< Presentation of Case >
A 38-year-old woman presented to the clinic with an excessive urine amount for about two weeks. This otherwise well woman has been diagnosed as having bipolar disorder for 5 years and currently receiving regular follow-up and olanzapine and lithium carbonate (400 mg/day) as an outpatient. Three weeks earlier prior to this visit, she started to experience significantly increased daily urine frequency/amount. She denied any symptoms suggestive of urinary tract infection, such as dysuria, burning sensation, suprapubic or flank soreness/pain. This increased urine frequency/amount greatly disturbed her life quality. She visited a urology clinic where urinary tract infection was excluded (see laboratory results). Therefore, she was transferred to the nephrology clinic for further management. She denied a history of exposure to heavy metal, toxic chemical substances or Chinese herbs. She occasionally drank alcohol and smoked.There was no family history of kidney disease or other systemic diseases.
At outpatient clinic, the physical examination revealed a well-developed middle-age woman without ill-looking. The height was 158 cm and weight 55 kg. The heart rate was 88 bpm, the temperature 36.7 ℃, and the blood pressure 112/68 mmHg in the absence of distress. There was no pale conjunctiva or icteric sclera. The tongue and oral mucosa were dry with sticky saliva. The heart beats were regular without murmurs. Auscultation of the lungs was normal. Abdominal examination was normal. No lower leg edema was noted but she appeared in moderatedly dehydrated status. The daily urine output was approximately 4 liters. She was admitted for intensive monitoring.
< Laboratory and Image Study >
1. CBC and differential count
Date |
WBC
K/μL |
Hgb
g/dL |
MCV
fL |
MCHC
% |
Hct
% |
Plt
K/μL |
Band
% |
Seg
% |
Lym
% |
OPD |
6.82 |
14.5 |
91 |
32 |
42.6 |
480 |
0 |
64 |
1.6 |
2. Biochemistry
Date |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
Ca mg/dl |
Glucose
mg/dl |
Albumin
g/dl |
URO OPD |
45 |
2.1 |
150 |
5.2 |
N/A |
125 |
N/A |
OPD |
49 |
2.2 |
151 |
5.1 |
11.6 |
N/A |
4.1 |
Admission-1 |
37 |
2.1 |
147 |
4.9 |
10.6 |
N/A |
N/A |
Admission-2 |
29 |
1.8 |
144 |
4.7 |
10.1 |
N/A |
N/A |
Previous renal function was within normal limit, blood glucose: random sampling
N/A: not applicable
3. Urinalysis
Date |
Appearance |
Specific gravity |
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult blood |
URO OPD |
yellow, clear |
1.001 |
6.5 |
-- |
-- |
-- |
-- |
OPD |
yellow, clear |
1.001 |
6.7 |
-- |
-- |
-- |
-- |
Admission-1 |
yellow, clear |
1.003 |
6.6 |
-- |
-- |
-- |
-- |
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells |
Cast |
Bacteria |
URO OPD |
0.1 |
-- |
<5 |
-- |
-- |
-- |
-- |
OPD |
0.1 |
-- |
<5 |
-- |
-- |
hyaline |
-- |
Admission-1 |
0.1 |
-- |
-- |
-- |
-- |
hyaline |
-- |
OPD-1: Urine osmolality: 180 mosm/kg H2O, plasma osmolality: 327 mosm/kg H2O
4. Li concentration at nephrology OPD: 2.3 mEq/L (0.6-1.2 mEq/L)
5. Renal sonography: Bilateral kidneys were of normal size. No obvious cystic lesion or mass was identified. No hydronephrosis. Compatible with parenchymal renal disease.
< Course and Treatment >
Based on the history and laboratory results, she was diagnosed as having lithium-induced polyuria or nephrogenic diabetes insipidus (NDI). Lithium carbonate was discontinued immediately and she was educated to drink more free water by herself in addition to daily infusion of 500 ml 5% Dextrose solution and low sodium diet. Three days after admission, her laboratory results improved gradually and she was discharged. Five days after discharge, she was prescribed with amiloride 5 mg daily without much effect on the daily urine amount. Her polyuria gradually resolved three weeks after discharge and amiloride was discontinued as well. She was transferred back to psychology department for further follow-up.
< Analysis >
Lithium常使用於biploar disorder的病患，lithium除了會造成較為人知的nephrogenic diabetes insipidus (NDI，polyuria無法對ADH治療產生反應)外，也會造成如renal tubular acidosis、chronic interstitial nephritis、acute renal failure或nephrotic syndrome。Lithium在腎絲球可被輕易的濾過，接著在collecting duct蓄積，之後在如同Na一般被重吸收，最後在medulla被濃縮，lithium-induced polyuria多是因為直接抑制了ADH在collecting duct的水分重吸收作用。臨床上使用lithium的病患有高達40%會表現polydipsia，而有近20%會表現polyuria(尿量超過3L/day)，雖然如此，但臨床上並不常見尿量多到需要立即停藥的病患。多數的li-induced NDI，在停藥後即會逐漸改善，但仍有病患的NDI在停藥後持續polyuria數年。由於尿量可同時由ADH及尿中溶質(主要是Na、K及urea)，因此在考慮治療lithium-induced polyuria時，就可利用這特性來選擇治療。臨床上lithium-induced NDI可使用amiloride，雖然amiloride亦屬於一種利尿劑，但使用amiloride可改善lithium-induced NDI病患腎臟的尿液濃縮功能及減少尿量。其作用機轉主要是基於lithium及Na在腎臟的相似特性。因為amiloride抑制distal tubule的上皮鈉離子通道 (epithelia Na channel)，進而阻斷distal tubule的Li重吸收。因為在腎小管lithium的特性如同Na一般，在distal tubule會被上皮鈉離子通道重吸收，因此當amiloride阻斷Na的重吸收時，也同時阻斷了lithium的重吸收，如此可進而降低lithium在腎臟中的濃度，以減低lithium對腎臟的傷害。利用amiloride的利鈉特性，且同時再輔以低鈉飲食，就可引起輕度的extracellular fluid (ECF)流失，進而導致GFR下降而接著減少尿量。因此雖然amiloride是利尿劑，但藉由其利尿及利鈉的作用反而可以治療polyuria，且同時並不會增加lithium的濃度。不過並非所有利尿劑都有相同的效果，雖然文獻中可見到以thiazide治療lithium-induced polyuria，但thiazide會增加血中lithium的濃度，所以並不建議當做第一線藥物。此外也有報告使用indomethacin來治療lithium-induced polyuria，原因是indomethacin屬於NSAID，可降低GFR及抑制urinary prostaglandin的合成。由於prostaglandin會抑制ADH在腎小管的作用，因此部份病患或也可使用indomethacin治療。不過由於這些病患被診斷時常已伴隨腎功能不正常，因此在使用indomethacin治療時，要特別注意，所以也不建議當做第一線藥物。
< References >
- Primer on Kidney Diseases. 4th edition.
- Clin J Am Soc Nephrol 3:1324-1331, 2008
- The Netherlands Journal of Medicine 2001;58:137-142
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Case Discussion
繼續教育考題