Pediatrics Intern Seminar Childhood Nepbrotic Syndrome Supervisors: 邱元佑 醫師 周信旭 醫師 Intern: 黃鈺堯

Patient Information CC: Generalized edema for 2+ weeks ● 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 Periorbital edema noted 92/12/08 Periorbital edema noted Generalized edema: face, limbs, scrotum, abdominal distension, oligouria W’t gain 20 kg → 22 kg (in days) 92/12/17 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 92/12/22 Transferred to 成醫 Ped ward by family’s request

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: -

Lab Results WBC Seg Lymph Mono Band CRP 13900↑ 80↑ 14↓ 6 - < 7.0 RBC Hb BUN Cr GOT GPT 5.27 14.1 19 0.5↓ 28 18 Plt Na K P Ca Cl 652k↑ 139 4.5 3.9 8.6 107

Lab Results Albumin T protein TG Cholesterol 3.0 5.6↓ 606↑ 433↑ C3 C4 ASLO IgG HbsAg 102 19.6 < 25.0 143↓ - ● CCr = 60.7 ml/min ● DPL = 11.9 g/24hrs ● Protein selective index = 0.056 < 0.1 (selevtive)

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

Discussion Treatments Methods for Childhood Idiopathic Nephrotic Syndrome

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

Pathophysiology

Yet to be identified

Pathophysiology Sialoprotein (-) / polyanionic glycosaminoglycans ● 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

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

Epidemiology Primary Nephritis (-) Primary extrarenal disease (-) ● 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

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

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

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

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

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

Oral Corticosteroid Try steroid therapy, hold renal biopsy ● 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

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

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

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

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

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

Cyclophosphamide

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

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

Cyclosporin

Cyclosporine

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

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

MMF

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

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

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.

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.

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

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

Corticosteroid Cyclosporine MMF Corticosteroid Cyclophosphamide

Dermatology Intern Seminar Pityriasis Rubra Pilaris Supervisor: 陳冠宇 醫師 許漢銘 醫師

References ● Coupland S. E., et al. Ocular Adnexal Lymphoma: Five... Survey of Ophthalmology. 47(5):470-490, 2002 Sept-Oct. ● Shields C. L., et al. Conjunctival Lymphoid Tumors: Clinical... Ophthalmology. 108(5):979-984, 2001. ● Coupland S. E., et al. Lymphoproliferative Lesions of the Ocular Adnexa. Ophthalmology. 105:1430-1441, 1998. ● Zhongxing Liao, et al. Mucosa-Associated Lymphoid Tissue Lymphoma With Initial Supradiaphragmatic Presentation: Natural... Int. J. Radiation Oncology Biol. Phys. 48(2):399-403, 2000. ● Blasi M. A., et al. Local Chemotherapy with Interferon-a for Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma. Ophthalmology. 108:559-562, 2001.

References ● Lee D. H., et al. Bilateral Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma Misdiagnosed as Allergic Conjunctivitis. Cornea. 20(4):427-429, 2001. ● Akpek E. K., et al. Conjunctival Lymphoma Masquerading as Chronic Conjunctivitis. Ophthalmology. 106:757-760, 1999. ● Sharara N., et al. Ocular Adnexal Lymphoid Proliferations: Clinical... Ophthalmology. 110:1245-1254, 2003.

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