- Email: [email protected]
Acute Renal Failure Induced by a Brazilian Variety of Propolis
CASE REPORT
Acute Renal Failure Induced by a Brazilian Variety of Propolis Yi-Jung Li, MD, Ja-Liang Lin, MD, Chih-Wei Yang, MD, and Chun-Chen Yu, MD ● Propolis is a resinous substance collected by honeybees and used in hive construction and maintenance. Cumulative evidence suggests that propolis may have anti-inflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties. In addition to topical applications, products containing propolis have been used increasingly as dietary supplements. Although reports of allergic reactions are not uncommon, propolis is reputed to be relatively nontoxic. Its systemic toxicity is rarely reported and hence may be underestimated. This is the first report of propolis-induced acute renal failure. A 59-year-old man required hemodialysis for acute renal failure. The patient had cholangiocarcinoma and had ingested propolis for 2 weeks before presentation. Renal function improved after propolis withdrawal, deteriorated again after reexposure, and then returned to a normal level after the second propolis withdrawal. This case indicates that propolis can induce acute renal failure and emphasizes the need for vigilance and care when propolis is used as a medicine or dietary supplement. Am J Kidney Dis 46: E125-E129. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Propolis; acute renal failure.
P
ROPOLIS IS a resinous product collected by honeybees from various plant sources and used in hive construction and maintenance. It has been applied in folk medicine since 300 BC. Cumulative evidence indicates that propolis has various biological activities, such as antiinflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties.1,2 Although reports of allergic reactions, usually contact dermatitis, are not uncommon, propolis is considered to be relatively nontoxic, with a no-effect level at 1,400 mg/kg/d in a murine study.2,3 Systemic toxicity of propolis seldom has been investigated and could be markedly underestimated. In patients with suspected druginduced organ damage, propolis often is regarded as a natural compound and an innocent bystander. Hence, the cause of systemic toxicity usually is unknown and rarely attributed to propolis. This report presents a case of reversible acute renal failure (ARF) caused by propolis in a 59-year-old man with cholangiocarcinoma. Hemodialysis therapy was initiated for ARF. Fortunately, renal function recovered after withdrawal of propolis. However, based on the uncertainty of propolis as the cause of ARF at that time, the patient continued ingesting propolis for underlying cholangiocarcinoma. Renal function deteriorated again after rechallenge and recovered again after withdrawal of propolis. This is the first report of ARF associated with propolis. CASE REPORT A 59-year-old man with a history of colon cancer posthemicolectomy in disease-free status presented to the emergency
department at Chang Gung Memorial Hospital (Taipei, Taiwan) with a report of shortness of breath, little urination, and leg edema for 1 week. Three months before this presentation, the patient had obstructive jaundice caused by newly diagnosed cholangiocarcinoma; his jaundice improved after percutaneous transhepatic cholangiography and drainage. Blood tests at follow-up at the outpatient clinic showed that blood cell counts and renal function were all within normal limits. The patient began taking propolis (Fig 1), 5 mL 3 times/d, 2 weeks before this presentation for the underlying cholangiocarcinoma. The clear propolis preparation was purchased from the drugstore and was not out of date. The patient did not take any other medicine before admission. The patient’s family had used the same propolis preparation without complication. On admission, blood pressure was 120/66 mm Hg, pulse was 106 beats/min, respiratory rate was 26 breaths/min, and temperature was 36.2°C. Physical examination identified pink conjunctiva, mildly icteric sclera, and crackle over bilateral lower-lung fields. Abdominal and cardiac examination findings were normal. There was pitting edema of the ankles. There was no skin erythema or rash. Laboratory results were as follows: white blood cells, 7,700/L (with 76% segments, 10% lymphocytes, 10% monocytes, 3% eosinophils, and 1% basophils); hemoglobin, 11.0 g/dL (110 g/L); platelets, 190 ⫻ 103/L (190 ⫻ 109/L); blood urea
From the Department of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan. Received June 22, 2005; accepted in revised form August 25, 2005. Originally published online as doi:10.1053/j.ajkd.2005.08.028 on October 21, 2005. Address reprint requests to Chun-Chen Yu, MD, Department of Nephrology and Clinical Toxicology, Chang Gung Memorial Hospital, 199 Tung-Hwa North Rd, Taipei 105, Taiwan. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4606-0031$30.00/0 doi:10.1053/j.ajkd.2005.08.028
American Journal of Kidney Diseases, Vol 46, No 6 (December), 2005: E125-E129
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LI ET AL
Fig 1.
nitrogen (BUN), 165 mg/dL (58.9 mmol/L); creatinine, 11.3 mg/dL (999 mol/L); bicarbonate, 14 mEq/L (14 mmol/L); sodium, 118 mEq/L (118 mmol/L); potassium, 8.7 mEq/L (8.7 mmol/L); alanine aminotransferase, 16 IU/L; and total bilirubin, 2.4 mg/dL (41.0 mol/L). Urinalysis showed protein of 150 mg/dL, 25 white blood cells per high-power field, and 2 to 5 red blood cells per high-power field. One percent of white blood cells in urine sediment were eosinophils. Blood, urine, and bile culture results were negative. The patient remained oliguric. To eliminate potential drug-induced ARF, all unnecessary regimens (antacids and
Propolis.
propolis) were discontinued immediately on admission. Renal sonography showed that the right and left kidneys measured 11.7 and 12.0 cm, respectively; there was increased cortical echogenicity. No hydronephrosis was detected. The patient received hemodialysis once on day 1. Renal function improved on day 3, with a BUN level of 57 mg/dL (20.3 mmol/L) and creatinine level of 4.4 mg/dL (389 mol/L). By day 6, BUN and creatinine levels decreased further to 22 mg/dL (7.85 mmol/L) and 2.1 mg/dL (186 mol/L), respectively. Urine output increased to 1,650 mL/d. The patient was free of uremic symptoms.
PROPOLIS-INDUCED ACUTE RENAL FAILURE
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Fig 2. Evolution of renal function (serum creatinine levels) over time (days), showing that renal function deteriorated after rechallenge with propolis (shaded rectangle, days 8 to 15) and improved after withdrawal of propolis. Hemodialysis (arrows) was performed days 1 and 15. To convert creatinine in mg/dL to mol/L, multiply by 88.4.
On day 8, despite being made aware of a risk for propolisinduced ARF, the patient insisted on taking propolis for the underlying cholangiocarcinoma. Against physician advice and with the patient’s consent, propolis was rechallenged. By day 11, a follow-up laboratory study showed a creatinine level of 3.1 mg/dL (277 mol/L) and normal blood cell counts and liver biochemistry test results. The high probability of propolis-induced ARF again was explained to the patient. However, the patient still wished to take propolis. After reexposure to propolis for 1 week, on day 15, the patient became oliguric and renal function deteriorated, with a BUN level of 85 mg/dL (30.3 mmol/L) and creatinine level of 7.6 mg/dL (672 mol/L). Neither skin rash nor fever was observed. During this admission, no contrast medium or other nephrotoxic agent was used. The only change in treatment regimen was the rechallenge of propolis. The patient was not volume depleted. Propolis was discontinued, and the patient again underwent hemodialysis. Renal function improved gradually, with a creatinine level of 2.6 mg/dL (230 mol/L) on day 18 and return to a normal level of 1.3 mg/dL (115 mol/L) on day 22. At discharge, day 29, the patient’s creatinine level decreased further to 1.1 mg/dL (97 mol/L). Liver biochemistry test results remained stationary, with an alanine aminotransferase level of 11 IU/L and total bilirubin level of 1.9 mg/dL (32.5 mol/L). A markedly increased immunoglobulin E titer of 994 mg/dL (9,940 mg/L) was noted. Figure 2
shows changes in renal function and their relationship to exposure to propolis. Because of rapid recovery of renal function after propolis withdrawal, the patient refused a renal biopsy for pathological diagnosis; therefore, corticosteroid was not prescribed. Table 1 lists laboratory test results at admission, before and after reexposure to propolis, and at discharge. To exclude heavy-metal contamination of the propolis, we performed heavy-metal analyses, and concentrations of lead (1.53 g/L), arsenic (17.42 g/L), and cadmium (3.02 g/L) were within normal limits.
DISCUSSION
This is the first report of propolis-induced ARF. Although the patient refused renal biopsy for a conclusive pathological diagnosis, the association between propolis and ARF was confirmed by the evolution of renal function after reexposure and withdrawal of propolis. During the admission, the patient’s liver biochemistry test results remained stationary, and there is no evidence of decompensated liver and hepatic encephalopathy. Therefore, hepatorenal syndrome was unlikely to be the cause of ARF. The
Table 1. Summary of Laboratory Tests at Admission, Before and After Reexposure to Propolis, and at Discharge Test
Admission
Before Propolis Reexposure
After Propolis Reexposure
White blood cells (⫻ 103/L) Hemoglobin (g/dL) Platelets (⫻ 103/L) BUN (mg/dL) Serum creatinine (mg/dL) Sodium (mEq/L) Potassium (mEq/L) Total bilirubin (mg/dL) Alanine aminotransferase (IU/L)
6.4 12.1 161 116 11.3 118 8.7 2.4 16
3.5 9.4 94 57 2.1 135 2.5 2.9 22
2.8 8.0 83 85 7.6 128 4.6 3.3 15
Discharge
11 1.1 2.8 1.9 11
NOTE: To convert white blood cells and platelets in ⫻ 103/L to ⫻ 109/L, multiply by 1; hemoglobin in g/dL to g/L, multiply by 10; serum creatinine in mg/dL to mol/L, multiply by 88.4; BUN in mg/dL to mmol/L, multiply by 0.357; total bilirubin in mg/dL to mol/L, multiply by 17.1; sodium and potassium in mEq/L to mmol/L, multiply by 1.
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absence of fever and leukocytosis, negative blood culture results, and improvement in renal function without antibiotic treatment suggested that sepsis was not likely to have induced ARF in this case. During the clinical course, no other nephrotoxic agent was prescribed, and rechallenge of propolis was the only change in treatment regimen that could have induced ARF. Humans have used propolis in folk medicine for more than 2,000 years. Although there is a lack of large-scale, prospective, controlled, clinical trials, propolis was reported to possess antiseptic, antimycotic, bacteriostatic, astringent, choleric, spasmolytic, anti-inflammatory, anesthetic, antioxidative, hepatoprotective, and antitumor properties.1,4 There are myriad preparations and uses of propolis. These applications include overthe-counter dermatological items, tablets, powder or capsules sold in health food stores, massmarketed dental floss, and even toothpaste. Sales of propolis in the United States were estimated at 40,000 lb/y by the primary producer.1 Current total sales likely are far greater than the estimate because honey and propolis production is primarily a cottage industry. Typical adverse effects of propolis are allergic reactions and skin or mucus membrane irritation. Severe adverse effects, such as laryngeal edema and anaphylactic shock, seldom have been reported.5 People often are reluctant to accept propolis as the cause of systemic toxicity based on its “natural food” property. Propolis intake commonly is overlooked in the clinical history of toxicology screening. This is the first report documenting ARF associated with propolis and emphasizes that propolis is not harmless and should be used with caution and taken into account in the list of differential diagnoses for drug-related ARF or ARF with undetermined cause. Because a kidney biopsy was not performed, precise changes in the kidney are unknown. This patient’s presentation is compatible with acute interstitial nephritis (AIN).6 Numerous drugs have the potential to cause AIN, particularly certain antibiotics or anti-inflammatory agents. Clinical presentation of AIN is diverse and varies depending on causative agents. Low-grade fever, fleeting skin rash, and mild arthralgia are typical presentations. Proteinuria, hematuria, eosinophilia, pyuria, and eosinophiluria are present in some patients. Degree of renal function impairment varies. Renal
LI ET AL
failure is more likely to occur in older patients. Reversal of renal failure and return to baseline renal function is the rule. Removal of the suspected agent followed by reversal of the renal lesion is strongly suggestive of a diagnosis. Such a diagnosis can be particularly convincing in the presence of systemic manifestation of a hypersensitivity reaction. AIN is confirmed best by renal biopsy. However, recurrence of the renal lesion after reexposure to the same agent, as in this case, is strong confirmation of the diagnosis. The presence of eosinophiluria and elevated immunoglobulin E level in this patient further suggests AIN. Steroid was not prescribed because of rapid recovery of renal function after propolis withdrawal. The component of propolis inducing ARF remains unknown. The composition of propolis depends on time, vegetation, and the collection area.7 Considerable variation exists in the chemical composition of propolis, even within such a country as Brazil, as in this case.8,9 Chemical analysis of propolis extracts indicated that propolis samples had high concentrations of aromatic acids, esters, and other derivatives, such as flavonoids, benzyl cinnamate, methyl cinnamate, caffeic acid, cinnamyl cinnamate, and cinnamoylglcine. These compounds are responsible for the proposed antibacterial, antifungal, antiviral, antiinflammatory, and anticancer properties of propolis.10 The composition of propolis is extremely complex. Although propolis obviously is an animal product, a considerable proportion of its components are plant derived. More than 300 substances have been identified in propolis.11,12 Therefore, it is very difficult to identify definitely the compound causing ARF. Furthermore, contamination by other toxic agents in the process of extracting, manufacturing, and storing propolis is another potential factor in propolis-induced ARF. However, contamination of other nephrotoxic agents is less likely in this case because the patient’s family had used the same propolis preparation without evidence of renal failure. Measurement of heavy-metal levels in honeybees and some of their products (pollen, propolis, and wax) can be considered a representative bioindicator of environmental pollution.13 To exclude the possibility of heavy-metal contamination, we analyzed the heavy-metal content of the propolis, and lead, arsenic, and cadmium concentra-
PROPOLIS-INDUCED ACUTE RENAL FAILURE
tions were within normal limits. Although the definite compound causing ARF in this case cannot be identified, we should be aware that propolis should not be presumed totally harmless and should be used with caution. The mechanism of propolis-induced ARF also remains unclear. Bioactive components in propolis, such as caffeic acid phenethyl ester, were shown to suppress the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism during inflammation.14,15 Moreover, caffeic acid phenethyl ester may exert its anti-inflammatory effect by inhibiting the inducible nitric oxide synthase pathway.16 However, inhibition of the cyclooxygenase and nitric oxide pathways can result in decreased kidney perfusion and thus induce ARF in select patients, as in the examples of nonsteroidal anti-inflammatory drug–related ARF.6,17,18 In summary, this is the first report of a case of propolis-induced ARF, in an older patient and confirmed by reexposure to the same agent. As an herbal remedy, propolis is used commonly and reputed for its therapeutic properties and relatively few systemic adverse effects. This report suggests that propolis can induce ARF and highlights the need for vigilance and care in using propolis as medicinal or dietary supplements. Additional study is required to evaluate the incidence of ARF induced by propolis. REFERENCES 1. Banskota AH, Tezuka Y, Kadota S: Recent progress in pharmacological research of propolis. Phytother Res 15:561571, 2001 2. Burdock GA: Review of the biological properties and toxicity of bee propolis (propolis). Food Chem Toxicol 36:347-363, 1998
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3. Raton JA, Aguirre A, Diaz-Perez JL: Contact dermatitis from propolis. Contact Dermatitis 22:183-184, 1990 4. Bankova V: Recent trends and important developments in propolis research. Evid Based Complement Alternat Med 2:29-32, 2005 5. Hsu CY, Chiang WC, Weng TI, et al: Laryngeal edema and anaphylactic shock after topical propolis use for acute pharyngitis. Am J Emerg Med 22:432-433, 2004 6. Rossert J: Drug-induced acute interstitial nephritis. Kidney Int 60:804-817, 2001 7. Midorikawa K, Banskota AH, Tezuka Y, et al: Liquid chromatography-mass spectrometry analysis of propolis. Phytochem Anal 12:366-373, 2001 8. Marcucci MC, Ferreres F, Custodio AR, et al: Evaluation of phenolic compounds in Brazilian propolis from different geographic regions. Z Naturforsch [C] 55:76-81, 2000 9. Park YK, Alencar SM, Aguiar CL: Botanical origin and chemical composition of Brazilian propolis. J Agric Food Chem 50:2502-2506, 2002 10. Sahinler N, Kaftanoglu O: Natural product propolis: Chemical composition. Nat Prod Res 19:183-188, 2005 11. Banskota AH, Tezuka Y, Prasain JK, et al: Chemical constituents of Brazilian propolis and their cytotoxic activities. J Nat Prod 61:896-900, 1998 12. Salatino A, Teixeira EW, Negri G, et al: Origin and chemical variation of Brazilian propolis. Evid Based Complement Alternat Med 2:33-38, 2005 13. Conti ME, Botre F: Honeybees and their products as potential bioindicators of heavy metals contamination. Environ Monit Assess 69:267-282, 2001 14. Maffia P, Ianaro A, Pisano B, et al: Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol 136:353-360, 2002 15. Mirzoeva OK, Calder PC: The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids 55:441-449, 1996 16. Song YS, Park EH, Hur GM, et al: Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Lett 175:53-61, 2002 17. Henao J, Hisamuddin I, Nzerue CM, et al: Celecoxibinduced acute interstitial nephritis. Am J Kidney Dis 39:13131317, 2002 18. Whelton A: Nephrotoxicity of nonsteroidal antiinflammatory drugs: Physiologic foundations and clinical implications. Am J Med 106:S13-S24, 1999 (suppl 5B)
Acute Renal Failure Induced by a Brazilian Variety of Propolis Yi-Jung Li, MD, Ja-Liang Lin, MD, Chih-Wei Yang, MD, and Chun-Chen Yu, MD ● Propolis is a resinous substance collected by honeybees and used in hive construction and maintenance. Cumulative evidence suggests that propolis may have anti-inflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties. In addition to topical applications, products containing propolis have been used increasingly as dietary supplements. Although reports of allergic reactions are not uncommon, propolis is reputed to be relatively nontoxic. Its systemic toxicity is rarely reported and hence may be underestimated. This is the first report of propolis-induced acute renal failure. A 59-year-old man required hemodialysis for acute renal failure. The patient had cholangiocarcinoma and had ingested propolis for 2 weeks before presentation. Renal function improved after propolis withdrawal, deteriorated again after reexposure, and then returned to a normal level after the second propolis withdrawal. This case indicates that propolis can induce acute renal failure and emphasizes the need for vigilance and care when propolis is used as a medicine or dietary supplement. Am J Kidney Dis 46: E125-E129. © 2005 by the National Kidney Foundation, Inc. INDEX WORDS: Propolis; acute renal failure.
P
ROPOLIS IS a resinous product collected by honeybees from various plant sources and used in hive construction and maintenance. It has been applied in folk medicine since 300 BC. Cumulative evidence indicates that propolis has various biological activities, such as antiinflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties.1,2 Although reports of allergic reactions, usually contact dermatitis, are not uncommon, propolis is considered to be relatively nontoxic, with a no-effect level at 1,400 mg/kg/d in a murine study.2,3 Systemic toxicity of propolis seldom has been investigated and could be markedly underestimated. In patients with suspected druginduced organ damage, propolis often is regarded as a natural compound and an innocent bystander. Hence, the cause of systemic toxicity usually is unknown and rarely attributed to propolis. This report presents a case of reversible acute renal failure (ARF) caused by propolis in a 59-year-old man with cholangiocarcinoma. Hemodialysis therapy was initiated for ARF. Fortunately, renal function recovered after withdrawal of propolis. However, based on the uncertainty of propolis as the cause of ARF at that time, the patient continued ingesting propolis for underlying cholangiocarcinoma. Renal function deteriorated again after rechallenge and recovered again after withdrawal of propolis. This is the first report of ARF associated with propolis. CASE REPORT A 59-year-old man with a history of colon cancer posthemicolectomy in disease-free status presented to the emergency
department at Chang Gung Memorial Hospital (Taipei, Taiwan) with a report of shortness of breath, little urination, and leg edema for 1 week. Three months before this presentation, the patient had obstructive jaundice caused by newly diagnosed cholangiocarcinoma; his jaundice improved after percutaneous transhepatic cholangiography and drainage. Blood tests at follow-up at the outpatient clinic showed that blood cell counts and renal function were all within normal limits. The patient began taking propolis (Fig 1), 5 mL 3 times/d, 2 weeks before this presentation for the underlying cholangiocarcinoma. The clear propolis preparation was purchased from the drugstore and was not out of date. The patient did not take any other medicine before admission. The patient’s family had used the same propolis preparation without complication. On admission, blood pressure was 120/66 mm Hg, pulse was 106 beats/min, respiratory rate was 26 breaths/min, and temperature was 36.2°C. Physical examination identified pink conjunctiva, mildly icteric sclera, and crackle over bilateral lower-lung fields. Abdominal and cardiac examination findings were normal. There was pitting edema of the ankles. There was no skin erythema or rash. Laboratory results were as follows: white blood cells, 7,700/L (with 76% segments, 10% lymphocytes, 10% monocytes, 3% eosinophils, and 1% basophils); hemoglobin, 11.0 g/dL (110 g/L); platelets, 190 ⫻ 103/L (190 ⫻ 109/L); blood urea
From the Department of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan. Received June 22, 2005; accepted in revised form August 25, 2005. Originally published online as doi:10.1053/j.ajkd.2005.08.028 on October 21, 2005. Address reprint requests to Chun-Chen Yu, MD, Department of Nephrology and Clinical Toxicology, Chang Gung Memorial Hospital, 199 Tung-Hwa North Rd, Taipei 105, Taiwan. E-mail: [email protected] © 2005 by the National Kidney Foundation, Inc. 0272-6386/05/4606-0031$30.00/0 doi:10.1053/j.ajkd.2005.08.028
American Journal of Kidney Diseases, Vol 46, No 6 (December), 2005: E125-E129
e125
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LI ET AL
Fig 1.
nitrogen (BUN), 165 mg/dL (58.9 mmol/L); creatinine, 11.3 mg/dL (999 mol/L); bicarbonate, 14 mEq/L (14 mmol/L); sodium, 118 mEq/L (118 mmol/L); potassium, 8.7 mEq/L (8.7 mmol/L); alanine aminotransferase, 16 IU/L; and total bilirubin, 2.4 mg/dL (41.0 mol/L). Urinalysis showed protein of 150 mg/dL, 25 white blood cells per high-power field, and 2 to 5 red blood cells per high-power field. One percent of white blood cells in urine sediment were eosinophils. Blood, urine, and bile culture results were negative. The patient remained oliguric. To eliminate potential drug-induced ARF, all unnecessary regimens (antacids and
Propolis.
propolis) were discontinued immediately on admission. Renal sonography showed that the right and left kidneys measured 11.7 and 12.0 cm, respectively; there was increased cortical echogenicity. No hydronephrosis was detected. The patient received hemodialysis once on day 1. Renal function improved on day 3, with a BUN level of 57 mg/dL (20.3 mmol/L) and creatinine level of 4.4 mg/dL (389 mol/L). By day 6, BUN and creatinine levels decreased further to 22 mg/dL (7.85 mmol/L) and 2.1 mg/dL (186 mol/L), respectively. Urine output increased to 1,650 mL/d. The patient was free of uremic symptoms.
PROPOLIS-INDUCED ACUTE RENAL FAILURE
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Fig 2. Evolution of renal function (serum creatinine levels) over time (days), showing that renal function deteriorated after rechallenge with propolis (shaded rectangle, days 8 to 15) and improved after withdrawal of propolis. Hemodialysis (arrows) was performed days 1 and 15. To convert creatinine in mg/dL to mol/L, multiply by 88.4.
On day 8, despite being made aware of a risk for propolisinduced ARF, the patient insisted on taking propolis for the underlying cholangiocarcinoma. Against physician advice and with the patient’s consent, propolis was rechallenged. By day 11, a follow-up laboratory study showed a creatinine level of 3.1 mg/dL (277 mol/L) and normal blood cell counts and liver biochemistry test results. The high probability of propolis-induced ARF again was explained to the patient. However, the patient still wished to take propolis. After reexposure to propolis for 1 week, on day 15, the patient became oliguric and renal function deteriorated, with a BUN level of 85 mg/dL (30.3 mmol/L) and creatinine level of 7.6 mg/dL (672 mol/L). Neither skin rash nor fever was observed. During this admission, no contrast medium or other nephrotoxic agent was used. The only change in treatment regimen was the rechallenge of propolis. The patient was not volume depleted. Propolis was discontinued, and the patient again underwent hemodialysis. Renal function improved gradually, with a creatinine level of 2.6 mg/dL (230 mol/L) on day 18 and return to a normal level of 1.3 mg/dL (115 mol/L) on day 22. At discharge, day 29, the patient’s creatinine level decreased further to 1.1 mg/dL (97 mol/L). Liver biochemistry test results remained stationary, with an alanine aminotransferase level of 11 IU/L and total bilirubin level of 1.9 mg/dL (32.5 mol/L). A markedly increased immunoglobulin E titer of 994 mg/dL (9,940 mg/L) was noted. Figure 2
shows changes in renal function and their relationship to exposure to propolis. Because of rapid recovery of renal function after propolis withdrawal, the patient refused a renal biopsy for pathological diagnosis; therefore, corticosteroid was not prescribed. Table 1 lists laboratory test results at admission, before and after reexposure to propolis, and at discharge. To exclude heavy-metal contamination of the propolis, we performed heavy-metal analyses, and concentrations of lead (1.53 g/L), arsenic (17.42 g/L), and cadmium (3.02 g/L) were within normal limits.
DISCUSSION
This is the first report of propolis-induced ARF. Although the patient refused renal biopsy for a conclusive pathological diagnosis, the association between propolis and ARF was confirmed by the evolution of renal function after reexposure and withdrawal of propolis. During the admission, the patient’s liver biochemistry test results remained stationary, and there is no evidence of decompensated liver and hepatic encephalopathy. Therefore, hepatorenal syndrome was unlikely to be the cause of ARF. The
Table 1. Summary of Laboratory Tests at Admission, Before and After Reexposure to Propolis, and at Discharge Test
Admission
Before Propolis Reexposure
After Propolis Reexposure
White blood cells (⫻ 103/L) Hemoglobin (g/dL) Platelets (⫻ 103/L) BUN (mg/dL) Serum creatinine (mg/dL) Sodium (mEq/L) Potassium (mEq/L) Total bilirubin (mg/dL) Alanine aminotransferase (IU/L)
6.4 12.1 161 116 11.3 118 8.7 2.4 16
3.5 9.4 94 57 2.1 135 2.5 2.9 22
2.8 8.0 83 85 7.6 128 4.6 3.3 15
Discharge
11 1.1 2.8 1.9 11
NOTE: To convert white blood cells and platelets in ⫻ 103/L to ⫻ 109/L, multiply by 1; hemoglobin in g/dL to g/L, multiply by 10; serum creatinine in mg/dL to mol/L, multiply by 88.4; BUN in mg/dL to mmol/L, multiply by 0.357; total bilirubin in mg/dL to mol/L, multiply by 17.1; sodium and potassium in mEq/L to mmol/L, multiply by 1.
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absence of fever and leukocytosis, negative blood culture results, and improvement in renal function without antibiotic treatment suggested that sepsis was not likely to have induced ARF in this case. During the clinical course, no other nephrotoxic agent was prescribed, and rechallenge of propolis was the only change in treatment regimen that could have induced ARF. Humans have used propolis in folk medicine for more than 2,000 years. Although there is a lack of large-scale, prospective, controlled, clinical trials, propolis was reported to possess antiseptic, antimycotic, bacteriostatic, astringent, choleric, spasmolytic, anti-inflammatory, anesthetic, antioxidative, hepatoprotective, and antitumor properties.1,4 There are myriad preparations and uses of propolis. These applications include overthe-counter dermatological items, tablets, powder or capsules sold in health food stores, massmarketed dental floss, and even toothpaste. Sales of propolis in the United States were estimated at 40,000 lb/y by the primary producer.1 Current total sales likely are far greater than the estimate because honey and propolis production is primarily a cottage industry. Typical adverse effects of propolis are allergic reactions and skin or mucus membrane irritation. Severe adverse effects, such as laryngeal edema and anaphylactic shock, seldom have been reported.5 People often are reluctant to accept propolis as the cause of systemic toxicity based on its “natural food” property. Propolis intake commonly is overlooked in the clinical history of toxicology screening. This is the first report documenting ARF associated with propolis and emphasizes that propolis is not harmless and should be used with caution and taken into account in the list of differential diagnoses for drug-related ARF or ARF with undetermined cause. Because a kidney biopsy was not performed, precise changes in the kidney are unknown. This patient’s presentation is compatible with acute interstitial nephritis (AIN).6 Numerous drugs have the potential to cause AIN, particularly certain antibiotics or anti-inflammatory agents. Clinical presentation of AIN is diverse and varies depending on causative agents. Low-grade fever, fleeting skin rash, and mild arthralgia are typical presentations. Proteinuria, hematuria, eosinophilia, pyuria, and eosinophiluria are present in some patients. Degree of renal function impairment varies. Renal
LI ET AL
failure is more likely to occur in older patients. Reversal of renal failure and return to baseline renal function is the rule. Removal of the suspected agent followed by reversal of the renal lesion is strongly suggestive of a diagnosis. Such a diagnosis can be particularly convincing in the presence of systemic manifestation of a hypersensitivity reaction. AIN is confirmed best by renal biopsy. However, recurrence of the renal lesion after reexposure to the same agent, as in this case, is strong confirmation of the diagnosis. The presence of eosinophiluria and elevated immunoglobulin E level in this patient further suggests AIN. Steroid was not prescribed because of rapid recovery of renal function after propolis withdrawal. The component of propolis inducing ARF remains unknown. The composition of propolis depends on time, vegetation, and the collection area.7 Considerable variation exists in the chemical composition of propolis, even within such a country as Brazil, as in this case.8,9 Chemical analysis of propolis extracts indicated that propolis samples had high concentrations of aromatic acids, esters, and other derivatives, such as flavonoids, benzyl cinnamate, methyl cinnamate, caffeic acid, cinnamyl cinnamate, and cinnamoylglcine. These compounds are responsible for the proposed antibacterial, antifungal, antiviral, antiinflammatory, and anticancer properties of propolis.10 The composition of propolis is extremely complex. Although propolis obviously is an animal product, a considerable proportion of its components are plant derived. More than 300 substances have been identified in propolis.11,12 Therefore, it is very difficult to identify definitely the compound causing ARF. Furthermore, contamination by other toxic agents in the process of extracting, manufacturing, and storing propolis is another potential factor in propolis-induced ARF. However, contamination of other nephrotoxic agents is less likely in this case because the patient’s family had used the same propolis preparation without evidence of renal failure. Measurement of heavy-metal levels in honeybees and some of their products (pollen, propolis, and wax) can be considered a representative bioindicator of environmental pollution.13 To exclude the possibility of heavy-metal contamination, we analyzed the heavy-metal content of the propolis, and lead, arsenic, and cadmium concentra-
PROPOLIS-INDUCED ACUTE RENAL FAILURE
tions were within normal limits. Although the definite compound causing ARF in this case cannot be identified, we should be aware that propolis should not be presumed totally harmless and should be used with caution. The mechanism of propolis-induced ARF also remains unclear. Bioactive components in propolis, such as caffeic acid phenethyl ester, were shown to suppress the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism during inflammation.14,15 Moreover, caffeic acid phenethyl ester may exert its anti-inflammatory effect by inhibiting the inducible nitric oxide synthase pathway.16 However, inhibition of the cyclooxygenase and nitric oxide pathways can result in decreased kidney perfusion and thus induce ARF in select patients, as in the examples of nonsteroidal anti-inflammatory drug–related ARF.6,17,18 In summary, this is the first report of a case of propolis-induced ARF, in an older patient and confirmed by reexposure to the same agent. As an herbal remedy, propolis is used commonly and reputed for its therapeutic properties and relatively few systemic adverse effects. This report suggests that propolis can induce ARF and highlights the need for vigilance and care in using propolis as medicinal or dietary supplements. Additional study is required to evaluate the incidence of ARF induced by propolis. REFERENCES 1. Banskota AH, Tezuka Y, Kadota S: Recent progress in pharmacological research of propolis. Phytother Res 15:561571, 2001 2. Burdock GA: Review of the biological properties and toxicity of bee propolis (propolis). Food Chem Toxicol 36:347-363, 1998
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3. Raton JA, Aguirre A, Diaz-Perez JL: Contact dermatitis from propolis. Contact Dermatitis 22:183-184, 1990 4. Bankova V: Recent trends and important developments in propolis research. Evid Based Complement Alternat Med 2:29-32, 2005 5. Hsu CY, Chiang WC, Weng TI, et al: Laryngeal edema and anaphylactic shock after topical propolis use for acute pharyngitis. Am J Emerg Med 22:432-433, 2004 6. Rossert J: Drug-induced acute interstitial nephritis. Kidney Int 60:804-817, 2001 7. Midorikawa K, Banskota AH, Tezuka Y, et al: Liquid chromatography-mass spectrometry analysis of propolis. Phytochem Anal 12:366-373, 2001 8. Marcucci MC, Ferreres F, Custodio AR, et al: Evaluation of phenolic compounds in Brazilian propolis from different geographic regions. Z Naturforsch [C] 55:76-81, 2000 9. Park YK, Alencar SM, Aguiar CL: Botanical origin and chemical composition of Brazilian propolis. J Agric Food Chem 50:2502-2506, 2002 10. Sahinler N, Kaftanoglu O: Natural product propolis: Chemical composition. Nat Prod Res 19:183-188, 2005 11. Banskota AH, Tezuka Y, Prasain JK, et al: Chemical constituents of Brazilian propolis and their cytotoxic activities. J Nat Prod 61:896-900, 1998 12. Salatino A, Teixeira EW, Negri G, et al: Origin and chemical variation of Brazilian propolis. Evid Based Complement Alternat Med 2:33-38, 2005 13. Conti ME, Botre F: Honeybees and their products as potential bioindicators of heavy metals contamination. Environ Monit Assess 69:267-282, 2001 14. Maffia P, Ianaro A, Pisano B, et al: Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol 136:353-360, 2002 15. Mirzoeva OK, Calder PC: The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids 55:441-449, 1996 16. Song YS, Park EH, Hur GM, et al: Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Lett 175:53-61, 2002 17. Henao J, Hisamuddin I, Nzerue CM, et al: Celecoxibinduced acute interstitial nephritis. Am J Kidney Dis 39:13131317, 2002 18. Whelton A: Nephrotoxicity of nonsteroidal antiinflammatory drugs: Physiologic foundations and clinical implications. Am J Med 106:S13-S24, 1999 (suppl 5B)