Nephrotic Syndrome

About a most common nephrologic ailment in children

1. - Volhard & Fahr CSN Vittal Nephrotic Syndrome

2. Nephrotic Syndrome Massive proteinuria - 40 mg/m 2 /hr (50 mg / kg / d or 3.5 gm/day) Hypoalbuminemia (<2.5 g/dL) Hypercholesterolemia (>220 mg/dL) With or without Edema ISKDC Definition : Nephrotic range of proteinuria = Urine Protein 3+ or 4+ Urine protein / creatinine ratio of > 2.0

3. Nephrotic Syndrome 2 to 7 cases per 100,000 childre 10-fold lower in adults Male-to-female ratio is reported to be 2:1 for children and 1:1 in adolescents and adults MCNS peaks between 2-5 years of age 92% of these will experience remission of their disease when treated Adolescents are more likely to have a more aggressive cause of the nephrotic syndrome Incidence of Idiopathic form

4. Nephrotic Syndrome - Children Etiology 90 % - primary glomerular abnormality (Idiopathic) Rest – part of renal involvement in different diseases

5. Classification Etiological Primary Secondary Pathological

6. Nephrotic Syndrome - Children Causes of Idiopathic NS [90%] Minimal Change NS ( 85 %) Mesangial Proliferation (5%) Focal Segmental Glomerulosclerosis (10%) Membranous nephropathy (1%)

7. Secondary Nephrotic Syndrome Systemic Diseases or Glomerular diseases (membranous nephropathy of MPGN) - [10%] Vasculitides SLE, Sarcoidosis, HSP, Rheumatoid arthritis, Wageners granulomatosis, Goofpasteur syndrome Metabolic Amyloidosis, Myxoedema, DM Infections Syphilis, Shunt nephritis, Hepatitis B and C, CMV, HIV Parasitic Plasmodium malariae, Toxoplasma Drugs Gold, Mercury, Penicillamine, Lithium, Ethosuccimide, NSAIDS Malignancies Lymphomas, Carcinomas Congenital / Inherited Alport syndrome, Nail - Patella syndrome

8. Secondary Nephrotic Syndrome Drug Induced - Penicillamine - Captopril - Gold - NSAIDs - Mercury - Procainamide - Chlorpropamide - Phynetoin - Trimethadione - Promethadione - Probenicid - Ethosuximide - Methimazole - Lithium Membranous nephropathy MCNS Proliferative GN

9. Idiopathic Nephrotic Syndrome - Children 3 Pathological Types Microscopy 1 Minimal Change Disease (73%) 2 Mesangial Proliferation (2-5%) 3 Focal Segmental Glomerular Sclerosis (7%) Light Negative Increase in mesangial cells & matrix Mesangial proliferation & scarring Immunofluorascence Negative Above Plus : 1+ mesangial IgM / IgA staining IgM & C3 staining in areas of scarring Electron Effacement of epithelial cell foot processes Effacement of epithelial cell foot processes + Increase in mesangial cells and matrix Segmental scarring and glomerular capillary obliteration

10. Idiopathic Nephrotic Syndrome - Children Pathological Types 1. Minimal Change Disease (85%)

11. Idiopathic Nephrotic Syndrome - Children Pathological Types 1. Minimal Change Disease (85%)

12. Idiopathic Nephrotic Syndrome - Children Pathological Types 1. Minimal Change Disease (85%) Idiopathic, Drugs, Malignancy, especially Hodgkin's lymphoma, hepatitis C, autoimmune disease (SLE), and diseases of intraglomerular coagulation

13. Idiopathic Nephrotic Syndrome - Children Pathological Types 2 Mesangial Proliferation (5%)

14. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (mesangiocapillary glomerulonephritis) MPGN types 1, 2, and 3 account for 44%, 20%, and 36% of cases, respectively. All 3 types appear similar by light microscopy and have increased mesangial cellularity and matrix expansion. By electron microscopy, type 1 shows normal-appearing GBM, with subendothelial electron-dense deposits. MPGN type 2 , also known as dense-deposit disease , appears to be a distinct disease and has thickening and increased electron density of the lamina densa of the GBM. In MPGN type 3 , deposits are present on both the subepithelial and the subendothelial sides of the GBM, as well as within the GBM. With special stains the GBM appears fenestrated, and deposits are covered by layers of new GBM

15. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (mesangiocapillary glomerulonephritis) Etiology: Type-1 MPGN: Caused by immune complex formation and deposition Of the classical pathway of complement consumption MPGN type 2: (Dense Deposit Disease), Mesangiocapillary GN thought to be the result of the presence of circulating autoantibodies called nephritic factors (NFs) that stabilize the C3 convertases activating the alternative ( NFa ) and respectively MPGN type 3: Activation of ( NFt ) pathways of complement activation Candidate gene on Chromosome 1

16. Idiopathic Nephrotic Syndrome - Children Pathological Types 3 Focal Segmental Glomerular Sclerosis (10%) idiopathic or secondary to a number of different causes (e.g., heroin abuse, HIV infection, sickle cell disease, obesity, reflux of urine from the bladder to the kidneys, and lesions associated with a single or remnant kidneys).

17. Disease processes associated with FSGS lesions Diabetic nephropathy Sickle cell disease HIV nephropathy Glomerulonephritides IgA nephropath MPGN Lupus nephritis Frasier syndrome, consisting of male pseudohermaphroditism (Mutations in WT1 gene) Diffuse mesangial sclerosis May be part of Denys-Drash syndrome

18. Idiopathic Nephrotic Syndrome Pathological Types 4 Membranous nephropathy (1%) most common pattern of idiopathic NS in white Americans - Hepatitis B, Sjögren's syndrome, Systemic lupus erythematosus (SLE), Diabetes mellitus, Sarcoidosis, Syphilis, Drugs, Malignancy

19. MCNS Nephrotic Syndrome (Nil Disease or Lipoid Nephrosis ) In 3 months to 16 years of age, 76% have minimal change nephrotic syndrome (MCNS) No glomerular abnormalities in light microscope Effacement of foot processes in electron microscopy Minimal deposition of mesangial matrix Serum complement (C 3 ) normal Circulating immune complexes absent

20. Pathophysiology of NS Increased permeability of glomerular capillary wall, which leads to massive proteinuria and hypoalbuminemia. In MCNS : T Cell dysfunction leads to alteration of cytokines which causes a loss of negatively charged glycoproteins within capillary wall In FSGS: A plasma factor produced by lymphocytes responsible Mutations in podocyte proteins (podocin, a – actinin 4) In Steroid resistant NS: Mutations in NPHS 1(nephrin) & 2(podocin) and WT1 or ACTN4 ( a -actinin) genes

21. Clinical Features Age of onset : 85 - 90% < 6 yrs yrs 30% adolescents may have MCNS Onset : insidious Initial episode & subsequent relapses may follow minor infections or insect bites, bee stings, poison ivy, etc.

22. Clinical Features COMMON : Anorexia, irritability, abdominal pain, diarrhoea and genital edema Frothy urine (high concentrations of protein) Edema may cause dyspnea (pleural effusion or laryngeal edema), Chest discomfort (pericardial effusion), arthralgia (hydrarthrosis), or abdominal pain (ascites or, in children, mesenteric edema). Edema may obscure signs of muscle wasting and cause parallel white lines in fingernail beds (Muehrcke's lines). UNCOMMON : Hypertension, Gross hematuria

23. Proteinuria - Parameters Urine routine: 1 + = 30 mg / dL 2 + = 100 mg / dL 3 + = 300 mg / dL 4 + = > 2 g / dL 24 hour Urine Protein Estimation: Mild : < 500 mg / m 2 / d Moderate : 500 – 1000 mg / m 2 / d Massive : > 1000 mg / m 2 / d 40 mg / m 2 / hr (Normal = 4 mg / m 2 / hr) [> 3 g / d]

24. Massive Proteinuria - Mechanism Loss of negatively charged sialoproteins and glycoproteins Increased size of pores Loss of foot processes Increased excretion or decreased absorption Release of platelet factor in glomeruli Increased thromboxane production

25. Protein Loss – Albumin – Thyroxine-binding protein – Cholecalciferol-binding protein – Transferrin – Metal binding proteins – Anti Thrombin III, Proteins C & S

26. Hypoproteinemia - Mechanism Increased loss Inadequate synthesis Increased catabolism

27. Oedema - Mechanism Massive proteinuria – hypoalbuminemia - i plasma oncotic pressure -> transudation of fluid from intravascular compartment to interstitial space. Under Fill Theory : Reduced renal perfusion leading to h production of renin-angiotensin aldosterone system Reduction of intravascular volume stimulates ADH Over Fill Theory : Defective excretion of sodium and water from kidney due to dysfunction h absorption of sodium and water from renal tubules Circulation of unknown antigen causing h capillary permeability i production of atrial natriuretic peptide Increased activity of aldosetrone & vasopressin Activities of various cytokins and physical factors within the vasa recti

28. Hyperlipidemia - Mechanism i conversion of VLDL in to LDL by i of lipoprotein lipase Loss of apolipoprotein ( apo CII) in urine i levels of HDL h synthesis of lipoproteins Abnormalities in regulatory enzymes like licithin -cholesterol acyltranferase and cholesterol ester transfer protein, lipoprotien lipase VLDL content is more increased Triglyceride levels are decreased when albumin level is < 1 g

29. Hypercoagulable State Occur when serum albumin < 2g/ dL Causes : – Urinary loss of antithrombin III, Factor IX, X, XI - > thrombin activity increase – Protein C, S activity or level decrease – Hyperfibrinogenemia – Platelet activation increase – Hyperlipidemia Combined with hypovolemia , immobility, increased incidence of infection

30. Idiopathic NS DD Protein losing enteropathy Hepatic failure CHF Acute or chronic GN PEM

31. Differential Diagnosis

32. Poststreptococcal glomerulonephritis Subacute bacterial endocarditis/visceral abscess/shunt nephritis Systemic lupus erythematosus Cryoglobulinemia Idiopathic membranoproliferative glomerulonephritis SERUM COMPLEMENT LEVELS IN GLOMERULAR DISEASES A REDUCED COMPLEMENT LEVEL A NORMAL COMPLEMENT LEVEL Minimal change nephrotic syndrome Focal segmental glomerulosclerosis Membranous nephropathy IgA nephropathy Henoch-Schönlein purpura Anti–glomerular basement membrane disease Pauci -immune rapidly progressive glomerulonephritis Polyarteritis nodosa Wegener's granulomatosis

33. SECONDARY” NEPHROTIC SYNDROME SYSTEMIC DISEASES Diabetes mellitus Systemic lupus erythematosus and other collagen diseases Amyloidosis (amyloid AL or AA associated) Vasculitic-immunologic disease (mixed cryoglobulinemia, Wegener's granulomatosis, rapidly progressive glomerulonephritis, polyarteritis, Henoch-Schönlein purpura, sarcoidosis, Goodpasture's syndrome) INFECTIONS Bacterial (poststreptococcal, congenital and secondary syphilis, subacute bacterial endocarditis, shunt nephritis) Viral (hepatitis B, hepatitis C, HIV infection, infectious mononucleosis, cytomegalovirus infection) Parasitic (malaria, toxoplasmosis, schistosomiasis, filariasis) MEDICATION RELATED Gold, mercury, and the heavy metals, Penicillamine, Nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 inhibitors, Lithium, Paramethadione, trimethadione, Captopril, “Street” heroin Others—probenecid, chlorpropamide, rifampin, tolbutamide, phenindione, pamidronate

34. SECONDARY” NEPHROTIC SYNDROME ALLERGENS, VENOMS, IMMUNIZATIONS, AND ASSOCIATED NEOPLASMS Hodgkin's lymphoma and leukemia-lymphomas (with minimal change lesion) Solid tumors (with membranous nephropathy) HEREDITARY AND METABOLIC DISEASE Alport's syndrome Fabry's disease Sickle cell disease Congenital (Finnish type) nephrotic syndrome Familial nephrotic syndrome Nail-patella syndrome Partial lipodystrophy OTHER Pregnancy related (includes preeclampsia) Transplant rejection Serum sickness Accelerated hypertensive nephrosclerosis Unilateral renal artery stenosis Massive obesity–sleep apnea syndrome Reflux nephropathy

35. Investigations

36. Urine Routine exam. : 3+ or 4 + proteinuria 24 hour urine protein >3.0 gm or 40 mg/m 2 / hr Spot Urine protein/ creatinine ratio : > 2.0 Urine protein selectivity Hyaline casts Microscopic hematuria in 20%

37. Hyaline Cast in urine

38. Blood S.Cholesterol ( > 250 mg/ dL ) S.Albumin (<2.5 gm / dL ) S. A/G ratio - reversal S.Creatinine Bl. Urea S . C3 and C4 levels CBC : Increased Hb , Platelets, Hct Normal

39. Imaging U/S : Nonspecific. Enlarged kidneys – due to tissue edema Increased echogenicity/Small Kidneys : Chronic kidney disease other than MCNS CXR: Pleural effusion Pulm edema - rare

40. Kidney Biopsy Indications: Patients younger than 1 year and older than 8 yrs Symptoms of systemic disease ( fever, rash, joint pain) Labs suggestive of sec nephroti c syndrome (Positive Ana, Positive anti-double stranded DNA antibody, Low complement) Elevated creatinine levels unresponsive to correction of volume depletion Family history of kidney disease Patients initially or subsequently unresponsive to steroid treatment.

41. Management - Principles Admission For establishment of diagnosis For exclusion of infection To wait for spontaneous remission Treat infections Supportive therapy Steroid therapy

42. Supportive Care Diet : Balanced adequate protein (1.5 – 2 gm/kg) Not > 30% calories from fats Avoid saturated fats Reduction in salt intake (1-2 g/d) for those with persistent edema Ensure physical activity Calcium and Vitamin D supplementation

43. Treatment of Initial Episode Prednisalone 2mg / kg / d in 2-3 divided doses for 4-6 weeks [60 mg / m 2 /d] Antacid dose steroid to prevent gastric irritation ?? After 6 wks, reduce dose 1.5 mg/kg/d [40 mg / m 2 /d ] as a single dose every other day morning slowly tapering in 2-3 months Then discontinue Shorter duration of initial therapy in not recommended. Steroid Therapy

44. Treatment of Initial Episode Acting through th e nuclear factor kappaB (NF- kB ) transcription pathway – inhibiting cytokine production and inhibiting T-Cell prouction and proliferation. Steroids – Mechanism of action

45. Diuretic Therapy Indications To prevent secondary infections after breakdown of skin To prevent GI and Resp. embarrassment To prevent urethral obstruction due to massive edema of scrotum Drugs Furosemide : 1-3 mg / kg / dose IV q12h Chlorthiazide : 10 mg / kg / d Spiranolactone : 3-4 mg /kg/ d in 3-4 div. doses 25% salt free albumin 0.5g / kg over 60 min Patients with persistent edema and weight gain above 7 - 10% are treated with oral frusemide

46. ISKDC Terminology Remission Urine albumin : Nil or Traces or <4 mg/m 2 / hr for 3 consecutive early morning specimen Response Urine free of protein in 8 wks. (Steroid sensitive) Late Response A response beyond 8 weeks

47. ISKDC Terminology Relapse Proteinuria 3+ plus edema or 40 mg/m 2 / hr for 3 consecutive early morning specimen (having been in remission previously) Frequent Relapse SSNS with 2 or more relapses in 6 mo. or > 4 relapses in 1 year

48. ISKDC Terminology Steroid Dependent NS SSNS with 2 or more consecutive relapses during tapering or within 14 days of stopping steroids. Steroid Resistant: Either do not respond to the initial treatment with prednisalone within 8 weeks of therapy 60mg/m 2 /d, or do so transiently and later cease to respond [2-5%] (FSGS= 80%, MPG = 20%, MCNS– rarely)

49. Treatment of Relapse Relapse often precipitated by URI Prednisalone 2 mg/kg/d until the urine is protein free for 3 consecutive days Thereafter – 1.5 mg/kg/d on alternate days for 4 wks and stop. (Total duration of therapy = 5 to 6 wks.)

50. Management of pt. with steroid sensitive NS Prednisalone 2 mg/kg daily forr6 wks., followed by 1.5 mg/kg on alt day for 6 wks . Infrequent relapses Frequent relapses Steroid resistant Therapy for relapse Prednisalone 2 mg/kg daily until remission, then 1.5 mg/kg on alt. days for 4 weeks Alternate day prednisalone to maintain remission Therapy based on renal histology Threshold <0.5 mg/kg on alt. days Threshold >0.5 mg/kg on alt. days / Steroid toxicity Alt. day prednisalone for 9-18 mo. Levamisole Cyclophosphamide Mycophenolate Tacrolimus Cyclosporine

51. Management of pt. with steroid sensitive NS Infrequent relapses Examine for infections, which should be treated before initiating steroid therapy. Prednisolone is administered at a dose of 2 mg/kg/day (single or divided doses) until urine protein is trace or nil for 3 consecutive days. Subsequently, prednisolone is given in a single morning dose of 1.5 mg/kg on alternate days for 4 weeks, and then discontinued. The usual duration of treatment for a relapse is 5-6 weeks . Prolongation of therapy is not necessary for patients with infrequent relapses

52. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent Following treatment of a relapse, prednisolone is gradually tapered to maintain the patient in remission on alternate day dose of 0.5-0.7 mg/kg, which is administered for 9 - 18 months. Levamisole at a dose of 2-2.5 mg/kg on alternate days for 12-24 months. Co-treatment with prednisolone at a dose of 1.5 mg/kg on alternate days is given for 2-4 weeks; its dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for 6 or more months . The chief side effect of levamisole is leukopenia ; flu-like symptoms, liver toxicity, convulsions and skin rash. The leukocyte count should be monitored every 12-16 weeks.

53. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent ( b) Cyclophosphamide at a dose of 2-2.5 mg/kg/day for 12 weeks. Prednisolone is co-administered at a dose of 1.5 mg/kg on alternate days for 4 weeks, followed by 1 mg/kg for the next 8 weeks;steroid therapy is tapered and stopped over the next 2-3 months. Therapy with cyclophosphamide should be instituted preferably following remission of proteinuria. Total leukocyte counts are monitored every 2 weeks; treatment is temporarily discontinued if the count falls below 4000/mm3. An increased oral fluid intake and frequent voiding prevents the complication of hemorrhagic cystitis; other side effects are alopecia, nausea and vomiting. The risk of gonadal toxicity is limited with a single (12 weeks) course of cyclophosphamide. The use of more than one course of this agent should preferably be avoided.

54. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent ( c) Calcineurin inhibitors: Cyclosporin ( CsA ) is given at a dose of 4-5 mg/kg daily for 12-24months. Prednisolone is co-administered at a dose of 1.5 mg/kg on alternate days for 2-4 weeks; its dose is gradually reduced by 0.15- 0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for six or more months. Occasionally, treatment with corticosteroids may be discontinued. Side effects of CsA therapy include hypertension, cosmetic symptoms (gum hypertrophy, hirsutism ) and nephrotoxicity ; hypercholesterolemia and elevated transaminases . Estimation of blood levels of creatinine is required every 2-3 months and a lipid profile annually. A repeat kidney biopsy, to examine for histological evidence of nephrotoxicity , should be done if therapy with calcineurin inhibitors is extended beyond 2 years

55. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent Tacrolimus is an alternative agent, administered at a dose of 0.1-0.2 mg/kg daily for 12-24 months. Side effects include hyperglycemia, diarrhea and rarely neurotoxicity (headache, seizures). The use of tacrolimus is preferred especially in adolescents, because of lack of cosmetic side effects(13). Blood levels of creatinine and glucose should be estimated every 2-3 months.

56. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent ( d) Mycophenolate mofetil (MMF) at a dose of 800-1200 mg/m2 along with tapering doses of prednisolone for 12-24 months. The principal side effects include gastrointestinal discomfort, diarrhea and leukopenia . Leukocyte counts should be monitored every 1-2 months; treatment is withheld if count falls below 4000/mm3.

57. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent Choice of agent Levamisole has a modest steroid sparing effect and is a satisfactory initial choice for patients with frequent relapses or steroid dependence. Treatment with cyclophosphamide is preferred in patients showing: significant steroid toxicity, ( ii) severe relapses with episodes of hypovolemia or thrombosis, and ( iii) poor compliance or difficult follow up, where 12 weeks therapy possible to ensure than long-term compliance.

58. Management of pt. with steroid sensitive NS Frequent relapsers & Steroid Dependent Choice of agent Treatment with CsA or tacrolimus is recommended for patients who continue to show steroid dependence or frequent relapses despite treatment with the above medications The lack of renal, hemodynamic and metabolic toxicity with Mycophenolate maleate makes it an attractive alternative to calcineurin inhibitors.

59. Frequent relapsers FRNS & Steroid Dependent SDNS Prednisalone 2 mg/kg/d (60 mg/m 2 /d) as single morning dose until patient has been free of protinuria for at least 3 consecutive days. Following remission, Prednisalone reducetd to 1.5 mg/kg/d (40mg/m 2 ) given as single dose on alt days and tapered over 3 months. A steroid sparing agent conisered once protinuria is in remission Alkylating agent : Cyclophosphamide, Chlorambucil Calcinuri n inhibitors: Cyclosporin A, Tacrolimus

60. Management of NS ACE Inhibitors : to prevent proteinuria Act by alteration of capillary permeability and reduction in glomerular hydrostatic pressure HMG coenzyme-A reductase inhibitors to reduce s. cholesterol Albumin Infusion : controversial Abdominal pain Hypotension Severe Oliguria Renal insufficiency

61. Management of NS Immunization Patients on prednisalone therapy are considered immunosuppressed – avoid live attenuated vaccines All patients should receive pneumococcal vaccine

62. Management of NS Investigational Treatments Rituximab : A chimeric anti-CD20 antibody that results in depletion of B Cells Plasmapheresis – esp with FSGS patients who have received kidney transplans Galactose : high affinity for circulating permeability factor (FSGS) after kidney transplant Zinc

63. Initial Steroid Resistance Mesangial proliferative GN Focal segmental glomerulosclerosis (FSGS) Membrano-proliferaive GN (MPGN) Type 1 : with intact BM Type 2: (30%) with dense deposits, persistent low serum C 3 , abundant immunonglobulin & C 3 deposits Membranous nephropathy

64. Initial Steroid Resistance Trial of pulse methylprednisalone (30 mg/kg) or dexamethasone First 6 doses given every other day followed by tapering for periods upto 18 months Cyclosporin A IVIG Mycophenolate mofetil

65. Steroid Adverse Effetcts Infection Obesity Growth delay Osteopenia Avascular necrosis of the hip Cataracts Hypertension Hyperglycemia Nephrolithiasis Hyperlipedemia

66. Complications Due to Disease Due to Treatment

67. A. Complications Due to Disease PEM due to protein loss Infections: S.pneumonia, H. influenza - VPDs Thrombotic complications Iron, copper, zinc, and vitamin D deficiencies Laryngeal edema - rarely

68. Infections Factors responsible : Urinary loss of Factor B and immunoglobulins, properdin B Defective CMI Defective opsonization Ascitic fluid – good culture medium Immunosuppressive drugs Malnutrition Peritonitis Pneumonia Osteomyelitis Cellulitis Arthritis

69. B. Complications Due to Treatment Steroids Cushingoid syndrome Hypertension due to salt retention Osteoporosis Susceptibility to infections Growth failure Cateracts Glaucoma Gastritis Peptic ulcer Hypokalemia Behavioural changes Cyclophosphamide Alopecia Leucopenia Infertility Hemorrhagic cystitis

70. Prognosis

71. Outcome of MCNS Most stop getting relapses by 11 to 15 yrs Full recovery Very small proportion – develop late steroid resistance Mortality : 1-4 % sec. to infections & hypovolemia

72. NS Variants Congenital: Develop within first 3 mo. Cong. Syphilis, Intrauterine infections Finnish Type : Autosomal recessive Mutations in the NPHS1 gene encoding nephrin or NPHS2 gene encoding podocin Leads to renal failure Elevated alpha fetoprotein in amniotic fluid & maternal serum Dany-Drash Syndrome : Wilms tumor, NS, Genital anomalies Diffuse mesangial sclerosis

73. Thank Q Vittal