Case Discussion      A 75-year-old male has been diagnosed as having hypertension (HTN) for 15 years for which he received atenolol and aspirin regularly. He had been otherwise healthy and the latest annual health check 6 months prior to this admission revealed blood urea nitrogen (BUN) and serum creatinine (Cr) of 21 mg/dl and 1.5 mg/dl, respectively. Three months before this admission, he had a traffic accident that resulted in fracture of the left hip joint. After surgery, he was prescribed with a non-steroid anti-inflammatory agent (NSAID) for pain control which he took for almost 1.5 months without interruption. Three weeks prior to the admission, he noted foamy urine, decreased urine output, lower leg edema, skin rash and facial swelling. One week prior to the admission, he visited a local clinic where severe proteinuria by urine dipstick test and impaired renal function were found; BUN was 36 mg/dl and Cr, 2.8 mg/dl. Furosemide was given and he was referred to our out-patient clinic (OPD). At OPD, he had clear consciousness. His blood pressure was 136/78 mmHg, pulse rate was 72 beats per minute, respirations 20 breaths per minute, and temperature 36.8oC. The conjunctiva was pink and the sclera was anicteric. Lungs were symmetrically expanded with clear breath sounds. The heart rhythm was regular and no cardiomegaly was detected. Abdominal examination was unremarkable. Moderate pitting edema of the lower extremities was noted. No lymphadenopathy was found at the neck, axillary and inguinal regions. Maculopapular rashes were found on the lower limbs. Laboratory results revealed nephritis-range proteinuria and hypoalbuminemia (Table 2). Based on the impression of nephrotic syndrome of unknown etiology, he was suggested to undergo renal biopsy. The NSAID was discontinued after this visit. < Laboratory and Image Study > Table 1. CBC and differential count Date WBC (K/μL) Hgb (g/dL) Hct (%) Plt (K/μL) Band (%) Seg (%) Eos (%) Baso (%) Lym (%) 5 days prior to the admission 7.4 12.7 36.6 185 N/A N/A N/A N/A N/A day 1 of hospitalization 7.5 12.8 37.1 189 0 60 2.1 0.3 5 OPD follow-up 7.6 12.7 36.4 187 N/A N/A N/A N/A N/A Table 2. Biochemistry  Date BUN (mg/dl) Cre (mg/dl) Na (mmol/l) K (mmol/l) AST (U/l) ALT (U/l) Bil (T) mg/dL Albumin (g/dl) Glucose (mg/dl) 5 days prior to the admission 39 3.5 138 3.8 32 N/A N/A 2.5 140 day 1 of hospitalization 35 3.4 137 3.9 N/A N/A N/A 2.4 120 OPD follow-up 1 27 2.5 139 3.8 N/A N/A N/A 3.0 N/A OPD follow-up 2 24 1.8 137 3.7 N/A N/A N/A 3.3 N/A Table 3. Urine analysis Date Appearance Specific gravity pH Protein (mg/dl) Glucose Ketone Occult blood 5 days prior to the admission foamy, clear 1.011 6.5 >100 -- -- -- day 1 of hospitalization foamy, clear 1.013 6.6 >100 -- -- -- OPD follow-up 1 clear 1.011 6.5 30 -- -- -- OPD follow-up 2 clear 1.012 6.8 10 -- -- -- Date Urobilinogen Bilirubin RBC WBC Epithelial cells Cast Bacteria 5 days prior to the admission 0.1 -- 10-20 50-100 1-3 -- -- day 1 of hospitalization 0.1 -- 10-20 50-100 -- -- -- OPD follow-up 1 0.1 -- <10 10 -- -- -- OPD follow-up 2 0.1 -- 1-5 -- -- -- -- 4. 24-hour urine total protein: 3.67 g; urine eosinophils: negative 5. CXR: Normal heart size and clear lung field. 6. Renosonography: Bilateral parenchymal renal disease without hydronephrosis. Normal kidney size. 7. Renal biopsy: Acute cellular infiltration, predominantly with T lymphocytes and particularly with eosinophilia in the interstitum. No tubular atrophy or fibrosis was found. No evidence of glomerular involvement.      < Course and Treatment >      Upon admission, he was treated with diuretics and renal biopsy was performed successfully. The pathology of the renal biopsy specimen suggested acute interstitial nephritis (AIN) which might result from the use of NSAID. His renal function improved gradually after discharge while he was followed as an outpatient. < 病例分析 > Acute interstitial nephritis (AIN)是臨床上一種急性但多為可逆的腎傷害，特徵為在interstitium可見到腫脹及發炎細胞的浸潤，但無纖維化及腎小管萎縮。雖然AIN在急性腎傷害中較不常見，但仍不可忽視，因為隨著病情的需要、人口年紀的老化，drug-induced AIN已成為AIN中重要的病因。雖然臨床上多使用AIN，但acute tubulointerstitial nephritis (ATIN)反而能較為正確的描述此疾病，因為renal tubule及interstitium皆受到影響。大部份的AIN多因由外來的抗原 (如infectious pathogens或藥物)的結構與腎臟本身的抗原類似而產生交互作用或以immune complex而沉澱在interstitium所致，而實驗研究發現cell-mediated immunity在AIN扮演的角色較重要。臨床上統計約有5至15%的acute renal failure是起因於AIN，雖然任何年紀皆可發生，但甚少發生在孩童。常見的AIN發生原因可分為三大類: 與感染相關、與藥物相關及與免疫或腫瘤有關 (Table 4)，在此將只討論drug-induced AIN (Table 5 )，尤其是NSAID相關之AIN。臨床上drug-induced AIN的發生機會與使用的劑量並無絕對關係，且drug-induced AIN多在使用後平均二星期或更長產生，不過也不是絕對。AIN病患的腎臟學表現通常為不具特異性的急性腎傷害症狀，包括oliguria、nausea、vomiting及malaise，但其實臨床表現可從無症狀而只有BUN/Cr的上升到全面性的hypersensitivity syndrome伴隨fever、skin rash、eosinophilia及oliguric renal failure。不同藥物引起之AIN症狀之間並無太大差別，但NSAID-induced AIN(如本例)比其他藥物造成的AIN相比，有更高的比例以nephrotic syndrome表現。而值得注意的是，NSAID-induced AIN多發生在50歲以上的病患，這可能與NSAID常在此族群使用有關。另外，不同NSAID之間引起nephrotic syndrome的可能性也不同，在被報告的病例中，fenoprofen 就約佔了50%。臨床上診斷NSAID-induced AIN不是十分容易，其中清楚的藥物史是最重要的，臨床診斷方法可分為非侵入性及侵入性。非侵入性的方法包括eosinophiluria及gallium scan。當尿中eosinophil數目佔尿中被染色之白血球總數的1%時為陽性，此檢查的優點是簡單且快速，但缺點是不同染色法的sensitivity及specificity不同，且不是每位病患都可發現eosinophil。另外也有報告指出當有AIN時，腎對gallium的吸收會增加，因此可用以診斷AIN，不過要考慮偽陰性及偽陽性且需要更多證據支持。但若病患不適合接受侵入性診斷方法時，可考慮接受Gallium 67 scan。侵入性的腎臟切片是唯一能確定診斷AIN的方法，且也可對預後預測有提供幫助(亦有反對說法)。在病理方面，AIN的最重要的病理變化是interstitium有inflammatory cells的浸潤(以T lymphocytes為主，還有monocytes/macrophages、plasma cells、eosinophils及少數neutrophils)，而浸潤通常是塊狀局部分佈於outer cortex及inner medula，且inflammatory cells的浸潤會造成interstitium腫脹而推擠分離(separate)相鄰的腎小管。治療Drug-induced AIN主要是先停止服用任何可疑藥物並加上支持性治療，預後在停藥後大多不錯，腎功能多可恢復正常或接近正常，至於steroid的使用則意見較分歧，若需要可試一星期prednisolone 1mg/kg/d。本例病患由於年紀大且亦須排除membranous nephropathy，因此安排腎臟切片。 < References > Comprehensive clinical nephrology, 3rd edition. Am Fam Physician 2003;67:2527-34. Kidney International 2001;60:804-17 繼續教育考題 1. (B) 有關AIN臨床上的特徵何種不正確？ A 任何年紀皆可發生 B 預後多不好 C 診斷以病史及切片為主，實驗室檢驗為輔 D 急性但多為可逆的腎傷害 2. (D) 何者是AIN常見的腎臟病理變化？ A Interstitial necrosis B Glomerular obsolescence C Interstitial fibrosis and tubular atrophy D Predominantly T lymphocytes infiltration in the interstitium 3. (C) 當懷疑出現NSAID-induced AIN時，何者是其較特有的臨床表現？ A Skin rash with renal dysfunction B  Eosinophiluria C Nephrotic syndrome D Oliguric renal failure 4. (A) 臨床上能幫助診斷drug-induced AIN的方法中，下列何者最不具特異性？ A Eosinophilia and skin rash B Gallium 67 scan C Renal biopsy and drug history D Eosinophiluria 5. (C) 當病患產生drug-induced AIN時治療方法不包括? A Supportive care B Discontinue culprit drugs C Hemoperfusion to remove drug metabolites D Short-term steroid treatment 6. (D) 當病患產生nephrotic syndrome時，何疾病不須馬上考慮？ A Minimal change disease B Membranous nephropathy C NSAID-induced AIN D IgA nephropathy 答案解說 (B) AIN是臨床上一種急性但多為可逆的腎傷害，特徵為在interstitium可見到腫脹及發炎細胞的浸潤，但無纖維化及腎小管萎縮。任何年紀皆可發生，但甚少發生在孩童。非侵入性的臨床診斷方法包括eosinophiluria及gallium scan。侵入性的腎臟切片是唯一能確定診斷AIN的方法，且也可對預後預測有提供幫助(亦有反對說法)。預後在停藥後大多不錯，腎功能多可恢復正常或接近正常，。 (D) 在病理方面，AIN的最重要的病理變化是interstitium有inflammatory cells的浸潤(以T lymphocytes為主，還有monocytes/macrophages、plasma cells、eosinophils及少數neutrophils)，而浸潤通常是塊狀局部分佈於outer cortex及inner medula，且inflammatory cells的浸潤會造成interstitium腫脹而推擠分離(separate)相鄰的腎小管。 (C) AIN病患的腎臟學表現通常為不具特異性的急性腎傷害症狀，包括oliguria、nausea、vomit及malaise，但其實臨床表現可從無症狀而只有BUN/Cr的上升到全面性的hypersensitivity syndrome伴隨fever、skin rash、eosinophilia及oliguric renal failure。不同藥物引起之AIN症狀之間並無太大差別，但NSAID-induced AIN(如本例)比其他藥物造成的AIN相比，有更高的比例以nephrotic syndrome表現。 (A) 臨床診斷drug-induced AIN，藥物史是非常重要的，臨床診斷方法可分為非侵入性及侵入性。非侵入性的方法包括eosinophiluria及gallium scan，侵入性的腎臟切片則是唯一能確定診斷AIN的方法，且也可對預後預測有提供幫助(亦有反對說法)。至於eosinophilia and skin rash則較不具特異性。 (C) 治療drug-induced AIN主要是先停止服用任何可疑藥物並加上支持性治療，預後在停藥後大多不錯，腎功能多可恢復正常或接近正常，至於steroid的使用則意見較分歧，但若有需要，可試一星期prednisolone 1mg/kg/d。而hemoperfusion並不是治療選項。 (D) IgA nephropathy亦會產生proteinuria但少以nephrotic syndrome表現，而其他三者皆以nephrotic syndrome表現為其特徵。