NEPHROTIC SYNDROME IN CHILDREN

SWARNA VENUGOPAL SPECIALIST : DR CAROLINE ENG

CLASSIFICATION

CRITERIA FOR DIAGNOSIS

Peripheral oedema Hypoalbuminemia (<25g/L) Hypercholesterolaemia (total cholesterol often >10 mmol/L) Proteinuria >40mg/m2/hour (>1g/m2/day) or an early morning urine protein creatinine index >200mg/mmol

CLINICAL FEATURES

More common in males than in females (2:1) Between the ages of 2 and 6 yr (reported as early as 6 mo of age and throughout adulthood) The initial episode and subsequent relapses may follow minor infections and, occasionally, reactions to insect bites, bee stings, or poison ivy. Mild edema, initially noted around the eyes and in the lower extremities. May initially be misdiagnosed as an allergic disorder because of the periorbital swelling that decreases throughout the day. With time, the edema becomes generalized, with the development of ascites, pleural effusions, and genital edema. Anorexia, irritability, abdominal pain, and diarrhea are common; hypertension and gross hematuria are uncommon.

DIFFERENTIAL DIAGNOSIS

INVESTIGATIONS
The following investigations should be performed in all children: Blood: FBC, U+Es; Creatinine; LFTs; ASOT; C3/C4 Urine: Urine culture and Urinary protein/creatinine ratio BP Urinalysis including glucose A urinary sodium concentration can be helpful in those at risk of hypovolaemia. Varicella status should be known in all children commencing steroids. Hepatitis B status may be appropriate in children at high risk.

MINIMAL CHANGE GLOMERULOPATHY

Epidemiology: It is most common reason of NS in children, accounting for 80-90% of young patients with nephrotic syndrome , while only 20-25% in adults. There appears to be a male preponderance, especially in children, in whom the male- tofemale ratio is 2~3 :1

MINIMAL CHANGE GLOMERULOPATHY

Pathology

No glomerular lesions by light microscopy No staining with antisera specific for immunoglobulins or complement components. Effacement of visceral epithelial cell foot processes

MINIMAL CHANGE GLOMERULOPATHY

Clinical features: The cardinal clinical feature is the relatively abrupt onset of NS development with heavy proteinuria, hypoalbuminemia, and hyperlipidemia. The edematous picture is typically what prompts parents of children to seek medical attention. Hematuria, hypertension and impaired renal function are not common.

COMPLICATIONS OF NEPHROTIC SYNDROME

1.

HYPOVOLEMIA Despite the excess of fluid in the tissues, there is less fluid in the vasculature. Abdominal pain, cold perpheries, poor pulse volume, hypotension (late sign), haemoconcentration, urinary sodium of < 10 mmol/l. Rx: Infuse human albumin at 0.5 to 1.0g/kg/dose fast. Other volume expanders like human plasma can be used. Do not give frusemide.

COMPLICATIONS OF NEPHROTIC SYNDROME

2.

SEVERE INFECTION Leakage of immunoglobulins. bacterial (primary peritonitis; bacteremia; septicemia; or cellulitis due to Streptococcus pneumoniae, Escherichia coli, and Klebsiella organisms) or viral (measles or varicella). Edema and malnutrition offer a favorable condition for infections. Rx: Parenteral penicillin and 3rd generation cephalosporin. **Consider antibiotic prophylaxis whilst
patients have significant proteinuria.

COMPLICATIONS OF NEPHROTIC SYNDROME

3.

HYPERCOAGULABILITY Thrombocytosis; elevated concentrations of plasma fibrinogen factors V, VII, VIII, and X; increased platelet aggregation; and accelerated thromboplastin generation.
Causing renal vein and deep vein thrombosis or central venous sinus thrombosis, and thus renal necrosis and damage. Rx: anti-thrombotic therapy after consulting paediatric nephrologist.

COMPLICATIONS OF NEPHROTIC SYNDROME

4.

5.
6. 7. 8. 9.

Growth and development delay Anemia Pulmonary oedema Hypothyroidism Hypocalcemia Vitamin D deficiency

MANAGEMENT
Initial episode of NS:

Prednisolone 60mg/m2/day for 4 weeks. If responding 40mg /m2/EOD for 4 weeks then taper at 25% monthly over 4 months. Normal protein diet with adequate calories. No added salt to the diet when child has oedema. Penicillin V 125 mg BD (1-5 years age),250 mg BD (6-12 years), 500 mg BD (>12 years) is recommended at diagnosis and during relapses, particularly in the presence of gross oedema. Careful assessment of the haemodynamic status - check for signs and symptoms which may indicate hypovolaemia or hypervolaemia. Fluid restriction - not recommended except in chronic oedematous states.

General Management:

GENERAL MANAGEMENT..

Diuretics is not necessary in steroid responsive NS but if required, use with caution as it can precipitate hypovolaemia. Human albumin (20-25%) at 0.5 - 1.0 g/kg can be used in symptomatic grossly oedematous states together with IV frusemide at 1-2 mg/kg to produce diuresis. Caution: fluid overload and pulmonary oedema can occur with albumin infusion especially in those with impaired renal function. Urine output and BP should be closely monitored.

ACUTE ADRENAL CRISIS: May be seen in children who have been on long term corticosteroid therapy (equivalent to 18 mg/m of cortisone daily) when they undergo situations of stress. Hydrocortisone at 2-4mg/kg/dose TDS or prednisolone at 1 mg/kg/day should be given.

ADVICE FOR PARENTS AND PATIENT

Counsel about the disease [high probability (85-95%) of relapse] Home urine albumin monitoring: once daily dipstix testing of the first morning urine specimen. consult the doctor if albuminuria > 2+ for 3 consecutive days, or 3 out of 7 days. Consult the doctor should patient become oedematous regardless of the urine dipstix result. Children on systemic corticosteroids or other immunosuppressive agents should be cautioned about contact with chickenpox and measles, and if exposed should be treated like any immunocompromised child who has come into contact with these diseases.

ADVICE FOR PARENTS AND PATIENT

Immunisation: While the child is on corticosteroid treatment and within 6 weeks after its cessation, only killed vaccines may safely be administered to the child. Live vaccines can be given 6 weeks after cessation of corticosteroid therapy. Pneumococcal vaccine should be administered to all children with NS. If possible, give when the child is in remission.

General considerations during Follow-up (NS children on long-term steroids)

Monitor Blood pressure Monitor growth (including bone age and pubertal stage where suitable) Monitor weight dietetic review where required Glycosuria / HbA1c Bone mineral density / calcium supplements Ophthmology review

RELAPSER
Urine Alb excretion >40mg/m2/hour or urine dipstick of 2+ for 3 consecutive days Treatment: I. Prednisolone treatment should be restarted 60mg/m2/day (max 80 mg) until urine is negative/trace for 3 days then, 2 40 mg/m /EOD (max 60 mg) for 4 weeks then stop

II. Salt restriction proteinuria >2+ a no added salt diet is advised

RELAPSER
**Breakthrough proteinuria in infections -doesnt need steroid induction if child remains well -remits with resolution if infection -if persist TREAT AS A RELAPSE

FREQUENT RELAPSER
2 relapses within the first 6 months of presentation OR 4 relapses within any 12 month period Treatment: I. Prednisolone 60mg/m2/day (max 80 mg) until urine is negative/trace for 3 days then, 40 mg/m2/EOD (max 60 mg) for 4 weeks then stop

FREQUENT RELAPSER

Long-term EOD oral prednisolone Slow tapering of prednisolone every 2 weeks is done to reach to a maintenance dose of 0.25-0.5 mg/kg/EOD given for prolonged periods of 9-12 months If child relapses while on low dose EOD prednisolone re-induce with steroid as for relapse Patients requiring prednisolone exceeding 1 mg/kg/EOD are likely to show adverse effects consider steroid sparing agents.

COMPLICATIONS OF PREDNISOLONE (long term)

Cushings syndrome ( central obesity, buffalo hump, moon-face, hyperhidrosis, thinning of skin, purple or red striae, proximal muscle weakness, hirsutism, baldness) Type II Diabetes Hypertension Osteoporosis Hypokalemic alkalosis Acne Amenorrhea Immunosupression (susceptible to infection) Glaucoma and cataracts Depression upon dose reduction

STEROID RESISTANT NEPHROTIC SYNDROME

Absence of remission despite therapy with 4 weeks of daily prednisolone in a dose of 2mg/kg/day Effective regimens: calcineurin inhibitors (tacrolimus, cyclosporine) intra-venous cyclophosphamide or combination of pulse corticosteroids with oral cyclophosphamide, and tapering doses of alternate day corticosteroids Supportive management (when indicated) :

STEROID DEPENDENT NEPHROTIC SYNDROME

Occurrence of 2 consecutive relapses during steroid therapy or within 2 weeks of its cessation.

Treatment

if the child is not steroid toxic, re-induce with steroids and maintain on as low a EOD dose prednisolone as possible. If the child is steroid toxic (short stature, striae, cataracts, glaucoma, severe cushingoid features) consider cyclophosphamide therapy. Cyclophosphamide therapy begin therapy when in remission after induction with corticosteroids. parents should be counseled about the effectiveness and side effects of cyclophosphamide therapy (leucopenia, alopecia, hemorrhagic cystitis, gonadal toxicity). - dose: 2-3 mg/kg/day for 8-12 weeks (cumulative dose 168 mg/kg) - monitor FBC and urinalysis 2 weekly

STEROID DEPENDENT NEPHROTIC SYNDROME

Relapses post cyclophosphamide treated as for relapses following the initial diagnosis of nephrotic syndrome, if the child does not have signs of steroid toxicity. should the relapse occur soon after a course of cyclophosphamide when the child is still steroid toxic, or if the child again becomes steroid toxic after multiple relapses, consult a paediatric nephrologist. Treatment options: cyclosporine and levamisole.

RENAL BIOPSY

Indicated in those with atypical features: Age <12 months or >12 years Increased BP Macroscopic hematuria Impaired renal function Decreased C3/C4 Failure to respond after 1 month of daily steroid therapy (steroid resistant)

CORRELATION OF NEPHROTIC SYNDROME AND ATOPY

Idiopathic NS can be precipitated by allergic reactions and has been associated with both aeroallergens (pollens, mold, and dust) and food allergies. Patients with idiopathic nephrotic syndrome also may show increased serum IgE levels.

CORRELATION OF NEPHROTIC SYNDROME AND ATOPY

Atopy in childhood idiopathic nephrotic syndrome study by Salsano ME et al from Unit of Nephrology and Paediatrics Dyalisis, Paediatrics Hospital Giovanni XXIII, Bari, Italy. Apr 2007. Aim: evaluate the immunoallergic pattern and their modulating serum cytokines in children with primary manifestation of NS, in order to analyse the correlation with disease activity and the outcome of childhood NS.

CONCLUSION: only 40% of atopic children had a positive allergic history and 51.4% of the nephrotic children had normal sIgE levels, both pre and posttreatment, indicating different aetiologies, as immune mechanisms, in the pathogenesis of NS. Therefore, specific IgE antibodies were not related to disease activity, suggesting that IgE production might be coincident in childhood NS.

CORRELATION OF NEPHROTIC SYNDROME AND ATOPY

Idiopathic Nephrotic Syndrome and Atopy: Is There a Common Link? study by Maher Abdel-Hafez et al. from Division of Pediatric Nephrology, University of Florida. Nov 2009. A review of the literature suggests that although some idiopathic NS cases may be associated with allergies, evidence that it is a type of allergic disorder or can be induced by a specific allergen is weak. Rather, it is likely that the proteinuria and increased IgE levels in patients with idiopathic NS are caused by increased levels of IL- 13 observed in these patients. Recent studies suggest that IL- 13, a known stimulator of IgE response, may mediate proteinuria in patients with MCD because of its ability to directly induce CD80 expression on the podocyte.

CORRELATION OF NEPHROTIC SYNDROME AND ATOPY

A study of the relationship between childhood nephrotic syndrome and allergic diseases - Lin CY, Lee BH, Lin CC, Chen WP. June 1990. Incidence of atopic diseases in 206 children with NS was studied. Boys with NS had three times higher incidence of bronchial asthma than the general population. Both boys and girls with NS had about three times more allergic rhinitis and ten times more atopic dermatitis than the general population. 100 of the 206 children with NS received renal biopsies and serum IgE levels were measured. During the acute nephrotic phase the geometric mean serum IgE levels in minimal change nephrotic syndrome patients was significantly elevated. These high serum IgE levels decreased in remission of NS and elevated again during relapse. The relationship between high serum IgE levels in NS patients and the incidence of allergic diseases showed that one third to one fourth of MCNS patients developed allergic diseases.

REFERENCES

Abdel-Hafez M, et al. Idiopathic nephrotic syndrome and atopy: is there a common link? Am J Kidney Dis. 2009 Nov;54(5):945-53. Epub 2009 Jun 25.

Salsano ME, et al. Atopy in childhood idiopathic nephrotic syndrome. Acta Paediatr. 2007 Apr;96(4):561-6. Epub 2007 Feb 26.
Lin CY, Lee BH, Lin CC, Chen WP. A study of the relationship between childhood nephrotic syndrome and allergic diseases. Chest. 1990 Jun;97(6):1408-11. Paediatric Protocols For Malaysian Hospitals (2nd Edition) http://emedicine.medscape.com Steroid dependent and steroid resistant nephrotic syndrome in children, treatment and outcomes at Tripoli Children Hospital - Dr. Naziha R. Rhuma, Dr. O. Fituri, Dr. A. Boaeshi, Dr. M. Turky, April 2006. Guideline for the Management of Nephrotic Syndrome; Renal Unit, Royal Hospital for Sick Children, Yorkhill Division, Oct 2007.