Case Discussion      A 67-year-old male patient was admitted to the hospital because of dizziness for 2 days. He had been a vegetarian and had diabetes mellitus for 13 years. He took nateglinide daily and his average fasting plasma glucose was around 120 mg/dL. He had been taking some Chinese herbs to improve liver function for 3 years, despite normal liver function profiles previously. He had been otherwise well until half a year earlier prior to this entry when he began to experience flatulence sensation and poor appetite. There was no weight loss over the 6 months. Two days before this admission, a sudden onset of dizziness developed. The dizziness sensation worsened when he changed position from supine to upright position. The symptom was persistent and could not be relieved by lying down or taking a rest. One day later, he presented to the Emergent Department of this hospital where macrocytic anemia (Hb 8.6 g/dL; mean corpuscular volume [MCV] 106fL) was found. He was ill-looking and leaned on the pillow in the bed. The conjunctivae was pale and leg was mildly edematous. He showed dyspnea with uremic odor. The blood pressure measured at the Emergent Department was 106/56 mmHg which was lower than what he usually recorded. Under the initially diagnosis of macrocytic anemia deficiency which may resulted to long time vegetarian, he was admitted for further management.      The patient did not have tarry or bloody stools, bowel habit change or small-caliber stools over the 6 months. He smoked every day and had a little social drinking. His family history is non-contributory.      At admission, the patient's consciousness was clear and alert. The blood pressure was 130/70 mmHg after he received fluid infusion and blood transfusion at ER. The blood pressure was 110/ 60 mmHg and the heart rate was 85 beats per minute. His conjunctivae were pale. The eye-ground examination showed no prominent of diabetes retinopathy. His breath sound was clear and the heart beats were regular without murmur. The abdomen was soft and flat. There was no abdominal tenderness. His liver and spleen was impalpable. His skin turgor was fair. There was no pitting edema or skin rash. The muscle power and deep tendon reflex were intact. The remainders of physical or neurological examination were unremarkable. < Laboratory data > 1. Hemogram at hospital admission                      WBC /μl RBC M/μl Hb g/dl Hct % MCV fL MCHC g/dl PLT K/μl 4610 2.51 7.6 26.6 106 32.3 189 Meta % Band % Seg % Eos % Baso % Mono % Lym % 0 0 68.6 2.2 0.2 4.1 24.9 2. Biochemistries and electrolytes at hospital admission BUN mg/dl Cre mg/dl Uric acid mg/dl Na mmole/L K mmole/L Ca mmole/L P mg/dl 24.1 2.4 4.7 137 4.6 2.09 2.5 T-Bil mg/dl D-Bil mg/dl Alb g/dl ALT U/L LDH U/L Glucose mg/dL   0.33 3.09 4.1 17 369 98   Variables Folic acid ng/ml Vit B12 pg/ml Fe μg/dl TIBC μg/dl Ferritin ng/ml Result 4.92 295 76 334 513 Normal Value 3.1~12.4 239~931 75~178 275~332 17.9~464 Variables    Stool OB    Ret.    %  Ret. index   HbA1c %                Result (-) 2.07 0.61 5.6   Variables U/O Ccr ml/min Protein loss g/day FEuric acid % FENa % Tubular reabsorption of phosphorus  % Result 2400ml  40 2.2 23.72 2.86 56.4 Normal value     <150 mg/day 5.5~11.1% <1% 83~93% Calculate fractional excretion (FE) of Substance S; FES= urine S * serum creatinine / urine creatinine * serum S 3. Urine Urinalysis at hospital admission Variables Sp Gr. PH Protein mg/dl Glucose g/dl Ketone OB Urobil EU/dl Result 1.015 6.5 100 0.1 - 2+ 0.1 Variables Bil RBC /HPF WBC /HPF Epi /HPF Cast /LPF Crystal Bacteria Result - - 0-2 - Gr(5-10) - - 4. Coagulation profiles at hospital admission BT (surgicut) min PT sec PT INR PTT sec 6 mins 12.7 1.14 26.8 5. Urine electrophoresis Variables Albumin % Alpha-1 % Alpha-2 % Beta % Gama % Result 16.4 15.5 35.3 27.6 5.2 < Course and treatment > After admission, he received folic acid and cobolamin supplement. The serum level of folic acid and Vitamin B12 were within lower limits. The reticulocyte production index and liver function were also within the normal ranges. Urine electrophoresis showed a high proportion of low molecular weight protein. The high FEuric acid, high FENa, and low tubular reabsorption of phosphorus were compatible with Fanconi's syndrome. The serum creatinine was mildly elevated; however, the anemia was severe. His past medical history was notable for taking Chinese herb. Taken together, all the clinical manifestations and laboratory data raised the suspicion of Chinese herbs nephropathy (CHN). Finally, he underwent renal biopsy. The renal specimen revealed marked tubular atrophy with significant interstitial fibrosis. The glomeruli were relatively spared. The pathology showed the classical findings of Chinese herb nephropathy.  < Discussion >            A new renal disease called 'Chinese-herb nephropathy' (CHN) has been reported to occur in women who have ingested slimming pills containing powdered extracts of the Chinese herb Stephania tetrandra (漢防己). Moderate to end-stage renal disease developed, requiring renal replacement therapy by dialysis or transplantation. Phytochemical analyses of the pills revealed the presence of aristolochic acids (AA) (馬兜鈴酸) instead of tetrandrine, suggesting the substitution of ST (漢防己) by Aristolochia fangchi containing nephrotoxic and carcinogenic AA. A typical histological feature of CHN is a progressive interstitial fibrosis leading to a severe atrophy of the proximal tubules, as documented by the urinary excretion rates of markers of tubular integrity (reduction of neutral endopeptidase enzymuria and high levels of microproteinurias). Removal of the native kidneys and ureters in patients with end-stage CHN revealed a high prevalence of urothelial carcinoma (46%). Tissue samples contained AA-related DNA adducts, which are not only specific markers of prior exposure to AA but are also directly involved in tumorigenesis. Exposure to Aristolochia species (馬兜鈴科) is associated with the development of renal interstitial fibrosis and urothelial cancer in humans. Health professionals should be aware that in traditional Chinese medicine, Aristolochia spp. are considered interchangeable with certain other herbal ingredients and are also sometimes mistaken for ST (漢防己), Akebia (木通莖精華), Asarum (細辛), Clematis spp. (鐵線蓮屬) and Cocculus spp. (木防己屬) in herbal remedies.    < References > Nortier JL, Vanherweghem JL. Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). Toxicology 2002;181-182:577-80. Guh JY, Chen HC, Tsai JF, Chuang LY. Herbal therapy is associated with the risk of CKD in adults not using analgesics in Taiwan. Am J Kidney Dis 2007;49:626-33. Hong YT, Fu LS, Chung LH, Hung SC, Huang YT, Chi CS. Fanconi's syndrome, interstitial fibrosis and renal failure by aristolochic acid in Chinese herbs. Pediatr Nephrol 2006;21:577-9.                         繼續教育考題 1. (E) 中草藥腎病變(Chinese herb nephropathy; CHN)典型臨床症狀是，何者正確？ A 腎衰竭常在毫無預期之情況下被發現 B 血壓通常正常或稍高 C 貧血較嚴重相對於腎功能之程度 D 尿液檢查無或輕微蛋白尿 E 以上皆是 2. (B) Fanconis'腎病變典型臨床症狀是，何者錯誤？ A Proximal renal tubule defect  B Oliguria C Wasting of many solutes such as glucose, amino-acids D Usually secondary to a systemic disease 3. (C) 典型的中草藥腎病變(CHN)病理變化，何者錯誤？ A 廣泛性的腎小管間質組織纖維化 B 腎小管嚴重萎縮及細胞消失 C 腎絲球本身構造不完整的 D 通常侵襲近端腎小管 4. (B) 下列哪些中草藥會造成腎病變，何者錯誤？ A 馬兜鈴 B 龍膽瀉肝湯 C 關木通 D  廣防己 5. (D) 中草藥腎病變(CHN)典型描述，何者錯誤？ A CHN develops as early as 2 months after exposure to the slimming regimen and as late as 3 years after discontinuation of the drug B The course to end-stage renal disease is subacute and faster than in other tubulointerstitial nephropathies C Rate of progression was inversely related to the duration of treatment with the Chinese herbs and seems to be dose- related. D The striking absence of an interstitial infiltrate suggests that steroid treatment would be benefical. 6. (C) 中草藥腎病變(CHN)典型描述，何者錯誤？ A The development of multifocal, recurrent papillary transitional cell carcinomas of the urothelium and bladder remains the most feared complications of CHN B Treatment of patients with these disorders requires continued vigilance, frequent urinary cytological evaluation, and scheduled cystoscopy for a lengthy period of time. C Some of the clinical aspects and morphological changes of CHN are different from the changes found in Balkan endemic nephropathy. D The proximal tubular lesions induced by daily aristolochic acid are characterized biochemically and histologically. 答案解說 它典型臨床症狀是不明原因的腎衰竭，腎衰竭常在毫無預期之情況下被發現，除了服用含中草藥的病史外，並無其他可查出來的原因，血壓通常正常或稍高，貧血較嚴重相對於腎功能之程度，尿液檢查無或輕微蛋白尿，無顯著尿液沈渣有時會有尿糖。雖然停藥，但腎功能的惡化會繼續進行且速度很快。 The Fanconi Syndrome is a generalized proximal tubule defect leading to urinary wasting of many solutes, such as glucose,amino-acids, phosphates and bicarbonates, that results in polyuria, growth failure and resistant rickets. It is an uncommon tubulopathy and is usually secondary to a systemic disease, metabolic disorder or drug toxicity.　 腎臟典型的病理變化是很廣泛性的腎小管間質組織纖維化，腎小管嚴重萎縮及細胞消失，而腎絲球本身構造是完整的，與區域性巴爾幹半島腎病變相似。這種病理變化明顯與一般藥物引起之腎間質腎炎明顯不同，因此才稱為中藥腎病變。 Aristolochic acid-associated nephropathy (馬兜鈴酸AAN) has been identified as a separate entity of progressive tubulo-interstitial nephropathy. Its characteristic pathological findings, including hypocellular interstitial fibrosis, intimal thickening of interlobular and afferent arterioles with glomeruli sparing or mild sclerosis, have been identified.