Case presentation Speaker: PGY 林亭妤 Supervisor: Dr. 邱元佑 2016-08-31

Basic Data Name: 陳O祥 Chart number: 143695XX Gender: male Age: 3-year-6-month-old Admission date: 2016/08/23 Body weight/height: 95.8cm/12.8kg

Chief Complaint Eyelid swelling off and on with scrotum swelling and lower limb edema for one week

Chief Complaint Eyelid swelling off and on with scrotum swelling and lower limb edema for one week

Present Illness Edema for one week Puffy eyelid and face in the morning, then scrotum swelling and lower leg edema was found in the afternoon Body weight increased about 1.5 kg during one week Abdominal distention and pain after meal Foamy urine was noticed by his mother No fever, cough, rhinorrhea, throat pain, dyspnea, diarrhea, dysuria, gross hematuria, or skin rash

Past History Birth history: G1P1, GA 38+5 wks, via C/S, BBW: 2790gm Growth and Development: BH: 95.7cm (5-15th) BW:12.8kg (5-15th) Developmental milestones: WNL Vaccination: as scheduled TOCC: denied Past history: Denied other major disease Denied OP history or hospitalization history Not known drug allergy history Current Medications: nil Family history: Mother: with nephrotic syndrome history and now remisson for many years

Physical Examination Vital Signs: TPR: 36.6/118/26, BP: 99/75mmHg Consciousness: clear General appearance: fair HEENT: Head: intact, conjunctiva: not pale, sclera: anicteric, puffy eyelid, no injected throat or tonsils Neck: supple, no JVE, no LAP, no discharge Chest: symmetric expansion, no deformity or accessory muscle use, bilateral clear breath sounds Heart: regular heart beat, no murmur Abdomen: distended abdomen, mild tenderness Genitalia: hydrocele (+) Extremities: warm, mild pitting edema (+) over bilateral legs Skin: no rash, petechiae or ecchymosis

Lab data at admission

Tentative diagnosis Suspected nephrotic syndrome Plan Check TG, Chol, IgA, C3, ANA, HbsAg Check 24hr urine protein Arrange renal echo Record BW, record I/O Started mediation with kidsolone 2mg/kg/day, if nephrotic syndrome is favored

Renal echo: negative finding Protein excretion: 124.58 mg/m2/hr > 40 mg/m2/hr ＊Protein excretion    normal: ≦ 4mg/m2/hr    abnormal: 4～40mg/m2/hr    nephrotic: ≧ 40mg/m2/hr or 50mg/kg/day Renal echo: negative finding

Hospital course Prednisone 2 mg/kg/day

Final diagnosis Nephrotic syndrome, favor minimal change disease

Discussion Nephrotic syndrome

Pediatric Nephrotic Syndrome A glomerular disease Nephrotic range proteinuria ＊normal: ≦ 4mg/m2/hr - protein excretion of > 3.5 g per day in adult - protein excretion of > 40 mg/m2/hr in children - a first morning protein : creatinine ratio of >2-3 : 1 Hypoalbuminemia (<2.5 g/dL) Edema Hyperlipidemia Annual incidence: 2-3 cases per 100,000 children per year the triad of clinical findings associated with large urinary losses of protein: hypoalbuminemia, edema, and hyperlipidemia.

Etiology Primary or idiopathic nephrotic syndrome (90%) minimal change disease (85%) focal segmental glomerulosclerosis (10%) membranoproliferative glomerulonephritis, membranous nephropathy, diffuse mesangial proliferation (5%) Secondary causes (10%) Genetic or congenital causes

Etiology Primary or idiopathic nephrotic syndrome (90%) Secondary causes (10%) systemic lupus erythematosus Henoch-Schonlein purpura malignancy (lymphoma and leukemia) infections (hepatitis B,C, HIV, and malaria) drugs: Penicillamine, Gold, NSAIDs, Interferon, Mercury, Heroin, Lithium Genetic or congenital causes

Presentation Edema (95%) first in areas of low tissue resistance (eg, the periorbital, scrotal, and labial regions in the face in the morning and predominantly in lower extremities later in the day Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea GI distress - ascites, bowel wall edema, or both Respiratory distress - massive ascites and thoracic compression or frank pulmonary edema, effusions, or both

Pathophysiology Massive proteinuria and hypoalbuminemia → Increased permeability of the glomerular capillary wall Idiopathic nephrotic syndrome: complex disturbances in the immune system, especially T cell–mediated immunity Focal segmental glomerulosclerosis: activated lymphocytes, mutations in podocyte proteins ＊Biopsy: fusion (effacement) of podocyte foot processes 三層過濾構造: 微血管內皮、腎絲球基底膜、包氏囊上皮(podocyte) 血球與大蛋白無法濾過 Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Pathophysiology Edema: the mechanism is incompletely understood Massive urinary protein→ hypoalbuminemia→ decrease in plasma oncotic pressure→ fluid shift from the intravascular compartment to the interstitial space Decrease intravascular volume ∙ activating the renin-angiotensin-aldosterone system → stimulates tubular reabsorption of sodium ∙ stimulates the release of antidiuretic hormone→ enhances the reabsorption of water in the collecting duct This theory does not apply to all patients with nephrotic syndrome because some patients actually have increased intravascular volume with diminished plasma levels of renin and aldosterone. Therefore, other factors, including primary renal avidity for sodium and water, may be involved in the formation of edema in some patients with nephrotic syndrome.

Pathophysiology Hyperlipidemia Increased risk of infections hypoalbuminemia stimulates generalized hepatic protein synthesis, including synthesis of lipoproteins urinary losses of lipoprotein lipase→ lipid catabolism ↓ Increased risk of infections loss of complement factor C3b, immunoglobulins use of immunosuppressive medication Hypercoagulable state vascular stasis ↑hepatic production of fibrinogen and other clotting factors ↓serum levels of anticoagulation factors ↑plasma platelet production, and ↑platelet aggregation

Minimal change nephrotic syndrome (MCNS) Age: 2-6 y/o Sex: 2:1 male 85% nephrotic syndrome in children Pathology findings Light microscopy: normal Immunofluorescence microscopy: negative Electron microscopy: effacement of the epithelial cell foot processes More than 95% of children with minimal change disease respond to corticosteroid therapy

Diagnosis Urine Urinalysis: 3+ or 4+ proteinuria, 20% of children with microscopic hematuria Spot urine protein/creatinine >2.0 Urinary protein excretion >40 mg/m2/hr Serum Creatinine value is usually normal Albumin <2.5 g/dL Cholesterol and Triglyceride: elevated Complement levels: normal ＊Renal biopsy is not routinely performed if the patient fits the standard clinical picture of MCNS

When to perform renal biopsy? Before treatment gross hematuria hypertension renal insufficiency less likely MCNS hypocomplementemia age <1 yr or >8 yr After treatment Steroid resistant (proteinuria ≧2+ after 8 wk of steroid therapy ) usually caused by FSGS (80%), MCNS, or mesangial proliferative glomerulonephritis.

Treatment Prednisone 60 mg/m2/day (2 mg/kg/day)(maximum:80 mg/day divided into 2–3 doses) for at least 4 wks (6 wks greater side effect, less relapse) 80 to 90% of children respond to steroid therapy (clinical remission, diuresis and urine protein: trace or negative) for 3 consecutive days within 3 wks Tapered to 40 mg/m2/day (1.5 mg/kg/day) QOD for at least 4 wks Slowly tapered and discontinued over the next 1-2 months  PPD test if pt without BCG vaccination prior to use of prednisolone Conventional protocol for prednisolone -60mg/m2/day or 2mg/kg/day tid for 4 wks -> a) If remission, change to full dose as a single dose in the morning qod for another 4 wks -> if still remission, gradually tapering till 0.5mg/kg/dose qod for total course about 10 months b) If not remission -> still full dose tid or qid for another 4 wks and refer to Ped. Nephrologist for biopsy or chemotherapy *Note: 減量過程中, 若有 urine protein↑ > 3+ ®  則治療過程重新開始F/U -     Complication of prednisolone and emotional support     If with abd. pain must suspect intravascular volume decrease or                                spontaneous bacterial peritonitis when in nephrotic stage

Treatment For severe edema Hospitalization: severe symptomatic edema(large pleural effusions, ascites, or severe genital edema) Sodium restriction, fluid restriction Loop diuretics (furosemide), orally or intravenously Albumin (0.5-1.0 g albumin/kg), as a slow infusion followed by furosemide (1-2 mg/kg/dose IV)

Relapse Many children with nephrotic syndrome experience at least 1 relapse (3-4+ proteinuria plus edema) Relapse rates 60-80% in the past→ 30-40% if treated with longer initial steroid courses Treatment 60 mg/m2/day (80 mg daily max) in a single am dose until the child enters remission (urine trace or negative for protein for 3 consecutive days) The prednisone dose is then changed to alternate-day dosing as noted with initial therapy, and gradually tapered over 4-8 wk

Treatment Steroid dependent: relapse while on alternate-day steroid therapy Frequent relapsers: respond well to prednisone therapy but relapse ≥4 times in a 12-mo period Steroid resistant: who fail to respond to prednisone therapy within 8 wk of therapy Alternative therapies Alkylating agents: Cyclophosphamide Calcineurin inhibitors: Cyclosporine, Tacrolimus Mycophenolate mofetil (MMF)  Levamisole Rituximab (anti-CD20 antibody )

Take home message Nephrotic syndrome: proteinuria(> 40 mg/m2/hr), hypoalbuminemia (<2.5 g/dL), edema, and hyperlipidemia 90% in children are idiopathic nephrotic syndrome - minimal change disease (85%) More than 95% of children with minimal change disease respond to corticosteroid therapy Children with onset of uncomplicated nephrotic syndrome between 1-8 y/o are likely to have steroid-responsive MCNS, and steroid therapy may be initiated without a diagnostic renal biopsy Children with steroid-responsive nephrotic syndrome is unlikely to develop chronic kidney disease, that the disease is rarely hereditary

Thanks for your attention !! garlicwei@hotmail.com