<Presentation of Case >
A 56-year-old man had been diagnosed as having stage 3 chronic kidney disease (CKD) and hypertension for 5 years. He recently experienced nausea, vomiting, leg edema and fatigue for 2 weeks due to rapid deterioration of renal function. His blood pressure was 134/84 mmHg on average while he had been receiving Aprovel (irbesartan) 125 mg/day for more than 2 years. He denied smoking but had occasional social drinking of beer once a week. There was no history of hepatitis. He started to make fruit and vegetable juice himself and took vitamin C supplement at a daily dose of 1000 mg since 3 months earlier before this presentation. According to his diet diary, he drank juice 500 ml/day. Meanwhile, he jogged twice a week without any exercise intolerance. There was no known family history of hereditary metabolic disorders or kidney diseases.
Two weeks earlier, he started to experience exercise intolerance even during less intensive exercise. Generalized malaise, legs edema, poor appetite, nausea and occasional vomiting developed. Daily urine amount decreased. He denied having taken any new medications and herbs or excessive alcohol ingestion. He was seen by his family doctor and then was transferred to our emergency department (ED) immediately for emergent hemodialysis (HD) when a diagnosis of acute on chronic renal failure related to irbesartan was made.
At ED, he had clear consciousness but appeared ill. The blood pressure was 164/90 mmHg, the pulse rate 86 beats per minute, the respiration rate 24 breaths per minute, and the temperature 36.8oC. The oxygen saturation was 92% while he was breathing ambient air. The conjunctiva was pale. Lungs were symmetrically expanded but with basal crackles. Examinations of the heart and abdomen were normal. There was mild to moderate pitting edema at both lower extremities. Because of the uremia-like symptoms and hyperkalemia (see results of laboratory tests), HD was initiated.
During the hospitalization, irbesartan was replaced by atenolol. The HD was continued but was tapered accordingly based on the urine amount and BUN/Cr levels. His daily urine amount was around 400 ml but gradually increased after ultrafiltration was reduced plus the prescription of diuretics. Renal ultrasonography revealed increased echogenicity and significant nephrocalcinosis of both kidneys. Percutaneous renal biopsy was performed and the most striking finding was the extensive deposition of calcium oxalate crystal. A diagnosis of angiotensin II receptor blocker-related nephrotoxicity and juice-induced oxalate nephropathy was made. Subsequent diet instruction for a low oxalate diet was given. His renal function did not completely return to the baseline, but no further HD was needed after discharge.
Results of laboratory tests and other exams
Table 1. CBC and differential count
Date |
WBC
K/μL |
Hgb
g/dL |
Hct (%) |
Plt
(K/μL) |
Baseline |
6.69 |
12.6 |
36.4 |
360 |
ED |
6.56 |
10.8 |
31.7 |
315 |
Day 3 |
6.32 |
11.6 |
34.4 |
354 |
Discharge |
6.48 |
12.1 |
35.9 |
355 |
Table 2. Biochemistry
|
Pre-HD BUN (mg/dl) |
Pre-HD Cre
(mg/dl) |
Na
(mmol/l) |
K
(mmol/l) |
Ca (mg/dL) |
Bicarbonate (mmol/l) |
Oxalate
(μmol/L) |
AST
(U/l) |
ALT
(U/l) |
Bil (T)
(mg/dL) |
Baseline |
45 |
4.1 |
137 |
4.1 |
9.8 |
23 |
-- |
22 |
-- |
-- |
ED |
98 |
9.8 |
131 |
6.8 |
9.1 |
18 |
14 |
20 |
18 |
0.9 |
Day 3 |
78 |
7.3 |
136 |
4.3 |
9.7 |
23 |
10 |
-- |
-- |
-- |
Discharge |
61 |
6.0 |
138 |
4.5 |
9.6 |
24 |
7 |
18 |
18 |
-- |
Table 3. Urine analysis
Date |
Appearance |
Specific gravity |
pH |
Protein
mg/dl |
Glucose |
Ketone |
Occult blood |
Baseline |
yellow, clear |
1.010 |
6.5 |
100 |
-- |
-- |
-- |
ER |
yellow, clear |
1.010 |
6.1 |
150 |
-- |
-- |
+ |
|
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Bacteria |
Baseline |
0.1 |
-- |
0 |
0-5 |
-- |
waxy |
-- |
ER |
0.1 |
-- |
0-5 |
5-10 |
-- |
waxy |
-- |
CXR (at ED): Mildly enlarged heart size with a cardiothoracic ratio of 0.55. Mild blunting of the costophrenic angles.
EKG: Sinus rhythm with hyperacute T waves.
Renal ultrasonography: Bilateral small kidneys with uneven renal cortical surface, Right: 9.6 cm, Left: 9.7 cm. Increased renal echogenicity with significant nephrocalcinosis of both kidneys. No hydronephrosis, mass or hyperechoic lesion was seen in the pelvis of the kidneys or ureters.
Renal biopsy: Extensive deposition of calcium oxalate crystal in the tubules. Mild to moderate interstitial fibrosis, tubular atrophy, arteriolosclerosis and obsolescent glomeruli were found.
< 病例分析 >
Oxalate(草酸)是許多食物代謝後產生的最終代謝產物，並經由腎絲球排到尿中。當尿中oxalate的濃度升高超到飽和程度，會導致hyperoxaluria，且oxalate會開始結晶，並在renal tubular epithelium、renal tubular lumen、pelvis及ureter造成沈積。一般是以calcium oxalate(草酸鈣)的形式造成微小鈣化，在超音波下會以increased echogenicity、nephrocalcinosis甚至進一步形成結石(草酸鈣)表現。由於腎臟是人體移除oxalate的唯一途徑，因此當腎功能不正常時，就會影響到oxalate的排泄，導致血中oxalate濃度升高，進一步造成hyperoxaluria的發生、增加calcium oxalate沈積，形成一個惡性循環，更惡化腎臟功能。不過也有報告指出hyperoxaluria的發生與否與oxalate結晶並沒有直接相關。在慢性腎病(chronic kidney disease)的病患，oxalate排泄已受到相當程度的影響，若飲食沒有節制，持續且不適當的服用高草酸食物或是高劑量vitamin (尤其是vitamin C)，反而會加速惡化腎功能，這也是本例病患發生急性腎功能惡化的主要原因。當血中oxalate濃度升高(oxalosis)，calcium oxalate也可以在腎臟以外的組織或器官沈積，如血管壁或心臟等。臨床上，oxalosis的嚴重程度與罹患慢性腎病的時間及嚴重程度相關，也被認為是慢性腎病惡化的一個原因。
引起hyperoxaluria的原因(Table 1)包括 1)遺傳性的primary hyperoxaluria。依突變的酵素不同分為三型，診斷primary hyperoxaluria前必須先排除secondary hyperoxaluria 2)腸胃道過度吸收。這尤其常見於腸胃道脂肪吸收異常的病患(如inflammatory bowel disease、pancreatic insufficiency或接受小腸繞道手術)。這是因為正常腸道中的calcium會與oxalate結合，進而減少腸胃道吸收oxalate，但當病患有脂肪吸收異常時，過多未被吸收的脂肪會結合並消耗腸胃道中的calcium，而減少可與oxalate結合的calcium，導致腸胃道吸收過多的oxalate 3)接受腎臟移植的病患。當病患接受腎臟移植後，”恢復”的腎功能開始排出體內過多的oxalate，進而導致hyperoxaluria，甚至可造成calcium oxalate沈積及移植腎功能急速惡化。也有一些primary hyperoxaluria的病患，是在腎臟移植後才被發現罹患primary hyperoxaluria 4)飲食或誤食導致的。因為許多食物帶有相當高含量的oxalate，或誤食ethylene glycol (抗凍劑)。本例病患已罹患慢性腎病、每天將多種蔬菜及水果打汁飲用、合併服用高劑量vitamin C、未有primary hyperoxaluria家族史，再加上超音波及renal biopsy的佐證，因此本病患應為飲食導致的secondary hyperoxaluria，並引起急性腎功能惡化，此外irbesartan的持續服用也可能加重其腎功能的惡化。
診斷hyperoxaluria方面，若以尿路結石表現，需檢驗尿中oxalate、calcium、citrate、sodium、magnesium、urate、urine PH及尿量，腎臟切片若發現calcium oxalate沈積，也可幫助診斷。但這些結果有時仍難以區分遺傳性的primary hyperoxaluria與其他原因造成的secondary hyperoxaluria，因此病史、家族史及飲食習慣在診斷secondary hyperoxaluria相當重要;治療方面，在慢性腎病的病患，主要是以預防為主，需要飲食控制及避免不必要的營養品補充，若是腎功能已嚴重受損，血液透析是可以幫助oxalate的移除，但效率並不佳。
< References >
1. Am J Med. 2013 Sep;126(9):768-72
2. N Engl J Med 2013;369:649-58
3. 腎臟與透析：民國 94 年 17 卷 1 期
Table 1. Cause of Calcium Oxalate Crystal Deposition in the Kidneys
(Modified from Am J Med 2013;126:768-72.)
Primary hyperoxaluria
Type 1, 2 and 3
Increased gastrointestinal tract absorption
Fat malabsorption
Ingestion
High oxalate food
Vitamin C
Ethylene glycol
Post renal transplantation
Renal insufficiency related
|
Case Discussion
繼續教育考題