| [Presentation of Case]
A 44-year-old woman presented with oliguria for 3 days following myomectomy. She had a history of iron deficiency anemia, for which she received iron supplement. A uterine myoma was incidentally found by transabdominal ultrasonography in 2003. Menorrhagia, distended abdomen, and dysmenorrhea developed since January 2013 and the symptoms worsened gradually. She was admitted to Chung Shan Hospital (Taipei) for laparotomic myomectomy on 27th , September, 2013. The intraoperative blood loss was estimated 750mL. However, decreased urine output (100-150 ml/day), generalized edema, weight gain (63 to 74 kg within 5 days), and progressive dyspnea developed after the operation. The renal-function test results revealed blood urea nitrogen (BUN) and creatinine (Cre) level of 79 and 11 mg/dL, respectively, on 02nd , October. Because of worsening dyspnea and oliguria, she was transferred to this hospital on 05th , October.
At the emergency department, the temperature was 37.7℃, the pulse rate 92 beats per minute, the respiratory rate 20 breaths per minute, the blood pressure: 114/91 mm Hg, and the oxygen saturation (SpO2) 95% while she was breathing oxygen at a flow rate of 3L/min with the use of nasal cannula. The physical examination revealed basal crackles at the bilateral lung fields. The hemogram revealed hemoglobin (Hb), 8.2g/dL) and BUN/Cre, 97.9/13.2 mg/dL. A test for the arterial blood gas revealed metabolic acidosis and respiratory alkalosis, with pH 7.38, pCO2 18 mmHg, pO2 71.3 mmHg HCO3- 10.8 mEq/L, and base excess (BE) -14.6). A chest radiograph revealed cardiomegaly and bilateral pleural effusions. Anuria developed despite administration of diuretics. She was admitted to the gynecology ward on the same day.
A nephrologist was consulted and emergent hemodialysis was instituted on 5th , October because of anuria, metabolic acidosis and fluid overload. However, acute desaturation and consciousness disturbance developed on 6th October. A follow-up chest radiograph revealed pulmonary edema and bilateral pleural effusions. Because of hypoxic respiratory failure, endotracheal intubation was performed and mechanical ventilator support was begun. The echocardiography on 6th , October revealed severe reduced left ventricular contractility (left ventricular ejection fraction [LVEF], 32.6%) and hypokinesia at the mid-level of LV and apex with relatively spared basal part, and a diagnosis of stress-induced cardiomyopathy (Takotsubo cardiomyopathy) was made. The other laboratory results are shown below:
She was unmarried and the menarche occurred at the age of 14 years. The interval and duration of menstrual cycle was 25 and 5 days, respectively. She did not smoke, consume alcohol or use of illicit drugs or herbal remedies.
[Laborotory examination 2013/10/05]
Hb |
Hct |
MCV |
PLT |
WBC |
Seg |
Eos |
Baso |
Mono |
Lym |
g/dL |
% |
fL |
K/μL |
/μL |
% |
% |
% |
% |
% |
8.2 |
22.2 |
83.1 |
284 |
7.94 |
79.0 |
5.0 |
0.0 |
7.0 |
8.0 |
T-bil |
D-bil |
AST |
ALT |
BUN |
CRE |
Na |
K |
Cl |
Ca |
mg/dL |
mg/dL |
U/L |
U/L |
mg/dL |
Mg/dL |
mmol/L |
mmol/L |
mmol/L |
mmol/L |
0.38 |
0.08 |
36 |
17 |
97.9 |
13.2 |
123 |
4.1 |
93 |
2.04 |
Mg |
P |
CK |
CK-MB |
Trop-I |
PH |
PCO2 |
PO2 |
HCO3 |
BE |
mmol/L |
mg/dL |
U/L |
U/L |
ng/mL |
|
mmHg |
mmHg |
mmol/L |
mmol/L |
0.85 |
9.3 |
22 |
12 |
0.49 |
7.38 |
18 |
71.3 |
10.8 |
-14.6 |
Sp. Gr. |
pH |
Protein |
Glucose |
RBC |
WBC |
Cast |
|
|
mg/dL |
mg/dL |
/HPF |
/HPF |
|
1.006 |
6.0 |
300(3+) |
(-) |
2-5 |
20-35 |
Granular 0-2 |
[Echocardiography]
|
2013/10/08 |
2013/10/15 |
LVEF(%) |
32.6 |
60.3 |
MR |
Moderate |
Mild |
TR |
Mild |
Trace |
Chamber size(cm) |
LA 3.9, LVEDD 4.3, LVESD 3.6 |
LA 4.0, LVEDD 4.4, LVESD 2.5 |
|
Hypokinesia over mid level of LV and apex with relatively spared basal part |
No regional wall abnormalities |
[Image]
2013/10/05 Chest radiography: bilateral pleural effusion; cardiomegaly.
[Treatment course]
Because of impaired renal function, continuous veno-venous hemofiltration was instituted from 06th to 08th , October, which was switched to intermittent hemodialysis on 09th , October. The renal sonography revealed no hydronephrosis. The data of FeUN and FeNa suggested an intrinsic cause of acute kidney injury. The urinalysis revealed no dysmorphic RBC, RBC/WBC casts, or eosinophils. The autoimmune profiles were all negative, and immunoelectrophoresis of an urine sample showed no monoclonal gammopathy. Because of unexplained renal failure, proteinuria, and acute kidney injury without recovery, a renal biopsy was performed. The pathology report revealed nephrocalcinosis with obvious crystal accumulation in the tubular lumens. The Von Kossa stain (specific to calcium phosphate crystal) showed strong positive. On review of her history, she reported having had taken one bottle of oral Fleet solution for bowel preparation the night before operation on 26th,September.A diagnosis of acute phosphate nephropathy was made. Oral and parenteral hydration were begun. The urine output increased gradually (700 ml/day) on 3rd,November. Hemodialysis was discontinued on 4th, November. During the following hospital stay, the urine output increased to about 2000 ml/day. She was discharged on 14th, November, 2013.
[病例解析]
急性磷酸鹽腎病變(acute phosphate nephropathy)最早是於西元2003年的新英格蘭醫學期刊(New England Journal of Medicine, NEJM)有完整的病例報告，Simon Desmeules等作者報告一位71歲女性為了做大腸鏡的準備工作，在服用90 ml的Phosphosoda進行清腸後，產生非特異性的全身倦怠症狀，而其血清肌酸酐(serum creatinine)數值，由原來基礎值的1.0 mg/dL，上升到4.5 mg/dL，在進行腎臟切片檢查後，發現腎小管內有大量的沉澱物，這些沉澱物在von Kossa's stain染色為陽性，在偏極光(polarized light)照射下沒有雙折射(nonbirefringent)，掃描式電子顯微鏡(Scanning electron microscopy)及能量色散X射線顯微分析(energy-dispersive x-ray microanalysis)指出，這些沉澱物是由鈣離子(calcium)及磷酸鹽離子(phosphate)所組成的羥磷灰石(hydroxyapatite)結晶，這位病患在一系列的檢查後，並沒有發現會造成腎鈣化症(nephrocalcinosis)的危險因子，在一年之後追蹤的血清肌酸酐數值，依然比之前的基礎值高(1.7 mg/dL)1。
急性磷酸鹽腎病變是患者在服用含磷酸鈉的水溶液後，可能導致急性腎損傷(acute kidney injury)的重要原因之一。根據Vala Kolbrun Palmadottir等人於2010年在冰島所做的回溯性研究統計，口服含磷酸鈉之水溶液後，急性磷酸鹽腎病變的發生率約為0.085%2。急性磷酸鹽腎病變的致病機轉主可分為兩個方面，其一是大量攝食磷酸鹽後，導致血中磷酸鹽濃度暴增，造成腎臟近曲小管對磷酸鹽的再吸收變差，進而使遠曲小管中的磷酸鹽濃度增加，故在遠曲小管內產生大量的磷酸鈣沉澱物。其二為服用Phosphosoda藥物後，會造成腹瀉及脫水，導致近曲小管及亨耳氏環的下降枝對於鈉離子及水分的再吸收增加，使得鈣離子及磷酸鹽的濃度在遠曲小管上升。此外脫水也會導致遠曲小管上皮細胞表現較多的玻尿酸(hyaluronan)及骨調素(osteopontin)，造成磷酸鈣結晶較易黏附於遠曲小管上皮3。
口服磷酸鈉水溶液從1990年代起，就開始被作為大腸鏡檢查前的清腸瀉劑，它主要的作用機轉是透過在腸道內產生高滲透壓，使得水分由腸胃道排出以幫助清腸。常見的建議處方為Fleet Phosphosoda，每次45 ml，每12小時服用一次，共服用兩個劑量(90 ml)，在服藥後約30至60分鐘開始發揮作用，藥效持續約4至6小時。和另一種大腸鏡常用的瀉劑聚乙二醇(polyethylene glycol)比較起來，口服磷酸鈉水溶液所需服用的體積較少，患者會有較高的遵醫囑性，且有較佳的清腸效果，但其缺點則是會導致暫時性的高磷酸血症(hyperphosphatemia)，使血中磷酸根濃度平均上升約4.1 mg/dL，一般在24小時內會緩解4。
除了口服磷酸鈉水溶液之外，由灌腸的方式來使用磷酸鈉水溶液，也可以導致急性磷酸鹽腎病變，。Ori Y.等人於2012年報告11位老年病患(61-89歲)，在使用Fleet enema通腸處理便祕之後，產生了急性腎衰竭，其中有3位使用高劑量(500-798 ml)，8位使用標準劑量(250 ml)，他們血中的磷酸含量皆有顯著上升(5.3-45 mg/dL)，其中有2位病患有接受血液透析治療，而有5位病患最後死亡，有1位病患在接受大體解剖後，發現在腎小管有磷酸鈣的結晶5。可見由灌腸的方式來給予磷酸鈉水溶液，也可能導致腎臟的傷害。
美國(the United States of America, USA)食品及藥物管理局(Food and Drug Administration, FDA)在2008年對市售口服Phosphosoda發出了警語，在其產品上註明有可能導致急性磷酸鹽腎病變及腎衰竭的風險，將Phosphosoda由成藥(over-the-counter, OTC)轉為處方藥(prescription drug)。美國除了口服水溶液之外，也有口服錠劑的劑型，包括VISICOL及OsmoPrep等產品。因此在臨床使用上，磷酸鹽水溶液有一些必須注意的禁忌症，包括心衰竭、腎衰竭、腹水、腸胃道阻塞、活性炎症性腸病(active inflammatory bowel disease, IBD)、高血鈉、高磷酸血症及低血鈣。
導致急性磷酸鹽腎病變的主要危險因子包括: (1)年齡偏高(大於60歲)、(2)慢性腎病(chronic kidney disease, eGFR 60 ml/min)、(3)高血壓(hypertension)、(4)使用血管收縮素轉換(酉每)抑制劑(angiotensin converting enzyme inhibitor, ACEI)或血管收縮素受體阻斷劑(angiotensin receptor blocker, ARB)、(5)使用利尿劑、(6)女性，另外，患有糖尿病或使用非類固醇抗發炎藥物(Non-steroidal anti-inflammatory drugs, NSAIDs)也會提高罹病風險。一位病患包含越多項的危險因子，其發生急性磷酸鹽腎病變的風險就越高3。
急性磷酸鹽腎病變的診斷條件，必須有近期內暴露於口服磷酸鈉清腸劑的病史，之後發生急性腎衰竭，不能併有高鈣血症，且在病理學檢查可見到急性或慢性的腎小管損傷及大量的磷酸鈣沉積於腎小管內。在臨床歷程上，可以急性且可逆的腎損傷(Acute and reversible kidney injury)或進展性腎功能失常(progressive renal dysfunction)來表現，在急性可逆腎損傷病患，常在使用磷酸鈉後24小時之內發生急性腎損傷，並合併有低血鈣症，甚至會導致心跳停止或死亡，而大多數的存活者(78%)可回復到正常或接近正常的腎功能狀態6。而在進展性腎功能失常者，常常一開始是無症狀且漸進的腎功能變差，在數天到數月之後才發現腎功能異常，大部分的病患會進展成慢性腎病甚至末期腎病的情況7，在我們這位患者就是類似的情形。
在病理學檢查的表現上，可見到大量的磷酸鈣沉積於腎小管內，這些沉積物是嗜鹼性圓形顆粒，不具有偏光性，且在von Kossa stain染色為陽性(註:von Kossa stain是以銀離子為試劑，與磷酸根發生反應)。沉積的部位主要在遠曲小管和急尿管，在腎皮質的分布量比腎髓質多7。在我們報告的這位病患，也有病理學上的典型表現。如果腎臟切片的時間距服用磷酸鈉水溶液小於三週，則在病理上可見到急性腎小管退化性病變(Acute tubular degenerative changes)及間質水腫(interstitial edema)；如大於三週以上再做腎臟切片，則可見到腎小管萎縮(tubular atrophy)及間質纖維化(interstitial fibrosis)3。
對於急性磷酸鹽腎病變的治療原則，首先要在服用磷酸鈉水溶液後，密切地監測腎功能變化，治療方針則以充分的水分補給為主，在一些特定的病患，也可評估進行血液透析治療。但最重要的還是，預防勝於治療，在一些較高風險會發生急性磷酸鹽腎病變的患者，並避免使用這類藥物，已給藥者要給予充足的水分，在高風險者考慮使用其他替代的通腸瀉劑。
在發生急性磷酸鹽腎病變之後的預後方面，在Glen S. Markowitz等作者於2005年所報告的21位病患追蹤資料顯示，原本這些病患的平均血清肌酸酐數值為1.0 mg/dL，在追蹤超過一年之後，只有4位病患的數值降至低於2.0 mg/dL，而且沒有任何一位病患降到生病前的基礎數值，可見急性磷酸鹽腎病變可以發生於腎功能原本正常的病患，也會對腎功能有長期的傷害7。
我們在這裡提出的個案是在進行子宮切除術前清腸準備時，曾經服用Fleet Phosphosoda來清腸，而在術後發生了急性腎衰竭，後來是由病理學檢查確診為急性磷酸鹽腎病變。這位病患是一位44歲的中年女性，本身並沒有高血壓或糖尿病等內科問題，但在術後有使用NSAIDs及gentamycin等可能會造成腎功能異常的藥物，另外在術中術後的大量出血，也可能會造成低血容積(hypovolemia)的情形，使得急性磷酸性腎病變的發生風險上升。因此，在急性腎功能損傷的病患的照顧上，病史的釐清是非常重要的，這樣才能幫助我們找出可逆或可處理的病因，來確實有效的治療病患。
參考文獻:
-
Desmeules S, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. The New England journal of medicine 2003; 349(10): 1006-7.
-
Palmadottir VK, Gudmundsson H, Hardarson S, Arnadottir M, Magnusson T, Andresdottir MB. Incidence and outcome of acute phosphate nephropathy in Iceland. PloS one 2010; 5(10): e13484.
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Markowitz GS, Perazella MA. Acute phosphate nephropathy. Kidney international 2009; 76(10): 1027-34.
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Vanner SJ, MacDonald PH, Paterson WG, Prentice RS, Da Costa LR, Beck IT. A randomized prospective trial comparing oral sodium phosphate with standard polyethylene glycol-based lavage solution (Golytely) in the preparation of patients for colonoscopy. The American journal of gastroenterology 1990; 85(4): 422-7.
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Ori Y, Rozen-Zvi B, Chagnac A, et al. Fatalities and severe metabolic disorders associated with the use of sodium phosphate enemas: a single center's experience. Archives of internal medicine 2012; 172(3): 263-5.
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Orias M, Mahnensmith RL, Perazella MA. Extreme hyperphosphatemia and acute renal failure after a phosphorus-containing bowel regimen. American journal of nephrology 1999; 19(1): 60-3.
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Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. Journal of the American Society of Nephrology : JASN 2005; 16(11): 3389-96.
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Case Discussion
繼續教育考題