Pediatrics Intern SeminarPediatrics Intern SeminarChildhood Nepbrotic SyndrChildhood Nepbrotic Syndr

omeome

Supervisors: 邱元佑 醫師 周信旭 醫師

Intern: 黃鈺堯

Patient InformationPatient 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 HistoryBrief History92/12/0892/12/08 Periorbital edema noted

Generalized edema: face, limbs, scrotum, abdominal distension, oligouriaW’t gain 20 kg → 22 kg (in days)

92/12/1792/12/17 新樓 Hospital admissionU/A: protein (+++), Alb: 1.7, cholesterol: 455Impression: nephrotic syndrome

Prednisolone + Albumin + Lasix

CXR: R’t pleural effusion s/p thoracentesis

92/12/2292/12/22 Transferred to 成醫 Ped ward by family’s request

● 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: -

Urine AnalysisUrine Analysis

Lab ResultsLab Results

Plt Na K P Ca Cl

652k↑ 139 4.5 3.9 8.6 107

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

Lab ResultsLab 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)

ImpressionImpression

Neprotic syndrome, r/o steroid-resistance

● Prednisolone 2 mg/kg/day since 12/17

● Albumin infusion x 6 courses

DiscussionDiscussion

Treatments MethodsTreatments Methodsforfor

Childhood Idiopathic NeChildhood Idiopathic Nephrotic Syndromephrotic Syndrome

● 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

Clinical CharacteristicsClinical Characteristics

PathophysiologyPathophysiology

Yet to be identified

● 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 restrictedLoss of size-selectivity → MN

PathophysiologyPathophysiology

Altered T-lymphocyte response↓

Plasma factor ?↓

Podocyte protein expression / function↓

Glomerular capillary wall permeability

Eddy A, et al., The Lancet, 2003

Pathogenesis Uncertain ?Pathogenesis Uncertain ?

● Incidence: 2 ~ 3 per 100000 children

● Idiopathic nephrotic syndrome 90%

PrimaryNephritis (-)Primary extrarenal disease (-)Onset: 2 ~ 7 y/oMale: female (2:1)Three common histologies

EpidemiologyEpidemiology

1.Minimal change nephroytic syndrome 85%Effacement of podocyte foot process95% steroid-responsive95% steroid-responsive

2.Focal segmental glomerulosclerosis 10%Juxtamedullary segmental scarring< 20% steroid-responsive< 20% steroid-responsiveProgressive, ESRD in 2 ~ 5 yrs

3.Membranous nephropathy 5%Increased mesangial cells / matrix50% steroid-responsive50% steroid-responsive

HistopathologyHistopathology

● Infection: Spontaneous peritonitis 2~ 6%

● Thromboembolic diseases: risk of renal vein thrombosis

ComplicationsComplications

● 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

Treatment GoalsTreatment Goals

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

Non - Specific TxNon - Specific Tx

1.1. First-line:First-line:Oral corticosteroidOral corticosteroid

2.Second-line:Pulse methylpredisolone, Cyclophosphamide, Cyclosporin

3.Other immunosuppressive agents:Levamisole, Mycophenolate mofetil

Specific TxSpecific Tx

● 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

Oral CorticosteroidOral Corticosteroid

● 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

Response to SteroidResponse to Steroid

1.First-line:Oral corticosteroid

2.2. Second-line:Second-line:Pulse methylpredisolone, Cyclophosphamide, Pulse methylpredisolone, Cyclophosphamide, CyclosporinCyclosporin

3.Other immunosuppressive agents:Levamisole, Mycophenolate mofetil

Specific TxSpecific Tx

● 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

Pulse MethylprednisolonePulse Methylprednisolone

● Buffalo hump / moon face

● Cutaneous striae

● Osteoporosis

● Hypertension

● Hyperglycemia

● Dyslipidemia

● Muscle weakness / fatigability

● Infection

Adverse Effects of SteroidAdverse Effects of Steroid

● 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 (EndoxaCyclophosphamide (Endoxan)n)

Cyclophosphamide

Side Effects of CyclophosphSide Effects of Cyclophosphamideamide

● Myelosuppression 32%

● Hemorrhagic cystitis 2.2%

● Bladder carcinoma

● Alopecia

● Gonadal toxicity: aspermia, amenorrhea

Latta K, et al., Ped Nephrology, 2001

● 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 (Sandimmun)Cyclosporin (Sandimmun)

CyclosporinCyclosporin

Cyclosporine

1.First-line:Oral corticosteroid

2.Second-line:Pulse methylpredisolone, Cyclophosphamide, Cyclosporin

3.3. Other immunosuppressive agents:Other immunosuppressive agents:Levamisole, Mycophenolate mofetilLevamisole, Mycophenolate mofetil

Specific TxSpecific Tx

● 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

Mycophenolate MofetilMycophenolate Mofetil(CellCept)(CellCept)

MMF

● 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

LevamisoleLevamisole

● 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

ConclusionConclusion

ReferencesReferences

● 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 Nep

hrology. 18:906-912, 2003. ● Schwarz A. New aspects of treatment of NS. J Am Soc Nephrol. 1

2: S44-47, 2001. ● Orth S., et al. The Nephrotic syndrome. NEJM. 338(17):1202-121

1, 1998. ● Ponticelli C, et al. Other immunosuppressive agents for FSGS. Se

minars in Nephrol. 23(2): 242-48, 2003. ● Tenbrock K., et al. Levamisole treatment in steroid sensitive and s

teroid resistant NS. Ped Nephrology. 12:459-462, 1998.

ReferencesReferences

● 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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● Spontaneous peritonitis 2~ 6%

Sepsis, pneumonia, cellulitis, UTI

Streptococcus pneumoniae, GNB common

● Protein deficiency, ↓immunoglobulin, ↓complement, ascites, immunosuppressive therapy

InfectionsInfections

● 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

Thromboembolic diseasesThromboembolic diseases

Corticosteroid

Cyclosporine

Corticosteroid

Cyclophosphamide

MMF

DermatologyDermatology Intern Seminar Intern SeminarPityriasis Rubra PilarisPityriasis Rubra Pilaris

Intern: 黃鈺堯Supervisor: 陳冠宇 醫師

許漢銘 醫師

ReferencesReferences

●● Coupland S. E., et al. Ocular Adnexal Lymphoma: Five... Coupland S. E., et al. Ocular Adnexal Lymphoma: Five... SurveySurvey of Ophthalmology. 47 of Ophthalmology. 47(5):470-490, 2002 Sept-Oc(5):470-490, 2002 Sept-Oct.t.

●● Shields C. L., et al. Conjunctival Lymphoid Tumors: CliniShields C. L., et al. Conjunctival Lymphoid Tumors: Clinical... cal... Ophthalmology. Ophthalmology. 108(5):979-984, 2001. 108(5):979-984, 2001.

●● Coupland S. E., et al. Lymphoproliferative Lesions of thCoupland S. E., et al. Lymphoproliferative Lesions of the Ocular Adnexa. e Ocular Adnexa. Ophthalmology. Ophthalmology. 105:1430-1441, 1998.105:1430-1441, 1998.

●● Zhongxing Liao, et al. Mucosa-Associated Lymphoid TisZhongxing Liao, et al. Mucosa-Associated Lymphoid Tissue Lymphoma With Initial Supradiaphragmatic Presesue Lymphoma With Initial Supradiaphragmatic Presentation: Natural... ntation: Natural... Int. J. Radiation Oncology Biol. Phys. Int. J. Radiation Oncology Biol. Phys. 4848(2):399-403, 2000.(2):399-403, 2000.

●● Blasi M. A., et al. Local Chemotherapy with Interferon-a Blasi M. A., et al. Local Chemotherapy with Interferon-a for Conjunctival Mucosa-Associated Lymphoid Tissue Lfor Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma. ymphoma. Ophthalmology. Ophthalmology. 108:559-562, 2001. 108:559-562, 2001.

ReferencesReferences

● ● Lee D. H., et al. Bilateral Conjunctival Mucosa-AssociaLee D. H., et al. Bilateral Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma Misdiagnosed as Alted Lymphoid Tissue Lymphoma Misdiagnosed as Allergic Conjunctivitis. lergic Conjunctivitis. Cornea. 20Cornea. 20(4):427-429, 2001.(4):427-429, 2001.

● ● Akpek E. K., et al. Conjunctival Lymphoma MasqueraAkpek E. K., et al. Conjunctival Lymphoma Masquerading as Chronic Conjunctivitis. ding as Chronic Conjunctivitis. Ophthalmology. Ophthalmology. 106:106:757-760, 1999. 757-760, 1999.

● ● Sharara N., et al. Ocular Adnexal Lymphoid ProliferatiSharara N., et al. Ocular Adnexal Lymphoid Proliferations: Clinical... ons: Clinical... Ophthalmology. Ophthalmology. 110:1245-1254, 2003. 110:1245-1254, 2003.

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