< Presentation of Case >
A 48-year-old man had been in his usual state of health until two months prior to this admission, when vague abdominal discomfort, a weight loss and night sweats developed. Family history was not contributory. He sought medical attention at a local clinic, where anemia was detected, with a hemoglobin of 10.8 g/dl and hematocrit, 31.4%. He was by a gastroenterologist at another hospital, where computed tomography (CT) revealed diffuse mesenteric infiltration, enlarged mesenteric lymph nodes, and moderate ascites. Pathology of CT-guided fine-needle biopsy of the lymph nodes confirmed the diagnosis of diffuse large B-cell lymphoma. He was hospitalized for chemotherapy with a regimen containing cyclophsphamide, vincristine, and prednisolone (COP). On admission, physical examination revealed a well-developed man with chronic ill-looking, but without distress. The heart rate was 80 bpm, temperature 36.8 ℃, and blood pressure 138/84 mmHg. There was mildly pale conjunctiva but no icteric sclera. No neck or auxiliary lymphadenopathy was found. The heart beat was regular without murmurs. Auscultation of the lung fields was normal. Abdomen examination indicated the presence of ascites but without hepatosplenomegaly. No lower leg edema was noted. He denied any systemic disease other than hypertension that had been well-controlled with angiotensin II receptor blocker for five years. He had a history of social drinking but no smoking.
After admission, administration of cyclophosphamide 1000 mg, vincristine 1.6 mg and dexamethasone 400 mg was begun. In order to prevent the potential side effect of chemotherapy, he was encouraged to have adequate fluid intake and was well-hydrated with normal saline 1200 ml/day plus allopurinol 100 mg twice a day. He had no immediate discomfort after the chemotherapy. On day 4 post-chemotherapy, he felt weakness, easy fatigue, shortness of breath and dramatically decreased urine output. The urine output was less than 100 ml/day and anuria was resistant to administration of high-dose intravenous diuretics. Meanwhile, the laboratory results showed azotemia and hyperkalemia (See laboratory results). A nephrologist was consulted, who made a diagnosis of acute renal failure due to tumor lysis syndrome. Hemodialysis treatment was instituted.
< Laboratory and Image Study >
1. CBC and differential count
Day after admission |
WBC
K/μL |
Hgb
g/dL |
MCV
fL |
MCHC
% |
Hct
% |
Plt
K/μL |
Band
%
|
Seg
%
|
Lym
%
|
OPD |
7.62 |
10.5 |
91 |
32 |
30.9 |
330 |
0 |
68 |
2.2 |
Admission |
7.68 |
10.7 |
92 |
33 |
30.8 |
320 |
0 |
69 |
2.1 |
Day 4 post C/T |
6.86 |
11.6 |
93 |
33 |
33.8 |
325 |
N/A |
N/A |
N/A |
Day 10 post C/T |
7.46 |
12.8 |
92 |
34 |
36.1 |
350 |
0 |
72 |
2 |
N/A: not applicable, C/T: chemotherapy
2. Biochemistry
Day after admission |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
Ca
mg/dl |
P
mg/dl |
GOT
U/l |
GPT
U/l |
Uric acid
mg/dl |
LDH
IU/l |
Albumin
g/dl |
OPD |
16 |
1.1 |
137 |
4.2 |
9.8 |
3.8 |
24 |
24 |
6.8 |
320 |
3.8 |
Admission |
18 |
1.2 |
137 |
4.1 |
9.8 |
3.9 |
N/A |
N/A |
N/A |
318 |
N/A |
Day 4 post C/T |
98 |
4.2 |
139 |
6.5 |
8.6 |
10.8 |
256 |
46 |
13 |
1588 |
N/A |
Day 10 post C/T |
39 |
2.2 |
140 |
4.1 |
9.6 |
4.8 |
26 |
25 |
6.5 |
286 |
N/A |
3. Urinalysis
Date |
Appearance |
Specific gravity |
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult blood |
OPD |
yellow, clear |
1.004 |
6.5 |
-- |
-- |
-- |
-- |
Admission |
yellow, clear |
1.002 |
6.7 |
-- |
-- |
-- |
-- |
Day 4 post C/T |
yellow, clear |
1.01 |
6.3 |
-- |
-- |
-- |
1+ |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Crystal |
OPD |
0.1 |
-- |
-- |
-- |
<5 |
-- |
-- |
Admission |
0.1 |
-- |
-- |
-- |
-- |
-- |
-- |
Day 4 post C/T |
0.1 |
-- |
>50 |
5-10 |
-- |
-- |
uric acid |
4. Renal sonography: Bilateral kidneys were of normal size. No cystic lesion or mass was identified. Multiple hyperechoic lesions in renal parenchyma were suspected. No hydronephrosis.
<Course and Treatment>
The clinical presentations of this patient who developed acute renal failure caused by tumor lysis syndrome soon after chemotherapy prompted the clinician to make the diagnosis of chemotherapy-related acute renal failure, based on the history of hematopoietic malignancy, timing of chemotherapy and the subsequent clinical presentations. Chemotherapeutic agent-related acute renal failure was less likely because these drugs generally do not cause notable nephrotoxicity. Because of the decreased urine output and life-threatening hyperkalemia, three consecutive sessions of hemodialysis were initiated, of which frequency was switched to every other day. During hemodialysis, ultrafiltration was restricted to a certain amount to monitor the recovery of his renal function. On day 10 after chemotherapy, his urine output returned to near 1000 ml/day and laboratory renal function improved. Therefore, hemodialysis was discontinued. The patient's renal function and urine output returned to pre-hospitalization level on the day of discharge.
<Analysis>
由於病患罹患diffuse large B-cell lymphoma、住院前腎功能正常、在chemotherapy之後出現急性腎衰竭，且急性腎衰竭的生化檢驗異常具有相當的特異性，所以進而依此診斷chemotherapy導致tumor lysis syndrome併發急性腎衰竭。Tumor lysis syndrome引起急性腎衰竭最主要的原因是大量腫瘤細胞因chemotherapy而死亡，進而釋放出uric acid，短時間內大量產生的uric acid沉積在腎小管引起阻塞進而影響腎臟功能，造成急性腎衰竭，因此也稱為acute uric acid nephropathy。在acute uric acid nephropathy時，由於腫瘤細胞大量死亡也釋放出大量的potassium及phosphate，而此又更加重急性腎衰竭的嚴重程度，同時急性腎衰竭所產生metabolic acidosis又會增加hyperkalemia的嚴重程度，進而形成一個惡性循環。
Acute uric acid (urate) nephropathy是一種好發生在某些特定病患，且在臨床及病理上有著相當特異表現的疾病。病理機制為在短時間內血清中uric acid的濃度快速上升所導致。因此，此疾病最常併發於短時間內有相當大量細胞生成及死亡的疾病，如血液腫瘤疾病之病患，尤其是在經過化學治療後。所謂的tumor lysis syndrome就是臨床表現除了underlying disease的表現以外，就是以急性腎衰竭為主要特徵。而此急性腎衰竭又具有hyperuricemia、hyperkalemia、metabolic acidosis、hypocalcemia及hyperphosphatemia。這些電解質異常，可以在化學治療後快速產生，但也有病例是因為tumor burden太大，而引起自發性的大量腫瘤細胞死亡，進而產生tumor lysis syndrome，但還是較化學治療後所產生的少見，且也可能不那麼嚴重。另外因uric acid濃度上升所引起的腎衰竭也可見於purine代謝異常的遺傳性疾病(如Lesch-Nyhan syndrome)、hemolysis、rhabdomyolysis、perinatal asphyxia、extreme exercise及因status epilepticus所引起的肌肉快速且持續的收縮而導致。而因uric acid濃度上升產生急性腎衰竭的危險因子，包括: dehydration及acidemia，同時要是病患還有同時使用可增加uric acid排出的藥物，如contrast medium，可更增加acute uric acid nephropathy的發生機會。
Acute urate nephropathy是因為uric acid沉積在renal tubules及collecting duct，進而增加腎絲球內壓力，造成GFR下降的臨床特徵，包括: 病患在短時間內尿量減少。由於uric acid特別容易在低pH且濃縮的尿液內沉積，因此在acute uric acid nephropathy時uric acid的沉積部位是以renal medulla及papilla為主。病理上的表現特徵為極輕微的間質細胞浸潤(interstitial cell infiltration)及renal tubule出現uric acid結晶。由於urate具有可溶性且間質並未受到影響，所以只要移除阻塞後，腎功能及病理變化大多都會恢復至治療前之程度。但是若是腎臟受損過於嚴重，還是可能造成慢性腎臟病(chronic kidney disease)。臨床上要診斷acute uric acid nephropathy，最重要的就是病史，在某些高風險病患(如血液腫瘤疾病之病患如leukemia及lymphoma，尤其是在經過化學治療後)，當出現oliguric acute renal failure、hyperkalemia、hyperphosphatemia、hypocalcemia伴有血清中uric acid濃度上升或尿液中出現uric acid結晶時，就要考慮acute uric acid nephropathy。但是要注意的是尿液中並不一定都會出現uric acid結晶且單靠血清中uric acid濃度上升不能診斷acute uric acid nephropathy。另外也可利用urinary uric acid/urinary creatinine ratio來幫助診斷。當在acute uric acid nephropathy時，這個比例會高於1。但要特別注意的是，這個公式並不適用於嬰幼兒及兒童，因為他們生長較快速，所以這個比例在孩童期大於1是正常的。
臨床上處理acute uric acid nephropathy的方法其實十分單純，可大致分為預防及治療兩部分，但是預防永遠是重於治療。在進行化學治療時給予足夠的水分補充，來維持一定的renal tubule流量、以NaHCO3靜脈注射來鹼化尿液(維持尿液PH大於7)及給予allopurinol減少uric acid的產生，一般都能避免acute tumor lysis syndrome及 acute uric acid nephropathy的發生。只要病患狀況允許，水份的補充可高達3000 ml/m2 of body surface area。如果病患尿液pH無法達到7以上，可再考慮加上口服acetazolamide輔助。另外在高風險病患，也要減少會增加uric acid排出的藥物如顯影劑。此外也可考慮使用rasburicase來下降uric acid的濃度。Rasburicase是利用基因重組從帶有Aspergillus flavus complementary DNA的酵母菌中所萃取出來的uricase (urate oxidase)。Rasburicase可將uric acid轉變為allantoin，由於allantoin具極高水溶性，且可輕易通過腎絲球，且並無腎毒性，因此可達到快速、安全且非侵入性而下降尿酸濃度的目的。Rasburicase的建議劑量為0.2 mg/kg/day，靜脈注射1至2小時，可給予3至7天，且在給予第一劑後的4至24小時後再開始進行化學治療。此藥物下降uric acid的效果遠高於allopurinol。當發生acute tumor lysis syndrome併發acute uric acid nephropathy時，積極治療方面就是以血液透析移除uric acid，並同時矯正電解質異常。由於血液透析移除uric acid的效率相當好，所以是治療acute uric acid nephropathy最有效的方法。由於peritoneal dialysis對於uric acid移除的效果較差，因此若是病患狀況不允許使用血液透析(hemodialysis)，也儘量以continuous arteriovenous或 venovenous hemofiltration或hemodiafiltration來取代。由於acute uric acid nephropathy是可逆性的，因此在進行血液透析時要注意保持病患的排尿量及ultrafiltration的平衡甚至負平衡，即可試著減少ultrafiltration以觀察尿量是否增加，不需要持續的增加ultrafiltration。
<References>
- Primer on Kidney Diseases. 4th edition.
- Ann Hematol, 2005;84:343-346.
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Case Discussion
繼續教育考題