NEPHROTIC SYNDROME

By Dr.Raman Kumar

DEFINITION

PROTEINURIANephrotic range

HYPOALBUMINEMIA

HYPERLIPIDEMIA

OEDEMA

Nephrotic Range Proteinuria

24 hour urine..40mg/m2/h…difficult

First morning urine sample…protein and creatinine ratio….more than 2-3:1

Classification of nephrotic syndrome

ETOLOGICAL CLASSIFICATION

Primary NEPHROTIC syndrome. Disease limited to kidney

Secondary NEPHROTIC syndrome. Other systems involved

HISTOLOGICAL CLASISIFICATION

MCDFSGNMNMPGN

Causes of secondary nephrotic syndrome

Membranous nephropathy (MN)[3]

•Hepatitis B •Sjogren's syndrome •Systemic lupus erythematosus (SLE) •Diabetes mellitus •Sarcoidosis •Syphilis •Drugs •Malignancy (cancer)

Focal segmental glomerulosclerosis (FSGS)[3]

•Hypertensive Nephrosclerosis •Human immunodeficiency virus (HIV) •Diabetes mellitus •Obesity •Kidney loss

Minimal change disease (MCD)[3]

•Drugs Malignancy, especially Hodgkin's lymphoma

Primary nephrotic syndrome

Diagnosis of exclusion

Primary nephrotic syndrome /idiopathic nephrotic syndrome

Steroid resistant INS (SRNS)

Steroid sensitive IN (SSNS)

response to steroids has a high correlation with histological subtype and prognosis

PATHOPHYSIOLOGY

PROTEINURIA / HYPOALBUMINIA

Immune pathogenesisDeregulation of T-cell subsets.

Circulating factorsCytokines/other molecules

Allergic responsePoison ivy, bee stings

PODOCYTE BIOLOGY

Effacement of podocytes is now thought to be the primary pathology.

-ve charge of the basement membrane is also important.

GENETICS.

NephrinTransmembrane protein encoded by NPHS 1 on chromosome 19.(FINISH type congenital NS.

PodicinEncoded by NPHS 2 on chromosome 1.Autosomal recessive.

Mutations in α-actinin-4, encoded by the gene ACTN4 on chromosome 19 and TRPC6 on chromosome 11, are associated with autosomal dominant forms of FSGS

PATHOPHYSIOLOGY continued….

Pathophysiology cont…

Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS receiving either albumin or dextran infusions

Patients with nephrotic syndrome are at increased risk for thrombosis.Abnormalities described in INS include increased platelet activation and aggregation; elevation in factors V, VII, VIII, and XIII and fibrinogen; decreased antithrombin III, proteins C and S, and factors XI and XII; and increased activities of tissue plasminogen activator and plasminogen activator inhibitor-1.

Decreased levels of Ig G and increased losses of factor B.

INVESTIGATIONS

ESTABLISH nephrotic syndrome

Nephrotic range proteinuria

Hypoalbuminemia

Hyperlipidemia

Primary or secondary nephrotic syndromes

If Primary,Whether in renal failure?....

Renal functions.

Investigations

Urea creatinine and electrolytes

CBC

Testing for hep B and C

Complement system

ANA,Anti double stranded DNA antibodies.

Imaging;U/S abdomen and chest.X ray chest.Genetic testing.

Renal biopsy

INTERPRETATIONS

Anemia , raised urea creatinine ,acidosis,hyperkalemia,hyperphosphatemia,indicateChronic renal disease.

Hyponatremia may be due to hyperlipidemia and due to water retention(pseudohyponatremia.

Raised Hb and haemetocrat indicates haemodilution.reduced intravascular volume. Platelet is raised.

Check liver enzymes..for Hepatitis B and C.and do screening for viruses.

MANAGEMENT OF NEPHROTIC SYNDROME

A trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney biopsy is not initially indicated.

patients aged 1-8 years with normal kidney function

Normal kidney functions

No macroscopic gross haemeturia

No symptoms of systemic disease.

Normal complement levels

Negative viral screen

No family hisory.

IMPORTANT DEFINITIONS

RESPONSE; protein free urine on 3 consecutive days within 7 days.

RELAPSE; protein +ve urine on 3 consecutive days within one week with edema.

FREQUENT RELAPSING NS; steroid sensitive nephrotic syndrome with 2 or more relapses in 6 months or more than 3 in one year.

STEROID DEPENDANT; responder who relapses while steroid is being tapered or within 14 days of stopping steroid treatment.

INITIAL NON RESONDER; no response during initial 8 weeks of therapy.

LATE NON RESPONDER; an initial steroid responder who fails to respond to 4 week treatment in relapse.

SSNS steroid sensitive nephrotic syndromeCorticosteroids

INDUCTION THERAPY

Exclude active infections and other contraindications to steroids

Oral prednisilone 60mg/m2/day…either single or divided doses for 4 weeks.

6 weeks therapy proves better .

MAINTAINANCE THERAPY

Oral prednisilone at 40mg/m2/day single morning dose at alternateDays for 4-6 weeks.

Longer duration of maintenance therapy results in fewer relapses.

Relapse therapy

For infrequent relapses steroid therapy may be resumed at 60mg/m2/day until proteinuria resolves..

Then switch to 40mg/m2/day for alternate days for 4 weeks.

Other therapy

Pneumococcal vaccines to all the patients.

Diuretic therapy for symptomatic edema. with furosamide 2mg/kg/day.

Anasarca with low intravascular volume ,albumin infusion, slow 1mg/kg/day can be considered.

HOME MONITORING

Home monitoring of urine protein and fluid status is important.

Parents should be trained to monitor first morning urine by dipstick.

Record of daily weight,urine protein and steroid dose should be kept in log book.

Any increase in urine protein or daily weight should be reported as early as possible.

TREATING FREQUENT RELAPSERS AND SDNS

ALKYLATING AGENTS

CyclophospamideChlorambucilNitrogen mustard

CALCINEURINE INHIBITORS

Cyclosporin Tacrolimus

LEVAMISOLE MYCOPHENOLATE MOFETIL

DOSING AND REGIMENS

Cyclophosphamide (2–2.5 mg/kg daily) is given orally for 8-12 weeks.

Steroids are usually overlapped with initiation of CYP then tapered

Patients must have weekly CBC counts to monitor for leukopenia.

Patients must also maintain adequate hydration and take CYP in the morning (not at bedtime) to limit the risk of hemorrhagic cystitis

CYCLOSPORIN

CSA can be used in those children who fail to respond to, or subsequently relapse after, treatment with CYP, or for children whose families object to use of CYP

Initial doses of CSA are started at 5–6 mg/kg daily divided every 12 hours, adjusted for trough concentrations of 50–125 ng/mL

Low-dose steroids are continued for a variable length of time

Kidney function and drug levels must be carefully monitored due to the risk of CSA induced nephrotoxicity.

Deterrence/Prevention

Yearly influenza vaccination is recommended to prevent serious illness in the immunocompromised patient, as well as to prevent this possible trigger of relapse.

Pneumococcal vaccination should be administered to all patients with INS to reduce the risk of pneumococcal infection. Vaccination should be repeated every 5 years while the patient continues to have relapses.

Routine childhood vaccines with live virus strains are contraindicated in patients taking steroids and until off steroid treatment for a minimum of 1 month.

Because of the high risk of varicella infection in the immunocompromised patient, in the nonimmune patient, post exposure prophylaxis with varicella-zoster immune globulin is recommended. Patient with varicella-zoster infection should be treated with acyclovir and carefully monitored

Routine, nonlive viral vaccines should be administered according to their recommended schedules