Case Discussion <Brief History>      A 65 year-old woman had been diagnosed as having diabetes mellitus (DM) with DM nephropathy and hypertension (HTN) for 15 years for which she had been receiving regular daily insulin injection as well as an angiotensin II receptor blocker (ARB). Despite insulin injection, the daily self-monitored glucose before and after meals were around 140 and 180 mg/dl, respectively. In addition to DM and HTN, she also had had recurrent episodes of urinary tract infection (acute pyelonephritis, APN) which might be related to the right ureteral stone; however, she refused to receive any invasive treatment to remove the ureteral stone. She usually visited the emergency room (ER) when fever, chills and flank pain developed to be hospitalized for parenteral antibiotic therapy at local hospitals.      Two months earlier prior to this admission, she began to develop right flank soreness and low grade fevers but without urinary symptoms, and therefore, she paid no attention to it. She also had poor appetite and blood glucose became poorly controlled. Intermittent passage of blood-tinged urine without pain, thirsty, and a weight loss of 4 kg occurred two weeks earlier before admission. On the day of admission, she complained of high fever, chills, breathless, cold sweating, hand tremors and mild right flank pain. There was no urinary frequency, dysuria, burning sensation on urination, chest pain, or bowel habit change. She ever received a 3-day course of an oral fluoroquinolone at a local clinic, without benefit. Physical examination on admission to this hospital revealed an ill-looking, obese but well-developed woman. Heart rate was 95 beats per minute, temperature 37.8 ℃, and blood pressure 146/86 mmHg. Conjunctiva was not pale and sclera was not icteric. Rapid and regular heartbeat was noted, and there was no cardiac murmur. Auscultation of the abdomen showed hyperactive bowel sounds. There was no shifting dullness or hepatosplenomegaly. Mild right flank percussion tenderness was also noted. Other examinations were unremarkable. <Laboratory and Image Study> 1. CBC/DC: Date WBC x 103/μL RBC x 106/μL Hemoglobin g/dL Hematocrit % MCV fL MCH pg MCHC g/dL platelet x 103/μL 2006/8/11 11.3 3.55 9.6 29.2 82.3 27.0 32.9 489 2006/8/15 10.54 3.71 10.1 30.5 82.2 27.2 33.1 423 2006/8/20 9.98 3.73 10.3  30.8 82.3 27 33  422 Date Blast Meta Band Segment Eosinophil Basophil Monocyte Lymphocyte 2006/8/11 0 0 0 78.1 1.4 0.2  4.6 15.7 2006/8/15 0 0 0 75.0 3.4 0.6  4.4 16.6 2006/8/20 0 0 0 75.0 3.8 0.2  4.3 16.7 2. Biochemistry Date Blood Urea Nitrogen (BUN) mg/dl Creatinine mg/dl Na mmol/l K mmol/l Cl mmol/l Ca mmol/l P mmol/l glucose mg/dl 2006/8/11 34 3.43 147.1 4.54 99.0 2.22 4.86 350 2006/8/15 72 6.86 143.0 4.35       280 2006/8/20 72 5.26 139.0 4.31   2.15 4.77 180   GOT (AST), U/l Total/Direct- Bilirubin mg/dl Lactate Dehydrogenase (LDH), U/l C-reactive protein mg/dl 2006/8/11 35.0 0.25/ 537 >12 2006/8/15 37.0   527 10.54  2006/8/20 36.0   497 7.66 3. Urine analysis:  Date Appearance Specific gravity pH Protein mg/dL Glucose g/dL Ketones Occult blood Urobilinogen EU/dL Bilirubin 2006/8/11 Red and turbid 1.020 6.0 >300 - ++ 4+ 0.1 - 2006/8/15 Red and turbid 1.020 6.0 >300 - - 4+ 0.1 - 2006/8/20 Red and turbid 1.026 6.0 >300 - - 4+ 0.1 - Date Nitrite WBC RBC /HPF WBC /HPF Epithelial Cell /HPF Cast /LPF Crystal Bacteria 2006/8/11 + + numerous numerous 10-15 - - + 2006/8/15 - + 30-40 numerous 3-5 - - - 2006/8/20 - + 5-10 5-10 - - - -  ABG (950811): pH 7.25, PCO2 23.1, PO2 137.1, HCO3 9.7, BE -16.1 < Course and Treatment >      Diabetic ketoacidosis (DKA) precipitated by urinary tract infection was diagnosed, and she was treated with intravenous insulin and fluid therapy. ARB was discontinued immediately because of the poor renal function. The blood glucose and renal function improved gradually, and no renal replacement therapy was introduced. However, bacterial culture of the first urine sample yielded growth of mixed flora, and the rest of urine samples were sterile after 2 weeks of incubation. A low grade fever was persistent despite antibacterial therapy. Renal sonography revealed hydronephrosis of the right kidney and scattered calcification in the renal parenchyma, but the ureteral stone was not detectable by sonography. Abdominal computed tomography without administration of contrast medium revealed a moderately dilated right ureter, pelvis, and a ureteral stone; and scattered calcified lesions in the renal parenchyma. Segmental stricture with calcification of the right ureter and a ureteral stone were suspected by retrograde pyelography. Because of sterile urine cultures, a poor response to antibacterial therapy, and segmental stricture of the right ureter, acid-fast smears and mycobacterial cultures of the urine samples were performed, which subsequently yielded growth of mycobacteria. An urologist performed cystoscopy to sample the pus from ureteral orifice in which sample acid-fast smears also showed positive and cultures grew mycobacteria. Anti-tuberculosis agents were administered and the fever and general condition improved later. In addition to tuberculosis of the urinary tract, this patient was also found to have pulmonary tuberculosis by chest X-ray follow-up and positive acid-fast smears of the sputum samples. She subsequently underwent nephrectomy because of non-functioning of the right kidney. < Analysis >       這位病患來院的表現為典型之diabetic ketoacidosis (DKA)，初期治療當以補充insulin，水分及注意電解質平衡為主。由於此病患本有diabetic nephropathy，雖無之前可供比較之檢驗報告，但DKA及ARB可能造成之腎功能之急性惡化，仍需列入考慮，故停用ARB可避免進一步併發症的產生。病患後續治療之方向，應在於探查引起DKA之主要原因。臨床上引起DKA的原因以insulin deficiency、infection or inflammation、ischemia or infarction、pancretitis、cholecystitis及iatrogenic原因等。由於病患平時血糖控制尚屬正常，且無特殊之缺血性相關症狀，但由於有發燒及體重減輕，因此惡性腫瘤、其他內分泌問題及感染等原因皆須考慮。由於感染乃其中較不可拖延之疑似診斷，病患本身為DM患者，屬於immunocompromised status，病患過去有反覆泌尿道感染病史及輸尿管結石，因此優先就泌尿道感染查起。起初病患的尿液檢驗為pyuria、hematuria及bacteriuria，因此初期當作細菌性泌尿道感染治療。但由於第一次尿液培養報告為mixed flora，並無特異菌種，而之後即使換藥也無法完全退燒，治療反應不佳；再加上之後尿液特徵為持續無菌性pyuria、hematuria，因此非典型之病原性之泌尿道感染必須考慮。由於病患輸尿管在retrograde pyelography下呈現segmental stricture且有鈣化現象，因此綜合以上發現，乃進一步針對tuberculosis (TB) 進行檢測。之後在尿液中也發現培養陽性之結核桿菌，因此至此疑似診斷為TB pyelonephritis。在用藥及開刀移除右腎 (幾乎已無功能) 後，病患情況穩定也無發燒，因此轉至門診繼續追蹤。而病理切片及最後培養報告也確定為Mycobacterium tuberculosis 。       泌尿道結核 (genitourinary tuberculosis, GUTB)，是一種常見的肺外結核，通常次發於有症狀或無症狀的原發結核病患身上，而最常見的原發部位仍是肺。病原通常是由原發部位經lymph drainage或血行轉移至腎臟。由於腎臟的血流豐富、腎絲球的O2 saturation及出球動脈端微血管的血液viscosity等，皆易使TB於此發展，腎髓質(renal medulla)是臨床上renal TB最好發的部位。TB在腎臟停留後，引起發炎反應並形成granuloma，但可以在潛伏數年之後又被活化，而當granuloma與renal tubules或pelvis相通時，就有機會在尿中檢測出TB，而後續的恢復通常伴隨著scar formation及狹窄、阻塞的發生。在ureteral orifice的恢復會造成逆流性 ”golf hole” ureter，及甚至引起膀胱的纖維化而引起”thimble bladder”。臨床上GUTB可以完全無症狀或類似其他疾病，大部分病患為20至40歲，而男與女為2比1。危險因子為接觸驗痰陽性的TB病患、流浪漢、社經地位低、immunosuppression、HIV/AIDS、DM及renal failure等。約25%的病患完全無症狀，而是在做其他檢查時發現，另25%的病患則以無症狀性的異常泌尿道檢查表現，通常是asymptomatic pyuria及hematuria。在有症狀性的病患則有75%以下泌尿道症狀表現，如frequency、urgency、dysuria、nocturia、frank pain及hematuria。而某些病患夜尿次數增加是則來自膀胱的發炎反應、膀胱容量減小(timble bladder)、喪失腎臟濃縮尿液功能及acidic urine等造成。有時無痛性gross hematuria也會是GUTB的表現。隨著疾病的進展，接著結石或tissue/blood clot的產生及ureteral stricture都會引起obstruction，甚至產生renal failure。特別的是在男性患者，70至80%會伴隨epididymitis、prostatitis、seminal vesculitis、orchitis、cold abscess或sinuses；在女性則只有5%會伴隨genital tuberculosis。至於constitutional symptoms，如fever、weight loss、night sweats、fatigue及anorexia則只發生在小於20%的患者。GUTB的診斷並不容易，通常需要實驗室檢查確定，50%的患者以sterile pyuria表現，而acid-fast smear並非十分可靠，因此培養是確定診斷的方法，而培養方法是連續將3至5天早晨的尿液送培養。其他如超音波、X-ray、電腦斷層，甚至此病患接受的retrograde pyelography都是輔助診斷及幫助判斷GUTB影響範圍的工具。治療的方法當以藥物為第一線，但須根據腎功能調整劑量。由於anti-TB藥物在泌尿道的濃度高及通常認為GUTB的病灶處菌數較少，因此內科治療通常是可靠的。但當感染無法控制或腎臟以無功能時，才會考慮外科介入，而ureteral stricture則可以repeated stenting處理。 < Reference > Comprehensive Clinical Nephrology. First edition. 繼續教育考題 1. (E) Genitourinary tuberculosis較不會出現的臨床表現為？ A  Flank pain B  Urine frequency C  Hematuria D  Asymptomatic E  Acute pyelonephritis-like symptom 2. (D) 腎臟生理上的何特徵使它成為genitourinary tuberculosis的好發部位之一，何者除外? A  腎臟的豐富血流 B  腎絲球的O2 saturation C  出球動脈端微血管的血液viscosity  D  有cortex及medulla的分別 3. (C) Genitourinary tuberculosis 在男女無差異的臨床表現，不包括？ A  發生年紀 B  發生部位 C  伴隨genital lesions的機會 D  發生症狀 4. (B) 臨床上無痛性巨觀血尿(gross hematuria)需優先考慮何者疾病，除了？ A  Urinary malignancy B  Thin basement membrane disease C  IgA nephropathy D  Post-streptococcal glomerular nephritis (PSGN) E  Genitourinary tuberculosis 5. (D) 何者不是產生genitourinary tuberculosis的危險因子？ A  Renal transplantation B  AIDS C  Renal failure D  接觸genitourinary tuberculosis但sputum acid-fast smear-negative的病患 6. (C) 何者是確定診斷genitourinary tuberculosis的方法？ A  Renal biopsy B  Consecutive acid-fast smears and mycobacterial cultures of urine samples C  Consecutive bacterial culture of urine samples D  Response to empirical anti-tubersulosis therapy E  Imaging study 答案解說 (E)  約25%的病患完全無症狀，而是在做其他檢查時發現；另25%的病患則以無症狀性的異常泌尿道檢查表現，通常是asymptomatic pyuria及hematuria。在有症狀性的病患，則有75%以下泌尿道症狀表現，如frequency、urgency、dysuria、nocturia、frank pain及hematuria。 (D)  由於腎臟的血流豐富、腎絲球的O2 saturation及出球動脈端微血管的血液viscosity等，皆易使tuberculosis於此發展，腎髓質(renal medulla)是臨床上renal tuberculosis最好發的部位。 (C)  臨床上，genitourinary tuberculosis可以完全無症狀或類似其他疾病，大部分病患為20至40歲，而男與女為2比1。在男性患者，70至80%會伴隨epididymitis、prostatitis、seminal vesculitis、orchitis、cold abscess或sinuses；在女性則只有5%會伴隨genital tuberculosis。 (B)  臨床上無痛性巨觀血尿(gross hematuria)需優先考慮urinary malignancy、genitourinary tuberculosis、IgA nephropathy、post-streptococcal glomerular nephritis (PSGN)。而thin basement membrane disease多以microscopic hematuria表現 (D)  臨床上，genitourinary tuberculosis的危險因子為接觸驗痰陽性的tuberculosis病患、流浪漢、社經地位低、immunosuppression、HIV/AIDS、DM及renal failure等。. (C)  Genitourinary tuberculosis的診斷並不容易，通常需要實驗室檢查確定，50%的患者以sterile pyuria表現，而acid-fast smears並非十分可靠，因此培養是確定診斷的方法，而培養方法是連續將3至5天早晨的尿液送培養。其他如超音波、X-ray、電腦斷層及retrograde pyelography都只是輔助診斷及幫助判斷genitourinary tuberculosis影響範圍的工具。