Nephrotic Syndrome

Reference from 21st edition of Nelson and 9th edition of Ghai

1. NEPHROTIC SYNDROME Dr.Himanshu Dave Department of Pediatrics NRCH , New Delhi

2. Nephrotic syndrome is the clinical manifestation of glomerular diseases associated with heavy ( nephrotic -range) proteinuria . Nephrotic -range proteinuria is defined as proteinuria > 3.5 g/24 hr ( or > 1 g/m2/day) or a urine protein:creatinine ratio > 2.

3. Clinical triad of nephrotic syndrome arises from the large urinary losses of protein, comprises of: 1) Hypoalbuminemia (≤2.5 g/ dL ) 2) Oedema ( due to fall in plasma oncotic pressure) 3) Hyperlipidemia (cholesterol>200mg/ dL ).

4. Affects 1-3 per 100,000 children < 16 yr of age. Most common cause of death in untreated nephrotic syndrome is “ Infection”. 80% of children with nephrotic syndrome respond to corticosteroid therapy.

5. Etiology of Nephrotic Syndrome Primary /Idiopathic Nephrotic Syndrome Minimal change disease ( most common) Focal segmental glomerulosclerosis Membranous nephropathy Glomerulonephritis associated with nephrotic syndrome– membranoproliferative GN, crescentic GN, immunoglobulin A nephropathy

6. GENETIC DISORDERS ASSOCIATED WITH PROTEINURIA OR NEPHROTIC SYNDROME: Nephrotic Syndrome (Typical) : 1] Finnish-type congenital NS (absence of nephrin ) 2] Focal segmental glomerulosclerosis (mutations in nephrin , podocin , MYO1E , α- actinin 4, TRPC6) 3] Diffuse mesangial sclerosis (mutations in laminin β2 chain) 4] Denys- Drash syndrome (mutations in WT1 transcription factor) 5] Congenital nephrotic syndrome with lung and skin involvement ( integrin α-3 mutation) 6] Mitochondrial disorders

7. (B) Proteinuria With or Without Nephrotic Syndrome : 1] Nail–patella syndrome 2] Alport syndrome (C) Multisystem Syndromes With or Without Nephrotic Syndrome: 1] Charcot-Marie-Tooth disease 2] Cockayne syndrome 3] Laurence-Moon- Biedl - Bardet syndrome

8. (D) Metabolic Disorders With or Without Nephrotic Syndrome : Alagille syndrome , α1 – Antitrypsin deficiency , Fabry disease , Glutaric acidemia , Glycogen storage disease , Hurler syndrome, Partial lipodystrophy , Mitochondrial cytopathies , Sickle cell disease

9. SECONDARY CAUSES OF NEPHROTIC SYNDROME : Infections: Endocarditis , Hepatitis B&C , HIV-1, Infectious mononucleosis , Cytomegalovirus , Malaria ,Syphilis (congenital and secondary) , Toxoplasmosis , Tuberculosis , Schistosomiasis , Filariasis .

10. (B) Drugs: Captopril , Penicillamine , Gold , NSAIDS, Pamidronate ( bisphosphonates ) , Interferon, Mercury , Heroin , Lithium Rifampicin , Sulfasalazine . (C) Immunologic or Allergic Disorders: Vasculitis syndromes, Castleman disease , Kimura disease, Bee sting , Snake venom , Food allergens , Serum sickness, Poison ivy, poison oak .

11. (D) Associated With Malignant Disease : Wilms Tumor , Lymphoma , Pheochromocytoma , Leukemia , Thymoma , Solid tumors . (E) Glomerular Hyperfiltration : Oligomeganephronia , Morbid obesity , Adaptation to nephron reduction

12. Pathogenesis of Nephrotic Syndrome ROLE OF PODOCYTES The underlying abnormality in nephrotic syndrome is an increased permeability of the glomerular capillary wall, which leads to massive proteinuria and hypoalbuminemia . Podocyte : - Structural support of capillary loop. - Major component of the glomerular filtration barrier to proteins. -Involved in synthesis and repair of the glomerular basement membrane. The slit diaphragm is one of the major impediments to protein permeability across the glomerular capillary wall.

13. Important component proteins of the slit diaphragm include nephrin , podocin , CD2AP, and α- actinin 4. Podocyte injury or genetic mutations of genes producing podocyte proteins may cause nephrotic -range proteinuria . Mutations in NPHS1, WT1, and NPHS2 are most common.

14. Genetic mutations of podocyte genes decreased by age: 66% in patients with congenital nephrotic syndrome to 15–16% in school age patients and adolescents. * In nephrotic syndrome : Decrease in number of functional podocytes , and altered slit diaphragm integrity. The end result is increased protein leakiness across the glomerular capillary wall into the urinary space.

15. ROLE OF THE IMMUNE SYSTEM : Minimal change nephrotic syndrome (MCNS) may occur after- - Viral infections - Allergen - Hodgkin lymphoma - T-cell lymphoma * Immuno suppression with drugs (corticosteroids and cyclosporine) provides additional evidence that immune system contributes to the overall pathogenesis of the nephrotic syndrome.

16. Clinical Consequences of Nephrotic Syndrome

17. EDEMA Most common presenting symptom of Nephrotic syndrome. Two opposing theories, the underfill hypothesis and the overfill hypothesis proposed as mechanisms causing nephrotic edema .

18. The underfill hypothesis : Nephrotic -range proteinuria leads to fall in plasma protein level corresponding decrease in intravascular oncotic pressure leads to leakage of plasma water into the interstitium , generating edema . As a result of reduced intravascular volume increased secretion of vasopressin and atrial natriuretic factor, which, along with aldosterone , results in increased sodium and water retention by tubules. Sodium and water retention therefore occur as a consequence of intravascular volume depletion .

19. This hypothesis does not fit the clinical picture of some patients with edema who have clinical signs of intravascular volume overload, not volume depletion. Such patients needs to be treated with ALBUMIN + DIURETICS to induce diuresis . ( NOT ALBUMIN ALONE)

20. The overfill hypothesis: N ephrotic syndrome is associated with primary sodium retention, with subsequent volume expansion and leakage of excess fluid into the interstitium . Epithelial sodium channel in the distal tubule – key role in sodium reabsorption in nephrotic syndrome.

21. Weaknesses of hypothesis : Numerous nephrotic patients present with pictue of intravascular volume depletion i.e , low blood pressure, tachycardia, and elevated hemoconcentration . Furthermore, amiloride , an epithelial sodium channel blocker, used alone is not sufficient to induce adequate diuresis .

22. The goal of therapy : Gradual reduction of edema with judicious use of diuretics, sodium restriction, and cautious use of intravenous albumin infusions, if indicated.

23. HYPERLIPIDEMIA Increase in cholesterol, triglycerides, low-density lipoproteins, and very-low-density lipoproteins. The high-density lipoprotein level remains unchanged or is low. Result of increased synthesis as well as decreased catabolism of lipids.

24. Increased Susceptibility to Infections Susceptible to infections such as cellulitis , spontaneous bacterial peritonitis, and bacteremia . Result of many factors, particularly hypoglobulinemia as a result of the urinary losses of immunoglobulin ( Ig ) G. Defects in the complement cascade from urinary loss of complement factors (C3 and C5), as well as alternative pathway factors B and D, lead to impaired opsonization of microorganisms.

25. I ncreased risk for infection with encapsulated bacteria and, in particular, pneumococcal disease . Spontaneous bacterial peritonitis presents with fever, abdominal pain, and peritoneal signs. Pneumococcus is the most frequent cause of peritonitis ,Gram -negative bacteria are also associated. Peritoneal leukocyte counts > 250 cells/µL are highly suggestive of spontaneous bacterial peritonitis.

26. Hypercoagulability Nephrotic syndrome is a hypercoagulable state resulting from multiple factors: 1] Vascular stasis from hemoconcentration and intravascular volume depletion 2] Increased platelet number and aggregability 3] Changes in coagulation factor levels. Increase in hepatic production of fibrinogen along with urinary losses of antithrombotic factors such as antithrombin III and protein S.

27. Idiopathic Nephrotic Syndrome

28. 90% of children with nephrotic syndrome. Associated with primary glomerular disease without an identifiable causative disease or drug Idiopathic NS includes multiple histologic types: 1] Minimal change disease 2] Mesangial proliferation 3] Focal segmental glomerulosclerosis 4] Membranous nephropathy 5] Membranoproliferative GN

29. PATHOLOGY In minimal change nephrotic syndrome 85% of total cases of nephrotic syndrome in children. Glomeruli appear normal or minimal increase in mesangial cells and matrix. Immunofluorescence microscopy : Negative Electron microscopy : Effacement of the epithelial cell foot processes. More than 95% of children with minimal change disease respond to corticosteroid therapy.

30. Mesangial proliferation Diffuse increase in mesangial cells and matrix on light microscopy. Immunofluorescence microscopy : Trace to 1+ mesangial IgM and/or IgA staining. Electron microscopy : Increased numbers of mesangial cells and matrix as well as effacement of the epithelial cell foot processes. 50% of patients with this histologic lesion respond to corticosteroid therapy.

31. In focal segmental glomerulosclerosis (FSGS) Glomeruli lesions are both focal (present only in a proportion of glomeruli ) and segmental (localized to ≥ 1 intraglomerular tufts). Light microscopy : Mesangial cell proliferation and segmental scarring. Immunofluorescence microscopy : Positive for IgM and C3 staining in areas of segmental sclerosis. Electron microscopy : Segmental scarring of glomerular tuft with obliteration of glomerular capillary lumen.

32. FSGS may be seen secondary to : - HIV infection - Vesicoureteral reflux -IV use of heroin and drugs abuse. 20% of patients with FSGS respond to prednisone.

33. Clinical Manifestations of MCNS Males:females = 2 : 1 Most commonly appears between ages of 2 and 6 yr. FSGS is most common variety in adults. The initial episode of idiopathic NS & subsequent relapses, may follow minor infections or reactions to insect bites or bee stings.

34. Children present with mild edema , initially noted around eyes and in lower extremities (Pitting in nature) With time, edema becomes generalized ( ascites , pleural effusions, and genital edema ). Anorexia, irritability, abdominal pain, and diarrhea are common. Important features of minimal change idiopathic NS are : Absence of hypertension and gross hematuria (the so-called nephritic features ).

35. The differential diagnosis of child with marked edema includes : Protein losing enteropathy Hepatic failure Heart failure Acute or chronic glomerulonephritis Protein malnutrition.

36. Diagnosis other than MCNS should be considered in: Children < 1 yr of age Positive family history of nephrotic syndrome Presence of extrarenal findings (e.g., arthritis, rash, anemia ) Hypertension or pulmonary edema Acute or chronic renal insufficiency Gross hematuria .

37. Diagnosis of Nephrotic Syndrome Confirmed by urinalysis with first morning urine protein:creatinine ratio and serum electrolytes, blood urea nitrogen, creatinine , albumin, and cholesterol levels. Rule out secondary forms of nephrotic syndrome (children ≥ 10 yr) by complement C3 level, antinuclear antibody, double-stranded DNA; hepatitis B and C and HIV in high-risk populations; and kidney biopsy (for children ≥ 12 yr, who are less likely to have MCNS).

38. Urinalysis : 3+ or 4+ proteinuria and microscopic hematuria in 20% of children. : A spot urine protein:creatinine ratio >2.0. : The serum creatinine value is usually normal, but abnormally elevated if there is diminished renal perfusion from contraction of the intravascular volume. : Serum albumin < 2.5 g/Dl : Serum cholesterol and triglyceride elevated. : Serum complement levels normal. Renal biopsy not routinely performed if patient fits the standard clinical picture of MCNS.

39. Treatment of the Initial Episode of Nephrotic Syndrome Tuberculosis must be ruled out prior to starting therapy with corticosteroids. Children with features that make MCNS less likely (gross hematuria , hypertension, renal insufficiency, hypocomplementemia , or age < 1 yr or > 12 yr) should be considered for renal biopsy before treatment.

40. Prednisone or prednisolone , single daily dose of 60 mg/m2 /day or 2 mg/kg/day to a maximum of 60 mg daily for 4-6 wk followed by alternate-day prednisone (starting at 40 mg/m2 qod or 1.5 mg/kg qod ) for a period ranging from 8 wk to 5 mo, with tapering of the dose. KDIGO Glomerulonephritis Work Group recommends at least 12 wk of steroid treatment. 80–90% of children respond to steroid therapy.

41. DEFINITION Response : Attainment of remission within the initial 4 wk of corticosteroid therapy. Remission : Urine protein:creatinine ratio of < 0.2 or < 1+ protein on urine dipstick testing for 3 consecutive days. # Most children with minimal change disease respond to daily prednisone therapy , within first 2-3 wk of treatment.

42. Relapse: Increase in the first morning urine protein:creatinine ratio > 0.2 or a reading of 2+ and higher for 3 consecutive days on Albustix testing. Frequently relapsing: Two or more relapses within 6 mo after the initial therapy or four relapses in a 12-mo period. Steroid dependent: ( 2 consecutive: According to Ghai ) Relapse during steroid tapering or within 2 wk of the discontinuation of therapy. Steroid resistance: Inability to induce remission within 4 wk of daily steroid therapy.

43. Managing the Clinical Sequelae of Nephrotic Syndrome OEDEMA Sodium restriction (<1,500 mg daily) Water/fluid restriction if the child is hyponatremic . Swollen scrotum elevated with pillows to enhance fluid removal by gravity. Diuresis by loop diuretics ( furosemide ), orally or intravenously. “ Extreme caution should be exercised”. Aggressive diuresis : lead to intravascular volume depletion and increased risk for acute renal failure and intravascular thrombosis .

44. In severe generalized edema with evidence of intravascular volume depletion (e.g., hemoconcentration , hypotension, tachycardia) : Intravenous administration of 25% albumin (0.5-1.0 g albumin/kg) as slow infusion followed by furosemide (1-2 mg/kg/dose intravenously) is sometimes necessary. Volume overload, with hypertension, heart failure, and pulmonary edema , is a complication of parenteral albumin therapy.

45. Dyslipidemia Dietary fat intake should be < 30% of calories Saturated fat intake of < 10% calories. Dietary cholesterol intake should be < 300 mg/day. Insufficient data to recommend use of HMG- CoA reductase inhibitors routinely in children with dyslipidemia .

46. Infections: Cellulitis , peritonitis, and bacteremia . In spontaneous bacterial peritonitis, peritoneal fluid should be analysed. The antibiotic must include Pneumococcus and Gram-negative bacteria. A third-generation cephalosporin is DOC.

47. Thromboembolism : Appropriate imaging studies to confirm presence of a clot. Anticoagulation therapy in children (heparin, low-molecular-weight heparin, and warfarin ) is effective.

48. Obesity and Growth: Glucocorticoids increase body mass index in children who are overweight when steroid therapy is initiated, and these children are likely to remain overweight. Anticipatory dietary counseling is recommended. Steroid-sparing strategies may improve linear growt in children who require prolonged steroids.

49. Relapse of Nephrotic Syndrome: Defined as a urine protein:creatinine ratio of > 2 or ≥ 3+ protein on urine dipstick testing for 3 consecutive days. Common in younger children and triggered by upper respiratory or gastrointestinal infections. Relapses are usually treated similar to the initial episode, except that daily prednisone courses are shortened .

50. Daily high-dose prednisone given until the child has achieved remission The duration of alternate-day therapy varies on the frequency of relapses of the individual child.

51. Steroid Resistance: Failure to achieve remission after 8 wk of corticosteroid therapy. Require further evaluation, including: - Diagnostic kidney biopsy - Evaluation of kidney function - Quantitation of urine protein excretion (in addition to urine dipstick testing)

52. Caused by FSGS (80%), MCNS, or membranoproliferative glomerulonephritis . Associated with 50% risk for end-stage kidney disease within 5 yr of diagnosis if patients do not achieve a partial or complete remission.

53. Alternative Therapies to Corticosteroids in the Treatment of Nephrotic Syndrome .

54. Candidates for alternative therapy : Steroid-dependent patients Frequent relapsers Steroid-resistant patients # Particularly if have severe corticosteroid toxicity ( cushingoid appearance, hypertension, cataracts, and/or growth failure)

55. CYCLOPHOSPHAMIDE : Prolongs duration of remission and reduces the number of relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome. Side effects : Neutropenia , disseminated varicella , hemorrhagic cystitis, alopecia, sterility, increased risk of future malignancy. 2 mg/kg as single oral dose for a total duration of 8-12 wk. Alternate-day prednisone therapy is continued during cyclophosphamide administration.

56. The white blood cell count must be monitored weekly and the drug should be withheld if the count falls below 5,000/mm3. The cumulative threshold dose above which oligospermia or azoospermia occurs in boys is > 250 mg/kg.

57. Calcineurin inhibitors (cyclosporine or tacrolimus ) : Recommended as initial therapy for steroid-resistant nephrotic syndrome. Monitored for side effects,including hypertension, nephrotoxicity , hirsutism , and gingival hyperplasia.

58. Dose: Cyclosporine- 4-5 mg/kg/day Tacrolimus - 0.1-0.2 mg/kg/day Duration: 12-36 months Side effects : Nephrotoxic , elevated SGOT/PT, hirsutism , gum hyperplasia, hypeetension , hyperlipidemia , hyperglycemia and neurotoxicity.

59. Mycophenolate : Maintain remission in children with steroid-dependent or frequently relapsing nephrotic syndrome. Dose: 600-1000 mg / m2/day or 20-25 mg/kg/day. Duration: 1-3 years. Side effects : GI discomfort, leukopenia .

60. Levamisole : Antihelmintic agent with immunomodulating effects shown to reduce risk of relapse in comparison to prednisone . Rituximab : 80% drug-free remission rate at 1 yr in patients with steroid-dependent nephrotic syndrome.

61. Angiotensin -converting enzyme inhibitors and angiotensin II receptor blockers as adjunct therapy to reduce proteinuria in steroid-resistant patients.

62. Treatment of Steroid resistant nephrotic syndrome A] Calcineurin inhibitor: Cyclosporine , Tacrolimus B] Cyclophosphamide : IV (6 pulses) or Oral (12 weeks).

63. C] High dose corticosteroids with cyclophosphamide : Methylprednisolone : 20-30 mg/kg IV ,Pulses on alternate days for 6 doses { Mendosa regimen} Prednisolone : Tapering doses for 18 months. 1.5 mg/kg qod * 4 weeks; 1.25 mg/kg * 4 weeks, 1 mg/kg * 4 months ; 0.5-0.75 mg/kg * 12-18 months

64. Cyclophosphamide : 2-2.5 mg/kg/day for 12 weeks { administered during 3 rd to 15 th weeks of prednisolone therapy}.

65. Immunizations in Children With Nephrotic Syndrome Pneumococcal vaccination (with the 13-valent conjugant vaccine and 23-valent polysaccharide vaccine) and influenza vaccination annually to the child and their household contacts. Defer vaccination with live vaccines until the prednisone dose is below either 1 mg/kg daily or 2 mg/kg on alternate days.

66. Live virus vaccines are contraindicated in children receiving corticosteroid-sparing agents ( cyclophosphamide or cyclosporine). Following close contact with varicella infection, give immunocompromised children taking immunosuppressive agents varicella -zoster immune globulin.

67. Immunize healthy household contacts with live vaccines to minimize the risk of transfer of infection to the immunosuppressed child, but avoid direct exposure of the child to gastrointestinal or respiratory secretions of vaccinated contacts for 36 wk after vaccination .

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