WFU

個人簡歷

2017年11月23日 星期四

預約沒有多囊腎的人生






小林是個三十出頭的多囊腎病友,大約國中時期就知道腎功能異常,三十歲就進入透析,也在我的門診定期追蹤。

一向話不多的他,今天照例回診,問完診、開完藥後,小林有點欲言又止的樣子,讓我多問一句

[還有甚麼問題嗎?]

[沒有沒有,沒有問題,嗯,是這樣的,黃醫師,我上個月結婚了!]

[真的啊!恭喜恭喜喔!]我看小林並沒有露出格外欣喜的樣子,可能他要說的不只如此。

[黃醫師,我不知道,我該不該生小孩。]

2017年11月15日 星期三

多囊腎,有藥醫




甚麼是自體顯性多囊腎?


自體顯性多囊腎是一種會造成腎臟功能缺損的遺傳疾病,在自體顯性多囊腎的患者中,大約百分之五十,在六十歲前會進入透析,也就是我們常聽到的洗腎。

自體顯性多囊腎的臨床診斷並不難,在患者三十歲以後,用超音波或電腦斷層,可以看到原本只有拳頭大小的腎臟,長出了大大小小的囊泡,囊泡的體積越來越大,最後壓迫了原先正常的腎臟組織,導致腎臟功能缺損。

圖片說明:右邊的電腦斷層,可以看到原本只有拳頭大的腎臟,因為大小囊泡撐大了腎臟,讓腎臟佔據了一整個腹腔。




值得注意的是,這種多囊腎疾病是會遺傳的,而且它的遺傳模式,是自體顯性遺傳。

甚麼是自體顯性遺傳呢?就是如果爸爸或媽媽其中一個,是多囊腎的患者,那他們生下的小孩子,有一半的機率會得到多囊腎;因此,多囊腎在家族中傳遞的比例很高,一個家族中,可能爸爸在洗腎、姑姑在洗腎、患者的兄弟姊妹也在洗腎。

該如何幫助這些出生就註定有多囊腎的患者,保存腎臟功能,延緩進入透析的時間,是國內外科學家、腎臟科醫師們,一直在努力的方向。


發現基因缺損,找到致病關鍵


由於基因解碼,很多之前無藥可醫、不知道究竟哪裡出問題的遺傳疾病,也開始有科學家,積極的尋找致病基因,並且研究這個基因,會造成甚麼功能缺損;這幾年間,藉由一再的測試、驗證、動物實驗之後,多囊腎的神秘面紗,也被緩緩揭開。

了解致病機轉,才有辦法研發新藥、對症下藥。

目前已知自體顯性多囊腎的致病基因有 PKD1、PKD2以及最近發現的GANAB與DNAJB11。

如果是因為PKD1與PKD2基因突變(截斷突變、切點突變、大片段缺失突變等)會有許多的致病機轉而導致多囊腎,其中一個機轉是細胞cAMP的上升,進而導致腎臟形成囊泡、以及腎功能惡化;早期的動物實驗中也發現,抑制抗利尿激素受器(vasopressin V2 receptor)可以減緩腎功能的惡化,因此,藥廠開始研發,能夠使用在人體上的抗利尿激素受器拮抗劑 。


自體顯性多囊腎新藥已經獲得美國歐洲及日本官方核准


有了新藥之後,還要做一系列的人體測試,才知道藥物的效果到底如何,以及會有甚麼副作用。

令人高興的是,2012年,有研究確定了抗利尿激素受體(vasopressin V2 receptor)拮抗劑,可以延緩早期自體顯性多囊腎患者腎功能的惡化速度(註1);日本厚生省以及歐洲藥物管理局,也相繼在2014、2015年核准了這個第一個、也是唯一的一個,可以使用在自體顯性多囊腎的患者上的藥(註2,3)。加拿大與韓國也隨後核准治療在自體顯性多囊腎,而美國與台灣在2018年也核准使用。

這就是治療自體顯性多囊腎的新藥:Tolvaptan。


新藥的效果以及適用時機


研究發現,自體顯性多囊腎患者,在早期腎功能還可以時(eGFR> 60 ml/min/1.73m2),開始使用Tolvaptan,可以讓水泡長大速度變慢接近一半(49%),也因此,讓腎功能惡化的速度跟著減緩26%(註1)。

這個月(2017年11月)最新的研究結果也發現,即使是多囊腎第四期,腎功能已經明顯缺損的患者,使用Tolvaptan之後,也能減緩腎功能惡化;而在使用後,平均每年可以減緩eGFR下降1.27 ml/min/1.73m2 (註4)。

除此之外,歐洲藥物管理局制定出適用的時機,在腎功能快速惡化的多囊腎患者(eGFR每年下降超過5 ml/min/1.73m2),或者基因檢測確認屬於PKD1基因嚴重突變者,適用Tolvaptan(註2);而日本則是核准,適用於所有的自體顯性多囊腎患者。

綜合以上的研究結果,得到一個簡單好記的結論:預估使用Tolvaptan四年,可以延後一年進入透析(註1),或是進入第五期慢性腎臟病的時間,可以由6.2年延長到9年(註4)。




新藥,台灣有嗎?


這個藥品,在台灣已經上市,於2018年7月衛福部的核准適應症為自體顯性多囊腎。於2019年7月納入有條件之健保給付,用藥前須事前申請。

新藥健保給付適應症


新藥有沒有副作用?

任何藥物要上市前,都要通過人體試驗來確認藥物可能帶來的副作用,仔細的紀錄、統計、分析,確定藥物有療效,而且不會有危害生命的情形之下,才可能通過人體試驗,申請到藥物許可而上市。

同樣的,治療自體顯性多囊腎的新藥Tolvaptan,在進行人體試驗時,發現因為藥物作用機轉的關係,會讓使用者有多尿、夜尿的情形;除此之外,大約百分之五的使用者,會肝功能異常。

因此,使用Tolvaptan,必須在腎臟科醫師的指導與監測之下,才能安全投藥。

可以取得新藥的醫療院所:


黃道揚醫師門診時段由此去_高雄


參考資料



註1:N Engl J Med 2012;367:2407–2418

註2:Nephrol Dial Transplant 2016;31:337–348

註3:Clin Exp Nephrol 2016; 20: 493–509

註4:November 4, 2017 DOI: 10.1056/NEJMe1714276




個人簡歷

Daw-Yang Hwang, MD, PhD    黃道揚 醫師



FB:基因診斷 黃道揚醫師

Email : dawyanghwangkmu@gmail.com


現職 


國家衛生研究院 助研究員

高雄醫學大學附設中和紀念醫院腎臟內科特約主治醫師

高雄醫學大學醫學系助理教授 (合聘)


學歷 


高雄醫學大學醫學士

美國凱斯西儲大學生理與生物物理博士

美國密西根大學/霍華德休斯醫學研究所 博士後研究員

美國波士頓兒童醫院/哈佛醫學院/霍華德休斯醫學研究所 博士後研究員


發表文獻

1: Lee JJ, Ho MC, Huang CY, Wen CH, Cheng YC, Hsu YH, Hwang DY, Lu HE, Chen HC,
Hsieh PCH. Induced pluripotent stem cells derived from an autosomal dominant
polycystic kidney disease patient carrying a PKD1 Q533X mutation. Stem Cell Res.
2017 Oct 28;25:83-87. doi: 10.1016/j.scr.2017.10.026. [Epub ahead of print]
PubMed PMID: 29121521.

2: Ho MC, Huang CY, Lee JJ, Hsu SH, Cheng YC, Hsu YH, Hwang DY, Lu HE, Chen HC,
Hsieh PCH. Generation of an induced pluripotent stem cell line, IBMS-iPSC-014-05,
from a female autosomal dominant polycystic kidney disease patient carrying a
common mutation of R803X in PKD2. Stem Cell Res. 2017 Oct 10;25:38-41. doi:
10.1016/j.scr.2017.10.005. [Epub ahead of print] PubMed PMID: 29055226.

3: Huang CY, Ho MC, Lee JJ, Hwang DY, Ko HW, Cheng YC, Hsu YH, Lu HE, Chen HC,
Hsieh PCH. Generation of induced pluripotent stem cells derived from an autosomal
dominant polycystic kidney disease patient with a p.Ser1457fs mutation in PKD1.
Stem Cell Res. 2017 Oct;24:139-143. doi: 10.1016/j.scr.2017.09.004. Epub 2017 Sep
15. PubMed PMID: 29034881.

4: van der Ven AT, Shril S, Ityel H, Vivante A, Chen J, Hwang DY, Laricchia KM,
Lek M, Tasic V, Hildebrandt F. Whole-Exome Sequencing Reveals FAT4 Mutations in a
Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report. Mol
Syndromol. 2017 Aug;8(5):272-277. doi: 10.1159/000477750. Epub 2017 Jul 1. PubMed
PMID: 28878612; PubMed Central PMCID: PMC5582506.

5: Hung CC, Lin HY, Hwang DY, Kuo IC, Chiu YW, Lim LM, Hwang SJ, Chen HC.
Diabetic Retinopathy and Clinical Parameters Favoring the Presence of Diabetic
Nephropathy could Predict Renal Outcome in Patients with Diabetic Kidney Disease.
Sci Rep. 2017 Apr 21;7(1):1236. doi: 10.1038/s41598-017-01204-6. PubMed PMID:
28432319; PubMed Central PMCID: PMC5430840.

6: Chuang LL, Hwang DY, Tsai KB, Chan HM, Chiang FY, Hsiao PJ. A cohort study on
10-year survival of sporadic medullary thyroid carcinoma with somatic RET
mutation. Kaohsiung J Med Sci. 2016 Nov;32(11):545-551. doi:
10.1016/j.kjms.2016.08.012. Epub 2016 Oct 14. PubMed PMID: 27847096.

7: Lim LM, Tsai NC, Lin MY, Hwang DY, Lin HY, Lee JJ, Hwang SJ, Hung CC, Chen HC.
Hyponatremia is Associated with Fluid Imbalance and Adverse Renal Outcome in
Chronic Kidney Disease Patients Treated with Diuretics. Sci Rep. 2016 Nov
14;6:36817. doi: 10.1038/srep36817. PubMed PMID: 27841359; PubMed Central PMCID:
PMC5108044.

8: Lin HC, Hwang DY, Lim KH. Targeted re-sequencing of TET2 in Taiwanese patients
with myelodysplastic/myeloproliferative neoplasms. Med Oncol. 2016 Aug;33(8):92.
doi: 10.1007/s12032-016-0808-y. Epub 2016 Jul 14. PubMed PMID: 27418193.

9: Vivante A, Hwang DY, Kohl S, Chen J, Shril S, Schulz J, van der Ven A, Daouk
G, Soliman NA, Kumar AS, Senguttuvan P, Kehinde EO, Tasic V, Hildebrandt F. Exome
Sequencing Discerns Syndromes in Patients from Consanguineous Families with
Congenital Anomalies of the Kidneys and Urinary Tract. J Am Soc Nephrol. 2017
Jan;28(1):69-75. doi: 10.1681/ASN.2015080962. Epub 2016 May 5. PubMed PMID:
27151922; PubMed Central PMCID: PMC5198271.

10: Kohl S, Chen J, Vivante A, Hwang DY, Shril S, Dworschak GC, Van Der Ven A,
Sanna-Cherchi S, Bauer SB, Lee RS, Soliman NA, Kehinde EO, Reutter HM, Tasic V,
Hildebrandt F. Targeted sequencing of 96 renal developmental microRNAs in 1213
individuals from 980 families with congenital anomalies of the kidney and urinary
tract. Nephrol Dial Transplant. 2016 Aug;31(8):1280-3. doi: 10.1093/ndt/gfv447.
Epub 2016 Jan 29. PubMed PMID: 26908769; PubMed Central PMCID: PMC4967727.

11: Kuo IC, Lin HY, Niu SW, Hwang DY, Lee JJ, Tsai JC, Hung CC, Hwang SJ, Chen
HC. Glycated Hemoglobin and Outcomes in Patients with Advanced Diabetic Chronic
Kidney Disease. Sci Rep. 2016 Jan 28;6:20028. doi: 10.1038/srep20028. PubMed
PMID: 26818011; PubMed Central PMCID: PMC4730215.

12: You-Hsien Lin H, Yen CY, Lim LM, Hwang DY, Tsai JC, Hwang SJ, Hung CC, Chen
HC. Microscopic Haematuria and Clinical Outcomes in Patients With Stage 3-5
Nondiabetic Chronic Kidney Disease. Sci Rep. 2015 Oct 16;5:15242. doi:
10.1038/srep15242. PubMed PMID: 26472621; PubMed Central PMCID: PMC4607953.

13: Lim LM, Zhao X, Chao MC, Chang JM, Chang WC, Kao HY, Hwang DY, Chen HC. Novel
Vitamin D Receptor Mutations in Hereditary Vitamin D Resistant Rickets in
Chinese. PLoS One. 2015 Sep 30;10(9):e0138152. doi: 10.1371/journal.pone.0138152.
eCollection 2015. PubMed PMID: 26422470; PubMed Central PMCID: PMC4589239.

14: Hilger AC, Halbritter J, Pennimpede T, van der Ven A, Sarma G, Braun DA,
Porath JD, Kohl S, Hwang DY, Dworschak GC, Hermann BG, Pavlova A, El-Maarri O,
Nöthen MM, Ludwig M, Reutter H, Hildebrandt F. Targeted Resequencing of 29
Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human
VATER/VACTERL Association. Hum Mutat. 2015 Dec;36(12):1150-4. doi:
10.1002/humu.22859. Epub 2015 Sep 14. PubMed PMID: 26294094; PubMed Central
PMCID: PMC4643331.

15: Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, Shril S, Hwang DY,
Weiss AC, Kaminski MM, Shukrun R, Kemper MJ, Lehnhardt A, Beetz R, Sanna-Cherchi
S, Verbitsky M, Gharavi AG, Stuart HM, Feather SA, Goodship JA, Goodship TH,
Woolf AS, Westra SJ, Doody DP, Bauer SB, Lee RS, Adam RM, Lu W, Reutter HM,
Kehinde EO, Mancini EJ, Lifton RP, Tasic V, Lienkamp SS, Jüppner H, Kispert A,
Hildebrandt F. Mutations in TBX18 Cause Dominant Urinary Tract Malformations via
Transcriptional Dysregulation of Ureter Development. Am J Hum Genet. 2015 Aug
6;97(2):291-301. doi: 10.1016/j.ajhg.2015.07.001. Epub 2015 Jul 30. PubMed PMID:
26235987; PubMed Central PMCID: PMC4862256.

16: Hwang DY, Kohl S, Fan X, Vivante A, Chan S, Dworschak GC, Schulz J, van Eerde
AM, Hilger AC, Gee HY, Pennimpede T, Herrmann BG, van de Hoek G, Renkema KY,
Schell C, Huber TB, Reutter HM, Soliman NA, Stajic N, Bogdanovic R, Kehinde EO,
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Epub 2015 May 31. PubMed PMID: 26026792; PubMed Central PMCID: PMC4497857.

17: Lin HY, Hwang DY, Lee SC, Kuo HT, Kuo MC, Chang JM, Tsai JC, Hung CC, Hwang
SJ, Chen HC. Urinary neutrophil gelatinase-associated lipocalin and clinical
outcomes in chronic kidney disease patients. Clin Chem Lab Med. 2015
Jan;53(1):73-83. doi: 10.1515/cclm-2014-0647. PubMed PMID: 25153411.

18: Yen JH, Chang CM, Hsu YW, Lee CH, Wu MS, Hwang DY, Chen BK, Liao HT, Wu MT,
Chang WC. A polymorphism of ORAI1 rs7135617, is associated with susceptibility to
rheumatoid arthritis. Mediators Inflamm. 2014;2014:834831. doi:
10.1155/2014/834831. Epub 2014 Apr 8. PubMed PMID: 24808640; PubMed Central
PMCID: PMC3997980.

19: Hwang DY, Chien SC, Hsu YW, Kao CC, Cheng SY, Lu HC, Wu MS, Chang JM. Genetic
polymorphisms of ORAI1 and chronic kidney disease in Taiwanese population. Biomed
Res Int. 2014;2014:290863. doi: 10.1155/2014/290863. Epub 2014 Mar 17. PubMed
PMID: 24745010; PubMed Central PMCID: PMC3976823.

20: Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, Stajic N,
Bogdanovic R, Reutter HM, Kehinde EO, Tasic V, Hildebrandt F. Mild recessive
mutations in six Fraser syndrome-related genes cause isolated congenital
anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2014
Sep;25(9):1917-22. doi: 10.1681/ASN.2013101103. Epub 2014 Apr 3. PubMed PMID:
24700879; PubMed Central PMCID: PMC4147986.

21: Wu YL, Hwang DY, Hsiao HP, Ting WH, Huang CY, Tsai WY, Chen HC, Chao MC, Lo
FS, Tsai JD, Yang S, Shih SL, Lin SP, Lin CL, Lee YJ. Mutations in
pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.
PLoS One. 2014 Mar 20;9(3):e90640. doi: 10.1371/journal.pone.0090640. eCollection
2014. PubMed PMID: 24651309; PubMed Central PMCID: PMC3961212.

22: Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM,
Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F. Mutations in 12
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23: Vivante A, Kohl S, Hwang DY, Dworschak GC, Hildebrandt F. Single-gene causes
of congenital anomalies of the kidney and urinary tract (CAKUT) in humans.
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24: Wang YK, Hwang DY, Wang SS, Hwang SJ, Chen LT, Kuo MC. Terlipressin-induced
hyponatremic encephalopathy in a noncirrhotic patient. Kaohsiung J Med Sci. 2013
Dec;29(12):691-4. doi: 10.1016/j.kjms.2013.08.003. Epub 2013 Sep 10. PubMed PMID:
24296059.

25: Saisawat P, Kohl S, Hilger AC, Hwang DY, Yung Gee H, Dworschak GC, Tasic V,
Pennimpede T, Natarajan S, Sperry E, Matassa DS, Stajić N, Bogdanovic R, de
Blaauw I, Marcelis CL, Wijers CH, Bartels E, Schmiedeke E, Schmidt D, Märzheuser
S, Grasshoff-Derr S, Holland-Cunz S, Ludwig M, Nöthen MM, Draaken M, Brosens E,
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26: Austin-Tse C, Halbritter J, Zariwala MA, Gilberti RM, Gee HY, Hellman N,
Pathak N, Liu Y, Panizzi JR, Patel-King RS, Tritschler D, Bower R, O'Toole E,
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Schueler M, Airik R, Otto EA, Leigh MW, Noone PG, Carson JL, Davis SD, Pittman
JE, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Dell SD, Rosenfeld M, Milla CE,
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Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59
and CCDC65 Defects as Causing Primary Ciliary Dyskinesia. Am J Hum Genet. 2013
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27: Lim LM, Chang JM, Wang IF, Chang WC, Hwang DY, Chen HC. Atypical X-linked
agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin
M deficiency patient. BMC Pediatr. 2013 Sep 27;13:150. doi:
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28: Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, Hjeij R,
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Olivier KN, Morgan LC, Werner C, Raidt J, Pennekamp P, Sun Z, Zhou W, Airik R,
Natarajan S, Allen SJ, Amirav I, Wieczorek D, Landwehr K, Nielsen K, Schwerk N,
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29: Wang HH, Hung CC, Hwang DY, Kuo MC, Chiu YW, Chang JM, Tsai JC, Hwang SJ,
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30: Lin HY, Lee SC, Lin SF, Hsiao HH, Liu YC, Yang WC, Hwang DY, Hung CC, Chen
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31: Chang JM, Hwang DY, Chen SC, Kuo MC, Hung CC, Hwang SJ, Tsai JC, Chen HC.
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