![Significant
steroid
toxicity
Hyperglycemia (fasting glucose >100 mg/dL,
post-prandial glucose >140 mg/dL, or HbA1c
>5.7%) [12]; obesity (body mass index
>equivalent of 27 kg/m2 in adults [13]); short
stature (height < 2 SDS for age [13]) with
height velocity (< 3 SDS for age [14]); raised
intraocular pressure; cataract(s); myopathy;
osteonecrosis; or psychosis
Difficult-to-
treat
steroid
sensitive
disease
Both of the following: (i) frequent relapses, or
significant steroid toxicity with infrequent
relapses; and (ii) failure of steroid sparing
agents (including levamisole,
cyclophosphamide, mycophenolate mofetil)](https://image.slidesharecdn.com/ssns-230226173245-206b8bd7/85/Steroid-Sensitive-Nephrotic-Syndrome-11-320.jpg)
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Steroid Sensitive Nephrotic Syndrome
- 1. Steroid Sensitive Nephrotic Syndrome: Revised Guidelines PRESENTER Dr. Sunil D Mulgund MODERATOR Dr. Rohit Khandelwal ADITI SINHA,ARVIND BAGGA, SUSHMITA BANERJEE,KIRTISUDHA MISHRA,AMARJEET MEHTA, INDIRA AGARWAL, SUSAN UTHUP, ABHIJEET SAHA, OM PRAKASH MISHRA8 AND EXPERT GROUP OF INDIAN SOCIETY OF PEDIATRIC NEPHROLOGY* From 1Division of Nephrology, Departments of Pediatrics, All India Institute of Medical Sciences, New Delhi; 2Institute of Child Health, Kolkata; 3Chacha Nehru Bal Chikitsalaya, Delhi; 4Sawai Man Singh Medical College, Jaipur; 5Christian Medical College, Vellore; 6Trivandrum Medical College, Thiruvananthapuram; 7Lady Hardinge Medical College, New Delhi; 8Institute of Medical Sciences, Benaras Hindu University, Varanasi, India. *List of expert group members provided in Annexure I. Correspondence to: Dr. Arvind Bagga, Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India. arvindbagga@hotmail.com
- 2. Steroid sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management.
- 3. Objective: To frame revised guidelines on diagnosis, evaluation, management and supportive care of patients with the illness. Process: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings.
- 4. Nephrotic syndrome, characterized by edema, heavy proteinuria (>1 g/m2 daily; >40 mg/m2/ hr) and hypoalbuminemia (serum albumin <3 g/dL), is among the most common kidney diseases in childhood. The condition has an annual incidence ranging from 1.2 to 16.9 per 100,000 children.
- 5. Kidney biopsy reveals minimal change disease in ~80% patients, and focal segmental glomerulosclerosis (FSGS) and mesangioproliferative glomerulonephritis (GN) in 7-8% each.
- 6. While the outcome in patients with SSNS is satisfactory, approximately 50% show frequent relapses or steroid dependence, and 3-10% show late steroid resistance. Workgroups were constituted to address key issues, including: (i) Evaluation at baseline and follow up, role of biopsy, genetic testing, and differential diagnosis; (ii) Management of the initial episode and subsequent relapses; (iii) Management of frequent relapses; and (iv) Supportive care and outcomes.
- 9. Remission Urine protein nil or trace (Up/Uc <0.2 mg/mg) for 3 consecutive early morning specimens Relapse Urine protein 3+ (Up/Uc >2 mg/mg) for 3 consecutive early morning specimens, having been in remission previously. Frequent relapses Two or more relapses in the first 6-months after stopping initial therapya; 3 relapses in any 6-months; or 4 relapses in one yr.
- 10. Steroid dependence Two consecutive relapses when on alternate day steroids, or within 14 days of its discontinuation Steroid resistance Lack of complete remission despite therapy with daily prednisolone at a dose of 2 mg/kg (or 60 mg/m2) daily for 6 weeks Stable remission Sustained remission or infrequent relapses during immunosuppressive therapy Complicated relapse Relapse associated with life-threatening complications: (i) hypovolemia requiring inpatient care, (ii) severe infection (peritonitis, cellulitis, meningitis), or (iii) thrombosis
- 11. Significant steroid toxicity Hyperglycemia (fasting glucose >100 mg/dL, post-prandial glucose >140 mg/dL, or HbA1c >5.7%) [12]; obesity (body mass index >equivalent of 27 kg/m2 in adults [13]); short stature (height < 2 SDS for age [13]) with height velocity (< 3 SDS for age [14]); raised intraocular pressure; cataract(s); myopathy; osteonecrosis; or psychosis Difficult-to- treat steroid sensitive disease Both of the following: (i) frequent relapses, or significant steroid toxicity with infrequent relapses; and (ii) failure of steroid sparing agents (including levamisole, cyclophosphamide, mycophenolate mofetil)
- 13. INVESTIGATIONS IN PATIENTS WITH STEROID SENSITIVE NEPHROTIC SYNDROME Essential at onset Urinalysis Complete blood counts Blood urea, creatinine, electrolytes, total protein, albumin, total cholesterol Tuberculin test ADDITIONAL EVALUATION, AT ONSET OR RELAPSE Chest radiography: Positive tuberculin test or history of contact; suspected lower respiratory tract infection Renal ultrasonography: Planned for kidney biopsy; presence of gross hematuria; suspected renal vein thrombosis Complete blood counts: Suspected systemic infection or hypovolemia
- 14. Blood urea, creatinine, albumin, electrolytes: Severe edema; hypovolemia/dehydration; oliguria/anuria; prolonged (>72 h) diuretic therapy Complement C3, C4, antinuclear antibody, antistreptolysin O: Gross, persistent microscopic hematuria; sustained hypertension; suspected secondary cause (systemic lupus, IgA vasculitis, C3 glomerulopathy) Serum transaminases; hepatitis B surface antigen; antibody against hepatitis C virus: History of jaundice or liver disease Periodic monitoring, if relapsing illness Blood creatinine; albumin, electrolytes
- 15. GUIDELINE 1: EVALUATION Following investigations to confirm the diagnosis of nephrotic syndrome: (i) urinalysis; and (ii) blood levels of urea, creatinine, albumin and total cholesterol. Urine microscopy is normal, except for hyaline or granular casts; occasional microscopic hematuria is not uncommon. Persistent microscopic hematuria or red cell casts suggests disease other than minimal change nephrotic syndrome, like infection related GN, C3 glomerulopathy, systemic lupus or vasculitis . Additional investigations are required for their diagnosis. Since patients with nephrotic syndrome do not have increased prevalence of urinary tract infections, routine urine cultures are not necessary.
- 16. Persistent microscopic hematuria or red cell casts suggests disease other than minimal change nephrotic syndrome, like infection related GN, C3 glomerulopathy, systemic lupus or vasculitis . Additional investigations are required for their diagnosis. Since patients with nephrotic syndrome do not have increased prevalence of urinary tract infections, routine urine cultures are not necessary.
- 17. With an estimated prevalence of bacteriologically positive pulmonary tuberculosis of 296 per 100,000 population in India, the risk of latent tuberculosis infection Tuberculin test is suggested prior to the first course of steroid treatment, especially with history of contact . Chest radiography is done in patients with positive tuberculin test; those with features of tuberculosis require appropriate therapy.
- 18. Patients with positive tuberculin reaction, but no radiological or bacteriological evidence of tuberculosis, should receive isoniazid prophylaxis for 6-months . The prevalence of hepatitis B in non-tribal Indian populations is low (2.4%; 95% CI, 2.2- 2.7%) , and routine screening is not required.
- 19. GUIDELINE 2: KIDNEY BIOPSY (i) persistent microscopic hematuria, gross hematuria, or acute kidney injury not attributed to hypovolemia; (ii) systemic features: fever, rash, arthralgia, low complement C3; (iii) initial or late corticosteroid resistance; (iv) prolonged (>30-36 months) therapy with calcineurin inhibitors (CNI), or reduced kidney function during their use. Kidney biopsy is recommended prior to initiating therapy with CNI.
- 20. The large majority of patients with SSNS show minimal change disease, and less commonly, FSGS or mesangioproliferative GN ,more than 90% children with minimal change disease, 50% with mesangioproliferative GN and 30% with FSGS have steroid sensitive disease. An adequate biopsy specimen should preferably include the corticomedullary junction and approximately 20 glomeruli to exclude the diagnosis of FSGS
- 21. GUIDELINE 3: THERAPY FOR THE FIRST EPISODE OF NEPHROTIC SYNDROME Therapy for the initial episode should comprise of prednisolone at a dose of 60 mg/m2/day (2 mg/kg/day, maximum 60 mg in 1-2 divided doses) for 6 weeks, followed by 40 mg/m2 (1.5 mg/kg, maximum 40 mg as single morning dose) on alternate days for the next 6 weeks, and then discontinued.
- 22. Based on pharmacokinetics and variations by age, prednisolone is preferably dosed by body surface area in children .However, estimation of body surface area involves complex formulae with variable results. Calculation using body weight is convenient, but results in relative underdosing, particularly in young children. Underdosing, using weight-based calculations, was associated with increased risk of frequent relapses in some , but not in all studies Experts therefore prefer to administer prednisolone based on body surface area for young children.
- 23. GUIDELINE 4: THERAPY OF RELAPSES Relapses to be treated with prednisolone at 60 mg/m2/day (2 mg/kg/day; maximum 60 mg) in single or divided- doses until remission (protein trace/nil for 3 consecutive days), followed by 40 mg/m2 (1.5 mg/kg, maximum 40 mg) on alternate days for 4-weeks.
- 24. Almost one-half of the relapses are precipitated by minor infections, usually of the upper respiratory tract. Remission is achieved by 7-10 days, and daily therapy is seldom necessary beyond 2 weeks. In case of persistent proteinuria, daily therapy with prednisolone may be extended, to maximum of 6-weeks. Lack of remission despite treatment with 6-weeks daily prednisolone indicates late steroid resistance that requires specific evaluation and management.
- 25. GUIDELINE 5: MANAGEMENT OF FREQUENT RELAPSES AND STEROID DEPENDENCE Two or more relapses in the first 6-months after stopping initial therapy; 3 relapses in any 6-months; or 4 relapses in one yr. Patients experiencing 4 relapses annually receive ~165- 200 mg/kg (4.6-5.6 g/m2) prednisolone, corresponding to 0.45-0.55 mg/kg (12.5-15.5 mg/m2) daily. As 12-weeks prednisolone therapy for the initial episode (~115 mg/kg; ~3.4 g/m2) might be associated with adverse effects , the risk of steroid toxicity in patients with 3 relapses in any 6-months or 4 relapses annually is considerable
- 26. NEED FOR STEROID-SPARING THERAPY Patient with significant steroid toxicity and fewer relapses (3 relapses/year; 2 relapses in 6-months). Occurrence of two relapses in 6-months during long-term therapy with corticosteroids or steroid-sparing agents.
- 27. MANAGEMENT OF FREQUENTLY RELAPSING OR STEROID DEPENDENT NEPHROTIC SYNDROME.
- 28. The initial strategy is to administer prednisolone at a dose of 0.5-0.7 mg/kg on alternate days. In patients with stable remission (sustained remission or infrequent relapses), therapy may be tapered to 0.2-0.3 mg/kg on alternate days for 6- 12 months. Daily therapy at the same dose for 5-7 days, during minor infections, prevents infection- associated relapses. Patients who relapse at steroid threshold >0.7 mg/kg or show steroid toxicity require therapy with steroid-sparing medications.
- 29. The choice of agents is based on disease severity, adverse effects, patient age, cost of therapy, and parental preference. Levamisole or mycophenolate mofetil (MMF) are preferred medications for mild disease. Patients with high steroid threshold (>1 mg/kg on alternate days), complicated relapses and those with significant steroid toxicity (Box I) may be treated with MMF at higher doses (1000-1200 mg/m2/day) or cyclophosphamide.
- 30. The use of cyclophosphamide is avoided in children <5-7 yr-old and in peri-pubertal boys due to reduced efficacy and risk of gonadal toxicity, respectively. Patients who relapse despite therapy with two or more steroid-sparing agents (difficult- to treat steroid sensitive disease) are considered for therapy with calcineurin inhibitors, and failing that, rituximab. The use of rituximab is avoided in young children due to the risk of hypogammaglobulinemia.
- 33. LEVAMISOLE The mechanism of action of levamisole as an antiparasitic agent appears to be tied to its agnositic activity towards the L-subtype nicotinic acetylcholine receptors in nematode muscles. This agonistic action reduces the capacity of the males to control their reproductive muscles and limits their ability to copulate. Although the exact mechanism of levamisole action in maintaining remission in patients with idiopathic nephrotic syndrome (INS) is still unknown, it is postulated that the drug enhances the Th1-mediated immune response and reciprocally downregulates the Th2 lymphocyte-mediated immune response. Recently, it was suggested that levamisoles mode of action is attributable to its direct effects on podocytes.
- 34. AROUND Rs. 50-90 FOR 10 TABLETS LEVAMISOLE
- 35. AROUND 20 -50 RS DEPENDING ON DOSAGE /10 TABLETS
- 36. Cyclophosphamide is an alkylating agent of the nitrogen mustard type. 2 An activated form of cyclophosphamide, phosphoramide mustard, alkylates, or binds, to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA, and to inhibition of protein synthesis. 300 500 RS FOR 10 TABLETS
- 37. MPM depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation 500 RS FOR 10 TABLETS
- 38. The mechanism of action of cyclosporine is as a calcineurin inhibitor, a cytochrome P450 3A4 inhibitor, and a P-glycoprotein inhibitor. Cyclosporin A (CsA) inhibits the synthesis of interleukins (IL), including IL-2, which is essential for the self-activation of T lymphocytes (LT) and their differentiation. 1950 RS FOR 10 TABLETS
- 39. Tacrolimus bonds to an immunophilin, FK506 binding protein (FKBP). This complex inhibits calcineurin phosphatise. 300- 500 RS /10 TABLETS
- 40. 30000-50000 PER INJECTION Complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity
- 41. GUIDELINE 6: MANAGEMENT OF HYPOVOLEMIA AND EDEMA Edema be empirically classified based on appearance and percentage weight gain from baseline, as mild (7% increase), moderate (8-15%) and severe (>15% increase) If urine protein is monitored regularly, the occurrence of more than mild edema is unusual. Patients with severe edema have marked hypoalbuminemia (serum albumin <1.5 g/dL), along with ascites and anasarca that interferes with daily activities . Intravascular volume depletion is common in patients with moderate or severe edema , and should be assessed before instituting therapy with diuretics.
- 44. GUIDELINE 7: INFECTIONS AND IMMUNIZATION Infections are the chief complication in patients with SSNS, accounting for 19-44% of hospitalizations . Contributing factors include the use of immunosuppressive agents, anasarca, and urinary losses of IgG and complement factors, that predispose to infection with encapsulated organisms . Peritonitis is the most common severe infection, followed by pneumonia and cellulitis.
- 46. VACCINES
- 48. CONCLUSIONS The present guidelines, based on best available evidence and expert guidance, provide directions for evaluation and management of SSNS in children. Recommendations, proposed by the Indian Society of Pediatric Nephrology, in 2001 and 2008, have been revised based on systematic reviews, published studies and expert opinion. The management of frequent relapses continues to be challenging, with morbidities associated with the disease as well as therapies.
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