Pediatric NEPHROLOGY: How to prepare NEPHROTIC SYNDROME for part II examine.

MANAGEMENT OF CHILDHOOD NEPHROTIC SYNDROME

Useful definitions:

Nephrotic syndrome	Presence of generalized edema, heavy proteinuria and hypoalbuminaemia.  Hypercholesterolemia (>200mg/dL), invariably present, is not conventionally included as a part of the diagnosis.
Heavy proteinuria and hypoalbuminaemia
Remission	Loss of edema and urine protein/creatinine ratio <0.02 or urinary total protein excretion <4 rng/rn2/hr or early morning (first void) urine dipstick negative/trace for 3 consecutive days.
Steroid responsive	Remission achieved with steroid therapy alone.
Relapse	Sustained proteinuria of urine protein/creatinine ratio >0.2 or early morning (first void) urine dipstick ≥2+ for 3 consecutive days (partial biochemical relapse) ± generalized edema + hypoalburnlnaemia (<2.5g/dL (full clinical relapse), having previously been in remission.
Infrequent relapses	Relapses after the first episode, but <2 episodes within first 6 months or <4 episodes within any subsequent one year period.
Frequent relapses	Relapses after the first episode, with ≥2 episodes within first 6 months or ≥4 within any subsequent one-year period.
Steroid dependence	Frequent relapsers with 2 consecutive relapses while on steroid therapy or within 2 weeks of cessation of steroid therapy.
Steroid resistance	Failure to achieve remission despite 8 weeks of daily high dose (60mg/m2/day) prednisolone therapy.

Classification:

A.      Congenital

B.      Acquired

a                  Primary

b                 Secondary

Acquired (Primary)

Subtypes	ISKDC Classification
Minimal change nephrotic syndrome (MCN)	76%
Focal segmental glomerulosclerosis (FSGS)	07%
Focal global sclerosis (FGS)	02%
Mesangial proliferative glomerulonephritis (MPG)	04%
Membranoproliferatlve glomerulonephritis (MPGN)	08%
Membranous nephropathy	02%
Chronic glomerulonephritis	01%

Acquired (Secondary)

A.      Autoimmune disease:  systemic lupus erythematosus and Henoch-Schonlein purpura

B.      Infections: Hepatitis A and B, Human immunodeficiency virus

C.      Hereditary nephritis: Alport syndrome

D.     Drugs: Hevy metal like mercury and penicillamine therapy

E.      Metabolic: Diabetic nephropathy

Clinical evaluation

§  History and clinical signs of systemic involvement:

Pallor

Rash

Petechiae

Arthritis

Hepatosplenomegaly

Hemoptysis

§  Family history of nephrotic syndrome, renal failure and hearing defects,

§  Drug history especially of traditional medicine.

Investigations to evaluate etiology

1. Step 1 (uncomplicated presentation):

§              Full blood count

§              Serum complements (C3, C4)

§              Anti-nuclear antibodies or anti-double-stranded DNA antibodies

§             Hepatitis B surface antigen

2. Step 2 (atypical presentation):

§             Hepatitis C antibody (indicated in nephritic-nephrotic syndrome)

§             ANCA (indicated in nephritic-nephrotic syndrome or evidence of leukocytoclastic vasculitis)

§             C3 nephritic factor (indicated in nephritic-nephrotic syndrome)

§              Serum immunoglobulins (lgG, IgM, IgA)

3. Step 3: Mutational analysis

       Congenital and infantile onset nephrotic syndrome:

•       WT1 exons 8 and 9 (Wilms tumor 1 protein)

•       NPHS1 (nephrin)

•       NPHS2 (podocin)

•       LAMB2 (Iaminin subunit beta-2) (congenital and infantile onset)

•       PLC£1 (phospholipase C, epsilon 1) (congenital and infantile onset)

§               Childhood onset steroid-resistent or steroid-dependent nephrotic syndrome:

•       WT1 exons 8 and 9 (Wilms tumor 1 protein)

•       NPHS1 (nephrin)

•       NPHS2 (podocin)

§              Adult onset FSGS

•       NPHS2 (podocin)

•       TRPC6 (transient receptor potential cation channel C, member 6)

•       ACTN4 (a-actinin4)

•       CD2AP (C02-associated protein)

•       MYH9 (myosin, heavy chain 9, non-muscle)

•       INP2 (inverted formil) 2)

4. Step 4 (steroid-resistant collapsing FSGS):

§             HIV antibody

§             Parvovirus IgM, IgG and PCR

Indications for renal biopsy

1.        Steroid resistance

2.       Age <1 year

3.       Age >10 years if steroid-dependent or resistant

4.      Hypertension

5.       Gross hematuria

6.      Hypocomplementemia

7.       Renal failure

8.      Family history of renal failure and deafness

Treatment

1.        Prednisolone

Indications: First episode of nephrotic syndrome and subsequent relapses.

Protocol

•       Children experiencing their first episode of nephrotic syndrome should be treated with prednisolone at 60 mg/m²/day (maximum of 60 mg/day) for 06 weeks followed by 40 mg/m² of prednisolone every alternate day for 06 weeks and gradual taper over 4 weeks for a total treatment course of 3-6 months.

•       Prednisolone should be given as single morning dose to minimize the side effects.

•       Children with first relapse and infrequent relapses should be treated with prednisolone 60 mg/m² /day (maximum 60 mg) minimum 14 days or until 3 days proteinuria free, then prednisolone 40 mg/m²/EOD for 4 weeks, tapering off over 3 months.

•       Children with frequently relapsing nephrotic syndrome should be placed on maintenance therapy after treatment of relapse, with alternate-day prednisolone 0.1-0.5 mg/kg/EOD for 3 to 6 months.

•       Children with steroid-dependent nephrotic syndrome should be placed on maintenance therapy with prednisolone 0.1-0.5 mg/kg/EOD for 9-12 months.

•       In children on maintenance alternate day prednisolone for 06 months, tapering of prednisolone is recommended, according to the difficulty in attaining remission.

•       If patient has proteinuria ≥2+ for more than 5 days ± having mild/gross edema and on EOD regime, consider increasing prednisolone to daily dose (02mg/kg/day) until 3 days proteinuria free, before reducing to EOD at the same dose, and continue tapering protocol.

•       Note: Prednisolone dose should not be reduced unless the patient has been proteinuria free for the entire period, i.e. negative or trace.

•       Monitor height, weight, blood pressure at each clinic visit.

•       Ophthalmologic screen for posterior subcapsular cataracts should be done at least on a yearly basis for those that have been on ≥6 months of prednisolone therapy.

•       Consider DEXA scan for bone mineral density in children on long-term (>1 year) daily prednisolone. Consider starting on calcium and vitamin D supplements.

 2.       Levamisole

Indications: Frequently relapsing or steroid-dependent nephrotic syndrome with unacceptable steroid side-effects, due to MCNS.

Protocol:

§                 Maintain prednisolone at 60 mg/m²/day until proteinuria tree for 2 weeks.

§                Start levamisole 2.5 mg/kg/EOD for 6-12 months.

§                Wean prednisolone to 40 mg/m²/EOD and taper over 8 weeks.

§                Monitor total white count (TLC) weekly for 1st 4 weeks, then every 2 weeks for the next 12              weeks, then monthly.

§                Main side effect is agranulocytosis.

§               Stop drug if:

•       TLC <3.0 x10⁹/L or absolute neutrophil count (ANC) <1.5 X10⁹/L.

•       Note: neutropenia tends to occur within the 1^st  3 months.

•       Purpuric rash develops (do not re-start).

§               Note: Levamisole tablet= 50 mg (Ketress )

3.       Cyclophosphamide

Indications: Frequently relapsing or steroid-dependent nephrotic syndrome with unacceptable steroid side-effects, due to MCNS.

Protocol:

§               Maintain prednisolone at 60 mg/m²/day (maximum 60 mg) until proteinuria free for at least 3         days. While on cyclophosphamide, the prednisolone dose should not exceed 60 mg.

§            Start cyclophosphamide 2.0-2.5 mg/kg/day preferably when patient is in remission. Continue·          for 8 weeks (frequent relapser) to 12 weeks (steroid-dependent).

§       If patient is steroid-resistant and edematous, ensure good urine output using albumin or              diuretics before starting cyclophosphamide, to prevent hemorrhagic cystitis.

§           Wean prednisolone to 40 mg/m2/EOD and taper off over 8-12 weeks.

§       Monitor total White Count (TLC) weekly for first 04 weeks, then every 02 weeks for next 08     weeks.

§  Stop drug if:

•       Febrile illness.

•       TLC <3000/dL or absolute neutrophil count (ANC) <1500/dL.

•       Platelet count <100 x10⁹/L.

§  Parents and patients should be informed of the potential risks of:

•       Sterility, if the cumulative dose exceeds 250 mg/kg, especially in the post-pubertal patient. Post-pubertal adolescent boys should be advised to consider sperm storage.

•       Malignancy (very low risk, unless the patient is given repeated courses for more than a year).

§  Note: Cyclophosphamide table= 50 mg (Imuran)

4.      Cyclosporine (CsA)

Indications: Steroid-resistant and steroid-dependent patients with MCNS who has failed cytotoxic therapy with alkylating agents such as cyclophosphamide AND with normal renal function. Nephrotic syndrome due to FSGS WITH normal renal function.

Protocol:

§  Check serum urea, creatinine, electrolytes, and liver function test before starting on CsA.

§  Give CsA 3-8 mg/kg/day given as BD dose to attain trough CsA levels at 100-300 mcg/L.

§  Monitor CsA levels and serum creatinine 2x for 1^st  week, then once in 2 weeks for 1^st  month, then 4-6 weekly.

§  If serum creatinine increases by 25% and CsA nephrotoxicity is suspected, reduce CsA dose by 20% to determine if this is the cause.

§  Use diltiazem 15-30 mg 12H to increase CsA levels increasing by 15 mg/dose until a maximum of 3 mg/kg/dose 8-12H (maxirnum dose per day = 60 mg 8H), Effect of diltiazem should be seen by 3 weeks.

§  Precaution: Stop diltiazem if heart rate s 60 beats/min, as diltiazem has been associated with sino-atrial block, Check ECG,

§  Response should be seen in 2 weeks to 1 month. If no response after 2 months, consider adding mycophenolate mofetil or changing to tacrolimus.

§  Taper prednisolone dosage as patient goes into remission.

§  If patient responds to CsA:

§  In MCNS, continue for 1 to 2 years before tapering off the CsA. If patient relapses again, re-start on CsA if they are steroid-dependent, and consider changing to mycophenolate mofetll especially for those with evidence of CsA toxicity on renal biopsy.

§  In FSGS, continue for up to 5 years before considering tapering the dose, and changing to mycophenolate mofetil.

•       Repeat renal biopsy should be considered at the end of 2 years to assess for nephrotoxic effects, especially in those where continuation of CsA beyond 2 years has been planned.

•       Advise on good dental hygiene to prevent gum hyperirophy. Refer to Dental service if there is severe gum hypertrophy.

§  Consider posterior reversible encephalopathy syndrome if patient has neurological symptoms.

§  Drug interactions:

•       Drugs decrease CsA levels: Phenytoin, isoniazid, carbamazepine, phenobarbitone, rifampicin, co-trimoxazole, warfarin.

•       Drugs increase CsA levels: Erythromycin, ketoconazole, cimetidine, methylprednisolone, diltiazem, verapamil, metoclopramide, fluconazole, vancomycin, imipenem, co-trimoxazole, grapefruit and grapefruit juice.

•       Drugs that potentiate nephrotoxicity when used with CsA: Aminoglycosides, amphotericin, acyclovir, co-trimoxazole, Nonsteroidal anti-inflarnmatory drugs (NSAIDs), phenobarbitone, rifampicin, captopril.

•       Other interactions:

Irnipenern: Central nervous systern disturbance including seizures

Digoxin: Increase in Digoxin levels

Furosernide: Decrease nephrotoxicity

HMG CoA reductase inhibitor: Rhabdornyolysis, rnyalgia and muscle weakness

5.       Mycophenolate Mofetil (MPA)

Indications: Patients who are still relapsing while on prednisolone and CsA Alternative drug In those with CsA toxicity,

Protocol:

§  MPA Dose: 600 mg/m²/dose 12H (15-23 mg/kg/dose 12H), Maximum dose:1 gm 12H

§  MPA + CsA Dose: 600 mg/m²/dose 12H (15-23 mg/kg/dose),Maximum dose:1 gm 12H

§  MPA + Tac. Dose: 300 mg/m²/dose 12H (08-12 mg/kg/dose),Maximum dose: 500 mg 12H

§  Dose adjustments required for renal impairment. Drug is not removed by hemodialysis.

§  Monitor full blood count (FBC) in a month and 3-monthly thereafter. Do a serum MPA level in one month. Trough levels range from 2-4 mg/L.

§  Omit if absolute neutrophil count <1.5 x1 0⁹/L.

§  Side effects:

•       Neutropenia (especially at 1-6 months), anemia, thrombocytopenia (rare)

•       Gastritis, peptic ulceration, abdominal colic, diarrhea, gastrointestinal hemorrhage and perforation.

•       Start ranitidine prophylactically at 3 mg/kg/dose nightly (maximum 150 mg). Increase the dose to BD if the patient complains of gastric pain. Alternatively, start omeprazole 1 mg/kg/dose nightly or twice daily (maximum 120 mg three times a day).

§  Drug interactions: Acyclovir and ganciclovir increase MPA levels. Antacids decrease MPA levels. Do not administer drugs simultaneously.

6.      Tacrolimus (Tae)

Indications: Patients who fail to respond within 2 months to GsA ± MPA therapy.

Protocol:

§  Check serum urea, creatinine, electrolytes, and liver function test before starting on Tac.

§  Dose: 0.15 mg/kg 12H, increasing to achieve trough Tac levels of 5-15 mcg/L.

§  Monitor Tac levels and serum creatinine 2x for 1^st week, then once in 2 weeks for 1^st  month, then 4-6 weekly.

§  If serum creatinine increases by 25% and Tae nephrotoxicity is suspected, reduce Tac dose by 20% to determine if this is the cause.

§  Consider using diltiazem to increase Tae levels.

§  Response should be seen in 2 weeks to 1 month. If no response after 2 months, consider adding mycophenolate mofetil.

§  Repeat renal biopsy should be considered at the end of 2 years to assess for nephrotoxic effects, especially in those where continuation of Tae beyond 2 years has been planned.

§  Major side effects include tubulopathy with hypomagnesemia, diabetes mellitus and posterior reversible encephalopathy syndrome.

§  Monitor 3-monthly serum magnesium levels and fasting blood glucose levels. Monitor 6-monthly HbA 1 c levels.

§  Drug interactions:

§  Agents that decrease Tac concentrations:  Phenytoin, isoniazid, carbamazepine, Dexamethasone, phenobarbitone, rifampicin, sodium bicarbonate, aluminum hydroxide.

§  Agents that increase Tac concentrations: Cimetidine, danazol, erythromycin, ketoconazole, methylprednisolone, diltiazem, fluconazole, itraconazol, co-trimoxazole, verapamil, grapefruit and grapefruit juice

7.       Rituximab

Indications: Steroid-dependent and steroid-resistant nephrotic syndrome not responding well to conventional treatment.

Protocol:

§  Pre-infusion Monitoring: FBC, liver function test, urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphate, uric acid, fasting glucose, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, serum IgG, IgM, IgA, varicella-zoster IgG, Hepatitis BsAg, 24-hour urinary protein excretion, creatinine clearance, urine microscopy, urine protein/creatinine ratio, serum complements C3, C4, lymphocyte subsets: CD3, CD4, CD8, CO19, CD20, CD25 on CD3

§  Doses:

Steroid-dependent	IV Rituximab 375mg/m2 2-weekly X 02doses
Steroid-resistant	IV Rituximab 375mg/m2 2-weekly X 04doses

§  Pre-medication 30 minutes prior to infusion

•       Paracetamol10-15 mg/kg (maximum 1 g)

•       IV Hydrocortisone 4-10 mg/kg (maximum 500 mg)

•       IV Diphenhydramine 1 mg/kg (maximum 50 mg)

§  IV Rituximab infusion:

•       Start at 50 mg/hr and increase by 50 mg every 30 minutes as tolerated by blood pressure (BP) and heart rate (HR).

•       Maximum infusion rate 400 mg/hour.

•       Monitor heart rate, respiratory rate (RR), blood pressure, temperature, oxygen saturation (Sp02) every 15 minutes for 1^st hour. Then hourly if no problems.

•       If BP falls <100/60 mm Hg, HR >120/minute, Sp02 <95% on room air, stop infusion and recheck. Inform Pediatric Nephrologist on-call immediately.

•       When parameters stabilize, restart infusion at previous tolerated rate.

§  Post-Rituximab Monitoring:

•       Lymphocyte subsets CD3, CD4, CD8, CD19, CD25 on CD3, on D1, D3, then monthly till CD 19 recovery

•       Daily urine protein dipstick monitoring

•       Monthly urine protein/creatinine ratio

•       Monthly 24-hour urine protein excretion until <0.3 g/day/1 .73m2

•       Full blood count on day 1, then weekly for 2 weeks, then monthly Liver function test, serum urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphate, uric acid rnonthly

•       Fasting triglycerides, total cholesterol, LDL-cholesterol, and HDL-cholesterol 3-monthly

•       Creatinine clearance 3-monthly

§  Complications:

Acute: Monitor patients for onset of cytokine release syndrome characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria/rash, nausea, vomiting, fatigue, headache, throat irritation, rhinitis, flushing and angioedema. The syndrome usually manifests itself within one to two hours of starting the first infusion.

Stop infusion immediately and give an analgesic/antipyretic, an antihistamine and occasionally oxygen, intravenous saline or bronchodilators and corticosteroids if required.

Resuming infusions after adverse reactions: Infusion can be initially resumed at not more than one-half the previous rate upon complete resolution of all symptoms, normalization of laboratory values and chest x-ray findings. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should seriously be considered.

Chronic:

Progressive multifocal leukoencephalopathy

Interstitial lung disease: Diagnosis should be considered in patients who present with fever, cough and breathlessness, with no clear evidence of infection. Prompt diagnosis and early institution of corticosteroid therapy is essential.

Erythema nodosum.

§  Pneumocystis jirovecii Prophylaxis: Co-trimoxazole oral 3 mg/kg/dose alternate day starting after the first dose of Rituximab, and continuing for 3 months after the last dose of Rituximab. Check G6PD status and exclude in G6PD-deficient patients.

8.      General Management

§  Diet:

•       Children on steroids: Normal calorie, low saturated fats, no refined sugars (10·14% protein, 40-50% poly- and monounsaturated fats, 40-50% carbohydrate).

•       Salt restriction only if edema is present.

•       Fluids as desired up to 1.5x requirem.ents. Restrict to 50% of maintenance if edema present

•       Protein requirements: High protein intake: no evidence of benefit unless there is massive loss preventing growth To avoid malnutrition, increase protein intake to compensate for protein loss.

§  Decrease proteinuria:

•       Angiotensin converting enzyme inhibitor (ACE inhibitor): Start on enalapril 0.1-1.0 mg/kg daily as 12H or 24H dose (maximum 40 mg daily) or ramipril 0.05-0.2 mg/kg once daily (maximum 10 mg). Consider giving the dose nightly if patient's blood pressure is low and patient has dizziness during the day

•       Angiotensin /I receptor blocker: Consider adding losartan 0.6-2.0 mg/kg daily (maximum 100 mg) if the proteinuria is still Significant

•       Aim to decrease proteinuria to at least less than nephrotic range, i.e. <2 g/day1.73m2 or protein : creatinine ratio <0.2 , and to increase serum albumin >30 g/L

•       Consider use of NSAIDs if patient remains nephrotic and preservation of renal function is not an issue

§  Decrease hypercholesterolemia:

•       Dietary restriction as above

•       HMG CoA reductase inhibitors:

-        Lovastatin 0.4-0.8 mg/kg nightly. Dose can be increased monthly, to a maximum of 12H dosing (maximum 40 12H)

-        AtoNastatin 0.2-1.6 mg/kg nightly. Dose can be increased monthly (maximum 80 mg nightly)

-        Lovastatin in combination with calcineurin inhibitors has the lowest risk of rhabdomyolysis Simvastatin has the highest risk of rhabdomyolysis

-        Monitor liver function test and serum creatine kinase monthly for first 3 months then 3-monthly

§  Decrease hypercoagulopathy

•       Avoid hypovolemia

•       Aspirin 3-5 mg/kg (maximum 100 mg) daily or anti-platelet agents such as dipyridamole 1·2 mg/kg (maximum 100 mg) 8H

•       Heparin or warfarin (if there has been a thrombotic event) Note: Stop aspirin, dipyridamole, heparin or warfarin at least one week prior to renal biopsy. Ensure bleeding time, prothrombin time and partial thromboplastin time are normal before proceeding with the procedure.

§  Control of Edema

•       Albumin infusion 20% 1 g/kg over 4 hours followed by IV furosemide 1-2 mg/kg mid-way and at end of infusion'

•       Consider 'chronic diuretic therapy’ in patients with intractable edema, using combination of:

-        Furosemide 1·2 mg/kg OM or BD

-        Spironolactone

-        0-10 kg: 6.25 mg BD

-        11-20 kg: 12.5 mg BD

-        21-40 kg: 25 mg BD

-        >40 kg: 25 mg 8H

•       Bumetanide 25-50 mcg/kg (maximum 3 mg) daily, increasing to 8-12H

Algorithm Management of Steroid-Resistant Nephrotic Syndrome

Algorithm Management of steroid-sensitive Nephrotic Syndrome