Nephrotic Syndrome

Child Health II

Speaker : Shriyans jain

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

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801

Why ‘nephrotic range’

• Defined as – protein excretion of > 40 mg/m2/hr– First morning protein : creatinine ratio of > 2-3 : 1

Other causes of proteinuria

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801

Incidence ( paediatric ) ?

• 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 1.5-6 years.• It affects more boys than girls, 2:1 ratio

http://www.kidney.org/site/107/pdf/NephroticSyndrome.pdf

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

- Nelson Textbook of Paediatrics, Vol 2, 19th edition, page 1802, table 521-1

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

- Nelson Textbook of Paediatrics, Vol 2,19th edition, page 1802, table 521-1

Idiopathic

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

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1804

Pathophysiology

http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2122/images/renalcorpuscle.jpg

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• Absence of – Hypertension – Gross hematuria

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1802

CLINICAL FEATURES Minimal Change Nephrotic Syndrome

Focal Segmental Glomerulosclerosis

Membranous Nephropathy

Age ( yr ) 2 - 6 2 - 10 40 - 50

Sex ( M : F ) 2 : 1 1.3 : 1 2 : 1

Nephrotic Syndrome 100 % 90 % 80 %

Asymptomatic proteinuria

0 10 % 20 %

Hematuria 10 – 20 % 60 – 80 % 60 %

Hypertension 10 % 20 % early infrequent

Rate of progression to renal failure

Non progressive 10 yrs 50 % in 10 – 20 yrs

Associated Conditions

Usually none None Renal vein thrombosis, SLE, Hepatitis B

- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2

DIFFERENTIALS

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

• < 1 year old• Family history of nephrotic Syndrome• Hypertension• Pulmonary edema• Gross hematuria• Extrarenal findings

Lab 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/m2/hr

• Serum Creatinine – normal or elevated• Serum albumin - < 2.5 gm/dl• Serum Cholesterol/ TGA levels – elevated• Serum Complement levels – Normal or low

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1804

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

Ghai Essential Paediatrics,8th edition, page 478

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

Idiopathic Lab Findings

Minimal Change Nephrotic Syndrome Raised BUN in 15 – 30 %Highly Selective proteinuria

Focal Segmental Glomerulosclerosis Raised BUN in 20 – 40 %

Membranous Nephropathy

MembranoproliferativeGlomerulonephritis

Type I Low C1, C4 , C3 – C9

Type II Normal C1, C4 , Low C3 – C9

- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2

Cause Light microscopy

Immunoflorescence Electron Microscopy

Minimal Change Nephrotic Syndrome

Normal Negative Foot process fusion

Focal Segmental Glomerulosclerosis

Focal sclerotic lesions

IgM, C3 in lesions Foot process fusion

Membranous Nephropathy

Thickened GBM

Fine Granular IgG Sub epithelial deposits

MembranoproliferativeGlomerulonephritis

Type I Thickened GBM, proliferation

Granular IgG, C3 Mesangial and subendothelial deposits

Type II Lobulation C3 only Dense deposits

- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2

Management

Initial Episode

• 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 )

Ghai Essential Paediatrics,8th edition, page 476, 477

Subsequent course

• 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

Ghai Essential Paediatrics,8th edition, page 479

Management of Relapse

• Parent Education• Symptomatic therapy for infections in case of

low grade proteinuria• Persistent proteinuria ( 3 - 4+ ) – – Prednisolone

( 2mg/kg/day until protein is negative for 3 days ) 1.5 mg/kg on alternate days for 4 weeks )

Ghai Essential Paediatrics,8th edition, page 479

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/m2 IV once a week )

Ghai Essential Paediatrics,8th edition, page 479, 480

Complications

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

Ghai Essential Paediatrics,8th edition, page 480, 481

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

Ghai Essential Paediatrics,8th edition, page 481

Management of SRNS

• Steroids + calcineurin inhibitors + ACE inhibitors / ARBs’ + HMG coenzyme-A + Diuretics

Ghai Essential Paediatrics,8th edition, page 481, 482

Prognosis

• Steroid Responsive NS : Good prognosis ( MCNS )

• Steroid Resistant NS : Poor prognosis ( FSGS )

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1806

Congenital Nephrotic Syndrome

• Presents in first 3 months of life• Anasarca, hypoalbuminaemia, oliguria

‘Finnish’ Type Nephrotic Syndrome• Antenatally detectable : – Raised AFP in maternal serum and amniotic fluid

• Complications– Failure o thrive– Infections– Hypothyroidism– Renal Failure ( 2 – 3 yrs )

Ghai Essential Paediatrics,8th edition, page 482