Star Fruit: A Hiccup in the Management of Kidney Disease

NOVEMBER 22, 2017
Patients with kidney disease must often follow a basic “renal” diet, which consists of controlled fluid intake, high protein, and low sodium, potassium, and phosphorus. This requires patients to limit or avoid numerous foods rich in these minerals, such as canned soups, bananas, and dairy, most of which are familiar to clinicians and simple to address during a visit. 

One food that isn’t common but rising in popularity, is star fruit. The National Kidney Foundation’s (NKF) Dietary Guidelines for Adults Starting on Hemodialysis instructs patients to always avoid star fruit.1 But why?

Star fruit, or carambola, is the five-ridged fruit of the Averrhoa carambola tree of the Oxalidaceae family. Although the fruit and its juice are widely available throughout the world, the plant is native to and largely consumed in the tropical countries of Latin America and Southeast Asia. The fruit is a source of fiber, potassium, and antioxidants, such as vitamin C.2 Among its traditional medicinal uses are its roles in fever, skin inflammations, and as a diuretic.3 In patients with kidney disease, however, consumption can be toxic and potentially fatal.
 
PRESENTATION AND MECHANISM OF TOXICITY
Hiccups are a common and often harmless myoclonus of the diaphragm. However, in patients with renal disease and recent star fruit ingestion, this spasm can be a sign of toxicity and occurs in up to 94% of patients who present with intoxication. Toxicity can also result in vomiting, weakness, confusion, convulsions, and death.2,4
 
Star fruit contains two molecules that are responsible for kidney damage and neurotoxicity: oxalate and the recently discovered caramboxin.
 
Oxalic acid’s effects on kidneys are well-known and well defined, partly due to its culpability in ethylene glycol toxicity and death. Oxalate crystallizes and forms obstructive deposits that cause direct tissue damage in the form of both apoptosis and acute tubular necrosis.5-7 Neurotoxic effects are due to the more elusive compound of interest, caramboxin. Garcia-Cairasco and colleagues conducted a bioguided isolation of the toxin and termed the new, “phenylalanine-like” molecule with 2 carboxylic acids. They also discovered its strong N-methyl-D-aspartate glutamatergic receptor agonist activity and justified the hyperexcitability of neurons in patients who experience this toxicity.8
 
Nephropathy without neurotoxic symptoms is possible, but the kidney damage that leads to accumulation of oxalate and caramboxin is thought to result in neurotoxicity.
 
LITERATURE AND TREATMENT
Although the NKF advises against consumption of star fruit in people with kidney disease, other guidelines don’t discuss this, and many clinicians are unaware of the effects. In the literature, however, the relationship between star fruit toxicity and kidney dysfunction is defined in several articles. Brown, et al, describes more than 50 cases of star fruit intoxication in patients with renal disease, reporting a 25% overall mortality rate and 75% mortality rate in those who experienced seizures.4 Their consolidation of case reports includes 32 uremic patients described by Neto, et al, in 2003. In this specific cohort, all patients promptly treated with hemodialysis survived. Patients with severe intoxication who were treated with peritoneal dialysis or received no treatment did not survive. Continued observation is essential for patients who do survive, as rebound effects, such as persistent hiccups, have been reported.2 Of note, most of the patients in this 32-patient cohort did not respond to drugs typically used for hiccups: chlorpromazine and metoclopramide.
 
Although several articles report no cases of star fruit toxicity in those with normal renal function, Neto, et al, (2009) described 5 cases of star fruit-induced acute kidney injury. Four patients had consumed large amounts of the fruit, and 1 ingested 300 mL of pure juice on an empty stomach.5 Molina, et al, also account 10 cases of star fruit-induced AKI, in which all patients recovered after low-dose steroids, hydration, and hemodialysis.9 
 
CONCLUSION
Although star fruit is not a principal part of most patients’ dietary habits, a literature search and a warning by the NKF highlight the importance of health professionals familiarizing themselves with the characteristics of star fruit and its toxicity. Just as grapefruit isn’t a staple in most patients’ diets, its interaction with CYP3A4 and ultimate impact on clinical effectiveness still prompts clinicians to counsel patients.  
 
Those without renal disease should take caution to not consume large amounts of the fruit or its products and ensure that ingestion does not occur on an empty stomach.
 
Note: Star fruit is not to be confused with star anise (Illicium verum), a different star-shaped fruit that yields a cooking spice. Although this species is safe for consumption, its morphological similarity to other members of the Illicium genus can lead to contamination and ultimately toxicities, such as emesis, diarrhea, and convulsions.10
 
References
1. National Kidney Foundation. Dietary guidelines for adults starting on hemodialysis. kidney.org/atoz/content/dietary_hemodialysis. Published 2015. Accessed November 20, 2017.
2. Neto MM, da Costa JA, Garcia-Cairasco N, Netto JC, Nakagawa B, Dantas M. Intoxication by star fruit (Averrhoa carambola) in 32 uraemic patients: treatment and outcome. Nephrol Dial Transplant. 2003;18(1):120-5.
3. Muthu N, Lee SY, Phua KK, Bhore SJ. Nutritional, medicinal and toxicological attributes of star-fruits (Averrhoa carambola L.): a review. Bioinformation. 2016;12(12):420-424. doi: 10.6026/97320630012420.
4. Brown AC. Kidney toxicity related to herbs and dietary supplements: online table of case reports. Part 3 of 5 series. Food Chem Toxicol. 2017;107(Pt A):502-519. doi: 10.1016/j.fct.2016.07.024.
5. Neto MM, Silva GEB, Costa RS, et al. Star fruit: simultaneous neurotoxic and nephrotoxic effects in people with previously normal renal function. NDT Plus. 2009;2(6):485-8. doi: 10.1093/ndtplus.sfp108
6. Fang HC, Lee PT, Lu PJ, et al. Mechanisms of star fruit-induced acute renal failure. Food Chem Toxicol. 2008;46(5):1744-52. doi: 10.1016/j.fct.2008.01.016. 
7. Miller C, Kennington L, Cooney R, et al. Oxalate toxicity in renal epithelial cells: characteristics of apoptosis and necrosis.  Toxicol Appl Pharmacol. 2000;162(2):132-41.
8. Garcia-Cairasco N, Moyses-Neto M, Del Vecchio F, et al. Elucidating the neurotoxicity of the star fruit. Angew Chem Int Ed Engl. 2013;52(49):13067-70. doi: 10.1002/anie.201305382. 
9. Molina M, Morales E, Navarro B, Moliz C, Praga M. La fruta estrella causa fracaso renal agudo. Nefrologia. 2017;37:221–222. doi: 10.1016/j.nefro.2016.09.011. 
10. George CK. Star anise. In: Peter KV, ed. Handbook of Herbs and Spices. 2nd ed. Cambridge, UK: Woodhead Publishing Series in Food Science, Technology and Nutrition. Vol 2. 2012:487–503.
 

Jola Mehmeti, PharmD Candidate 2018
Jola Mehmeti, PharmD Candidate 2018
Jola Mehmeti is a final-year PharmD candidate (’18) at the UConn School of Pharmacy. She earned a B.S. in Pharmacy Studies at UConn (’15) and MBA from Sacred Heart University (’17). She is a CITI-certified researcher with investigative and work experience at a large tertiary care center in Hartford, Connecticut. Connect with her on LinkedIn or send a message to contact@jolamehmeti.com.
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