兒童腎臟科病例分享

兒童腎臟科病例例分享 ⾼高雄長庚兒童醫院

兒童腎臟科主治醫師 盧姵真

兒童腎臟科業務範圍 •

多尿尿、尿尿床、⾎血尿尿、蛋⽩白尿尿、泌泌尿尿道感染、膀胱輸尿尿管逆流、 腎絲球炎、腎⼩小管功能異異常、腎病症候群。

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除此之外，提供腎臟超⾳音波掃描，配合逆流性膀胱尿尿道攝影、 核⼦子醫學掃描、電腦斷層攝影及靜脈腎盂攝影可檢查各種腎 臟及尿尿路路病變與畸型(包括雙套輸尿尿管、輸尿尿管膨出、輸尿尿道 腎盂交界處阻塞、輸尿尿管膀胱交界處阻塞、⾺馬蹄腎等)。

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如有重症病患罹患性腎臟衰竭本科協助病患做透析治療(⾎血液 透析、腹膜透析)。本科對於未明原因的腎炎可提供腎臟切片 檢查，做正確的病理理診斷。

⼤大綱 •

泌泌尿尿道感染ㄢ（Urinary Tract Infection）

•

輸尿尿管膀胱逆流 (Vesico-ureteral Reflux)

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泌泌尿尿道阻塞 (Urinary Tract Obstruction)

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腎絲球病變 (Glomerulonephritis)

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末期腎病變 (End Stage Renal Disease)

Urinary Tract Infection (UTI) • • • •

資料庫：MEDLINE, EMBASE databases

時間：1966 through October 2005.

Search terms：urinary tract infection, cystitis, pyelonephritis, prevalence and incidence.

Inclusion Criteria

① children 0–19 years of age presenting with symptoms of UTI (including fever alone),

② urine cultures as the gold standard

③ defined a positive urine culture as 10*4 for catheterized specimen, 10*3 for suprapubic specimen, and 10*5 for clean catch or bag specimens.

Urinary Tract Infection (UTI) •

•

Exclusion Criteria

① languages other than English,

② evaluated only a high risk subgroup

③ in developing countries,

④ evaluated only a low risk subgroup

⑤ evaluated only children with other symptomatic illnesses

⑥ contained fewer than 10 subjects,

⑦ used bags to collect urine specimen in more than 25% of subjects with UTI without confirming results using more accurate methods.

Eighteen of the 51 articles met all inclusion criteria.

Urinary Tract Infection

根據到⾨門診或急診的兒科病⼈人中，泌泌尿尿道感染的機率是7.8%

三個⽉月以下的男嬰, UTI佔發燒病⼈人比例例最⾼高：8.7 % （男>女）

以UTI的機率來來說，沒割包⽪皮的病⼈人是有割包⽪皮的病⼈人的9-10x

• •

林林⼝口長庚2011年年度的兒科 急診發燒病⼈人

Methods:

• Time

• From January 2011 to December 2011

• Age

• One day to 36 months.

• Inclusion Criteria:

• Growth of a single urinary tract pathogen with at least > 105 colony-forming units (CFU)/mL in urine specimens.

Urinary Tract Infection

三歲以內，女性UTI的比例例約11.2%，不同age group沒有差 異異性。 男性UTI比例例，⼀一歲以內⾼高達14%，接下來來遞減。

Pathogens of UTI

E. coli 佔 UTI 的⼤大宗。

UTI Leads to Renal Damage?

泌泌尿尿道功能性和結構異異常導致泌泌尿尿道感染和腎功能惡惡化。 在兒童，最常⾒見見的異異常是逆流性腎病變（ Vesicoureteral Reflux）。

Vesico-ureteral Reflux (VUR) •

In a cohort of pediatric patients with UTI, VUR was diagnosed in 33% of cases. - Wu at al. Childhood Urinary Tract Infection: A Clinical analysis of 597 cases.

Acta Paediatr Taiwan.2004; 45:328-33

Vesico-ureteral Reflux (VUR)

Vesico-ureteral Reflux (VUR)

Forest plots of odds ratios on a log scale of scarring after acute

by patient

by renal unit

Forest plots of renal cortical abnormality rates by reflux grade

VUR Incidence

VUR & Renal Pelvic Diameter(RPD)

超⾳音波沒有問題不代表沒有VUR。

Febrile Urinary Tract Infection Recurrent Febrile Urinary Tract Renal and Bladder Ultrasonography Voiding Cystoureterography Hydronephrosis, Scarring, or others

Case Report •

1 year-old female / 75.8 cm (50th-85th) / 10.5 kg (85th-97th)

• • •

1st UTI at the age of 3 months (U/C: E. coli) 2nd UTI at the age of 5 months (U/C: E. coli) 3rd UTI at the age of 10 month (U/C: E. coli)

Further Exam

• •

Renal sonography (at the age of 3 months & 5 months ) VCUG (at the age of 5 months, 12 months )

Therapy

•

Prophylactic antibiotics was given at the age of 11 months. (Cephalexin 10mg/kg/dose once daily x 3 months)

Patient

Hospitalization

L’t Kidney: 6.1 x 3.2 cm

R’t Kidney: 5.6 x 2.7 cm

L’t Gr. III~IV reflux

L’t Kidney: 6.1 x 3.2 cm

L’t Gr. III~IV reflux

R’t Kidney: 5.6 x 2.7 cm

Personal Choice -> Continuous Antibiotic Prophylaxis (CAP)

Case Report Patient

•

7 month-old male / 8 kg (50th-85th)

Hospitalization

•

1st UTI at the age of 4 months (U/C: E. coli)

Further Exam

• •

Renal sonography (at the age of 4 months ) VCUG (at the age of 7 months )

• •

Observation Follow-up VCUG one year later

Option

L’t Hydronephrosis

L’t Gr. V reflux

L’t Hydronephrosis

L’t Gr. V reflux

Personal Choice -> Observation

VUR Resolution Rate Follow-up Times Between 12 and 48 months.

VUR Resolution Rate

VUR級數越⾼高，resolution rate越低。

VUR Resolution Rate Calculator

https://apps.childrenshospital.org/clinical/vurcalculator/

The Management of VUR in Children 2010 American Urological Association (AUA) Guildline

The child with VUR less than one year of age •

VUR with a history of a febrile urinary tract infection.

• •

Recommendation: Continuous antibiotic prophylaxis

VUR in the absence of a history of febrile urinary tract infections

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VUR Gr.III-V

• •

Recommendation: Continuous antibiotic prophylaxis

VUR Gr.I-II

•

Option: Continuous antibiotic prophylaxis

The child with UTI and VUR more than one year of age •

Recommendation: Treatment of bladder/bowel dysfunction (BBD).

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Child with BBD and VUR

• •

Child with VUR, UTI but no BBD

• •

Recommendation: Continuous antibiotic prophylaxis

Option: Continuous antibiotic prophylaxis

Child with VUR but no febrile UTI or BBD or renal cortical anomalies

•

Option: Observation

Surgical Intervention •

2010 AUA Guildline

•

1997 AUA Guildline

•

•

Age < 1 year

Circumcision

• •

Patient: Infant male with VUR

Anti-reflux or re-implantation

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Child with Breakthrough UTI (BTUTI)

•

•

Persistant unilateral Grades III–IV reflux.

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Persistant bilateral Grades III–V reflux.

Age 1-5 year

• •

Bilateral Grade V reflux.

Age 6-10 year

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Bilateral Grades III–IV reflux

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Grade V reflux.

Surgical Intervention •

2010 AUA Guildline

•

1997 AUA Guildline

•

•

Age < 1 year

Circumcision

• •

Patient: Infant male with VUR

Anti-reflux or re-implantation

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Child with Breakthrough UTI (BTUTI)

•

•

Persistant unilateral Grades III–IV reflux.

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Persistant bilateral Grades III–V reflux.

Age 1-5 year

• •

Bilateral Grade V reflux.

Age 6-10 year

•

Bilateral Grades III–IV reflux

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Grade V reflux.

Surgical Repair is operator-dependent.

Continuous Antibiotic Prophylaxis (CAP) in the Treatment of VUR •

Time

•

•

Child less than one year of age

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VUR with a history of a febrile urinary tract infection.

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VUR grades III–V who is identified through screening

Child more than one year of age

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Child with BBD and VUR

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Child with VUR, UTI but no BBD

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Material and Method

• Multicenter, randomized, placebo-controlled trial.

• 607 children aged 2–71 months with grade 1–4 VUR diagnosed after a first or second febrile or symptomatic UTI.

• Study participants received trimethoprimsulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up DMSA renal scans.

CAP & Renal Scar

CAP無法降低Renal Scar的風險。

Role of CAP

CAP無法降低UTI的機率。CAP -> personal choice

VUR in Children and Adult •

The exact incidence of RN in children or adults is not known. The diagnosis is difficult in patients who may have already undergone the natural resolution of VUR by the time RN is diagnosed. -Mattoo at al. Adv Chronic Kidney Dis. 2011 September ; 18(5): 348–354. doi: 10.1053/j.ackd.2011.07.006.

Case Report Patient

• • • • •

16 year-old male / 167.9cm / 69.2 kg Age 15 year, nausea and vomiting for 1 week, elevated serum creatinine in 屏東基督教醫院 BP: 140/92 mmHg

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Urine routine: no proteinuria, hematuria, glucosuria, or pyuria.

BUN/Crea: 14/ 1.64 (mg/dL), Na/K = 139/ 3.4 (meq/L), Ca/Pi= 9.5 /3.9 (mg/dL) , Uric acid: 9.8 mg/dL, HCO3-: 25.2 meq/L Hb:15.6 g/dL, PLT: 99*10*3/uL

Exam

• • •

Renal sonography DTPA VCUG

Option

• •

Observation anti-reflux ?

Admission

Clinical Course 2017/9/2

Hb:15.6, PLT: 99, BUN/Crea: 14/1.64 (mg/dL)

TPCR: 153.8 mg/g, Albumin: 4.8 g/dL

2017/9/6

Hb:16.4, PLT: 93, Crea: 1.69 (mg/dL), iPTH 46.3 pg/mL

C3/C4: 116/23.70 (mg/dL), ANA: Negative, A-DSNA< 40.5 unit/mL

Serum Electrophoresis: no significant diagnostic abnormal pattern

2017/9/9

Hb:16.5, PLT: 97, Crea: 1.75 (mg/dL)

2017/9/22

Hb:15.6, PLT: 110, Crea: 1.62 (mg/dL)

Clinical Course 2017/9/2

Hb:15.6, PLT: 99, BUN/Crea: 14/1.64 (mg/dL)

TPCR: 153.8 mg/g, Albumin: 4.8 g/dL

eGFR = 42(Schwartz); 56(MDRD)

2017/9/6

Hb:16.4, PLT: 93, Crea: 1.69 (mg/dL), iPTH 46.3 pg/mL

C3/C4: 116/23.70 (mg/dL), ANA: Negative, A-DSNA< 40.5 unit/mL

Serum Electrophoresis: no significant diagnostic abnormal pattern

2017/9/9

Hb:16.5, PLT: 97, Crea: 1.75 (mg/dL)

2017/9/22

eGFR = 41(Schwartz); 54(MDRD)

eGFR = 39(Schwartz); 52(MDRD) Hb:15.6, PLT: 110, Crea: 1.62 (mg/dL)

eGFR = 43(Schwartz); 57(MDRD)

Bilateral small kidneys

DTPA

DTPA

eGFR(R’t)=30.1; eGFR(L’t)=24.9; eGFR(Total)=55 ml/min

Bilateral VUR Gr.III

Bilateral VUR Gr.III

Cause of Chronic Kidney disease -> VUR Personal Choice -> Observation

Reflux Nephropathy in Adults

Complications of Reflux Nephropathy •

Hypertension

•

The relationship between renal scarring and hypertension was first demonstrated in 1937.- Butler AM. CHRONIC PYELONEPHRITIS AND ARTERIAL HYPERTENSION. The Journal of clinical investigation. 1937; 16:889–97. [PubMed: 16694535]

•

Hypertension occurs in 34–38% of adult reflux nephropathy patients with renal scarring. - Zhang et al. A long term follow up of adults with reflux nephropathy. N Z Med J. 1995; 108:142–4. [PubMed: 7761049]. Kohler et al.

Vesicoureteral reflux diagnosed in adulthood. Incidence of urinary tract infections, hypertension, proteinuria, back pain and renal calculi. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 1997; 12:2580–7.

Complications of Reflux Nephropathy •

Proteinuria

•

Overt proteinuria, which has been reported in 21% of adult patients with reflux nephropathy(RN). Kohler et al. Vesicoureteral reflux diagnosed in adulthood. Incidence of urinary tract infections, hypertension, proteinuria, back pain and renal calculi. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 1997; 12:2580–7.

—

Complications of Reflux Nephropathy •

Focal Segmental Glomerular Sclerosis (FSGS)

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In a histological review of 86 pediatric nephrectomy specimens from patients with VUR, FSGS was found in 18 (21%) patients, 9 of whom were less than 5 years old. -Mattoo at al. Adv Chronic Kidney Dis. 2011 September ; 18(5): 348–354. doi:10.1053/j.ackd.

2011.07.006.

•

No significant association between the presence or absence of FSGS and age, gender, presence or absence of obstruction, and severity of hypoplasia and/or Postnatally acquired cortical loss. - Hinchliffe SA, Kreczy A, Ciftci AO, Chan YF, Judd BA, van Velzen D. Focal and segmental glomerulosclerosis in children with reflux nephropathy. Pediatr Pathol. 1994; 14:327–38.

Complications of Reflux Nephropathy â&#x20AC;˘

Renal failure

â&#x20AC;˘

According to 2008 North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) report, RN is the fourth commonest cause for chronic kidney disease in 8.4% of the children and is seen in 5.2% of transplanted patients and 3.5% of dialysis patients. -NAPRTCS. North American Pediatric Renal Transplant Cooperative Study (NAPRTCS); 2008 Annual Report. 2008.

Urinary Tract Obstruction •

Urinary tract obstruction (UTO) can lead to hydroureter, hydronephrosis, and even renal failure.

•

UTO can result from a wide variety of environmental causes or genetic mutations.

•

Even the subtypes of UTO (such as UPJ obstruction, UVJ obstruction, etc) are heterogeneous and may have drastically different etiology.

Urinary Tract Obstruction

Case Report • • • •

2 year 4 month-old male / 85cm (15th-50th) / 12.8kg (50th-85th) Left uretero-pelvic junction obstruction Left double J tube at the age of 10 months Removal of L’t double J at the age of 1 year 10 months

Admission

•

Age 1 year 11 months, admission in 阮阮綜合醫院 due to UTI for one week, then transferred to ⾼高雄長庚醫院.

Exam

• •

Age 1 year 11 month, renal sonography and abdominal CT Age 2 year, antegrade pyelography

• •

Age 1 year 11 months, left percutaneous nephrostomy Age 2 year, uretero-pelvic pyeloplasty

Patient

Operation

兒童慢性腎臟病(CKD) •

常⾒見見的先天性腎臟及泌泌尿尿道異異常（ CAKUT），包括膀胱輸尿尿 管逆流、泌泌尿尿道阻塞、腎缺失或發育不全、嬰兒型多囊腎等。

•

台灣⼀一項利利⽤用全⺠民健保資料庫兩兩百萬⼈人隨機取樣檔案的研究顯 ⽰示，2003 年年 20 歲以下的兒童及青少年年 CKD 盛⾏行行率約1.92⼈人 /百⼈人，發⽣生率約 0.31⼈人/百⼈人，然⽽而該研究並未包含CAKUT 兒童。

•

⼤大部分研究均顯⽰示，CAKUT 為兒童 CKD 最常⾒見見的原因，甚 ⾄至超過 50%，因此該研究對兒童 CKD 實際盛⾏行行率與發⽣生率恐 有嚴重低估之虞。

兒童慢性腎臟病(CKD) •

•

根據台灣⼀一項多中⼼心回溯性 調查，共收錄 757 名 1 ∼ 18 歲罹患 CKD 兒童及青少 年年，平均年年齡為 7.4 歲，男 性占52.3 % 。 病因⽅方⾯面，如國外⽂文獻，同 樣以「先天性泌泌尿尿系統異異常 （CAKUT）」為最常⾒見見病 因，占 47.8%，其次為腎絲 球腎炎（GN）占 37.2%

台灣兒童慢性腎臟病比例例

3%5% 15% 39%

38%

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

兒童腎絲球疾病

Primary

Secondary

GN (%)

GN (%)

USA

IgAN (22) a

LN (13) a

Brazil

FSGS (25) b

LN(42) b

Italy

IgAN (37) b

LN (26) b

Spain

IgAN (17) a

LN (11) a

Czech Republic

IgAN (34) b

LN (23) b

Hungary

IgAN (15) a

LN (7) a

Macedonia

MN (13) b

Romania

MPGN (29) b

LN (29) b

Serbia

Non-IgA

LN (76) b

Country America

Worldwide distribution of glomerular diseases: the role of renal biopsy registries

Europe

mesangioproliferative (25) b UK

IgAN (39) b

Asia China

IgAN (45) b

LN (54) b

Korea

IgAN (28) b

LN (9) b

Saudi Arabia

FSGS (21) b

LN (57) b

Australia

IgAN (34) a

LN (14) a

Middle East

a

Percentage of total glomerular diseases. b Percentage of primary or secondary glomerulonephritis.

Signs of Glomerulonephritis Headache Hypertension Puffy Eyelids Lethargy Wight Gain Edema

Proteinuria Hematuria Oligouria

௚

Evaluation •

Clinical Manifestations

•

Family History & Medical History

•

Urinalysis, Total Protein/Creatinine Ratio

•

Renal Sonography

•

Renal Function & Electrolyte Survey

•

Blood Survey ( ASLO, ANA, Anti-DNA antibodies) , complement studies, and ANCA.

•

Renal biopsy

Case Report • •

5 year 6 month-old male / 103.7 cm (3rd-15th) / 16.4 kg (3rd-15th) At age 5 year, generalized edema for 3-4 days and weight gain 1kg (15→16.1kg)

• • • •

Albumin 1.5mg/dL, BUN/Crea: 13/0.27 mg/dL Urine routine: protein 4+ C3 /C4: 134 /24.20 (mg/dL), ANA: Negative A-DSDNA: 92.5 (Negative)

Course

• •

Diagnosed as Nephrotic Syndrome Prednisolone 2mg/kg/day for 1 month, and then tapper in 1 month (2017/2/2-4/2)

Relapse

• •

Nephroric syndrome relapse Prednisolone 2mg/kg/day for 1 month, and then tapper in 1 month (2017/5/2-7/2)

Patient

Admission

Renal Boiopsy Indication Proteinuria • proteinuria with renal impairment(GFR) • asymptomatic proteinuria>2gm/day, independent of renal function Nephrotic syndrome • definition: proteinuria>3gm/day, albumin<3.5mg/ dl, hyperlipidemia and edema • under 1 y/o or over 10 years (MCD>90% in 1-5 y/o) Persistent proteinuria and hematuria • with renal impairment Acute renal failure • urinary sediment containing RBC casts • to reverse correctable factors Chronic renal failure with normal-sized kidneys • paraprotein-associated disease • herbal medication related • FSGS-high recurrence after renal transplantation Renal allograft dysfunction • scheduled renal allograft renal biopsy • chronic rejection, tubulo-interstitial damage, arterial lesion, recurrence of primary disease or de novo GN, drug toxicity systemic disorders • lupus nephritis

Not suggested in • isolated minor proteinuria • hematuria with normal GFR, no H/T, no hypocomplementemia Contraindication • small, shrunken kidneys( difficult to find and enter, bleeding tendency) • asymmetrical kidneys with significant discrepancy in function • obstructed kidneys • uncontrolled hypertension • single kidney • horseshoe kidney • coagulation defect(bleeding tendency, thrombocytopenia, intrinsic coagulation defect) • reflux nephropathy • acute urinary infection • sepsis • incorporative patients

2017@Uptodate

Renal Boiopsy

Case Report Patient

Admission

GN study

Further Exam

• • •

14 year-old male / 152cm (3rd-15th) / 51.7kg (50th-85th) Vomiting and leg jitters for one week Urine routine showed proteinuria, hematuria 6 months ago (school screen)

• • • • • • • •

BP 200/121 mmHg ; Leg Gr.I pitting edema BUN/Crea: 101/13.1 (mg/dL) ; Ca/P: 6.1/ 10.1(mg/dL) ; Hb: 5.7 (g/dL) Gas pH: 7.218, HCO3-:14.1 mmole/L, PCO2: 35.3 mmHg Urine routine: RBC: 258/uL, protein: 3+ ; TPCR: 3692 mg/g

• • •

Renal sonography Blood smear Renal biopsy

p-ANCA&c-ANCA: < 0.2 IU/mL, ENA< 0.03 C3: 74.1 mg/dL, C4: 24.9 mg/dL ANA: negative, A-DSDNA < 40.5 U/mL ASLO: 235 IU/mL, IgA: 415 mg/dL

Renal Sonography

L’t Kidney: 8.1 x 3.6 cm

R’t Kidney: 8.9 x 4.1 cm

Clinical Course 2017/6/17

BUN/Crea: 100/13.01 (mg/dL)

2017/6/18

BUN/Crea: 100/13.48 (mg/dL) H/D 3 times on 2017/6/18, 2017/6/20, 2017/6/22

2017/6/25

BUN/Crea: 108/11.12 (mg/dL) Regular H/D 3 times per week since 2017/6/26

2017/7/04

Renal Biopsy

2017/7/18

PD tube insertion

2017/7/25

PD training

Renal Biopsy

Seventeen glomeruli on the section. Fifteen of them are sclerotic.

60% of the tubules are atrophy.

80% of the interstitium are fibrotic.

Vessels are unremarkable.

ImmunoFluorescence Study IgG

IgA

IgM

C3

C1q

Lambda

ImmunoFluorescence Study IgG

IgM

IgA

Kappa

C3

C1q

Lambda

Clinical Course 2017/6/17

BUN/Crea: 100/13.01 (mg/dL)

2017/6/18

BUN/Crea: 100/13.48 (mg/dL) H/D 3 times on 2017/6/18, 2017/6/20, 2017/6/22

2017/6/25

BUN/Crea: 108/11.12 (mg/dL) Regular H/D 3 times per week since 2017/6/26

2017/7/04

Renal Biopsy

2017/7/18

PD tube insertion

2017/7/25

PD training

Renal Replacement Therapy

Renal Replacement Therapy

Renal Replacement Therapy

END