Normal glomerulus

Minimal change disease

Minimal change disease

The term nephrotic syndrome is applicable to any condition with heavy proteinuria, hypoproteinemia, and edema.

It is a disorder of glomerular permselectivity that may be primary or secondary to an overt systemic disease.

In children the most common variety is

MCNS with a characteristic response to

corticosteroid therapy

But a few patients with MCNS do not

respond to steroids , and a few steroid

responders have histology other than

MCNS.

Nephrotic syndrome: edema, plasma albumin less 2.5 gm/dl, proteinuria >40 mg/m2/h

Remission: urinary protein excretion < 4 mg/m2/h or dipstick neg/trace for 3 consecutive days

Steroid response: remission achieved with steroid therapy alone

Late responder: remission occurring after 4 weeks prednisolone 60 mg/m2/day without other drugs

Relapse: urinary protein excresion >40 mg/m2/h or dispstick 2+ for 3 consecutive days having previously been in remission

Frequent relapses: two or more relapses within 6 months of initial response or 4 or more in 12 months

Steroid dependence: two consecutived relapses occurring during corticosteroid treatment or within 14 days of cessation

Steroid resistance: failure to achieve response in spite 8 weeks of prednisolone 60 mg/m2/day

Early nonresponder: steroid resistance in the initial episode

Late nonresponder: steroid resistance developing in a patient who had previously been steroid responsive

Children with steroid-resistant NS may have one of several different histologic appearances in the glomeruli, being most common FSGS.

It is not clear if MCNS and FSGS should be consider two different entities or different ends of a single spectrum of disease.

Current opinion is to include both conditions

under the single label of Idiopathic

Nephrotic Syndrome, dividing into steroid-

sensitive (SSNS) and steroid-resistant (SRNS).

Patients with SRNS have higher risk for

extrarenal complications as well as

progression to CRF and ESRD, with high

recurrence in the graft after transplantation.

Prevalence is ~16/100000 children, annual

incidence of 2-7/100000 children

Ratio M/F is 2/1, in younger children. This

male predilection disappears in teenagers

and adults

3/4 less than 6 years

Median ages at time of presentation

varies according to histopathological

diagnosis: 3 years for MCNS, 6 years for

FSGS and 10 years for MPGN

Majority of patients that have SSNS has

MCNS. The risk of progressing to CRF and

ESRD for SRNS is 40% in 5 years.

Familial incidence

› European survey 63 of 1877 nephrotic

children had affected siblings

Familial NS bred true with respect to

histopathology and steroid response

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

Physical exam

› Accumulates in

gravity dependent

tissues

› Puffiness around

eyes

› Genital edema is

generally painful

Pathogenesis

› 80% of oncotic pressure due to albumin

› Below 2 g/dL edema accumulates

› Intravascular volume depletion

› Renin-aldosterone activation

Classic teaching

Not all patients are hypovolemic

Bacterial infections› Prone to bacterial sepsis

› Cellulitis

› IgG levels low

› Factor B levels low

› Lymphocyte function impaired

Viral Infections› Measles may induce remission in NS

› Relapse preceded by viral infection

Serious risk of thrombosis

Increased fibrinogen concentration

Antithrombin III concentration reduced

Platelets hyperaggregable

Increased blood viscosity

Hct may be elevated

Hyponatremia is common

Plasma creatinine is elevated in 33% of

patients

Albumin

› Hypoalbuminemia due to loss via the kidney

Urinary excretion

Proximal tubular cells catabolism

Immunoglobulins

› IgG levels reduced

› IgM levels elevated

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

Lp(a) levels are elevated

Broad, waxy casts

Lipid droplets

Low urine sodium

High osomolality

> 40 mg/hour * m2

Urine protein/creatinine ratio > 2

Unusual to see tubular proteinuria

Pretreatment

› Obligatory

Onset age < 6 months

Macroscopic hematuria

Microscopic hematuria and HTN

Low C3

Renal failure

› Recommended

Onset between 6-12 months or > 12 years

Persistent HTN of hematuria

Post treatment

› Steroid resistance

› Frequent relapsers

Goals› Reduce urinary protein excretion

› Reduce tissue fluid retention

› Prevent infection

› Minimize complication

Therapeutic Management› Low salt diet

› Corticosteroids

› Albumin and lasix

› Immunosuppressants

Low protein

› Decreases albuminuria

› Malnutrition

Salt restriction

› During edema

Calorie control

› Steroids

Gram negative coverage for peritonitis

Streptococcal immunization

Varicella

› VZIG if exposed

Immunizations

› No live viruses while on daily steroids

Controversial

Indication- Hypovolemia

› Abdominal pain

› Hypotension

› Oliguria

› Renal insufficiency

High dose steroids

› 2 mg/kg/day (max 80 mg)

› 60 mg/m2 (max 80 mg)

3 accepted protocols

80% respond within 2 weeks

The intensity and duration of the initial

corticosteroid regime influences the rate

of relapse of NS

60 mg/m2/day until remission

Change to alternate day

Taper over 1-3 months

Individualized for each patient

Usually tapered over 6 months- 1 year

Cushingoid habitus

Obesity

Striae

Hirsutism

Acne

Growth failure

Avascular necrosis

Osteoporosis

Peptic ulceration

Pancreatitis

Posterior lens opacities

Myopathy

Increased ICP

Susceptibility to infection

High-dosecorticosteroid therapyproduces a characteristic “moon face” appearance.

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

Alkylating Agents

› Cyclophosphamide

› Chlorambucil

Levamisole

Cyclosporine

MMF

Rituximab

8 weeks of 3 mg/kg/day

› 69% of children with SRNS remain in remission

for 1 year

› 44% for 5 years

Younger children do worse

Steroid dependent children do worse

2 mg/kg/day may or may not have any

benefit

0.2 mg/kg/day for 8 weeks

Sterility

› 10% incidence of azospermia with repeated

doses

› Low incidence with chlorambucil < 8 mg/kg

total

› Puberty

Leukopenia

Malignancy

Antihelmithic with immunomodulating

properties

2.5 mg/kg/qOD for 2 months

British association for Pediatric Nephrology

5 mg/kg/day

Used with steroids

Patients usually respond well

Cyclosporine dependence is common

Long term side effects unknown

#1 cause of nephrotic syndrome in children

Loss of foot processes

Pathogenesis unknown

Good prognosis