Aristolochic acid-induced Fanconi's syndrome and nephropathy presenting as hypokalemic paralysis

CASE REPORT

Aristolochic Acid–Induced Fanconi’s Syndrome and Nephropathy Presenting as Hypokalemic Paralysis Sung-Sen Yang, MD, Pauling Chu, MD, PhD, Yuh-Feng Lin, MD, An Chen, MD, PhD, and Shih-Hua Lin, MD ● Hypokalemic paralysis rarely is seen as the presenting feature in patients with Fanconi’s syndrome. We describe a 60-year-old man who presented with the inability to ambulate on awakening in the morning. The pertinent history revealed he had consumed Chinese herbs for leg edema for 5 months. Physical examination was unremarkable except for extracellular fluid volume depletion and total paralysis of both lower extremities. Laboratory investigation showed hypokalemia (1.8 mEq/L), hyperchloremic metabolic acidosis (Clⴚ, 111 mEq/L, and HCO3ⴚ,14.0 mEq/L), hypophosphatemia (0.9 mg/dL) with hyperphosphaturia, hypouricemia (1.3 mg/dL) with hyperuricosuria, and glycosuria, consistent with Fanconi’s syndrome. Mild renal insufficiency (serum creatinine, 1.7 mg/dL) also was noticed. Blood and urine screens for heavy metals, autoantibodies, and monoclonal gammopathy were negative. A renal biopsy specimen revealed typical findings of aristolochic acid–associated nephropathy. Aristolochic acids were detected in the consumed Chinese herbs. This case highlights that consumption of Chinese herbs containing aristolochic acids may cause Fanconi’s syndrome and should be considered as a cause of hypokalemic paralysis. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: Aristolochic acids (AAs); Chinese herb; Fanconi’s syndrome; hypokalemic paralysis.

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YPOKALEMIC paralysis is a potentially reversible cause of acute muscle weakness associated with low serum potassium levels. Although potassium replacement therapy usually is required to hasten recovery and to avoid the life-threatening complications of cardiac arrhythmia and respiratory failure, a vigorous search for the underlying cause is mandatory to avoid missing a treatable cause.1 Hypokalemic periodic paralysis resulting from an acute shift of potassium into cells is a major diagnostic entity. Among hypokalemic periodic paralysis, familial periodic paralysis is the most common cause in Western countries, whereas thyrotoxic periodic paralysis is the most common cause in Asia.2 Excessive renal excretion of potassium also is a cause of hypokalemic paralysis.3 To the best of our knowledge, Fanconi’s syndrome rarely has been reported as a cause of hypokalemic paralysis. We describe a 60-year-old man who manifested acute hypokalemic paralysis resulting from Fanconi’s syndrome induced by the use of Chinese herbs containing aristolochic acids (AAs). CASE REPORT A 60-year-old Chinese man presented to the emergency department with muscle weakness and the inability to ambulate on awakening in the morning. He had noticed mild weakness of his lower extremities for 2 days. He denied anorexia, nausea, vomiting, or diarrhea. He did not take any other medicines. Five months before admission, he started to take a Chinese herb mixture with unknown components in

powder called Kidney-Protection, 4 g four times a day, whenever he noticed leg edema, presumably resulting from alcoholic liver disease. At that time, normal renal function was noted. The family history was noncontributory. Physical examination showed blood pressure, 120/70 mm Hg; pulse rate, 92 beats/min; respiratory rate, 18 breaths/ min; and temperature, 37.1°C. His consciousness was alert, and extracellular fluid volume apparently was contracted. Neurologic examinations indicated that the muscle strength of the lower extremities was paralyzed with areflexia and that of the upper extremities was 2/5 normal with decreased bicep reflexes. The remainder of the physical examination was unremarkable. Routine blood studies revealed hemoglobin, 11.2 g/dL; white cell count, 7,800/␮L; and platelet count, 110,000/␮L. Urinalysis showed pH 6.5, protein (3⫹), glucose (3⫹), and negative Bence-Jones protein. The relevant biochemistry on admission is shown in Table 1. Albumin, 3.7 g/dL; aspartate aminotransferase, 85 IU/L; alanine transaminase, 34 IU/L; and creatinine phosphokinase, 657 IU/L were noted. Plasma thyroid function tests were within normal limits. Abdominal sonography revealed a fatty liver and bilaterally normal kidney size with increased renal echogenicity.

From the Division of Nephrology, Department of Medicine, and Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Received August 1, 2001; accepted in revised form November 9, 2001. Address reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, No. 325, Section 2, Chung-Kung Road, Neiho 114, Taipei, Taiwan. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 1523-6838/02/3903-0025$35.00/0 doi:10.1053/ajkd.2002.31425

American Journal of Kidney Diseases, Vol 39, No 3 (March), 2002: E14

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YANG ET AL Table 1.

Serial Biochemical Studies in a Patient Taking Chinese Herb Admission

Plasma pH Na⫹ (mEq/L) K⫹ (mEq/L) Cl⫺ (mEq/L) HCO3⫺ (mEq/L) Uric acid (mg/dL) Inorganic P (mg/dL) Glucose (mg/dL) BUN (mg/dL) Creatinine (mg/dL) Protein (g/dL) CPK (IU/L) Urine pH Glucose Protein Na⫹ (mEq/d) K⫹ (mEq/d) UAG (mEq/L) UOG (mOsm/kg H2O) FE(PO4) (%) FE(UA) (%) TTKG

1M

6M

7.33 136 1.8 111 14.0 1.3 0.9 104 7.0 1.7 7.4 657

7.32 7.34 140 142 3.0 2.8 110 102 17.0 18.0 1.4 3.6 1.5 2.2 106 128 11.0 18.0 1.9 2.5 — — 55 —

6.5 3⫹ 3⫹ 108 48 16 77 70 69 8.0

7.0 3⫹ 2⫹ 102 75 34 64 32 55 6.3

5.0 2⫹ 2⫹ 160 90 28 70 45 52 7.4

Abbreviations: UAG, urine anion gap ⫽ urine ([Na⫹]⫹[K⫹]⫺[Cl⫺]); UOG, urine osmolar gap ⫽ [(measured ⫺ calculated) urine osmolality]; FE(PO4), fractional excretion of phosphate [(UPO4 ⫻ PCr)/(PPO4 ⫻ UCr)] ⫻ 100; FE(UA), fractional excretion of uric acid [(UUA ⫻ PCr)/(PUA ⫻ UCr)] ⫻ 100; TTKG, transtubular potassium concentration gradient [(U/P[K⫹])/(U/P[Osm])].

Fanconi’s syndrome was established based on the laboratory findings. Aggressive potassium chloride supplementation, 160 mEq/d, was given to treat hypokalemic paralysis. The patient’s muscle strength increased 1 day after potassium chloride supplementation. When plasma K⫹ reached 3.6 mEq/L, an intravenous bicarbonate loading test (2 to 3 mEq/h) was employed to test hydrogen secretion function of the renal tubules. It revealed increased fractional excretion of bicarbonate (30.8%) at plasma HCO3⫺ 24 mEq/L and urine-blood carbon dioxide gradient (⌬U-B PCO2) 30 mm Hg at urine pH 7.6. Immunologic surveys for autoantibodies and complement were negative. Plasma and urine immunoelectrophoresis did not reveal any monoclonal gammopathy. Blood and urine heavy metal analyses, including lead, copper, mercury, and cadmium, were within normal limits. A renal biopsy specimen showed aristolochic acid–associated nephropathy (AAN) characterized by acellular interstitial fibrosis but intact glomeruli (Fig 1). AAs were detected in the herbal mixture using high-performance liquid chromatography (25␮g in each 1 g of herb powder: AA-I, 72%; AA-II, 28%). Determination of glycyrrhizic acid in the consumed herb mixture by high-performance liquid chromatography was negative. The patient was persuaded to stop taking herbs and was put on oral potassium citrate (6.5 g /d) and active vitamin D3 (0.25 ␮g/d) for irreversible Fanconi’s syndrome. No paralysis occurred, but plasma potassium levels were subnormal after continuing the same dose of potassium citrate and active vitamin D3 supplementation. The patient’s renal function remained substantially impaired (Table 1).

DISCUSSION

Although the differential diagnosis of hypokalemia is extensive, the causes of hypokalemic paralysis are much more narrow. Lin et al4 reported that the measurement of blood and uri-

Fig 1. Photomicrograph of renal biopsy specimen shows acellular interstitial fibrosis but intact glomeruli. (H&E, original magnification ⴛ250.)

ARISTOLOCHIC ACID NEPHROPATHY AND FANCONI’S SYNDROME Table 2.

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Chinese Herb–Induced Fanconi’s Syndrome Case No.

Reference Age/sex Hemoglobin (g/dL) pH Na⫹ (mEq/L) K⫹ (mEq/L) Cl⫺ (mEq/L) HCO3⫺ (mEq/L) BUN/Cr (mg/dL) Urine pH Purpose Duration (mo) Intake (g/d) Renal function reversible AAs (␮g/g herb)

1

2*

3

4

5

6

7

8*

8 35/M 14.8 7.29 134 3.4 105 19 17/1.7 5.0 Obesity 2 — No (⫹/⫺)†

9 66/M — 7.38 128 1.0 103 14 52/3.7 7.0 — — — Yes ND

10 43/F 13.6 7.37 140 3.4 112 20 13.8/1.1 6.5 Limb coldness 24 6.0 No 3.1

10 60/M 11.0 — 140 2.8 109 19 16.6/2.0 — Limb coldness 8 6.0 No 15.1

10 19/F 7.2 — — 3.0 — 15 24/3.7 — — 48 — No 77

10 34/M 6.8 — — 3.7 — 20 28/2.1 — — 24 2.0 No (⫹)

11 49/M — — — — — — —/1.6 — — — — Yes (⫹)

Present case 60/M 11.2 7.33 136 1.8 111 14 7.0/1.7 6.5 Leg edema 5 16.0 No 25

Abbreviations: BUN, blood urea nitrogen; Cr, creatinine; AAs, aristolochic acids; ND, not done. *Case with hypokalemic paralysis. †Aristolochiace herb might be one of the components.12

nary electrolytes and acid-base parameters may provide potentially valuable clues to help make a differential diagnosis. In this case, hyperchloremic metabolic acidosis with high urinary K⫹ excretion (high transtubular potassium concentration gradient, 8.0) was noted initially. The possibility of hypokalemic periodic paralysis, such as thyrotoxic, familial, or sporadic periodic paralysis, was ruled out because it usually presents with normal acid-base and low urinary K⫹ excretion. The causes of metabolic alkalosis and excessive K⫹ wasting, such as primary aldosteronism, diuretic abuse, and Bartter’s or Gitelman’s syndrome, also were excluded. Positive urine anion gap (⫹16 mEq/L) and low urine osmolar gap (77 mEq/L), an index of low NH4⫹ excretion, point to the diagnosis of renal tubular acidosis, however.5 The diagnosis of Fanconi’s syndrome was made based on the findings of glucosuria with normal blood glucose level, hypouricemia and hypophosphatemia with high fractional excretion rate of uricosuria, phosphaturia, and proteinuria (Table 1).6 Impaired proximal hydrogen secretion was shown by a bicarbonate loading test with increased fractional excretion of bicarbonate (30.8%). Fanconi’s syndrome can be inherited or acquired.6 Because there was no family history and the mature age of onset, the inherited type could

be ruled out in this case. The acquired causes of Fanconi’s syndrome, such as heavy metal-induced nephrotoxicity, renal metabolic disorder, autoimmune disease, and monoclonal gammopathy, were excluded. The Chinese herb as the causative agent of Fanconi’s syndrome in this case is supported by the following: First, the patient had a pertinent history of Chinese herb use before the development of Fanconi’s syndrome. Second, AAs, which have been assumed to be the major culprit for Chinese herb–induced nephropathy first reported by Vanherweghem JL et al,7 were detected in the consumed herbal mixture. Third, there have been several reported cases describing the association of Fanconi’s syndrome with the use of Chinese herbs (Table 2).8-12 A similar case of Fanconi’s syndrome and hypokalemic paralysis was reported by Lee et al.9 No further information about the components of the herb or detection of AAs was mentioned in their report, however, and the renal function was reversible after the herb was withdrawn. AAN has two clinical variants: subacute renal failure with severe anemia and Fanconi’s syndrome. In the former group,7,13,14 women are affected predominantly. The anemia is relatively more severe than in other kidney diseases with similar degrees of renal failure. In the latter

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group, male-to-female ratio (8:5) was slightly higher than that reported from Japanese patients (4:5).12 Mild-to-moderate anemia and renal function impairment usually are discovered only after admission. Hypokalemia usually was present. Most cases of AAN with Fanconi’s syndrome have been reported in Asian countries8-10,12; only one has been reported from Europe until now.11 The discrepancy might be due to the difference in constituents, the amount of ingested AAs, the racial difference, and the unknown phytotoxins interacting with AAs.15 In both groups, most patients experience a permanent decline of renal function, and AA-containing herb usage often is mentioned. The duration of herb consumption ranges from 2 to 48 months.7-12,14 Hypokalemia in Fanconi’s syndrome usually is mild to moderate in degree.16 Profound hypokalemia (1.8 mEq/L) with muscle paralysis and rhabdomyolysis was the presenting feature in this case. The cause of hypokalemia in Fanconi’s syndrome is basically due to low potassium intake and renal potassium wasting. The renal potassium wasting may be due to the following: First, bicarbonaturia resulting from impaired proximal tubule bicarbonate reabsorption would increase urine potassium loss.17 Second, increased distal delivery of sodium from reduced proximal sodium reabsorption leads to extracellular fluid volume depletion and secondary hyperaldosteronism.18 Third, impaired distal hydrogen secretion causing compensatory hypersecretion of potassium in distal renal tubules is possible. Urine pH is variable in patients with proximal renal tubular acidosis, depending on the severity of the metabolic acidosis. Urine pH is usually less than 5.3 when metabolic acidosis is severe in proximal renal tubular acidosis.18 In this case, however, urine pH was greater than 5.3 (6.5) with markedly low serum bicarbonate (14 mEq/ L), reflecting coexisting impaired distal hydrogen excretion. This is supported by the finding of subnormal ⌬U-B PCO2 (30 mm Hg) in the bicarbonate loading test of this patient.19 Finally, the patient took Chinese herbs to treat his leg edema based on the belief of its diuretic action. The effect, albeit unproven, may cause more K⫹ excretion, worsening the degree of hypokalemia. Although licorice commonly is used in Chinese herbs and can cause hypokalemia,1 glycyrrhizic acid, contained in the licorice, was not detected

YANG ET AL

from the consumed herb mixture. All of these above-mentioned factors found in this case could lead to profound hypokalemia if the potassium intake were not increased simultaneously. Acute treatment of Fanconi’s syndrome– associated paralysis requires only K⫹ supplementation at first.1 Aggressive correction of metabolic acidosis with bicarbonate infusion would lower plasma potassium concentration further because of alkali-induced potassium shift20 and possibly urine potassium losses resulting from bicarbonaturia.17 Long-term treatment is directed toward the consequences of excessive urinary loss of electrolytes and bicarbonate. Treating with potassium citrate, active vitamin D, phosphate supplement, and sufficient fluid intake would reduce the complications of metabolic acidosis, electrolyte imbalance, osteomalacia, and volume depletion.21 In conclusion, we describe a 60-year-old man who presented with hypokalemic paralysis and irreversible subacute renal failure after taking unknown components of mixed crude Chinese herbs containing AAs. AAN may be the cause of Fanconi’s syndrome and present as hypokalemic paralysis. Reviewing the contents in Chinese herbs and avoiding those with AAs or unknown components may prevent this complication. REFERENCES 1. Stedwell RE, Allen KM, Binder LS: Hypokalemic paralyses: A review of the etiologies, pathophysiology, presentation, and therapy. Am J Emerg Med 10:143-148, 1992 2. Ko GTC, Chow CC, Yeung VTF, Chan HHL, Li JKY, Cockram CS: Thyrotoxic periodic paralysis in a Chinese population. QJM 89:463-468, 1996 3. Halperin ML, Kamel KS: Potassium. Lancet 352:135140, 1998 4. Lin SH, Lin YF, Halperrin ML: Hypokalemia and paralysis. QJM 94:133-139, 2001 5. Smulders YM, Frissen PH, Slaats EH, Silberbusch J: Renal tubular acidosis: Pathophysiology and diagnosis. Arch Intern Med 156:1629-1636, 1996 6. Roth KS, Foreman JW, Segal S: The Fanconi syndrome and mechanisms of tubular transport dysfunction. Kidney Int 20:705-716, 1981 7. Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R: Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet 341:387-391, 1993 8. Izumotani T, Ishimura E, Tsumura K, Goto K, Nishizawa Y, Morii H: An adult case of Fanconi syndrome due to

ARISTOLOCHIC ACID NEPHROPATHY AND FANCONI’S SYNDROME

a mixture of Chinese crude drugs. Nephron 65:137-140, 1993 9. Lee CT, Wu MS, Lu K, Hsu KT: Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure—a rare presentation of Chinese herbal nephropathy. Ren Fail 21:227-230, 1999 10. Tanaka A, Nishida R, Yokoi H, Kuwahara T: The characteristic pattern of aminoaciduria in patients with aristolochic acid-induced Fanconi syndrome: Could aminoaciduria be the hallmark of this syndrome? Clin Nephrol 54:198202, 2000 11. Krumme B, Endmeir R, Vanhaelen M, Walb D: Reversible Fanconi syndrome after ingestion of a Chinese herbal ‘remedy’ containing aristolochic acid. Nephrol Dial Transplant 16:400-402, 2001 12. Tanaka A, Nishida R, Yoshida Y, Koshikawa M, Goto M, Kuwahara T: Outbreak of Chinese herb nephropathy in Japan: Are there any difference from Belgium? Int Med 40:296-300, 2001 13. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL: Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 24:172-180, 1994 14. Yang CS, Lin CH, Chang SH, Hsu HC: Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 35:313-318, 2000

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15. Tanaka A, Nishida R, Maeda K, Sugawara A, Kuwahara T: Chinese herb nephropathy in Japan presents adultonset Fanconi syndrome: Could different components of aristolochic acids cause a different type of Chinese herb nephropathy? Clin Nephrol 53:301-306, 2000 16. Sebastian A, McSherry E, Morris Jr RC: Renal potassium wasting in renal tubular acidosis (RTA): Its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. J Clin Invest 50:667-678, 1971 17. Sebastian A, McSherry E, Morris Jr RC: On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA). J Clin Invest 50:231-243, 1971 18. Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorder (ed 5). New York, McGraw-Hill, 2001, pp 612-627 19. Gougoux A, Vinay P, Lemieux G, Richardson RM, Tam S, Goldstein MB, Stinebaugh BJ, Halperin ML: Effect of blood pH on distal nephron hydrogen ion secretion. Kidney Int 17:615-621, 1980 20. Bia MJ, DeFronzo RA: Extrarenal potassium homeostasis. Am J Physiol 240:F257-268, 1981 21. Johannes B: Fanconi syndrome, in Davison AM, Cameron JS, Grunfeld JP, Kerr DNS, Rits E, Winearls CG (eds): Oxford Textbook of Clinical Nephrology. New York, NY, Oxford Medical Publications, 1998