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

2. 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: cm (75~90%)
CC: Generalized edema for 2+ weeks

4. 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

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

6. 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

7. 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 = < 0.1 (selevtive)

8. 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

9. Discussion Treatments Methods for Childhood Idiopathic Nephrotic Syndrome

10. 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

11. Pathophysiology

12. Yet to be identified

13. 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

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

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

16. 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

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

18. 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

19. 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

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

21. 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

22. 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

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

24. 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

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

26. 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

27. Cyclophosphamide

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

29. 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

30. Cyclosporin

31. Cyclosporine

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

33. 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

35. MMF

36. 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

37. 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

38. 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: , 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): , 1998.
● Ponticelli C, et al. Other immunosuppressive agents for FSGS. Seminars in Nephrol. 23(2): , 2003.
● Tenbrock K., et al. Levamisole treatment in steroid sensitive and steroid resistant NS. Ped Nephrology. 12: , 1998.

39. References
● Day C., et al. MMF in the treatment of resistant idiopathic NS. Nephrol Dial Transplant. 17: , 2002.
● Barletta G., et al. Use of MMF in steroid dependant and resistant NS. Ped Nephrology. 18: , 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): , 2001.

40. Thank you !

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

43. 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

44. Corticosteroid
Cyclosporine
MMF
Corticosteroid
Cyclophosphamide

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

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

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

60. Thank you !!!