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EVIDENCE BASED MANAGEMENT OF STEROID RESISTANT NEPHROTIC SYNDROME IN CHILDREN. DR NAUREEN AKHTAR Assistant Professor Department of Pediatric Nephrology The Children’s Hospital & the Institute of Child Health Lahore Pakistan. DEFINITION. Renal glomerular filtration system.
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EVIDENCE BASED MANAGEMENT OF STEROID RESISTANT NEPHROTIC SYNDROME IN CHILDREN DR NAUREEN AKHTAR Assistant Professor Department of Pediatric Nephrology The Children’s Hospital & the Institute of Child Health Lahore Pakistan
Saleem MA. New developments in steroid-resistant nephroticsyndrome. PediatrNephrol May 2013;28(5): 699–709.
Decreased glucocorticoid receptor expression in peripheral blood mononuclear cells one of the pathophysiological mechanisms for steroid resistance in children HammadA, Yahia S, Gouida MS, BakrA,El-FarahatyRM. Low expression of glucocorticoid receptors in children with steroid-resistant nephrotic syndrome. PediatrNephrol2013;28(5):759–63.
SRNS (10-20%) • Clinical features • Age < 1 or > 8 years • Gross hematuria • Persistent diastolic hypertension • Laboratory features • Persistent azotemia • Failure of response to steroids – after 4 weeks of steroids @ 60 mg/m2/d
Renal biopsy - SRNS • Focal segmental glomerulosclerosis ( FSGS ) • Mesangioproliferative GN
Shah SSH, Akhtar N, Sunbleen F, et al.Histopathological patterns in paediatric idiopathic steroid resistant nephrotic syndrome J Ayub Med CollAbottabad Jul - Sep 2015;27(3):633-6.
FSGS • Glomerular hypertrophy is common and when such hypertrophy is found in minimal change disease, it is somewhat predictive of further development to FSGS • On electron microscopy, the lesion is characterized by the presence of paramesangial and subendothelial, finely granular, osmiophilic deposits.
Mesangioproliferative glomerulonephritis Light microscopy - Diffuse mesangial proliferation with an increased number of mesangial cells and mesangial matrix Electron microscopy - foot process fusion similar to the changes observed in MCD. Mesangialhypercellularityassociated with prognostic significance with a higher rate of progression to renal failure
EVIDENCE BASED MANAGEMENT
Kidney Disease: Improving Global Outcomes (KDIGO) : • Recently published clinical practice guidelines on glomerulonephritis including SRNS • Recommendations are based upon a systemic review of the available literature using evidence-based principles • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group (2012) KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter Suppl2:139–274 • Uhlig K, Macleod A, Craig J, Lau J, Levey AS, Levin A, Moist L, Steinberg E, Walker R, Wanner C, Lameire N, Eknoyan G (2006) Grading evidence and recommendations for clinical practice guidelines in nephrology. A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 70:2058–2065
International Study of Kidney Disease in Children, The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr. 981;98(4):561–4. (2) MurnaghanK, Vasmant D, Bensman A. Pulse methylprednisolone therapy in severe idiopathic childhood nephroticsyndrome. ActaPaediatr Scand. 1984;73(6):733–9. (3) KDIGO Clinical Practice Guideline for Glomerulonephritis. Kid Intl June 2012; 2(2)
CALCINEURIN INHIBITORS (CNIs)
Calcineurininhibitor (CNI) as initial therapy for children with SRNS • CNI be continued for a minimum of 6 months for 18 – 24 months in case of complete remission • CNI be continued for a minimum of 12 months when at least a partial remission is achieved by 6 months • Low-dose corticosteroid therapy be combined with CNI therapy • KDIGO Clinical Practice Guideline for Glomerulonephritis. Kid Intl June 2012; 2(2)
Choudhry S, Bagga A, Hari P, Sharma S, KalaivaniM, Dinda A. Efficacy and safety of tacrolimusversus cyclosporine in children with steroid-resistant nephrotic syndrome: a randomized controlled trial. Am J Kidney Dis. 2009;53(5):760–9.
Tacrolimus was associated with higher efficacy and lower renal toxicity in comparison to CsA, with no difference in the rate of relapse Wang W, Xia Y, Mao J, Chen Y, Wang D, Shen H, et al. Treatment of tacrolimus or cyclosporine A in children with idiopathic nephrotic syndrome. PediatrNephrol. 2012;27(11):2073–9.
Shah SSH & Hafeez F. Childhood idiopathic steroid resistant nephrotic syndrome, different drugs and outcome . Ayub Med Coll Abbottabad 2016;28(2):249–53 .
Shah SSH & Hafeez F. Childhood idiopathic steroid resistant nephrotic syndrome, different drugs and outcome . Ayub Med Coll Abbottabad 2016;28(2):249–53
NO RESPONSE • STOP STEROIDS & CALCINEURIN INHIBITORS TRIPLE REGIME ACEIs/ARBs METHYLPREDNISOLONE MMF ( 15 mg/kg/week ) ( 250 – 500 mg/m2/day Max ) LombelRM, Hodson EM & Gipson DS. Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO. PediatrNephrol 2013; 28(3), 409–414 X 4-8 weeks x 24 months
MMF started after at least four weekly MP infusions were completed • ACE inhibitors most frequently used – enalapril = 0.05–0.1mg/kg/day • captopril = 0.25–0.5mg/kg/day • ARBs – losartan = 0.5–2.0mg/kg/day • Whenever a relapse occurred, and if previous benefit had been established, the patient was treated with additional short-term intravenous MP infusions • at the original dose of 15 mg/kg/week and/or albumin infusions MontaneB, Abitbol C, Chandar J, Strauss J, Zilleruelo G. Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. PediatrNephrol. 2003;18(8):772–7.
Partial remission Complete remission MontaneB, Abitbol C, Chandar J, Strauss J, Zilleruelo G. Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. PediatrNephrol. 2003;18(8):772–7.
Cyclophosphamide used in a dose of :- • 2 mg/kg/day orally (protocol I) • 400 mg/m2/dose IV monthly boluses x 6 months (protocol II) and • 400 mg/m2/dose IV monthly boluses x 6 months followed by 3 • boluses at 3 months interval • Complete and sustained remission =43.1% • IV CYP has significantly better efficiency (31.3%) when compared • with the oral course (11.8%). Cucer F, Miron I, Müller R, Iliescu Halitchi C, Mihaila D. Treatment withCyclophosphamide for steroid-resistant nephrotic syndrome in children. Maedica(Buchar). 2010 Jul;5(3):167-70.
MENDOZA PROTOCOL WEEKS MPP = 30 MG/KG NUMBER OF PULSES PREDNISOLONE 1 – 2 3 X per week 6 -- 3 – 10 1 x per week 8 60 mg/m2 EOD 11 – 18 1 x every 2 weeks 4 followed by 19 – 50 1 x every 4 weeks 8 tapering 51 – 82 1 x every 8 weeks 4 MPP = 30 MG/KG NUMBER OF PULSES Cyclophosphamide/Chlorambucil added if remission not achieved by 10 weeks Cyclophosphamide -Total cumulative dose (PO) = 150 – 250 mg/kg as single morning dose Chlorambucil – 0.2 mg/kg/day Mendoza SA, Reznik VM, Griswold WR, Krensky AM, Yorgin PD, Tune BM. Treatment of steroid resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents. PediatrNephrol. 1990;4(4):303–7.
VINCRISTINE REGIMEN ThalgahagodaS. Pulsed Vincristine Therapy in Steroid-Resistant Nephrotic Syndrome. BioMed Research International Volume 2017
Rajesh G. Krishnan . Malcolm G. Coulthard . Nadeem E. Moghal. • Is there a role for vincristine in nephrotic syndrome? • Pediatr Nephrol (2006) 21: 597 • KausmanJY, Lei Y, Jones CL, Johnstone L, Powell HR. • Vincristine in steroid dependent nephrotic syndrome. • PediatrNephrol(2005) 20:1416–1419 • GoonasekeraCD, Koziell AB, Hulton SA, Dillon MJ. • Vincristine and focal segmental glomerulosclerosis: do we need • a multicentre trial? • PediatrNephrol(1998) 12:284–289 • Almeida MP, Almeida HA, Rosa FC. • Vincristine in steroid resistant nephrotic syndrome. • PediatrNephrol(1994) 8:79–80
INDICATIONS • Continued massive proteinuria and hypoalbuminemia despite exposure to adequate courses of immunosuppressive therapy • with high levels of the circulating permeability factor DC Cattran. https://www.uptodate.com/.../treatment-of-primary-focal-segmental-glomerulosclerosis. Nov 28, 2016
Refractory primary FSGS - the addition of plasmapheresis seemed beneficial in some individuals MitwalliAH. Adding plasmapheresis to corticosteroids and alkylating agents: does it benefit patients with focal segmental glomerulosclerosis? NephrolDial Transplant. 1998;13(6):1524.
RITUXIMAB Aggressive B cell suppression by rituximab + A cocktail of other immunosuppressive agents - CNIs, MMF, mizoribinemay be beneficial. Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, et al. Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressantsfor childhood steroid-resistant nephroticsyndrome. PediatrNephrol. 2014; 29:1181–7.
Galactosetreatment has shown reduction in proteinuria in • unresponsive FSGS patients. The effect lasted as long as galactose was given. Om P. Mishra et al. Oral galactose in children with focal and segmental glomerulosclerosis: a novel adjunct therapy. Clin Kidney J (2014) 7: 83–85 . Dogra S et al. Steroid-resistant nephrotic syndrome: a persistent challenge for pediatric nephrology. PediatrNephrol 2017; 32(6):965–974
. Lombel RM, Hodson EM & Gipson DS. Treatment of steroid-resistant nephrotic syndrome in children: new guidelines from KDIGO. PediatrNephrol 2013;28(3),409–414
FUTURE TRIALS ADALIMUMAB- monoclonal anti-tumor necrosis factor-alpha (TNF-α) antibody that binds TNF-α and prevents it from activating TNF-α receptors. TNF-α is an inflammatory cytokine which increases glomerular endothelial cell permeability to albumin & has direct cytotoxicity to glomerular mesangial and epithelial cells. Joy MS, Gipson DS, Powell L, MacHardy J, Jennette JC, Vento S, Pan C, Savin V, Eddy A, Fogo AB, Kopp JB, CattranD, Trachtman H (2010) Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): Report of the FONT (Novel Therapies for Resistant FSGS) Study Group. Am J Kidney Dis 55(1):55–60
FUTURE TRIALS • (contd.) ABATACEPT – targets CD80 & down-regulates the T cell response decreasing proteinuria Garin EH, Reiser J, Cara-Fuentes G, Wei C, Matar D, Wang H, Alachkar N, Johnson RJ (2015) Case series: CTLA4–IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. PediatrNephrol 30(3):469–477
PROGNOSIS Overall, the prognosis of steroid-resistant idiopathic nephroticsyndrome is poor, with > 50% children progressing to end-stage renal failure. Gipson DS, Chin H, Presler TP, Jennette C, FerrisME, Massengill S, et al. Differential risk of remission and ESRD in childhood FSGS. PediatrNephrol.2006;21(3):344–9. This explains why intensive treatment regimens have been tried.