1120224-兒童蛋白尿與腎病症候群的診斷與治療

1. 高雄榮總 兒童腎臟科
邱益煊 醫師
2023.2.24 醫師公會演講
兒童蛋白尿與腎病症候群
的診斷與治療

2. 演講大綱
 Proteinuria in children
 Nephrotic syndrome in children

3. Proteinuria in Children

4. Protein in normal urine
• Normal urine contains protein
• Composition of urinary proteins
– Albumin 40%
– Tamm-Horsfall Protein 40%
– Immunoglobulins 15%
• IgA, IgG, β2-microglobulin
– Other plasma proteins 5%
• parathyroid hormone, vasopressin, insulin, vitamins,
various binding proteins

5. Normal 24 hours Urine Protein
Age Total, mg mg/m2
Premature babies (5-30 days) 14-60 88-377
Full-term babies (7-30 days) 15-68 68-309
Infants (2-12 months) 17-85 48-244
Children 2-4 years 20-121 37-223
4-10 years 26-194 31-234
10-16 years 29-238 22-181
Source : Miltenyl M, Clin Nephrol 1979; 12:216

6. Definition of proteinuria
• Normal
– < 4 mg/m2/hr or 150 mg/day
– Urine Protein/Creatinine ratio < 0.2
• Proteinuria
– > 4 mg/m2/hr or 150 mg/day
– Urine Protein/Creatinine ratio > 0.2
• Heavy proteinuria (Nephrotic range proteinuria)
– > 40 mg/m2/hr or 1 gm/day
– Urine Protein/Creatinine ratio > 2

7. Epidemiology
• Prevalence
–School survey : 0.08% - 6%
• Highest in adolescent
• Greater in girl

8. Prevalence of Proteinuria in
Schoolchildren
No. with proteinuria/ Prevalence
Study Group N0. screened %
Canadian girls, 5-14 years 1 125/23,427 0.53
Finnish boys and girls, 8-15 years 2 223/8,954 2.5
Virginian girls, 6-8 years 3 24/804 2.98
Texan boys and girls, 6-12 years4 736/12,252 6
Texas boys and girls, 1-17 years 5 125/2,288 5.46
Japan boys and girls 6
age 6-11 years 3,719/118,915 0.08
age 12-14 years 9,063/173,107 0.37
1 Silverberg DS, Can Med Assoc J 1973 2 Vehaskari VM, J Pediatr 1982
3 Kunin CM, Pediatrics 1968 4 Dodge WF, J Pediatr 1976
5 Gutgesell M, Pediatrics 1978 6 Murakami M, ped Nephrol 1991

9. Epidemiology
• Prevalence
–Taiwan urine screening : 0.66% with
heavy proteinuria (6,744/10,288,620)

10. False-positive and False-negative
Results of Tests for Proteinuria
Methods False-Positive False-negative
Dipstick Highly concentrated urine Dilute urine
Highly alkaline buffered Light chains of
urine (PH > 8) immunoglobulin
Gross hematuria
Pyuria
Skin cleanser chlorhexidine
Quarternary ammonium compounds
Phenazopyridine
Sulfosalicylic acid Highly concentrated urine Dilute urine
Gross hematuria
Pyuria
Radiologic contrast media
High levels of penicillins, cephalosporins
Metabolites of sulfonamide
Tolbutamide, tolmetin

11. Origins of Proteinuria
• Glomerular proteinuria
• Tubular Proteinuria
• Overload Proteinuria
• Proteinuria due to
hemodynamic alterations

12. Causes of proteinuria in children
Transient Proteinuria
• Fever
• Dehydration
• Exercise-induced
• Congestive heart failure
• Extreme cold
• Epinephrine infusion
• Seizures
• Emotional stress
• Orthostatic proteinuria

13. Causes of proteinuria in children
Persistent Proteinuria
• Glomerular
– Congenital or hereditary : congenital nephrotic
syndrome, Alport syndrome
– Acquired
• Primary or idiopathic : minimal change disease,
FSGS, membranoproliferative GN, membranous
GN, IgA nephropathy, unclassified chronic GN
• Secondary : Infection , Multisystem disorders,
Drugs ,Neoplasia, Miscellaneous

14. Causes of proteinuria in children
Persistent Proteinuria
• Glomerular
– Acquired
• Secondary
– Infection : postinfectious GN, shunt nephritis, subacute bacterial
endocarditis, hepatitis B, Secondary syphilis, malaria, schistosomiasis,
AIDS, etc.
– Multisystem disorders : SLE, Henoch-Schonlein purpura, hemolytic
uremic syndrome, DM, other collagen vascular diseases ( i.e..
Polyarteritis nodosa, Wagner’s granulomatosis, vasculitis,
rheumatoid arthritis, etc.), Good pasture syndrome, amyloidosis, etc.
– Drugs : Penicillamine, NSAID, captopril, gold salts, “street” heroin,
trimethadione, lithium, mercury, etc.
– Neoplasia : leukemia, lymphoma, carcinoma
– Miscellaneous : chronic renal transplant rejection, reflux
nephropathy, renal vein thrombosis, sickle cell anemia, renal artery
stenosis, hypertension, etc.

15. Causes of proteinuria in children
Persistent Proteinuria
• Tubular
– Congenital or hereditary : Fanconi syndrome, oculocerebral-
renal syndrome ( Lowe syndrome), Lawrence-Moon-Biedl
syndrome, Batter syndrome, renal tubular acidosis, cystinosis,
oxalosis, medullary cystic disease, polycystic kidney disease,
renal dysplasia, Wilson disease, hereditary fructose intolerance,
glycogen storage disease, galactosemia, etc.
– Acquired : interstitial nephritis, pyelonephritis, renal transplant
rejection, acute tubular necrosis, sarcoidosis, nephrocalcinosis,
hypercalcemia, gout, hypokalemia, drugs (aminoglycosides,
methicillin, cyclosporine, analgesics, lithium, cisplatin), metal
toxicity (lead, aluminum, mercury, etc.), obstructive uropathy,
reflux nephropathy, balkan nephropathy, etc

16. Causes of proteinuria in children
Persistent Proteinuria
• Overload
– Light chains : plasma cell dyscrasias, multiple
myeloma
– Lysozyme : monocytic and myelocytic
leukemias
– Myoglobin : rhabdomyolysis
– Hemoglobin : hemolysis

17. 實驗室檢查
• 小便檢查
– 小便常規檢查：蛋白尿、血尿、白血球
– 24小時尿液檢查：蛋白尿、尿中肌酸酐廓清率
– Urine immunoelectrophoresis
• 血液檢查
– 血中白蛋白、膽固醇、腎臟功能、肝臟功能、鈣、鈉、
鉀等電解質
– 免疫學檢查：如抗核抗體(ANA)、補體(C3、C4)、免疫球
蛋白(IgG, IgM, IgA) 、ASOT
– HbsAg , Anti-HbsAb , Anti-HCV Ab
• Abdominal ultrasound
• Renal biopsy

18. Indications for renal biopsy
in proteinuria
• Persistent heavy proteinuria
• Progressive proteinuria with hematuria
• All forms of Nephrotic Syndrome except that
caused by steroid-responsive Minimal Change
Disease
• Family’s need to know a specific diagnosis

19. Management of proteinuria
• Treat underlying disorder
• Treat complications
• ACEI and/or ARB for proteinuria > 0.5 gm/day

20. Nephrotic syndrome
in Children

21. Definition of Nephrotic Syndrome
• Nephrotic syndrome (NS) is a common
chronic illness in childhood
• Clinical Criteria
– Edema
– Proteinuria (＞ 40 mg/m2/hr)
– Hypoalbuminemia ( Alb＜ 2.5 g/dl )
– Hyperlipidemia (Cholesterol > 200 mg/dl)

23. Causes of Nephrotic Syndrome
• primary glomerular disease
• multisystem disease
• familial and metabolic disease
• infections
• allergens, venoms, immunizations
• neoplastic
• medications
• others

24. Causes of Nephrotic Syndrome
• Primary diseases (90%)
– Minimal change disease (MCD, MCNS) (85%)
(including IgM nephropathy)
– Focal Segmental Glomerulosclerosis(FSGS) (10%)
– Mesangial Proliferative GN(5%)
– Others: IgA nephropathy, Membranous nephropathy
• Secondary diseases (10%)
– Lupus nephritis
– Purpura nephritis
– Infection associated
– HBV-associated membranous nephropathy
– others

25. Epidemiology
• Annual incidence 2-4 per 100,000 children per year
and prevalence of 16 per 100,000 children
» Eddy AA, Lancet 2003;362:629-39
» McEnery PT, PCNA 1982;29:875-894
• Male predominant, M:F=2:1
• Peak age : 2-6 years old
• An upper respiratory infection or minor infection may
precipitate the initial episode or subsequent relapses
• History of an atopic illness is present in 30-60% of
patients
• Review of family history: 1-3% have an affected
sibling
• Associated with HLA-DR7, -DR3, -B8, -A11, -DQ4, -
DQ8, -DR4, -DR11

26. Causes of Nephrotic Syndrome
Clinical Pediatric Nephrology, 3rd ed, p342)

27. 臨床症狀
• 眼皮、下肢水腫
• 全身水腫
• 尿起泡泡，蛋白尿
• 尿量減少
• 腹痛、腹瀉、腹水
• 呼吸急促、胸腔積水
• 血尿
• 高血壓
• 腎功能下降或急性腎衰竭

28. 鑑別診斷
• with marked edema
– protein-losing enteropathy
– hepatic failure
– congestive heart failure
– acute or chronic glomerulonephritis
– protein malnutrition.
• diagnosis other than MCNS:
– the presence of age <1 yr
– a family history
– extrarenal findings (arthritis, rash, anemia)
– hypertension or pulmonary edema
– acute or chronic renal insufficiency
– hematuria

29. Common Pathophysiologic Defect
of Nephrotic Syndrome

30. Common Pathophysiology
• The underlying abnormality in nephrotic
syndrome is an increase in permeability of the
glomerular capillary wall
• Leads to massive proteinuria and
hypoalbuminemia.
• The cause of the increased permeability is not
well understood.
• In minimal change disease, it is possible that T-
cell dysfunction leads to alteration of cytokines

31. Mechanisms of Nephrotic Edema
• Underfill hypothesis
• Overflow hypothesis

32. Mechanisms of Nephrotic Edema

33. Mechanisms of Nephrotic Edema

34. Pathogenesis of Hypoalbuminemia
• Loss from the body
• Normal rate of synthesis
• Increased rate of catabolism
• Decreased intake of dietary protein
• Changes in albumin distribution

35. Consequences of Hypoalbuminemia
• Edema
• Hyperlipoproteinemia
• Prone to develop acute renal failure
• High incidence of toxic reactions
with drugs
• Platelet hyperaggregability

36. Lipoprotein Abnormalities
Serum albumin Plasma lipoproteins
(g/dl) VLDL LDL1 LDL2 HDL2 HDL3
2.0~3.5
1.0~2.0
< 1.0
nl or nl or
nl
or nl

37. Increased susceptibility to Infection
• Urinary losses of immunoglobulins and properdin factor
BInsufficient immunoglobulin production
• Inadequate antibody responses
• Inadequate opsonization
• Defective cell-mediated immunity
• Immunosuppressive therapy, malnutrition, and
edema/ascites
• Spontaneous bacterial peritonitis is the most frequent
type of infection
• Strep. pneumoniae and E. coli are the most common
organisms
• Pneumococcal vaccine is suggested while in remission

39. Thromboembolism
• Incidence in children is 2–5%
• Both arterial and venous thromboses may be seen, including
renal vein thrombosis, pulmonary embolus, sagittal sinus
thrombosis, and thrombosis of indwelling arterial and
venous catheters.
• incidence: 2-62% by venography ( 35% )
• The risk of thrombosis is related to
– increased prothrombotic factors (fibrinogen,
thrombocytosis, hemoconcentration, relative
immobilization)
– decreased fibrinolytic factors (urinary losses of
antithrombin III, proteins C and S).

40. 診 斷
• 病史詢問
• 身體理學檢查
• 實驗室檢查
• 放射線檢查
• 腎臟組織穿刺檢查

41. 實驗室檢查
• 小便檢查
– 小便常規檢查：蛋白尿、血尿、白血球
– 24小時尿液檢查：蛋白尿、尿中肌酸酐廓清率
• 血液檢查
– 血中白蛋白、膽固醇、腎臟功能、肝臟功能、鈣、
鈉、鉀等電解質
– 免疫學檢查：如抗核抗體(ANA)、補體(C3、C4)、
免疫球蛋白(IgG, IgM, IgA) 、ASOT
– HbsAg , Anti-HbsAb , Anti-HCV Ab

42. 放射線檢查
• 胸部、腹部X-光檢查
• 腎臟超音波檢查
• 其他

43. Indications for renal biopsy
• At onset
– < 1 y/o , > 8 y/o at first attack
– Features suggesting a diagnosis other than MCD
• Persistent microscopic or macroscopic hematuria, low C3 level
• Sustained hypertension
• Impaired renal functions not attributable to intravascular
hypovolemia
• Presence of extra-renal features, eg. Arthritis, rash,
lymphadenopathy
• After initially therapy
– Frequent relapse
– Steroid-dependent
– Steroid-resistance – initial or late
– Change in clinical course ,e.g., development of features of GN
( hematuria, hypertension, renal insufficiency, hypocomplementemia)
– Prior to beginning treatment with cytotoxic drugs or Cyclosporin A

44. 治 療
• 支持性療法
–急性期：臥床休息
–飲食調整：減少鹽分、膽固醇攝取
–減少水分攝取
–補充適量蛋白質
–適度的運動

45. 治 療
• 藥物治療
– 類固醇
– 免疫抑制劑：Endoxan, Leukeran
– 抗排斥藥物：如環孢靈素(Ciclosporin)、
Tacrolimus (FK-506), Mycophenolic Acid
(MMF, Myfortic acid)等
– Angiotensin-converting enzyme (ACE)
inhibitors and angiotensin II blockers
– 其他：如利尿劑、PGE1、白蛋白補充、鈣
片….. 等

46. Albumin treatment
• Albumin infusion IVD for 1 hr
( 1gm/kg/day, Max : 25% 2 BT /day ), then
Lasix 1mg/kg IVD for 10 min
• Albumin : oncotic agent，not nutrition
supply
• Indication: NS with anasarca, CHF or
pulmonary edema, decreased urine
output
!! 救急不救窮 !!

47. Corticosteroid treatment
• Prednisolone 5 mg tab
• Prednisolone solution
– Kidsolone Solution
– Ingredient: Prednisolone Sodium Phosphate
1.344mg/ml
(Equivalent to Prednisolone 1ml=1 mg)
• Methylprednisolone, 10-30 mg/kg (Max. 1
gm/day), for pulse therapy

48. • Electrolytes, metabolism, endocrine system
– Cushing’s syndrome
– Diabetes mellitus
– Adrenal atrophy
– Growth retardation
– Hypogonadism, delayed puberty
– Increased Na+ retention and K+ excretion
• Cardiovascular system
– Hypertension
– Dyslipidemia
– Thrombosis
– Vasculitis
• Immune system
– Increased risk of infection (e.g., Candida)
– Re-activation of latent viruses (e.g., CMV)
• Gastrointestinal
– Peptic ulcer
– Gastrointestinal bleeding
– Pancreatitis
Side effects of Corticosteroids
Moon face, buffalo hump, central
obesity, hirsutism, osteoporosis, growth
retardation, and glucose intolerance

50. Side effects of Corticosteroids
• Skin
– Atrophy, striae rubrae distensae
– Delayed wound healing
– Steroid acne, perioral dermatitis
– Erythema, telangiectasia, petechia, hypertrichosis
• Skeleton and muscle
– Muscle atrophy/myopathy
– Osteoporosis
– Bone necrosis
• Eye
– Glaucoma
– Cataract
• CNS
– Disturbances in mood, behavior, memory, and cognition
– Steroid psychoses, steroid dependence
– Cerebral atrophy

51. Side effects of Corticosteroids

52. Cattran DC, Kidney Int 2007, 72:1429-1447

54. Alkylating agents
Cyclophosphamide: Endoxan
• 2-3 mg/kg/day, po, qd, for 8-12 weeks
• Impair DNA transcription by attaching alkyl chains
to purine bases
• Side effects:
– Hemorrhagic cystitis
– Neutropenia
– disseminated varicella
– Alopecia
– Oligospermia or azoospermia in male, accumulative
dose < 250 mg/kg, the risk of oligospermia is owe
– Risk of ovarian failure in female
– Risk of developing malignancies

55. • 0.2 mg/kg/day, po, qd, 8-12 weeks
• Impair DNA transcription by attaching alkyl chains to
purine bases
• Side effects:
– Immunocompromised state and prone to infection
– Leucopenia and thrombocytopenia
– Risk of gonadal damage: cumulative should be kept < 8
mg/kg to avoid oligospermia
– Risk of malignancies
– Seizures
Alkylating agents
Chlorambucil: Leukeran

56. • 300-1200 mg/m2/day, po, bid
• Max dose: 2 gm/day
• Mechanism:
– Inhibit Adhesion molecular expression
– Inhibit iNOS expression in endothelial cells
– Inhibit Mesangial cells proliferation
– Inhibit Muscle cell proliferation
• Side effects:
– Nausea, vomiting, dyspepsia
– Diarrhea, abdominal pain
– Leucopenia
– anemia
Mycophenolate mofetil (MMF)
Myfortic Acid

57. Cattran DC, Kidney Int 2007, 72:1429-1447

58. Cattran DC, Kidney Int 2007, 72:1429-144

59. Cyclic polypeptide(11 AAs) produced
by the soil fungus Tolypocladium
inflatum gams
Macrolide produced by
Streptomyces tsukubaensis
Calcineurin Inhibitors:
Cyclosporine (CsA) & Tacrolimus (TAC)

60. Calcineurin Inhibitors:
Cyclosporine (CsA) & Tacrolimus (TAC)

61. Cyclosporine (CsA)
Several mechanisms have been postulated to explain
CSA-induced reduction in proteinuria in NS
• The inhibition of interleukin (IL)-2 production[1]
• Induce stabilization of the podocyte [2,3]
• Reduction in glomerular plasma flow or
ultrafiltration pressure, which reduces proteinuria
on a haemodynamic basis [4]
1. Borel JF, Agents Actions 1994, 43:179-186
2. Faul C, Nat Med 2008, 14:931-938
3. Bensman A, Pediatr Nephrol 2010, 25:1197-1199
4. Meyrier AY, Kidney Int 2009, 76:487-491

62. • 3-6 mg/kg/day, po, qd-bid
• Maintain whole blood trough level at 50-150 ng/ml
• Side effects:
– Gum hypetrophy
– Hirsutism
– Hypertension
– Hyperkalemia, hypomagnesemia
– Nephrotoxicity
– Hepatotoxicity
– GI upset
Cyclosporin (CsA)

63. • 0.15 mg/kg/day, po, bid
• Keep trough level at 5-10 mcg/L
• Side effects:
– Hypertension
– Tremor
– Headache, insomnia
– Abnormal renal function
– Hyperkalemia, hyperglycemia, hypophosphatemia
– Leucopenia
– pruritis
Tacrolimus (FK-506)

64. Levamisole
• 2.5 mg/kg, po, qod
• T-cell immunomodulatory effect
• Side effects:
– Usually mild and generally well tolerated
– Gastrointestinal disturbance
– Rash
– Agranulocytosis (rare)

65. Rituximab
• Rituximab is a chimeric monoclonal
antibody， anti-CD-20 antigen present on B
cells.
• Rituximab is an approved therapeutic agent
for B-cell lymphomas and rheumatoid
arthritis.
• Data from the literature also support its off-
label use in nephrotic syndrome
Pediatr Nephrol (2010) 25:461–468
Pediatr Nephrol (2010) 25:957–959

66. Rituximab
Pediatr Nephrol (2010) 25:461–468
Pediatr Nephrol (2010) 25:957–959

67. Take home message
• 兒童蛋白尿是兒童健檢常見的問題，其嚴重的表現為腎病症候
群，是兒童常見腎臟疾病，也是兒童慢性腎臟病重要原因之一
• 腎病症候群的臨床典型症狀包括：一、身體水腫；二、嚴重蛋
白尿；三、血漿白蛋白濃度降低；四、高膽固醇血症
• 腎病症候群的治療可分兩大類：一是支持性療法；二是藥物治
療，最重要的藥是類固醇。為了防止水腫和高血壓，鹽分和水
分要控制，而蛋白質適量即可，不需刻意補充蛋白質攝取。
• 在預後方面，大多數兒童的腎病症候群屬微小變化型，對類固
醇的治療皆可以達到緩解，部份反覆復發者亦多隨著年紀的增
加而漸漸減少再發的次數而痊癒。
• 因此正確的診斷與正確的治療觀念，教育民眾與醫師的配合正
確使用藥物，對兒童腎病症候群的治療是最重要的。

68. 謝謝您的參與!