Reversible Fanconi syndrome after ingestion of a Chinese herbal remedy containing aristolochic acid
Bernd Krumme,
Roland Endmeir,
Maurice Vanhaelen1 and
Dieter Walb
Department of Nephrology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany
1 Laboratory of Pharmacognosy and Bromatology, Institute de Pharmacie, Bruxelles, Belgium
Keywords: Chinese herbs nephropathy; Fanconi syndrome; interstitial nephropathy
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Introduction
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Chinese herbs nephropathy (CHN) has been recognized as a separate entity of renal disease after ingestion of herbal medicine and had been primarily detected in Belgium [1]. It is characterized by a severe interstitial fibrosis, frequently progressing to end-stage renal failure (ESRF) [2]. In addition, tubular dysfunction as well as cellular abnormalities and cancer of the urothelium have been reported [3]. There is a striking histological similarity to the balkan endemic nephropathy, although the latter progresses much more slowly to ESRF [4].
Aristolochic acids, nephrotoxic and carcinogenic compounds have repeatedly been implicated in the pathogenesis of the syndrome [2]. They were recently identified in two patients in the UK who developed end-stage renal disease after ingesting Chinese herb remedies for the treatment of eczema [5].
We describe here a 49-year-old male patient presenting with severe bone pain and proximal myopathy due to Fanconi syndrome, which occurred after ingestion of a Chinese herbal remedy (Akebia 14®, distributed as a herbal food combination in both Europe and the United States). We demonstrate that this Chinese medicine also contained aristolochic acids. The Fanconi syndrome was reversible after interruption of the Chinese remedy.
The present case extends the clinical and pathophysiological spectrum of CHN. It is the first example in Europe of a reversible Fanconi syndrome due to the ingestion of Chinese herbs containing aristolochic acid. It highlights the health hazards of Chinese herbal preparations prescribed for various reasons.
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Case
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A 49-year-old Caucasian man was referred for nephrological evaluation. Four months previously he was found by chance to have renal glucosuria in the presence of a normal glucose tolerance test, an alkaline phosphatase serum level of 141 U/l, a serum creatinine level of 1.61 mg/dl and an erythrocyte sedimentation reaction (ESR) of 3 mm/h. Two months later he was seen by a nephrologist, by which time he had developed progressive joint pain. The following laboratory values were documented: creatinine 1.41.87 mg/dl, hypouricaemia (uric acid 1.4 mg/dl), an elevated serum alkaline phosphatase level (291 U/l) and a renal glucosuria, as well as tubular proteinuria of 813 mg/24 h. Inter-stitial nephritis was diagnosed. A kidney biopsy was refused by the patient. Steroids, 100 mg/day, tapered slowly, failed to improve the joint pain. NSAIDs (diclofenac/ibuprofen) were prescribed. The patient was referred to a rheumatology department for persistent joint pain and subsequently for nephrological evaluation.
On admission, the patient was on 50 mg prednisone per day, diclofenac and nifedipine. He complained of severe pain in both ankles, knees, hips and the vertebral spine, which was barely alleviated by medication. He had a waddling gait accompanied by difficulties in getting up from the sitting position and was unable to walk without crutches. All other clinical findings were normal except an increased blood pressure of 160/80 mm Hg. Upon further questioning, the patient revealed that he had been transiently treated for hyperuricaemia 2 years ago and for prostatism 20 months previously by a Chinese herbal remedy, and 9 months previously by Akebia 14® (eight tablets/day), also a Chinese remedy.
Laboratory examination revealed (normal values in parentheses): ESR 4 mm/h, serum protein electrophoresis normal, phosphate 0.260.39 mmol/l (0.81.6), uric acid 1.7 mg/dl (38), total alkaline phosphatases 449 U/l, creatinine 1.1 mg/dl, intact PTH 87.6 pg/ml (1065), 25 (OH2)D3 19.3 ng/ml (949), 1.25(OH2)D3 3.8 pg/ml (19.967). All other findings, including serum potassium and bicarbonate levels, were normal. The urinary sediment was found to be normal by phase contrast microscopy, with the exception of some granular casts. Urinary protein excretion was <120 mg/24 h, but showed a tubular-type protein distribution on SDS electrophoresis. Glucosuria was 64 g/24 h with normal serum glucose concentrations. There was a massive, generalized aminoaciduria. A test for Bence Jones protein was negative. A bone scan showed an increased bone turnover in the right ankle and in both hips, but was not typical of osteomalacia. A bone biopsy (Prof. Delling, Hamburg) showed moderate osteomalacia and osteoporosis.
The presence of aristolochic acids I and II was demonstrated by high-performane liquid chromatography (HPLC) and by thin layer chromatography in the tablets of Akebia 14® provided by the patient (Figure 1
). Furthermore, the microscopic analysis of the tablets' components indicated that one of the vegetal powders corresponds most probably to the root of an Aristolochia species.

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Fig. 1. Detection at 254 nm of aristolochic acids I and II separated by HPLC. The lower curve shows the chromatogram of aristolochic acids I and II (standard) and the upper curve the chromatogram of an extract of Akebia 14® tablets pre-purified by preparative thin-layer chromatography. Identification was achieved by comparison of UV spectra (data not shown).
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Akebia 14® was withdrawn and the patient was administered calcitriol and oral phosphate. Steroids were tapered over the next 6 weeks. Pain was treated symptomatically. The course was uneventful except for an episode of gastrointestinal bleeding due to a duodenal ulcer. Bone pain disappeared and the patient eventually resumed his professional activities. Fanconi syndrome disappeared, including the components of glucosuria and aminoaciduria. Serum alkaline phosphatase level, parathyroid hormone and the bone scan converted to normal (Figure 2
). Serum creatinine reverted from a peak value of 1.6 mg/dl to 1.34 mg/dl at last follow-up (Cockcroft creatinine clearance 72 ml/min). No cellular abnormalitis were detected in the patient's urine sediment. Blood pressure normalized without medication.

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Fig. 2. The plot shows the course of serum phosphate (normal, 0.81.45 mmol/l), uric acid (normal, 2.47 mg/dl), creatinine (normal, 0.41.3 mg/dl) and alkaline phosphatase [normal, 40170 U/l (right y-axis)] levels of the patient during treatment with calcitriol and oral substitution with phosphate.
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Discussion
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Since the first description of CHN in Belgium, several associated renal lesions have been reported [3,6,7]. In particular, selective and more generalized tubular dysfunction has been described in CHN patients [810], including two cases of reversible Fanconi syndrome in Japan. In the case report of a Japanese man, re-exposure to Chinese crude drugs led to relapse of an acquired Fanconi syndrome [11]. Aristolochic acids, as potential nephrotoxic agents leading to DNA adducts in exposed patients [12], have been implicated in the genesis of the syndrome and been demonstrated in incriminated herbal remedies in Belgium, the UK [5], Japan [9] and recently Taiwan [13].
Our patient presented with severe joint and bone pain and evidence of proximal myopathy, leading to hospitalization in a rheumatology department. Hallmarks of the biochemical findings were hypophosphatemia, hypouricaemia (in the face of previously documented hyperuricaemia), glucosuria, generalized aminoaciduria and tubular proteinuria, five cardinal symptoms of the Fanconi syndrome. In addition, he was deficient in calcitriol and had mild hyperparathyroidism. His joint and bone pain was related to a histological moderate osteomalacia (due to calcitriol and phosphate deficiency), since not only the symptoms of the proximal myopathy (waddling gait) but also the barely treatable severe pain disappeared completely with the administration of calcitriol and phosphate. Our patient did not have hypokalemia and renal tubular acidosis. The final prognosis of kidney damage is as yet unclear.
Our case fits the diagnostic criteria of CHN, adds to the variability of the clinical spectrum of CHN, and is the first example of reversible Fanconi syndrome after ingestion and interruption of an aristolochic acids-containing Chinese remedy in Europe. Progression of renal failure could be stopped by administering steroids to our patient, similar to the experience of a Belgian group. They reported a slower progression of renal failure in CHN patients treated with steroids rather than without [14]. However, the symptoms of the Fanconi syndrome worsened during that time with the ongoing ingestion of the Chinese remedy. They only improved and returned to normal after cessation, thus arguing for a causal relation. Other causes of Fanconi syndrome such as the familial form, multiple myeloma nephrotic syndrome or the ingestion of heavy metals could be ruled out in our patient. Unrecognized sequelae of tubular dysfunction might occur more frequently with aristolochic acid-containing Chinese herbs ingested for shorter periods of time. Health authorities must be involved in the prevention of CHN.
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Acknowledgments
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We thank Drs Bolton and Alsheimer and the Wilhelm Fresenius Klinik Wiesbaden for referring the patient.
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Notes
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Correspondence and offprint requests to: Dr Bernd Krumme, Deutsche Klinik für Diagnostik, Fachbereich Nephrologie, Aukammallee 33, D-65191 Wiesbaden, Germany. 
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Received for publication: 10. 4.00
Accepted in revised form: 2.10.00