Korea-JapanThe 8th Pediatric

Nephrology Seminar 2010

May 29 (Sat), 2010

Hotel Gyeongju Kyoyuk Munhwa Hoekwan, Gyeongju, Korea

慶州 敎育文化會館

Sponsored by

The Korean Society of Pediatric Nephrology

The Japanese Society of Pediatric Nephrology

Invitation to

the 8th Korea-Japan Pediatric Nephrology Seminar, 2010

Dear Colleagues and Friends,

I would like to thank you for your participation to the 8th Korea-Japan Pediatric Nephrology

Seminar 2010, which will be held on May 29, 2010 in Hotel Gyeongju Kyoyuk Munhwa

Hoekwan, Gyeongju, Korea.

This program will be focused on clinico-pathological discussion of difficult and/or interesting

pediatric nephrology cases. In addition, a built up separate session for poster presentations is

prepared, also.

The Seminar shall provide a good opportunity to share ideas and interest in improving the care

of children with critical renal diseases for pediatric nephrologists and renal pathologists from

Korea and Japan. Especially in this year, the Seminar will be held in Gyeongju, the capital city

of ancient Shilla dynasty. Thus, it will be a good chance not only to promote friendship but also

taste the old traditional culture and history of Korea.

Sincerely yours,

Prof. Yong Hoon Park, M.D.

President

The Korean Society of Pediatric Nephrology

Department of Pediatrics

College of Medicine

Yeungnam University

Daegu, Korea

Organizing CommitteesThe 8th Korea–Japan Pediatric Nephrology Seminar, 2010

1

KOREA

Organizing Committee

Yong Hoon Park Yeungnam University

Kee Hwan Yoo Korea University

Kee Hyuck Kim NHIC Ilsan Hospital

Hae Il Cheong Seoul National University Children’s Hospital (Liaison officer)

Pathologists

Kyung Chul Moon Seoul National University

An Na Seo Kyungpook National University

Woon Yong Jung Korea University

Advisors

Pyung-Kil Kim Kwandong University

Jae Seung Lee Yonsei University

Yong Choi Seoul National University

Chong Guk Lee Ilsan Paik Hospital

Office

Department of Pediatrics

Seoul National University Children’s Hospital

28 Yongon-Dong, Chongro-Gu, Seoul 110-744, Korea

Tel + 82-2-2760-2810

Fax + 82-2-743-3455

E-mail cheonghi@snu.ac.kr

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JAPAN

Organizing Committee

Yuhei Ito Kurume University

Michio Nagata University of Tsukuba

Takahashi Sekine Toho University

Kazumoto Iijima Kobe University

Shori Takahashi Nihon University (Liaison officer)

Pathologists

Michio Nagata University of Tsukuba

Satoshi Hisano Fukuoka University

Hiroshi Kitamura National Hospital organization Chiba-east Hospital

Advisors

Iekuni Ichikawa Tokai University

Takashi Igarashi The University of Tokyo

Office

Department of Pediatrics

Nihon University Surugadai Hospital

1-8-13 Kanda-Surugadai, Chiooda-Ku, Tokyo, Japan 101-8309

Tel + 81-3-3293-1711

Fax + 81-3-3293-1798

E-mail shori@med.nihon-u.ac.jp

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PROGRAM: May 29 (Sat), 2010

Registration 09:00 – 09:20 AM

Opening Remark 09:20 – 09:30 AM Dr. Yong Hoon Park (Yeungnam University)

Case O-1 09:30 – 10:00 AM

A case of strongly-suspected membranoproliferative glomerulonephritis with acute

nephritic syndrome leading to chronic renal failure

Seiji Tanaka1, Atsushi Hiroshima1, Yuno Yoshimoto1, Kosuke Ushijima1, Yuhei Ito1, Satoshi

Hisano2

Department of Pediatrics, Kurume University Medical Center1

Department of Pathology, Fukuoka University School of Medicine2

Pathological commentary: Dr. Satoshi Hisano (Fukuoka University)

Chairperson: Dr. Kee Hwan Yoo (Korea University)

Case O-2 10:00 – 10:30 AM

Idiopathic membranous nephropathy and hypogammaglobuminemia presenting as

nephrotic syndrome

Hyung Eun Yim1, Kee Hwan Yoo1, Woon Yong Jung2, Young Sook Hong1, Joo Won Lee1

Departments of Pediatrics1 and Pathology2, College of Medicine, Korea University, Seoul, Korea

Pathological commentary: Dr. Woon Yong Jung (Korea University)

Chairperson: Dr. Kunimasa Yan (Kyorin University)

Case O-3 10:30 – 11:00 AM

The pathogenesis and clinical manifestations of in a patient with Juvenile

nephronophthisis

Daishi Hirano1, Amane Endo1, Hitohiko Murakami2, Motoshi Hattori3, Shuichiro Fujinaga1

Division of Nephrology, Saitama Children’s Medical Center1

Division of Pathology, Saitama Children’s Medical Center2

Division of Nephrology, Tokyo Women`s Medical University Hospital3

Pathological commentary: Dr. Michio Nagata (University of Tsukuba)

Chairperson: Dr. Young Seo Park (Asan Medical Center)

Coffee break 11:00 – 11:15 AM

4

Case O-4 11:15 – 11:45 AM

Rhabdomyolysis with acute renal failure and severe hypothermia in a 15-year-old obese

boy

Se Jin Park, Jae Il Shin, Ji Hong Kim, Jae Seung Lee

The Institute of Kidney Disease, Department of Pediatrics, Yonsei University College of

Medicine, Seoul, Korea

Pathological commentary: None

Chairperson: Dr. Kenichi Satomura (Osaka Medical Center and Research Institute for

Maternal and Child Health)

Case O-5 11:45 AM – 12:15 PM

The regulatory mechanism of TRPC6 activation by FSGS-causing mutations

Shoichiro Kanda1,2, Yutaka Harita1,2,5, Takashi Sekine2,6, Yoshio Shibagaki3, Takashi Igarashi2,

Takafumi Inoue4, Seisuke Hattori1,3

Division of Cellular Proteomics (BML), Institute of Medical Science, Tokyo1

Department of Pediatrics, University of Tokyo, Tokyo2

Dept of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo3.

Dept of Life Sci and Med Bioscience, Faculty of Science and Engineering, Waseda Univ, Tokyo4

Dept of Molecular Biology, Yokohama City Univ, Graduate School of Med Science, Kanagawa5

Pathological commentary: None

Chairperson: Dr. Su Yung Kim (Pusan National University Yangsan Children’s Hospital)

Lunch and Business meeting 12:15 – 13:30 PM

Poster presentation 13:30 PM – 15:00 PM

Chairperson: Dr. Il Soo Ha (Seoul National University Children’s Hospital)

Chairperson: Dr. Yoshitsugu Kaku (Fukuoka Children’s Hospital)

Case O-6 15:00 – 15:30 PM

A Case of systemic amyloidosis associated with cyclic neutropenia

Hyun Kyung Lee1, Kyoung Hee Han1, Yun Hye Jung1, Hee Gyoung Kang1, Il Soo Ha1, Hae Il

Cheong1, Yong Choi2

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea1

Department of Pediatrics, HaeUnDae Paik Hospital, Busan, Korea2

Pathological commentary: Dr. Kyung Chul Moon (Seoul National University Hospital)

Chairperson: Dr. Kenichi Miura (The University of Tokyo)

5

Case O-7 15:30 – 16:00 PM

Rapid deterioration of renal function owing to thrombotic microangiopathy in a boy with

systemic lupus erythematosus and antiphospholipid syndrome

Shunsuke Noda1, Koichi Kamei1, Akiko Tsutsumi1, Tomohiro Udagawa1, Masao Ogura1,

Nakagawa Satoshi2, Kentaro Matsuoka3, Itou Shuichi1

Department Nephrology and Rheumatology1, Department of Intensive Care2

Department of Pathology3, National Center for Child Health and Development

Pathological commentary: Dr. Hiroshi Kitamura (Chiba-east National Hospital)

Chairperson: Dr. Ja Wook Koo (Sanggye Paik Hospital)

Case O-8 16:00 – 16:30 PM

Renal amyloidosis in a child with non-cystic fibrosis related bronchiectasis

Eun Ae Yang, Dong Won Lee, Myung Chul Hyun, Cheol Woo Ko, Min Hyun Cho

Department of Pediatrics, Kyungpook National University School of Medicine,

Pathological commentary: Dr. An Na Seo (Kyungpook National University)

Chairperson: Dr. Hiroshi Saito (Nihon University)

Closing address 16:30 – 16:40 PM

Dr. Yong Hoon Park (Yeungnam University)

Banquet at YoSeok-Gung 18:00 -

Welcoming address Dr. Yong Hoon Park

Congratulatory address Dr. Yuhei Ito

Awarding ‘Hiroto prize’ Dr. Shori Takahashi and Dr. Yong Hoon Park

Proposal of a toast Dr. Pyung Kil Kim

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POSTER PRESENTATION: Case P-1 ~ Case-12

May 29 Sat, 2010 13:30 PM – 15:00 PM

Chairpersons

Dr. Il Soo Ha (Seoul National University Children’s Hospital)

Dr. Yoshitsugu Kaku (Fukuoka Children’s Hospital)

Case P-1

A case of IgM nephropathy diagnosed with frequently relapsing of steroid dependent

nephrotic syndrome

Mika Nishimura, Shinya Yato, Kohei Maekawa, Junko Sawaki, Chiaki Takahashi, Hiromu Mae,

Masuji Hattori, Takakuni Tanizawa

Department of Pediatric, Hyogo College of Medicine

Case P-2

Children who developed renal failure after oseltamivir treatment

Joo Hoon Lee, Young Seo Park

Department of Pediatrics, Asan Medical Center, Seoul, Korea

Case P-3

Type-1 diabetes revealed with steroid therapy at onset of nephrotic syndrome

Rika Fujimaru, Hiroshi Yamada

Department of Pediatrics, Osaka City General Hospital, Osaka, Japan

Case P-4

Tacrolimus-induced encephalopathy in post-kidney transplantation

Kim Myoung Uk, Sae Yoon Kim, Jung Youn Choi, Yong Hoon Park

Department of Pediatrics, Yeungnam University, College of Medicine, Daegu, Korea

7

Case P-5

High-dose candesartan and erythropoietin combination therapy in diabetic nephropathy

with nephrotic syndrome

Hiroshi Saito, Ayako Yoshida, Junichi Suzuki, Ishige Wada, Tatsuhiko Urakami, Shori Takahashi

Department of Pediatrics, Nihon University

Case P-6

Chronic kidney disease due to bilateral cystic kidneys

Min Sun Kim1, Dae-Yeol Lee1, Mung Jae Kang2

Dept of Pediatrics1 and Pathology2, Chonbuk Nat’l Univ Medical School, Jeonju, Korea

Case P-7

Renal pathology with normal urinalysis in Fabry disease

Takahiro kanai1, Takane Ito1, Jyun Odaka1, Takashi Saito1, Jyun Aoyagi1, Masahisa Kobayashi2,

Toya Ohashi3, Mariko Y Momoi1

Department of Pediatrics, Jichi Medical University1

Department of Pediatrics, The Jikei University School of Mediceine2

Dept of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine3

Case P-8

A case of hypertension with renal artery stenosis detected by school health examination

Hyung Jung Kim, Jae Uk Bae, Byung Ok Kwak, Jae Sung Son, Kyo Sun Kim

Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Korea

Case P-9

Early onset of nephrotic syndrome after cord blood stem cell transplantation

Ken-ichiro Miura, Takashi Sekine, Komei Ida, Hiroshi Terashima, Masaru Takamizawa, Ayaka

Furuya, Junko Takita, Katsuyoshi Koh, and Takashi Igarashi

Department of Pedatrics, University of Tokyo

8

Case P-10

Histologic changes of IgA nephropathy during long term follow-up

Beom Jin Lim1, Chang Min Moon2, Ji Sun Song3, Hyeon Joo Jeong1, Pyeong Kil Kim2

Department of Pathology, Yonsei University, College of Medicine, Seoul, Korea1

Departments of Pediatrics2 and Pthology3, Kwandong University, College of Medicine

Case P-11

3 cases of childhood onset asymptomatic systemic lupus erythematosus

Junko Sawaki, Mika Nishimura, Kouhei Maekawa, Chiaki Takahashi, Hiromu Mae, Masuji

Hattori, Takakuni Tanizawa

Department of Pediatrics, Hyogo College of Medicine, Hyogo, Japan

Case P-12

Dense deposit disease improved with steroid pulse therapy.

저자

소속

9

Case O-1

A case of strongly-suspected membranoproliferative glomerulonephritis with acute

nephritic syndrome leading to chronic renal failure

Seiji Tanaka1, Atsushi Hiroshima1, Yuno Yoshimoto1, Kosuke Ushijima1, Yuhei Ito1, Satoshi

Hisano2

Department of Pediatrics, Kurume University Medical Center1

Department of Pathology, Fukuoka University School of Medicine2

Introduction: An acute nephritic syndrome present in about 25% of membranoproliferative

glomerulonephritis (MPGN). Renal function is usually nomal but rare patient may deteriorate

rapidly. We report a case of atypical MPGN with acute nephritic syndrome leading to chronic

renal failure (CRF) within half a year.

Case: A 9-year-old boy with no particular family and past histories had right hip joint pain a

month after tonsillitis, and was treated with oral NSAIDs. Several days later, he had facial

edema, and underwent a medical examination at his local clinic. As a result of the examination,

he was diagnosed with nephritic syndrome, which led to hospital admission. After the admission,

the disease was followed up with oral prednisolone, but negative protein reaction was not

observed, leading to a renal biopsy. LM revealed no crescent, but endocapillary proliferative

changes and focal double contours. IF showed deposition of C3 and IgG, and EM did mesangial

interposition and humps. Although streptococci were denied by the laboratory results and

MPGN was considered as a differential diagnosis, AGN was diagnosed from the clinical course.

After that, deterioration of the renal function was observed, which led to the initiation of

peritoneal dialysis. Because treatment with peritoneal dialysis and oral prednisolone showed a

tendency toward improvement in the renal function, oral cyclosporine was added to the

treatment. However, 3 months after improvement of the renal function, it deteriorated again. For

this reason, a second biopsy was performed 9 months after the first one. The second biopsy

also confirmed the presence of focal double contours, with no crescent and with marked

glomerulosclerosis. Although MPGN type 1 was suspected by the pathological findings and

clinical course, rapid deterioration of the renal function was clinically observed, and the deposits

showed no histologically typical patterns. After that, oral administration of prednisolone was

conducted, but remission could not be expected, which led to end-stage renal failure.

Conclusions: It is rare case that the MPGN without crescent leading to CRF within half a year.

Because the present case showed atypical symptoms and histological finding, it was difficult for

this patient to treat appropriately.

10

Case O-2

Idiopathic membranous nephropathy and hypogammaglobulinemia presenting as nephrotic

syndrome

Hyung Eun Yim1, Kee Hwan Yoo1, Woon Yong Jung2, Young Sook Hong1, Joo Won Lee1

Department of Pediatrics1 and Pathology2, College of Medicine, Korea University

Background: Idiopathic membranous nephropathy (MN) is an organ-specific autoimmune

glomerular disease. It is a relatively rare cause of nephrotic syndrome in children and the true

pathogenesis has been a long-lasting mystery. Various forms of hypogammaglobulinemia

including common variable immunodeficiency and selective IgA deficiency can occur in patients

with autoimmune diseases. There have also been several reports on IgA deficiency and MN.

We describe here the rare case of hypogammaglobulinemia and idiopathic MN presenting as

nephrotic syndrome.

Case: A 13-year old boy was admitted with generalized edema and gradual weight gain by 6 kg

for 2 months. He had a 1-year history of microscopic hematuria detected on school mass

screening. During infant period, he had been treated intermittently as bronchiolitis and otitis

media but not significant. At visit, he had mild respiratory symptom, however, he had taken no

medication. The physical examination revealed abdominal distension and pretibial pitting

edema. The chest radiography showed ill-defined opacity in right middle lobe suggesting lesions

such as pneumonia. The results of laboratory tests revealed: leukocyte count 13,800 /uL; Hb

12.0 mg/dL; platelets 297,000 /uL; c-reactive protein 5.54 mg/L; BUN 14.5 mg/dL; creatinine

0.39 mg/dL; serum total protein 3.6 g/dL; serum albumin 1.8 g/dL; total cholesterol 396 mg/dL;

24-hour urine protein 7.7 g/day; and the urinalysis showed no abnormal findings except

proteinuria. The C3, C4, CH50, C1q, rheumatoid factor, anti-neutrophil antibody, anti-dsDNA

antibody, anti-glomerular basement membrane antibody, and anti-neutrophil cytoplasmic

antibody were all normal. Hepatitis B and C virus antigens were negative, and antibody titer of

syphilis and mycoplasma were not specific. Immnological studies revealed: IgG 138 mg/dL

(normal range 700-1650 mg/dL); IgA < 5mg/dL (29-270 mg/dL); IgM 100 mg/dL (normal range

50-260 mg/dL); IgD < 0.41 (normal range <15.27 mg/dL); IgE 1.0 IU/mL (normal range 1.4-155

IU/mL). IgG subclass was markedly decreased. CD 56+ T cells were mildly decreased,

however, other T cell counts showed normal range of subsets. Abdominal sonography and

DMSA scan were non-specific. A diagnosis of nephrotic syndrome and hypogammaglobulinemia

was made and oral steroid (60 mg/m2/day) was started. Renal biopsy showed diffusely

11

thickened glomerular capillary wall with subepithelial fuchsinophilic deposits and short 'spikes'

on silver stain suggesting MN (Stage II). IgG, C3, C4, C1q, Kappa and Lambda deposits were

found on immunofluorescence. Methylprednisolone pulse therapy was administered from the

15th hospital day because hypoalbuminemia and severe proteinuria (5 g/day) were persisted.

After 7 pulses heavy proteinuria persisted (5.6 g/day), therefore, cyclosporine (5mg/kg/day) was

added. Chest CT showed bronchiectasis with coexisting pneumonia and atelectasis. The

cultures of fungus, mycobacterium tuberculosis and pneumocystis carinii were all negative. On

the 29th hospital day, intravenous immunoglobulin was administered due to persistent

hypogammaglobulinemia and pneumonia. IgG was increased to lower normal value (716

mg/dL). IgM was normal (109 mg/dL). IgA deficiency was unchanged (< 5mg/dL). On the 39th

hospital day, he was discharged with decreased proteinuria (825 mg/day). However, he had a

recurrence of pneumonia 1 month later and proteinuria increased (spot urine protein to

creatinine ratio 5.3). Six months later after discharge, IgA deficiency maintained (< 5mg/dL), IgG

was lower normal (789 mg/dL), and IgM was normal (133 mg/dL). IgG4 subclass and IgE

deficiency also continued. He continues to take alternative-day deflazacort, cyclosporine,

enalapril and prophylactic antibiotics during the 6-month follow up and heavy proteinuria has

persisted (spot urine protein to creatinine ratio 4.7).

Points of Discussion:

1. Which type of hypogammaglobulinemia does the patient have?

2. What is the association of hypogammaglobulinemia and MN?

3. Is the immunoglobulin replacement therapy useful for him? What is the most appropriate

treatment for him?

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Case O-3

The pathogenesis and clinical manifestations of in a patient with Juvenile

nephronophthisis

Daishi Hirano1, Amane Endo1, Hitohiko Murakami2, Motoshi Hattori3, Shuichiro Fujinaga1

Division of Nephrology, Saitama Children’s Medical Center1

Division of Pathology, Saitama Children’s Medical Center2

Division of Nephrology, Tokyo Women`s Medical University Hospital3

Juvenile nephronophthisis (NPHP1) is caused by mutations of the NPHP1 gene. The NPHP1

gene encodes for nephrocystin-1, which is located at the cell-cell junction and the cell-matrix

interface. Although it is uncertain exactly how the defects in the various NPHP genes lead to

renal disease, it is thought that mutations in the NPHP1 gene alter cilia function via defects in

intracellular signaling pathways, resulting in the inability of the ciliary mechanosensors to

correctly sense luminal flow rates. The inability of renal tubular cells to perceive luminal fluid

flow due to dysfunctional ciliary function results in dysregulated tissue growth and subsequent

development of renal cysts.

We report on a patient with Juvenile nephronophthisis with a large deletion in the NPHP1 gene

associated with the absence of expression of nephrocystin in the renal biopsy specimen.

Case report:

A-14-year old girl was admitted to our hospital because of anemia and renal insufficiency. On

admission the blood pressure was 100/70 mmHg. She weighted 38.9kg (-1.7SD). The

hemoglobin was 7.5 g/dl, blood urea nitrogen 89 mg/dl, creatinine 6.81 mg/dl. Urinalysis showed

hyposthenuria and proteinuria. An abdominal echogram showed slightly small kidneys in size

with cortical increased echogenecity. Based on these findings, the diagnosis of chronic renal

failure was made and peritoneal dialysis was indicated.

Renal biopsy specimens contained 22 glomeruli with 17 glomeruli showing global sclerosis. The

interstitial architecture was markedly destroyed with severe interstitial fibrosis and moderate

round cell infiltration. Irregular thickening of tubular basement membrane and tubular atrophy

with cyst development were observed. In addition, immune-staining was performed using anti-

nephrocystin antibody. Expression of nephrocystin in renal tubule was not found in the patient.

We performed molecular analysis of the NPHP1 gene, and found a large deletion in the NPHP1

gene.

13

Case O-4

Rhabdomyolysis with ARF and severe hypothermia in a 15-year-old obese boy

Se Jin Park, Jae Il Shin, Ji Hong Kim, Jae Seung Lee

The Institute of Kidney Disease, Department of Pediatrics, Yonsei Univ College of Medicine

We report the case of a 15-year-old obese boy who presented with thigh pain and gait

disturbance due to rhabdomyolysis. Both thigh pain and gait disturbance occurred about 4 days

before he visited our emergency room and were aggravated. There was no history of strenuous

exercise and trauma, but ganglioneuroma was previously removed by surgery at other hospital

in 2008. Laboratory findings showed that serum Na 198 mmol/L, K 3.3 mmol/L, Cl 152 mmol/L,

tCO2 27 mmol/L, BUN 52 mg/dL, and creatinine 1.6 mg/dL. Muscle enzymes were elevated

(creatine kinase 30,800 IU/L and LDH 1,833 IU/L). He also showed intermittent mild hypoxemia

(O2 saturation 85%) and hypercapnea (pCO2 69.6 mmHg) due to hypoventilation. Intermittent

fever, bradycardia (heart rate <50/min) and some endocrinologic abnormalities (Prolactin 35.84

ng/mL, T3 75.11 ng/dL, fT4 0.53 ng/dL) were observed. Rhabdomyolysis and acute renal failure

resolved gradually with fluid and conservative therapy without dialysis.

One year later, he came to emergency room due to severe hypothermia and bradycardia (HR

30/min). Heating the patient did not normalize the body temperature, but administration of

intravenous immunoglobulin (IVIG) rapidly resulted in the recovery of body temperature and

bradycardia.

We suspected a rare, but recently known ROHHADNET syndrome (rapid-onset obesity with

hypoventilation, hypothalamic, autonomic dysregulation and neural tumor) for diagnosis with the

evidence of obesity, previous ganglioneuroma, hypothermia and endocrinological abnormalities.

Our patient is the first case in the world, to the best of our knowledge, who had Rhabdomyolysis

in ROHHADNET syndrome and successful treatment with IVIG that improved severe

hypothermia and bradycardia.

In conclusion, this very rare syndrome should be included as one of the differential diagnosis of

Rhabdomyolysis and the good response to the IVIG may suggest the autoimmune nature of this

syndrome.

Points of discussion:

1. Can rhabdomyolysis be one of the manifestations in ROHHADNET syndrome?

2. What is the cause of this syndrome? Is it an autoimmune process?

3. Can genetic study be possible for earlier recognition, guidelines of appropriate treatment &

better characterization of the molecular origin on this syndrome?

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Case O-5

The regulatory mechanism of TRPC6 activation by FSGS-causing mutations

Shoichiro Kanda1,2, Yutaka Harita1,2,5, Takashi Sekine2,6, Yoshio Shibagaki3, Takashi

Igarashi2, Takafumi Inoue4, Seisuke Hattori1,3

Division of Cellular Proteomics (BML), Institute of Medical Science, Tokyo1

Department of Pediatrics, University of Tokyo, Tokyo2

Dept of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo3.

Dept of Life Sci and Med Bioscience, Faculty of Science and Engineering, Waseda Univ, Tokyo4

Dept of Molecular Biology, Yokohama City Univ, Graduate School of Med Science, Kanagawa5

Department of Pediatrics, Toho University6

In kidney, blood is filtered through glomeruli forming primitive urine. Recent studies revealed

that the intercellular junction between the glomerular epithelial cells, called slit diaphragm (SD),

is the molecular constituents of this glomerular filter, and that the major component of SD is an

SD-specific transmembrane protein, nephrin. Recently mutations of a SD component, TRPC6,

have been reported to cause FSGS (Winn M, et al. Science, 2005). However, the mechanism

how the channel activity of TRPC6 is involved in the pathogenesis remains unclear, because

some mutations in TRPC6 enhance its activity, while others do not (Reiser J, et al. Nat. Genet,

2005). Meanwhile there are accumulating lines of evidence that SD serves as a platform

conducting phosphorylation-mediated signals and that TRPC6 is also known to be regulated by

its tyrosine phosphorylation (Hisatsune, et al, J Biol. Chem, 2004).

During the investigation of the role of the phosphorylation of SD components, we found that

nephrin binds to phosphorylated TRPC6. The phosphorylation of the tyrosine residue critical for

this interaction was also essential for the insertion of TRPC6 in the plasma membrane. The

same tyrosine residue was one of the PLC-γ1 binding sites, and PLC-γ1 was necessary for the

phosphorylation-dependent membrane traffic of TPRC6. Coexpression of nephrin in cultured

cells disturbed the TRPC6-PLC-γ1 interaction and interfered the surface expression and the

channel activation of TRPC6. These results indicate that nephrin blocked the TRPC6-PLC-γ1

interaction, and suppressed the phosphorylation-dependent surface expression and channel

activation of TRPC6. Interestingly, FSGS-causing mutations dramatically weaken the nephrin-

TRPC6 interaction, resulting in exaggerated membrane expression and Ca2+ channel activity of

TRPC6 in living cells. Collectively, our results correlate the FSGS mutations with dysregulated

TRPC6 activity, which may underlie the pathogenesis of the disease.

15

These data not only propose a model by which TRPC6 mutations cause podocyte injury, but

also may indicate the possibility that down regulation of nephrin observed in most proteinuric

states may cause dysregulation of calcium homeostasis. Furthermore, our result that nephrin

blocks TRPC6 activation may provide a novel strategy of treatment for injured podocytes in

future.

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Case O-6

A case of systemic amyloidosis associated with cyclic neutropenia

Hyun Kyung Lee, Kyoung Hee Han, Yun Hye Jung, Hee Gyoung Kang, Il Soo Ha, Hae Il Cheong, Yong Choi*

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea

Department of Pediatrics, HaeUnDae Paik Hospital, Inje University, Busan, Korea*

Cyclic neutropenia is a rare disease characterized by regular cyclic fluctuation in the numbers of

neutrophils. Patients with this disease suffer from recurrent infections at a regular interval of

nearly three weeks. Although cyclic neutropenia is benign in general, few patients develop

reactive amyloidosis due to recurrent infections.

In summer 2007, a 14-year-old girl visited a hospital because of a huge palpable goiter and she

was diagnosed with chronic thyroiditis by a thyroid function test and fine needle aspiration

biopsy. Then, she was followed up without medication, In Aug. 2008, she was admitted to the

hospital due to colitis. At that time, her thyroid function test revealed hyperthyroidism and she

began to take propylthiouracil. On Oct. 22, 2008, she was transferred to another hospital due to

neutropenia (WBC 2,900 and absolute neutrophil count 800). Propylthiouracil was discontinued.

On Dec. 18, 2008, synthyroid medication was started to reduce huge goiter. On Dec. 29, 2008,

she developed mesenteric lymphadenitis with recurrent neutropenia. At that time, proteinuria

(1+ ~2+ by dipstick) was detected incidentally. Other lab findings were as follows; serum

protein/albumin 7.8/2.9 g/dL, 24 hour urine protein 0.96 g/day, C3/C4 85.8/22.8 mg/dL,

BUN/creatinine 10.4/1.2 mg/dL, ANA (1+, speckled pattern) and anti-ds DNA (-). On Feb. 24,

2009, she was transferred to our hospital due to azotemia (BUN/creatinine 39.7/1.6 mg/dL)

On admission, Her height and weight were 154 cm (10-25 percentile) and 36.5 kg (<3

percentile). She has diffuse fixed hard huge goiters on physical examination. Her initial lab

findings showed neutropenia (WBC 2.48x10x1033/uL, /uL, ANC 62), azotemia (BUN/creatinine 10.4/1.2

mg/dL), proteinuria (1+ by dipstick, protein/creatinine 0.69), euthyoid thyroid function (T3 132

ng/dL, Free T4 1.46 ng/dL, TSH 3.67 uIU/ml), negative autoimmune titer (C3/C4 110/25 mg/dL,

Anti ds-DNA (-), RF (-), ANA (-), ANCA (-), RNP (-), jo-1 (-), SSA-Ro/La (-/-)). Bone marrow,

thyroid and renal biopsies were done to rule out malignancy or autoimmune disease. However,

the results of biopsies showed maturation arrest of myeloid cells, renal and thyroid amyloidosis.

Echocardiographic findings also suspected cardiac dysfunction and myocardial wall thickening

with whitish deposition of amyloid fibrils. We checked serum protein- and immuno-

17

electrophoresis, serum amyloid A, tuberculosis infection evidence for distinction between

amyloid AA or AL. Serum protein- and immuno-electrophoresis didn't suggest monoclonal

gammopathy. Serum amyloid A level was 601.8 ug/mL. Mantoux test and chest PA were

negative. In addition, retrospective review of her clinical courses revealed that she had a cyclic

pattern of recurrent infections with neutropenia at the regular intervals of nearly three weeks.

Thus, we concluded she has systemic amyloidosis AA associated with cyclic neutropenia. The

ELA2 gene (encoding neutrophil elastase 2) analysis revealed a de novo heterozygous c.597+5

G>A mutation (IVS4+5 G>A). Recombinant human granulocyte colony-stimulating factor (rhG-

CSF) is an usual effective treatment for congenital neutropenia. However, she has not

responded to rhG-CSF effectively and her cardiac and renal functions are gradually going down.

Therefore, now, we are planning a stem cell transplantation for her cyclic neutropenia.

18

Case O-7

Rapid deterioration of renal function owing to thrombotic microangiopathy in a boy with

systemic lupus erythematosus and antiphospholipid syndrome

Shunsuke Noda1, Koichi Kamei1, Akiko Tsutsumi1, Tomohiro Udagawa1, Masao Ogura1,

Nakagawa Satoshi2, Kentaro Matsuoka3, Itou Shuichi1

Department Nephrology and Rheumatology1, Department of Intensive Care2 and

Department of Pathology3, National Center for Child Health and Development

Introduction: Antiphospholipid antibody syndrome (APS) is a rare clinical condition in children.

In children, APS mainly occurs as secondary APS complicated with SLE. In fact, 20% of

childhood SLE patients are positive for lupus anticoagulant or β2GPI-dependent anti-cardiolipin

antibodies (aCA), but few such patients suffer from thrombosis. We encountered a boy with SLE

and APS who presented with rapid deterioration of renal function owing to thrombotic

microangiopathy (TMA). He was positive for not only aCA and lupus anticoagulant but also anti-

phosphatidylserine-prothrombin complex antibodies (aPS/PT).

Case report: A 9-year-old boy with SLE was transferred to our hospital because of acute renal

and cardiac failure. He was diagnosed based on fever, butterfly-shaped erythema,

pancytopenia, low serum complement, serum anti-dsDNA antibodies (273 IU/ml) and anti-

nuclear antibodies. At onset, renal function was already impaired (Cr, 1.16 mg/dl; BUN, 85

mg/dl). APTT was prolonged (85 s) and aCA (21.6 U/ml) were positive. He was initially treated

with two courses of methylprednisolone pulse therapy (MPT). However, his renal function

started to deteriorate, and he developed oliguria, dyspnea and hypertension. Cardiac ultrasound

revealed a poor left ventricular ejection fraction (43%). His consciousness level was alert. Brain

SPECT and MRI were normal. Laboratory tests on admission were: Hb, 10.5 g/dl; plt, 7.0×104

/μl; BUN, 92 mg/dl; Cr, 2.2 mg/dl. Poikilocytes were detected in the peripheral blood. He was

suspected of complication with TMA or APS. Plasma exchange, continuous hemodialysis, MPT

and intravenous cyclophosphamide successfully ameliorated the cardiac and renal failure. A

renal biopsy at 6 days after admission showed multiple microvascular thrombi, diffuse

mesangiolysis, ruptured glomeruli and cortical necrosis compatible with TMA. ISN/RPS grading

for lupus nephritis was impossible because of severe mesangiolysis. Subsequently, aPS/PT

(>50 U/ml; normal, >2 U/ml) positivity, anti-ADAMTS13 antibody negativity and normal von

Willebrand factor activity were revealed. These findings indicated that the TMA may be caused

by APS. A second biopsy revealed collapsing glomeruli (40%), diffuse interstitial fibrosis and

19

infiltration. His present treatment is 6 mg of prednisolone daily, 400 mg of mycophenolate

mofetil and 2 mg of candesartan. The SLE and APS disease activities are completely

suppressed, but serum Cr remains elevated (1.2 mg/dl).

Discussion: In general, the renal complications of APS are renovascular thrombosis or APS

nephropathy. However, our patient clinically and pathologically developed TMA. TMA is rare in

APS. Interestingly, our patient was aPS/PT-positive. Recent investigations revealed severe

pathogenicity of aPS/PT, which induce a hypercoagulable status and cause recurrent fetal loss

or thrombosis in multiple organs. In a previous report, two adult patients with SLE and APS with

high aPS/PT titers developed TMA. Our report describes the first pediatric patient with TMA

caused by aPS/PT. Not only anti-ADAMTS13 antibodies but also aPS/PT can be pathogenic

autoantibodies causing TMA. Further investigations of aPS/PT are required.

20

Case O-8

Renal amyloidosis in a child with non-cystic fibrosis related bronchiectasis

Eun Ae Yang, Dong Won Lee, Myung Chul Hyun, Cheol Woo Ko, Min Hyun Cho

Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea

A 10-year-old girl was referred to our hospital for evaluation of abnormal infiltration of both lung

fields visible on a chest X-ray performed as one of the preoperative evaluations. On past

medical history, she had recurrent sinusitis and bronchiolitis from infancy and was diagnosed

with nasal polyp and surgical removal was decided. Several evaluations of the causes of this

abnormal infiltration were performed, especially for tuberculosis, but AFB stain, PCR and culture

of sputum and urine were all negative and a Mantoux test was also negative. So, she was

diagnosed with simple infectious bronchiolitis with bronchitis. When she was 13-years-old, she

was readmitted with severe pneumonia and respiratory failure. A CT scan showed multifocal

bronchiectasis and extensive bronchiolitis. She was supported by mechanical ventilation for

nearly one month and by the parenteral treatment of antibiotics for pseudomonas infection

proven by culture of sputum. The laboratory findings of this girl were as follows: pH 7.37 and

pCO2 35 mmHg on arterial blood gas analysis, white blood cell count 22,860/mm3, hemoglobin

9.3 g/dL, platelet count 757,000/mm3, erythrocyte sedimentation rate 83 mm/hour, C-reactive

protein 11.18 mg/dL, blood urea nitrogen 4.4 mg/dL, serum creatinine 0.42 mg/dL, total protein

4.8 g/dL, and albumin 1.8 g/dL. Cold agglutinin and antibody to mycoplasma were negative.

Urinalysis showed protein (++), occult blood (+) and urine protein during 24 hours was 2,090

mg/m2. Immunologic studies showed normal levels of Ig G, A, M, and α1-antitrypsin except for a

mild elevation of IgE. To elucidate the cause of bronchiectasis, several additional tests including

a sweat test and biopsy of nasal mucosa were performed. Six months later after an

improvement of her respiratory condition, an USG-guided renal biopsy was performed to reveal

the cause of proteinuria. On LM, there were many segmental homogeneous deposits of amyloid

with positive Congo red staining in the glomeruli. Immunohistochemistry revealed positive

staining of the AA amyloid and EM showed relatively straight, non-branching, randomly

arranged amyloid fibrils in the mesangium of the glomeruli and these fibrils were approximately

10 nm in diameter. At that time, serum amyloid A was remarkably elevated (62.0 mg/L, normal

range: <8.0 mg/L).

Point of discussion:

1. Is bronchiectasis the major cause of renal amyloidosis in this child?

21

2. If YES, what is the most possible mechanism of renal amyloidosis originated from

bronchiectasis?

3. What is the optimal treatment for renal amyloidosis?

22

Case P-1

A case of IgM nephropathy diagnosed with frequently relapsing of steroid dependent

nephrotic syndrome

Mika Nishimura, Shinya Yato, Kohei Maekawa, Junko Sawaki, Chiaki Takahashi,

Hiromu Mae, Masuji Hattori, Takakuni Tanizawa

Department of Pediatric, Hyogo College of Medicine

Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis with mesangial

deposition of IgM. IgM nephropathy is characterized by proteinuria, especially nephrotic

syndrome. It is frequently dependent or resistant to steroid therapy and some cases develop to

renal insufficiency.

We report a case of 10 year old girl diagnosed IgM nephropathy after frequent relapses of

nephrotic syndrome. Proteinuria was initially detected by a routine school urinalysis. Proteinuria

was 0.3 g/day which is less than 3.5 g. On a blood examination, serum total protein was 5.8g/dl

and albumin was 2.8g/dl, but edema wasn’t seen on physical examination. Although these

further examination doesn’t meet the diagnosis criteria of nephrotic syndrome, dipyridamole is

started for persistent proteinuria.We diagnosed nephrotic syndrome from laboratory data and

the clinical course during a follow up period.

The patient reached complete remission of proteinuria after an initial eight-week course of

corticosteroid therapy. However, twice relapses occured within six months and it led to steroid

dependent nephrotic syndrome. In addition, steroid therapy caused short stature (-2.1SD),

moon-face and elevated intraocular pressure.

A renal biopsy showed 11 glomeruli. Light microscopy indicates mild mesangial hypercellularity

and extracellular matrix accumulation without sclerosis. Immunofluorescent microscopy shows

deposition of IgM in a mesangial pattern. Electron dense deposits in the mesangial regions were

observed by electron microscopy.The diagnosis of IgM nephropathy was made from these

pathological findings.

Additional treatment with oral cyclosporine was effective and the patient remained in remission

now although we are reducing a dosage of steroid.

IgM nephropathy has to be considered when we encounter steroid dependent or resistant

nephrotic patients for its unfavorable prognosis. Extensive studies are necessary to confirm

proposed IgM nephropathy.

23

Case P-2

Children who developed renal failure after oseltamivir treatment

Joo Hoon Lee, Yoon Jung Lee, Yong Mee Cho, Young Seo Park

Department of Pediatrics, Asan Medical Center

Introduction: In April 2009, a novel influenza A (H1N1) virus was identified in Mexico and has

since spread rapidly worldwide. As a consequence, a surge of pediatric patients has been

presenting to emergency departments and physician's offices across the country during this

2009-2010 flu season and many of them were treated with oseltamivir. We report 2 cases that

were treated with oseltamivir due to H1N1 infection or flu-like symptoms and developed

azotemia.

Case 1: A sixteen-year-old girl was admitted on November 2, 2009 due to headache which

developed 2 months ago and aggravated since one day ago. She had cough since 2 weeks ago

and had been treated with oseltamivir for four days due to positive result of H1N1 PCR study at

local out-patient clinic. Blood pressure was 178/128 mmHg. Laboratory findings were as follows:

Hb 9.5 g/dL, WBC 8,100/mm3, Platelet 113K/mm3, BUN/Cr 42/4.2 mg/dL, IgG/A/M: normal,

C3/C4/CH50: normal, HBsAg/Ab all negative, HCV Ab negative, rennin 13.9 ng/mL/hr,

aldosterone 446 pg/mL, Urine albumin 2+, RBC 3-5/HPF, 24hr urine protein 1173 mg/day, H1N1

real time RT-PCR negative in respiratory and urine sample/positive in CSF sample. Brain MRI

revealed ill-defined T2 and FLAIR change in both cerebellar hemisphere, periventricular white

matter and pons. Renal Doppler showed asymmetric kidney and renal artery (right kindey and

renal artery were smaller than that of left). Hypertension was treated with diuretics, calcium

channel blocker and angiotensin converting enzyme inhibitor. Serum creatinine increased up to

5.1 mg/dL but slowly decreased thereafter. Urine output was well preserved. On December 1

2009, kidney biopsy was performed due to persistent azotemia (Cr 2.3 mg/dL) and proteinuria,

and results were as follows: 1. Focal mesangial proliferative glomerulonephritis with diffuse

mesangial Ig A deposit consistent with IgA nephropathy (HAAS classification III), focal and

global glomerular sclerosis, focal segmental glomerulosclerosis, 2. Moderate interstitial

inflammation and severe fibrosis, moderate tubular atrophy, and moderate arterial intimal

fibrosis, which strongly suggestive of chronic tubulointerstitial nephritis. Biopsy specimen H1N1

PCR was negative. Deflazacort was added and her creatinine was maintained around 2.3

mg/dL and urine albumin 1+ on follow-up.

24

Case 2: A thirteen-year-old boy was admitted due to azotemia on November 24, 2009. He had

fever one week ago and was treated with oseltamivir. The serology test for H1N1 was negative.

He developed nausea and back pain six days ago and vomiting accompanied since two days

ago. Abdomen CT was performed at local clinic and revealed swollen both kidneys with delayed

renal perfusion. Serum BUN/Cr was checked which was 28/2.6 mg/dL. On admission, blood

pressure was 135/91 mmHg. Laboratory findings were as follows: Hb 12.5 g/dL, WBC

11,100/mm3, PLT 216 K/mm3, BUN/Cr 24/3.5 mg/dL, Urine analysis was normal. He had no

treatment and the creatinine level slowly declined without other symptoms. Serum creatinine

was 0.7 mg/dL on last follow-up (January 28, 2010).

Conclusion: We report 2 cases that had renal failure after treatment with oseltamivir. The

relationship between azotemia and oseltamivir is not conclusive yeat, and further recruitment of

cases are needed.

25

Case P-3

Type-1 diabetes revealed with steroid therapy at onset of nephrotic syndrome

Rika Fujimaru, Hiroshi Yamada

Department of Pediatrics, Osaka City General Hospital, Osaka, Japan

Objective: Simultaneous occurrence of nephrotic syndrome (NS) and type-1 diabetes is rare.

We here report a case of type-1 diabetes revealed with steroid therapy at the onset of NS and

discuss problems in its clinical management.

Case Report: A seven-year-old boy visited our hospital because of severe proteinuia. He has a

past history of surgical treatment for right vesicoureteric reflux at the age of 11 months. His

family history includes a grandfather with type-2 diabetes. Physical examinations revealed no

obesity, normal blood pressure and mild edema. Laboratory examinations showed normal renal

function, hypoalbuminemia (2.6 g/dl) and proteinuria (3.5g/day) without glycosuria and

hematuria. Ultrasound examinations showed a small right kidney and DMSA scintigraphy

demonstrated an uptake defect in the superior pole of the left kidney. He was started on

angiotensin-converting enzyme inhibitor (ACEI). One month later, renal biopsy was performed

because of persisting proteinuria. Diagnosis of minimal change disease was made and full-dose

prednisolone (PSL) was started with ACEI. Complete remission was attained at the 6th day,

when he developed hyperglycaemia (647mg/dl) and glycosuria. Anti-GAD antibodies were

negative. Steroid-induced diabetes (SDM) was suspected. Insulin therapy was started and PSL

was tapered and discontinued. Although hyperglycemia was resolved, NS recurred in about 2

weeks. Attempting to avoid PSL, his relapsed NS was treated with Mizoribine (MZR). But the

treatment failed, thus PSL (2mg/kg/day) was resumed, which was followed by a recurrence of

hyperglycaemia the next day. This time his diabetes was managed by daily doses of insulin and

it was maintained until PSL was discontinued. Two months later, however, hyperglycaemia

recurred with flu while NS was in remission. Ani-IA-2 antibodies were positive, which strongly

suggested the diagnosis of type-1 diabetes. He was put on the insulin therapy. Currently, he

remains in remission of NS with MZR and ACEI alone and is receiving insulin.

Conclusions: The present paper describes the case of a boy with slowly progressive type-1

diabetes which seemed to start at the onset of NS. Though simultaneous occurrence of these

two states is very rare, one should always consider the possibility of type-1 diabetes even if

SDM is the first suspect as in the present case. Rapid tapering of steroids and commencement

of insulin therapy are the essential choice. To maintain remission of NS, immunosuppressants

may be needed.

26

Case P-4

Tacrolimus-induced encephalopathy in post-kidney transplantation

Kim Myoung Uk, Sae Yoon Kim, Jung Youn Choi, Yong Hoon Park

Department of Pediatrics, Yeungnam University, College of Medicine, Daegu, Korea

An 11-year old girl with renal hypoplasia was born premature at 32 weeks gestation with

neonatal sepsis, urinary tract infection, renal failure and atrial septal defect. She has been ill

with chronic renal insufficiency and failure since then. She received a preemptive living-related

donor kidney(donor: mother).

Our immunosuppression protocol has consisted of tacrolimus (0.1 mg/kg/dose, bid),

mycophenolate mofetil, and prednisolone. Postoperatively, her renal function was good without

acute rejection episode except mild hypertension required treatment with a long-acting calcium

channel blocker. On D12, blood pressure was elevated at 160/100 mmHg. She complained of

nausea, headache, drowsy mentality, and urinary incontinence, and developed a left-side

hemiparesis. Labetalol was injected intravenously with larger dosage of calcium channel

blocker. Her serum tacrolimus level was 9 ng/mL. Tacrolimus was discontinued and replaced by

cyclosporin. Serum electrolytes, glucose, liver enzymes, calcium, phosphate, albumin,

magnesium, and acid-base status were normal. The creatinine was 0.69 mg/dL.

Electrocardiogram was unremarkable with normal sinus rhythm. Brain MRI revealed a high-

signal intensity at right frontal lobe affecting mainly white matter in T2-weighted images,

suggesting ischemic infarction. MR angiography showed stenosis of both anterior and middle

cerebral artery and miminal stenosis at both posterior cerebral artery. Electroencephalogram

showed background rhythm 8 Hz alpha activity with intermixed 3-4 Hz slow wave on left

occipital region with no epileptiform discharge. Three days later, she had normal mentality and

maintained normal blood pressure with left hemiparesis. Follow-up MRI was performed on D19

and showed new lesions of high signal intensity on T2 FLAIR and diffusion-weighted images,

and low signal intensity on ADC in both cerebral hemispheres with improved cerebral artery

stenosis. Ten days later, MRI showed further improvement, but brain SPECT showed mild

reduction of uptake in both anterior cingulate gyrus and left thalamus. One month after onset of

symptoms, angiography showed complete resolution of stenosis. However, presenting as a mild

fine motor disability of both hands and mild dysarthria, atrophy at both centrum semiovale at 4

months showed progression to encephalomalacia. There were no further episodes during

follow-up.

We report a case of tacrolimus-induced encephalopathy during tacrolimus therapy after renal

transplantation.

27

Case P-5

High-dose candesartan and erythropoietin combination therapy in diabetic nephropathy

with nephrotic syndrome

Hiroshi Saito, Ayako Yoshida, Junichi Suzuki, Ishige Wada, Tatsuhiko Urakami,

Shori Takahashi

Department of Pediatrics, Nihon University

Background: Three patients with diabetic nephropathy with nephrotic syndrome due to

juvenile-onset type 1 diabetes mellitus were treated with a high-dose angiotensin II receptor

blocker (ARB) and erythropoietin (EPO) combination therapy, which resulted in the remission of

nephrotic syndrome and long-term suppression of renal impairment.

Patients: Patients are 37~40-year-old female who developed type 1 diabetes mellitus at the

age of 12~17. They developed nephrotic syndrome at the age of 29~33 and renal histology

revealed diffuse global glomerulosclerosis consistent with diabetic nephropathy. Their eGFR

were 24.3~60.0 ml/min. All 3 patients received candesartan at a dose gradually increased up to

11~16 mg/day with concomitant erythropoietin (EPO) for their renal anemia. They achieved

remission of nephrotic syndrome 5 to 27 months after the escalation of candesartan dosage,

and the progression of renal impairment was retarded in two patients. Since subsequent

reduction of candesartan dose in one patient resulted in a relapse of nephrotic syndrome, she is

currently undergoing an escalated dose of candesartan again.

Discussion: All 3 patients were at risk for early transition to end-stage renal disease. Dose

escalation of ARB up to double the maximum dose for patients with renal insufficiency with

careful monitoring of changes in serum electrolyte and renal clearance function aimed at

elimination of proteinuria resulted in remission of nephrotic syndrome and suppressed

progression of renal impairment. ARB itself has a potential to enhance a renal anemia.

Therefore we combined EPO together with ARB as prevention of renal anemia. On the other

hand, EPO has recently been known as a potent renal protective agent, so it is possible to

suppress the progression of renal impairment with the additional effect.

Conclusion: The high-dose ARB/EPO combination therapy has the potential to serve as an

effective treatment strategy for Stage IV diabetic nephropathy.

28

Case P-6

Chronic kidney disease due to bilateral cystic kidneys

Min Sun Kim1, Dae-Yeol Lee1, Mung Jae Kang2

Department of Pediatrics1 and Pathology2, Chonbuk Nat’l Univ Medical School, Jeonju, Korea

Background: Chronic kidney disease (CKD) in children younger than 5 years is most

commonly a result from congenital abnormalities such as renal hypoplasia, dysplasia and/or

obstructive uropathy. In addition, polycystic kidney disease(PKD) is  one cause of CDK.   Both

kidneys in polycystic disease are markedly enlarged, and multicystic dysplastic kidney (MCDK)

presents by ultrasonography as a large cystic nonreniform mass. The MCDK is nonfunctional

and usually unilateral. If bilateral, it is fatal. We report a patient with chronic kidney disease due

to bilateral cystic kidneys.

Case: A 4-year-old girl was referred to our hospital due to short stature. Her height and body

weight were 89.2 cm (<3 percentile)  and 11.0 kg (<3 percentile). She had no dysmorphic

feature and no family history of renal disease. Initial laboratory findings ware as follows; serum

urea nitrogen 37 mg/dL, creatinine 2.25 mg/dL, alkaline phosphatase 1693 IU/L, total protein 6.6

g/dL, albumin 4.6 g/dL, AST 38 IU/L, ALT 18 IU/L, total calcium 9.5 mg/dL, phosphorus 4.2

mg/dL. Urinalysis did not show proteinuria and hematuria. Ultrasound and CT of the kidney

demonstrated that right kidney has multiple variable sized cysts with increased the length and

parenchymal echogenicity, and left kidney has multiple small cysts with atrophic change (right

8.5, left 2.1 cm). Renal biopsy, which was performed on right kidney 5 years later, revealed one

normal glomerulus with mild interstitial fibrosis and tubular atrophy. However, any cystic lesion

and dysplasia were not observed. Ultrastructural examination disclosed focal foot process

effacement without any electron dense deposit. When she was 5-year-old, growth hormone

therapy with oral calcium and vitamin D supplement was started.

Points of discussion:

1. What is the cause of chronic kidney disease in this patient?

2. Do both kidneys have a same disease or two different diseases?

3. Is a gene study helpful to confirm the diagnosis?

29

Case P-7

Renal pathology with normal urinalysis in Fabry disease

Takahiro kanai1, Takane Ito1, Jyun Odaka1, Takashi Saito1, Jyun Aoyagi1,

Masahisa Kobayashi2, Toya Ohashi3, Mariko Y Momoi1

Department of Pediatrics, Jichi Medical University1

Department of Pediatrics, The Jikei University School of Mediceine2

Dept of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine3

Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme

α–galactosidase A. Glycosphigolipids, predominantly globotriaosylceramide (GL-3),

progressively accumulate in vascular endothelial cells, which results in multi-organ failure.

Nephropathy is a dominant complication of Fabry disease, and with up to half of the patients

developing end-stage renal failure by their 50s. The large individual variation and often

progressive nature of these changes raises questions concerning the appropriate timing of the

initiation of enzyme replacement therapy (ERT). However, recent data showed a limited effect of

ERT on progressive organ damage when treatment was initiated at a late stage.

We present here a case with normal urinalysis but with pathological renal damage in Fabry

disease.

Case: A 13-year-old boy was consulted our hospital for burning soles and palms which had kept

for 3 years. His mother and grandfather had also same symptom. His grandfather died of heart

failure, and they had not received a diagnosis of Fabry disease. Blood test revealed extreme

low activity of α–galactosidase A (0.1 nmol/mg protein/h; reference level, 50-110 nmol/mg

protein/h), and elevated serum GL-3 level (8.3 μg/mL; reference level, less than 7.0 μg/mL). His

serum creatinine level was 0.48 mg/dL, and urinalysis revealed negative proteinuria and

hematuria. Urinary β2-microgloblin level was 544.0 μg/L. He did not present any other signs and

symptoms of Fabry disease (hypohidrosis, gastrointestinal disturbances, thermal sensation loss,

angiokeratomas, and corneal opacities). Echocardiography and magnetic resonance imaging of

brain demonstrated normal function and structue. After informed consent, which approved by

the ethics committee of Jichi Medical University, we performed renal biopsy for renal damage

assessment. Twenty six glomeruli were observed. It demonstrated diffuse vacuolated podocytes

and tubular cells by light microscopy, and showed segmental focal foot processes effacement

and whorled zebra body in glomerular visceral epithelial cells by electron microscopy.

Agalsidase beta (1 mg/kg/dose div) was administrated every other week, which provided relief

30

from acroparesthesia. He has kept normal renal function and normal urinalysis for one year.

Conclusion: To our knowledge, this is the first report of renal pathology of classic Fabry patient

with only acroparesthesia.　Our case reveals two facts; in Fabry disease, normal urinalysis did

not promise normal renal tissue, and podocyte injury did not necessarily induced proteinuria.

Further studies are needed for establishing appropriate starting time of ERT in Fabry disease,

and understanding of podocyte function in anti-proteinuria.

31

Case P-8

A case of hypertension with renal artery stenosis detected by school health examination

Hyung Jung Kim, Jae Uk Bae, Byung Ok Kwak, Jae Sung Son, Kyo Sun Kim

Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Korea

Introduction: Renovascular hypertension (RVHT) is defined as systemic hypertension (HT)

result from renal arterial occlusion, and in classical definition, BP normalize when arterial

occlusion is relieved. But in practice, most cases of HT cannot normalize completely though

occlusion relieved. And it is important untreated RVHT aggravates preexisting HT or threatens

viability of poststenotic kidney that induces sodium retention with congestive heart failure. In this

case, 7-years-old boy detected HT incidentally by school health examination, and we detected

his left main renal artery stenosis with trifurcation. We applied balloon angioplasty and obtained

partial improvement of HT.

Case: A 7-years-old boy visited out-patient clinic because of high BP detected school health

examination, and he has intermittent headache and abdominal pain for 6months. At first time,

his BP was measured 137/93mmHg, and his grandmother had family history of HT and type 2

diabetes mellitus. We applied 24hrs ambulatory BP monitoring, and his BP was measured

197/125mmHg (systole 138~248mmHg, diastole 83~180mmHg) at day time (8AM~10PM),

160/91mmHg (systole 143~184mmHg, diastole 70-125mmHg) at night time(10PM~8AM). His

BP of both extremities was 180/130mmHg on right arm, 170/130mmHg on left arm,

160/120mmHg on right leg, 170/115mmHg on left leg. Laboratory findings revealed as follows:

renin activity: 3.58ng/ml/hr, aldosterone 66.8pg/ml, VMA 2.52mg/day, metanephrine 133ug/day,

normetanephrine 210ug/day, ACTH 16.9pg/mL, cortisol 13.79 ug/dL. Fundoscopic finding

shows minimally increased vascular tortuosity. Ultrasonography with doppler and enhanced

abdominal CT revealed left renal artery stenosis. We obtained angiography and confirmed left

renal artery stenosis with trifurcation (90% occlusion). We performed balloon angioplasty and

partial revascularization was done. His BP decreased to 130/90mmHg at resting time, and po

medication persists with enalapril and atenol.

Conclusion: In children, sometimes HT is detected by school health examination incidentally.

So it should be performed systematized health examination with screening methods. And these

children has secondary HT with underlying disease frequently, further evaluation must be

performed including 24hrs ambulatory BP monitoring. And it is clinically important that

appropriate treatment of HT prevents to progress renal injury and congestive heart failure, and

other hypertensive complications.

32

Case P-9

Early onset of nephrotic syndrome after cord blood stem cell transplantation

Ken-ichiro Miura, Takashi Sekine, Komei Ida, Hiroshi Terashima, Masaru Takamizawa,

Ayaka Furuya, Junko Takita, Katsuyoshi Koh, and Takashi Igarashi

Department of Pedatrics, University of Tokyo

Background: Nephrotic syndrome (NS) is a rare complication associated with hematopoietic

stem cell transplantation (HSCT). Previous reports implicate that it is associated with chronic

graft versus host disease (cGVHD) and invariably occurs later than 6 months after

transplantation (Tpl). We report the 6-year-old boy who presented with NS only 61 days after

cord blood stem cell Tpl was performed.

Patient: A 4-year-old boy was diagnosed as having T cell ALL. After remission was achieved,

allogenic bone marrow Tpl was performed. Six months later, a recurrence was noted in thymus,

and cord blood stem cell Tpl was performed after the second remission was achieved at the age

of 6. Tacrolimus and methotrexate were administered for GVHD prophylaxis. Acute GVHD

involving skin and gut was noted on day 13 and hemophagocytic syndrome developed on day

15 after Tpl. Steroid was started and engraftment was achieved on day 21. After tacrolimus was

switched from intravenous infusion to oral administration on day 30, pleural effusion without

lymphoblasts developed on day 52. U/A revealed trace proteinuria. On day 61, prominent

edema was noted and U/A revealed massive proteinuria (6.3 g/day) without hematuria. Serum

albumin level was 1.4 g/dl and total cholesterol level was 384 mg/dl. A diagnosis of NS was

made and steroid was reinstituted and complete remission was achieved in 3 weeks. Serum

cytokine analyses on day 52 revealed that interleukin (IL)-4, IL-6, and IL-8 levels were elevated

but interferon gamma, IL-12, and tumor necrosis factor alpha levels were within normal range.

Discussion: About 50 cases of NS associated with HSCT have been reported in relation to

cGVHD and withdrawal of immunosuppressive agents. Renal histology revealed membranous

nephropathy or minimal change disease in most cases. We described a patient with NS on day

61 after HSCT. Renal biopsy was not performed because it would not ethically be validated.

Pleural effusion was not caused by NS, but more likely by GVHD, because proteinuria was trace

when pleural effusion was evident. Although the classical definition of cGVHD includes onset of

later than 100 days after HSCT, dry skin and elevation of Th2 cytokines in the present patient

may suggest that NS and pleural effusion were associated with cGVHD. To our knowledge, this

is the earliest occurrence of NS after HSCT. Hematologists and nephrologists should be aware

of this condition even in early periods after HSCT.

33

Case P-10

Histologic changes of IgA nephropathy during long term follow-up

Beom Jin Lim1, Chang Min Moon2, Ji Sun Song3, Hyeon Joo Jeong1, Pyeong Kil Kim2

Department of Pathology, Yonsei University, College of Medicine1

Department of Pediatrics2 and Pathology3, Kwandong University, College of Medicine

Introduction: Renal biopsy is a mandatory procedure for the diagnosis of IgA nephropathy.

However, studies on histologic change after long term follow-up period are rare and we know

little about the natural course of IgA nephropathy in association with histologic change.

Methods: From our patients’ file, we retrieved 20 patients with IgA nephropathy, to whom renal

biopsies had been performed more than 2 times (3 times in 3 patients and 4 times in 1 patient)

for the initial diagnosis and follow-up after long term period. The initial and follow-up biopsies

were classified or scored by Haas classification and Oxford classification. The changes of these

parameters were compared with the evolution of hematuria and proteinuria.

Results: The patients were treated with angiotensin-converting enzyme inhibitors in

combination with angiotensin receptor blocker (in subclass II or above) and short-term

cyclosporine (in patients showing nephrotic syndrome). During follow-up, none of the patients

developed chronic renal failure. Mean period between initial and the last follow-up biopsies were

10.8 years (range; 5.2~16.6 years). Histologic improvement was observed in 4 cases by both

Haas and Oxford classification, and in another 3 cases by Haas classification only. Deterioration

of histologic parameters was observed in 2 cases by both Haas and Oxford classification. The

other 2 cases demonstrated deterioration only by Haas or Oxford classification, respectively.

These changes were not always in parallel with clinical parameters.

Conclusion: By the long term follow-up renal biopsies in IgA nephropathy, we discovered that

histologic changes cannot be completely predicted by clinical parameters or vice versa.

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Case O-11

3 cases of childhood onset asymptomatic systemic lupus erythematosus

Junko Sawaki, Mika Nishimura, Kouhei Maekawa, Chiaki Takahashi, Hiromu Mae,

Masuji Hattori, Takakuni Tanizawa

Department of Pediatrics, Hyogo College of Medicine, Hyogo, Japan

Introduction: Systemic lupus erythematosus (SLE) is a well known autoimmune disease in

which numerous autoantibodies are produced. It causes disorders in multiple organs. The

principal clinical manifestations are skin rashes, arthritis, fever and glomerulonephritis, but

hemolytic anemia, thrombocytopenia, and central nervous system involvement are also

common. Here we report of 3 pediatric patients with SLE. They lacked physical symptom, but

blood or urine findings. Their initial manifestations are thrombocytopenia or proteinuria, and

diagnosis were done with laboratory data.

Case Reports:

Case 1: A 10-years-old girl was transferred to our hospital due to thrombocytopenia (platelet

1.9x104/ul). On admission, diagnosis was idiopathic thrombocytopenic purpura (ITP), so steroid

therapy was started. But laboratory studies showed that antinuclear antibody (ANA) positive,

anti-dsDNA antibody positive, hypocomplementemia and lymphopenia. 6 months after she was

diagnosed as SLE, she had proteinuria. Renal biopsy showed ISN/RPS classification type II

lupus nephritis.

Case 2: A 8-years-old girl was transferred to our hospital due to thrombocytopenia (platelet

2.7x104/ul). On admission, she also was diagnosed as ITP and treated with steroid. Her

laboratory studies showed that ANA positive, anti-dsDNA antibody positive, anti-cardiolipin

antibody positive, hypocomplementemia. She had no urinary findings, and renal biopsy showed

type I upus nephritis.

Case 3: A 12 years-old-girl was transferred to our hospital due to nephritic syndrome. 6 months

before admission, asymptomatic proteinuria and hematuria was pointed out by school urinary

screening system. Laboratory studies showed that proteinuria (3g/day), hematuria, ANA

positive, anti-dsDNA antibody and other outoimmune antibodies positive, hypocomplementemia

and lymphopenia. Renal biopsy showed type V+IV lupus nephritis. She was treated with

methylprednisolone pulse therapy and mizoribine.

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Conclusion: Lupus Nephritis (LN) occurs in approximately 60-80% of pediatric patients,

sometimes it may be the first manifestation of SLE. Clinical features of LN are various from

asymptomatic urinary abnormalities to severe nephrotic syndrome or rapidly progressive renal

failure. The onset of LN is frequently asymptomatic. Therefore renal biopsy plays an important

role in the management of the patients with SLE.

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Case O-12

Dense deposit disease improved with steroid pulse therapy.

Background:　Membranoproliferative glomerulonephritis type II (MPGN type II) is a rare

disease, characterized by electron dense deposit in lamina densa, and is known as Dense

Deposit Disease(DDD). About 50% of the patients with DDD develop end-stage renal

disease(ESRD) within 10 years;however an effective treatment for DDD has not been

established. We present an 8-year-old girl with DDD, and her nephritic condition improved with

steroid pulse therapy.

Case:　An 8-year-old girl was referred to our center due to proteinuria and hematuria detected

in a school urinary screening program. There was no family history of renal diseases. Her

physical examination and laboratory data showed her height at 121cm, weight at 23kg with no

systemic edema, blood pressure at 110/50mmHg, serum creatinine(s-Cr) level at 0.44 mg/dL,

serum albumin(s-Alb) level at 3.2 g/dL, total cholesterol level at 262 mg/dL, serum C3 level at

10 mg/dL, C4 level at 24 mg/dL, CH50 level at 15.8 U/mL, urinary protein/creatinine ratio at 2.9,

and red blood cell counts in urinary sediment at >100/high power field(HPF). A renal biopsy

revealed diffuse mesangial proliferation and matrix increase with double contour of all glomeruli

by the light microscope, and intense staining of C3 along mesangial area under

immunofluorescence. Electron microscopy revealed extremely electron-dense deposit along the

lamina densa and in mesangial area. Steroid pulse therapy (methylpredonizolone, mPSL)

15mg/kg/day, for three days on alternate days）was administered. Following for eight of weeks

oral predonizolone(PSL 1mg/kg/day), the dose was maintained on alternate days for 26 months.

Proteinuria and hematuria disappeared eight months later. She had persistent

hypocomplementemia, and 21 months after discontinuation of steroid therapy she had relapse

of proteinuria and hematuria. Her urinary protein/creatinine ratio was 1.6. Red blood cell counts

in urinary sediment was 16-17/HPF. Serum C3 was 10 mg/dL.

Discussion:　There is no established therapy for DDD. But her hematuria and proteinuria

disappeared after steroid pulse therapy. Hypocomplementemia was also slightly improved. This

suggests steroid pulse therapy has some effect as the therapy of DDD.

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