in maintaining remission. • In relapsing SSNS, long duration of alternate-day prednisone is more effective than the standard duration therapy for relapse originally recommended by the ISKDC

44. Corticosteroids- Maintenance • Individualized for each patient • Usually tapered over 6 months- 1 year

45. Steroid • 4 weeks: intensive (daily) treatment • 8 weeks: 1.5 mg/kg/d (one dose every other morning) • 8 weeks: 1.0 mg/kg/d (one dose every other morning) • 8 weeks: 0.5 mg/kg/d (one dose every other morning)

46. Relapse • No predictors of relapse • Relapses as responsive • 25% spontaneously remit • Treatment deferred 5 days • Intensification of relapse treatment has little effect on subsequent relapse rate

47. Corticosteroids- Relapse • 60 mg/m2/day until remission • Change to alternate day • Taper over 1-3 months

48. Steroid Toxicity • Cushingoid habitus • Obesity • Striae • Hirsutism • Acne • Growth failure • Avascular necrosis • Osteoporosis

49. Steroid Toxicity • Peptic ulceration • Pancreatitis • Posterior lens opacities • Myopathy • Increased ICP • Susceptibility to infection

50. Indications for Alternative Therapy-SSNS • Relapse on Prednisone Dosage >0.5 mg/kg/alt day plus: • Severe steroid side effects • High risk of toxicity- diabetes • Unusually severe relapses • Relapses on Prednisone Dosage >1.0 mg/kg/alt day