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Pediatrics Intern Seminar Childhood Nepbrotic Syndrome

Pediatrics Intern Seminar Childhood Nepbrotic Syndrome. Supervisors: 邱元佑 醫師 周信旭 醫師 Intern: 黃鈺堯. Patient Information. ● 黃啟展 ● 5 y/o male ● 5 y/o male ● G3P3NO, NSD, Full term ● BW: 21.1 kg (25~50%) Ht: 109.2 cm (75~90%). CC: Generalized edema for 2+ weeks. Brief History.

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Pediatrics Intern Seminar Childhood Nepbrotic Syndrome

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  1. Pediatrics Intern SeminarChildhood Nepbrotic Syndrome Supervisors: 邱元佑 醫師 周信旭 醫師 Intern: 黃鈺堯

  2. Patient Information ●黃啟展 ●5 y/o male ●5 y/o male ●G3P3NO, NSD, Full term ●BW: 21.1 kg (25~50%) Ht: 109.2 cm (75~90%) CC: Generalized edema for 2+ weeks

  3. Brief History 92/12/08 Periorbital edema noted Generalized edema: face, limbs, scrotum, abdominal distension, oligouria W’t gain 20 kg → 22 kg (in days) 新樓 Hospital admission U/A: protein (+++), Alb: 1.7, cholesterol: 455 Impression: nephrotic syndrome Prednisolone + Albumin + Lasix CXR: R’t pleural effusion s/p thoracentesis 92/12/17 92/12/22 Transferred to 成醫 Ped ward by family’s request

  4. Urine Analysis ● SG: 1.015 ● BIL: - ● pH: 8.0 ● ERY: 10 ● LEU: 15 ● WBC: 1 - 3 ● NIT: - ● RBC: 1 - 2 ●PRO: > 300● Epith: 0 - 1 ● Glu: - ● Cast: - ● KET: - ● Crystal: - ● UBG: normal ● Bacteria: -

  5. Lab Results

  6. Lab Results ●CCr = 60.7 ml/min ●DPL = 11.9 g/24hrs ●Protein selective index = 0.056 < 0.1 (selevtive)

  7. Impression Neprotic syndrome, r/o steroid-resistance ●Prednisolone 2 mg/kg/day since 12/17 ●Albumin infusion x 6 courses

  8. DiscussionTreatments MethodsforChildhood Idiopathic Nephrotic Syndrome

  9. Clinical Characteristics ●Proteinuria > 40 mg/m2/hr (> 1 g/m2/24hrs) ●Hypoproteinemia Total protein < 5.5 g/dL; Alb < 2.5 g/dL ●Hyperlipidemia Cholesterol > 250 mg/dL ●Edema Periorbital,lower limbs,scrotum, generalized, pitting

  10. Pathophysiology

  11. Yet to be identified

  12. Pathophysiology ●Charge-selective barrier: Sialoprotein (-) / polyanionic glycosaminoglycans 69 ~ 150 kd restricted (i.e. Albumin) Loss of charge-selectivity → MCNS ●Size-selective barrier: Pore size in GMB > 150 kd restricted Loss of size-selectivity → MN

  13. Pathogenesis Uncertain ? Altered T-lymphocyte response ↓ Plasma factor ? ↓ Podocyte protein expression / function ↓ Glomerular capillary wall permeability Eddy A, et al., The Lancet, 2003

  14. Epidemiology ●Incidence: 2 ~ 3 per 100000 children ●Idiopathic nephrotic syndrome 90% Primary Nephritis (-) Primary extrarenal disease (-) Onset: 2 ~ 7 y/o Male: female (2:1) Three common histologies

  15. Histopathology 1. Minimal change nephroytic syndrome 85% Effacement of podocyte foot process 95% steroid-responsive 2. Focal segmental glomerulosclerosis 10% Juxtamedullary segmental scarring < 20% steroid-responsive Progressive, ESRD in 2 ~ 5 yrs 3. Membranous nephropathy 5% Increased mesangial cells / matrix 50% steroid-responsive

  16. Complications ●Infection: Spontaneous peritonitis 2~ 6% ●Thromboembolic diseases: risk of renal vein thrombosis

  17. Treatment Goals ●Non-specific: relieve S/S and secondary effects ●Specific: immunosuppressive therapy aimed at modulating the immune component of the disease ●Minimize complications and those of immunosuppressive drugs

  18. Non - Specific Tx Severe edema: Pleural effusion, ascites, scrotal edema ●Restricted water / salt (< 2 g/day) ●25% Albumin ivd (1 g/kg/day) ●Furosemide (1 ~ 2 mg/kg/4hrs) ●Monitor vol. depletion, e- disturbance, renal function

  19. Specific Tx 1. First-line: Oral corticosteroid 2. Second-line: Pulse methylpredisolone, Cyclophosphamide, Cyclosporin 3. Other immunosuppressive agents: Levamisole, Mycophenolate mofetil

  20. Oral Corticosteroid ●1 ~ 8 y/o: steroid-responsive MCNS 87% Try steroid therapy, hold renal biopsy ●Prednisolone (2 mg/kg/day; 60 mg/m2/day) po divided dose ●Proteinuria (1+ or less) for 4 consecutive days → “steroid-responsive” ●75% MCNS remission by 2 wks ●Prednisolone (60 mg/m2/day) qod for 4 wks

  21. Response to Steroid ●Steroid-resistant: Proteinuria (2+ or more) after 1 month of daily Prednisolone use Renal biopsy indicated ●Steroid-dependent: Relapse (proteinuria + edema) after switching to or terminating qod Prednisolone Tx ●Frequently relapsing: > 2 relapses in 6 months of initial response or > 4 relapses in any 12 months > 60% relapse in steroid-responsive cases

  22. Specific Tx 1. First-line: Oral corticosteroid 2. Second-line: Pulse methylpredisolone, Cyclophosphamide, Cyclosporin 3. Other immunosuppressive agents: Levamisole, Mycophenolate mofetil

  23. Pulse Methylprednisolone ●10 ~ 30 mg/kg bolus (Max: 1000 mg) iv qod x 6 doses Weekly pulse x 4 wks Every-other-week pulse x 4 doses ●Combination with oral corticosteroids, cyclophosphamide, or cyclosporin ●Remission rate: 64% (27/42) in steroid-resistant NS by 13.1±12.5 wks Kirpekar R, et al., Am J of Kidney Disease, 2002

  24. Adverse Effects of Steroid ●Buffalo hump / moon face ●Cutaneous striae ●Osteoporosis ●Hypertension ●Hyperglycemia ●Dyslipidemia ●Muscle weakness / fatigability ●Infection

  25. Cyclophosphamide (Endoxan) ●Alkylating agent used in C/T ●Interferes DNA cross-link covalently ●For steroid-resistant / dependent / frequently relapsing NS ●2 ~ 2.5 mg/kg/day for 8 ~ 12 wks ●Combined Prednisolone qod Tx ●Remission: 25 ~ 30% steroid-unresponsive p’ts Eddy A, et al., The Lancet, 2003

  26. Cyclophosphamide

  27. Side Effects of Cyclophosphamide ●Myelosuppression 32% ●Hemorrhagic cystitis 2.2% ●Bladder carcinoma ●Alopecia ●Gonadal toxicity: aspermia, amenorrhea Latta K, et al., Ped Nephrology, 2001

  28. Cyclosporin (Sandimmun) ●Immunosuppressant for transplantation ●Calcineurin inhibitor:↓IL-2,IL-3,IL-4, GM-CSF, TNF-α→ ↓T cell proliferation ●5 ~ 6 mg/kg/day + oral Prednisolone use ●Remission rate: 85% for steroid-responsive NS ●Side effects: gingival-hyperplasia, hirsutism, risk of cyclosporin-induced vasculopathy ●High nephrotoxicity: monitor renal function Eddy A, et al., The Lancet, 2003

  29. Cyclosporin

  30. Cyclosporine

  31. Specific Tx 1. First-line: Oral corticosteroid 2. Second-line: Pulse methylpredisolone, Cyclophosphamide, Cyclosporin 3. Other immunosuppressive agents: Levamisole, Mycophenolate mofetil

  32. Mycophenolate Mofetil(CellCept) ●Prevents allograft rejection ●Suppress de novo purine synthesis: ↓T cell / B cell / smooth muscle cell / fibroblast proliferation ●0.8 ~ 1.2 g/m2/day ●Leukopenia, GI discomfort, diarrhea, malaise, splenomegaly Barletta G, et al., Ped Nephrology, 2003

  33. MMF

  34. Levamisole ●Antihelmintic drug ●Immunomodulatory effect ? ●2.5 mg/kg qod, median 10 months ●↓relapse in frequently relapsing NS ●Risks of leukopenia, hepatoxity, agranulocytosis, vasculitis, encephalopathy Tenbrock K, et al., Ped Nephrology, 1998

  35. Conclusion ●Steroid-responsiveness: most important prognostic factor ●Oral Prednisolone first-line drug ●Alkylating agents, immuno uppressants for steroid-resistant/dependant, frequently relapsing nephrotic syndrome ●Levamisole, MMF require larger trials for efficacy

  36. References ● Nelson 17th edition ● Eddy A., et al. Nephrotic syndrome in childhood. The Lancet. 362:629-39, 2003. ● Habashy D., et al. Interventions for steroid-resistant NS. Ped Nephrology. 18:906-912, 2003. ● Schwarz A. New aspects of treatment of NS. J Am Soc Nephrol. 12: S44-47, 2001. ● Orth S., et al. The Nephrotic syndrome. NEJM. 338(17):1202-1211, 1998. ● Ponticelli C, et al. Other immunosuppressive agents for FSGS. Seminars in Nephrol. 23(2): 242-48, 2003. ● Tenbrock K., et al. Levamisole treatment in steroid sensitive and steroid resistant NS. Ped Nephrology. 12:459-462, 1998.

  37. References ● Day C., et al. MMF in the treatment of resistant idiopathic NS. Nephrol Dial Transplant. 17:2011-13, 2002. ● Barletta G., et al. Use of MMF in steroid dependant and resistant NS. Ped Nephrology. 18:833-837, 2003. ● Yorgin.P. Pulse methylprednisolone Tx of idiopathic steroid resistant NS. Ped Nephrology. 16:245-50, 2001. ● Kirpekar R., et al. Clinicopathgologic correlates predict... Am J of Kidney Diseases. 39(6):1143-1152, 2001.

  38. Thank you !

  39. Infections ●Spontaneous peritonitis 2~ 6% Sepsis, pneumonia, cellulitis, UTI Streptococcus pneumoniae, GNB common ●Protein deficiency, ↓immunoglobulin, ↓complement, ascites, immunosuppressive therapy

  40. Thromboembolic diseases ● Risk of renal vein thrombosis, pulmonary emboli, deep vein thrombosis ● Urine loss of antithrombin III Fibrinogen + clotting factors synthesis Platelet abnormalty: thrombocytosis, ↑aggregability Hyperviscosity Hyperlipidemia

  41. Corticosteroid Cyclosporine MMF Corticosteroid Cyclophosphamide

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