Nephrotic Syndrome

NEPHROTIC SYNDROME DR AQEEL ALGHAMDI MBBS,DCH,JBCP,ABP,FBN consultant pediatric nephrology

Definition Manifestation of glomerular disease, characterized by nephrotic range proteinuria and a triad of clinical findings associated with large urinary losses of protein : hypoalbuminaemia, edema and hyperlipidemia

nephrotic range Defined as – protein excretion of > 40 mg/m 2 /hr – First morning protein : creatinine ratio of > 2-3 : 1

Incidence 2 – 7 cases per 100,000 children per year Higher in underdeveloped countries ( South east Asia ) Occurs at all ages but is most prevalent in children between the ages years. It affects more boys than girls, 2:1 ratio

Etiology Genetic Secondary Idiopathic or Primary

Genetic causes Finnish type Congenital Nephrotic Syndrome Focal Segmental Glomerulosclerosis Diffuse Mesangial Sclerosis Denys-Drash Syndrome Nail – Patella Syndrome Alport Syndrome Charcot-Marie-tooth disease Cockayne syndrome Laurence-Moon-Beidl-Bardet Syndrome Galloway-Mowat Syndrome

Secondary causes Congenital – Oligomeganephronia Infectious – Hepatitis (B,C), HIV-1, Malaria, Syphilis, Toxoplasmosis Inflammatory – Glomerulonephritis Immunological – Castleman Disease, Kimura Disease, Bee sting, Food allergens Neoplastic – Lymphoma, Leukemia Traumatic ( Drug induced ) – Penicillamine, Gold, NSAIDS, Pamidronate, Mercury, Lithium

Idiopathic Minimal Change disease ( >80 % ) Mesangial proliferation Focal segmental Glomerulosclerosis Membranous Nephropathy Membranoproliferative glomerulonephritis

Pathophysiology

Complex disturbances in immune system Genetic Mutations / Mutations in proteins Extensive effacement of podocyte foot processes Increased permeability of the glomerular capillary wall Massive proteinuria Hypoalbuminaemia Edema

Clinical Features

Edema – Mild to start with – peri orbital puffiness, lower extremities – Progression to generalized edema, ascites, pleural effusion, genital edema Decreased urine output Anorexia, Irritability, Abdominal pain and diarrhoea – Hypertension +/- – Gross hematuria +/-

CLINICAL FEATURESMinimal Change Nephrotic Syndrome Focal Segmental Glomerulosclerosis Membranous Nephropathy Age ( yr ) Sex ( M : F ) 2 : 11.3 : 12 : 1 Nephrotic Syndrome100 %90 %80 % Asymptomatic proteinuria 010 %20 % Hematuria10 – 20 %60 – 80 %60 % Hypertension10 %20 % earlyinfrequent Rate of progression to renal failure Non progressive10 yrs50 % in 10 – 20 yrs Associated Conditions Usually noneNoneRenal vein thrombosis, SLE, Hepatitis B

D Protein losing enteropathy Hepatic failure Heart failure Acute/Chronic Glomerulonephritis Protein Malnutrition

Investigations Urine Examination Complete Blood Count & Blood picture Renal parameters : – Spot Urine Protein : Creatinine ratio – Urinary protein excretion – protein selectivity ratio Liver Function Test Renal Biopsy ???

Urinalysis - 3+ to 4+ proteinuria Renal Function – Spot UPC ratio > 2.0 – UPE > 40 mg/m 2 /hr Serum Creatinine – normal or elevated Serum albumin - < 2.5 gm/dl Serum Cholesterol/ TGA levels – elevated Serum Complement levels – Normal or low

C3 and antistreptolysin O Chest X ray and tuberculin test ANA Hepatitis B surface antigen Additional Tests

Indications for Biopsy Age below 12 months Gross or persistent microscopic hematuria Low blood C3 Hypertension Impaired renal Function Failure of steroid therapy

IdiopathicLab Findings Minimal Change Nephrotic SyndromeRaised BUN in 15 – 30 % Highly Selective proteinuria Focal Segmental GlomerulosclerosisRaised BUN in 20 – 40 % Membranous Nephropathy Membranoproliferative Glomerulonephritis Type ILow C1, C4, C3 – C9 Type IINormal C1, C4, Low C3 – C9

CauseLight microscopy ImmunoflorescenceElectron Microscopy Minimal Change Nephrotic Syndrome NormalNegativeFoot process fusion Focal Segmental Glomerulosclerosis Focal sclerotic lesions IgM, C3 in lesionsFoot process fusion Membranous Nephropathy Thickened GBM Fine Granular IgGSub epithelial deposits Membranoprolifer ative Glomerulonephriti s Type IThickened GBM, proliferation Granular IgG, C3Mesangial and subendothelial deposits Type IILobulationC3 onlyDense deposits

MANAGMENT High protein diet Salt moderation Treatment of infections If significant edema – diuretics Aldosterone antagonist ( Fursemide, spironolactone ) Corticosteroid therapy with Prednisolone or prednisone – ( 2mg/kg per day for 6 weeks followed by 1.5 mg/kg single morning dose on alternate days for 6 weeks )

Relapse – Infrequent Relapsers : 3 or less relapses per year – Frequent Relapsers : 4 or more relapses per year Steroid therapy – Steroid dependant : relapse following dose reduction or discontinuation – Steroid resistant : Partial or no response to initial treatment

Management of Relapse Parent Education Symptomatic therapy for infections in case of low grade proteinuria Persistent proteinuria ( ) – – Prednisolone ( 2mg/kg/day until protein is negative for 3 days ) 1.5 mg/kg on alternate days for 4 weeks )

Frequent Relapses Alternate Day prednisolone Steroid sparing agents – Levamisole ( 2 – 2.5 mg/kg ) – Cyclophosphamide ( 2 – 2.5 mg/kg/day) – Mycophenolate Mofetil ( 20 – 25 mg/kg/day ) – Cyclosporin ( 4 – 5 mg/kg/day ) – Tacrolimus (0.1 – 0.2 mg/kg/day ) – Rituximab ( 375mg/m 2 IV once a week )

Complications Edema Infections Thrombotic complications Hypovolaemia and Acute renal Failure Steroid Toxicity

Steroid Resistant Nephrotic Syndrome Diagnosis – Lack of response to prednisolone therapy for 4 weeks Indication for renal biopsy, BBVS Etiology – 10 – 20 % - Genetic ( Mutations in genes encoding podocyte proteins ) Indications for mutational analysis : – Congenital Nephrotic Syndrome – Family History of SRNS – Sporadic resistance to steroids – Girls with steroid resistant FSGS

Management of SRNS Steroids + calcineurin inhibitors + ACE inhibitors / ARBs’ + HMG coenzyme-A + Diuretics

Prognosis Steroid Responsive NS : Good prognosis ( MCNS ) Steroid Resistant NS : Poor prognosis ( FSGS )

Congenital Nephrotic Syndrome Presents in first 3 months of life Anasarca, hypoalbuminaemia, oliguria { Finnish’ Type } Antenatally detectable : – Raised AFP in maternal serum and amniotic fluid Complications – Failure o thrive – Infections – Hypothyroidism – Renal Failure ( 2 – 3 yrs )