1. Case presentation
Speaker: PGY 林亭妤
Supervisor: Dr. 邱元佑

2. 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

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

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

5. 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

6. 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

7. 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

8. Lab data at admission

9. 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

10. Renal echo: negative finding
Protein excretion: 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

11. Hospital course
Prednisone 2 mg/kg/day

12. Final diagnosis
Nephrotic syndrome, favor minimal change disease

13. Discussion
Nephrotic syndrome

14. 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.

15. 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

16. 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

17. 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

18. 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: , 2008, and by permission of the American Physiological Society (

19. 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.

20. 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

21. 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

23. 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

24. 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.

25. 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

26. 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 ( g albumin/kg), as a slow infusion followed by furosemide (1-2 mg/kg/dose IV)

27. 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

28. 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 )

29. 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

30. Thanks for your attention !!