5 Nov 2024
Lotfi El Bahri explains the grave issues posed by this fruit when consumed by dogs, and how to treat them.
Lotfi El Bahri
Job Title
Image © pilipphoto / Adobe Stock
You are presented with a two year old French bulldog female weighing 9.5kg at your emergency veterinary hospital.
Upon returning home from a day out, the owner found their dog reluctant to greet them in the usual manner. The dog got up with difficulty. The owner noted vomiting and diarrhoea, with vomitus containing numerous grapes.
The dog’s owner remembers having left in the kitchen a grape bagel purchased fresh from the grocery store. Dog owners are often unaware of the danger involved when their pets eat grapes or raisins.
Grapes can be extremely toxic to dogs. Poisoning from red grapes, green grapes, seeded or seedless grapes, vine grapes, fermented grapes, raisins, currants (fresh and dried) and sultanas have all been reported in dogs. Dogs may also get into the garbage to ingest these fruits. Any breed or size, male or female, may be affected.
Tartaric acid (TA) and the potassium bitartrate salt, fundamental components of grapes and raisins, are considered as toxic agents leading to acute kidney injury (AKI) in dogs.
TA is found in high concentrations in grapes containing as much as 2%, with a range between 0.35% and 1.1%. Quite a variation in the amount of TA in grapes has been noted, and this can vary depending on the cultivar or variety of grape, growing conditions, early and late harvests, and size of the fruit.
In general, grapes and raisins that are more acidic tend to have higher levels of TA. Cooking removes some, but not all, of the TA in grapes.
TA is also present in high concentrations in tamarinds (Tamarindus indica L), between 8% and 18%. AKI in dogs can also occur following ingestion of cream of tartar (potassium bitartrate salt, a common baking ingredient), tamarind pods or tamarind paste.
TA exists in three distinct isomeric forms. The form of TA found naturally in grapes and wine is the L-(+)-TA isomer. The most important organic acids in grapes are TA and maleic acid (MA), comprising about 70% to 90% of the total grape’s acidity. Dogs are species with unique sensitivity to TA, as well as other organic dicarboxylic acids such as MA. The lowest reported dosage to cause AKI is 19.6g/kg bodyweight for grapes, and 2.8g/kg bodyweight for raisins. However, as few as four to five grapes may be fatal in a dog weighing 8.2kg.
Great variation exists in the susceptibility of dogs to grapes and their dried products.
Some dogs are reported to remain asymptomatic after ingesting up to 1kg of raisins, while others died following the ingestion of a handful. TA exerts toxic effects through the following mechanisms.
TA (2, 3-dihydrosuccinic acid) is an organic dicarboxylic acid [COOH-(CHOH)2-COOH], highly soluble in water.
It is a strong acid with pKa (negative base 10 logarithm of the acid dissociation constant Ka) values of 2.98. TA is an acute irritant, inducing gastritis and ulcers in the gastrointestinal (GI) tract.
Several reports noted a correlation of ingestion of grapes, raisins or currants and AKI in dogs. The characteristic lesion is severe diffuse renal tubular degeneration or necrosis – especially in the proximal tubules. The presence of a gold-brown pigment in the tubule lumens implies a precipitation of toxic principle, causing toxic damage. TA has similar mechanism of toxicity than MA. MA (butenedioic acid; HOOC-CH=CH-COOH) is an organic dicarboxylic acid, with pKa values of 1.92 (the smaller the value of pKa, the stronger the acid).
Administration of 400mg/kg intraperitoneal MA in C57BL/6 mice induces renal tubular cell dysfunction. The levels of blood urea nitrogen (BUN) and serum creatinine are significantly increased. Mitochondrial dysfunction in tubular epithelial cells plays a critical role.
At the renal cellular level, mitochondrial dysfunction results from increasing mitochondrial reactive oxygen species, uncoupled mitochondrial respiration and decreasing adenosine triphosphate (ATP) production.
Neurological signs associated with grape and raisin toxicosis are of variable severity, mainly localised to the forebrain, and appear before uraemia emerges. Hypercalcaemia can explain neurotoxicity of grapes and raisins. Hypercalcaemia blocks sodium movement through voltage-gated sodium channels, causing reduced depolarisation. This explains lethargy, muscle weakness and tremors.
“Nutrition is very important in cases of acute renal injury, even early during hospitalisation.”
The clinical signs appear usually within 6 to 12 hours of ingestion of grapes. They include the following.
GI signs include:
Neurological signs dominate the early clinical signs and include:
Renal signs include:
No antidote exists. Ingestion of grapes and raisins is potentially life-threatening with AKI. Treatment is largely supportive.
“Some preventive advice to owners includes: keep grapes out of reach. Store grapes and raisins securely in closed containers, and keep them in areas inaccessible to your dog.”
Severe hyperkalaemia is a medical emergency because of the risk of life-threatening cardiac arrhythmias.
The treatment of hyperkalaemia requires a combined treatment approach.
Terbutaline binds to β2 receptors in erythrocytes, liver and muscle cells, stimulating adenylate cyclase that converts ATP to 3’5’-cyclic adenosine monophosphate. This stimulates the sodium-potassium ATP pumps, resulting in intracellular K+ uptake.
Terbutaline sulphate can be administered slowly at 0.01mg/kg IV. The onset of action is about 30 minutes following administration, with a duration of action of about two hours.
Severe vomiting should be treated by antiemetics such as maropitant (neurokinin-1 antagonist; 1mg/kg IV every 24 hours). Alternatively, administer a serotonergic antagonist such as ondansetron (0.5mg/kg to 1mg/kg IV slow bolus [two to three minutes] every 8 to 12 hours) or dolasetron (0.6mg/kg IV slow bolus every 24 hours). Metoclopramide (dopaminergic antagonist) is contraindicated (excitatory effects can occur).
Sucralfate (salt of sucrose complexed to sulfated aluminium hydroxide) binds to ulcer sites of the GI tract, stimulates healing and protects them. Give a loading dose of 3g to 6g orally four times a day then 0.5g to 1g on an empty stomach at least one hour before meals. Proton pump inhibitors (PPIs) include omeprazole (0.5mg/kg to 1g/kg IV every 12 hours), pantoprazole (1mg/kg IV) and lansoprazole (0.6mg/kg to 1mg/kg IV every 24 hours). Sucralfate delays, but does not decrease the extent of the absorption of PPIs.
Correction of metabolic acidosis (lactic acidosis) can be carried out with sodium bicarbonate 8.4% solution at 1ml/Lb* to 2.5ml/Lb* bodyweight CRI, depending on the severity of the acidosis, over a four-hour period.
Vitamin K1 improves homeostasis (initial dose of 2.2 mg/kg SC, the preferred parenteral route of administration). A second injection can be given 12 to 18 hours later. Vitamin K1 IV can cause anaphylaxis, and haematomas may form at IM sites. Also, transfuse canine fresh frozen plasma, which is canine whole blood separated from its cellular components and frozen within eight hours of collection. It contains all coagulation factors and fibrinogen (15ml/kg to 20ml/kg every 8 to 12 hours, at a maximum rate of 3ml/minute to 6ml/minute).
Hypertension is a common abnormality associated with acute oliguric and anuric renal failure due to the activation of the renin-angiotensin system. If not controlled, hypertension can lead to worsening glomerular disease. In dogs, angiotensin-converting enzyme inhibitors are the first-line treatment. Enalapril (0.25mg/kg to 1mg/kg orally every 12 to 24 hours) and benazepril (0.25mg/kg orally every 12 to 24 hours) are the most recommended in dogs.
Treatment of grape and raisin toxicosis includes early GI tract decontamination. As grapes can remain within the stomach of dogs for up to 12 hours, emesis could be used until at least 12 hours post-ingestion.
Emesis should be induced only if the patient is asymptomatic. Administer apomorphine 0.03mg/kg IV (preferred) or 0.04mg/kg IM.
If injectable formulations are not available, use of tablets placed in the conjunctival sac can be considered. Place a 0.025mg crushed tablet and dissolve in physiological saline. Instil in the conjunctival sac and rinse with water or saline solution (0.9% solution) after emesis has occurred. After emesis, flushing of the conjunctival sac to avoid protracted vomiting may be recommended. Alternatively, use xylazine (1.1mg/kg SC or IM).
To prevent further absorption of TA from the GI tract, administer one dose of activated charcoal (AC; 1g/kg to 4g/kg) mixed with water to make a 20% slurry (1g/5ml water) via a nasogastric tube as soon as possible post-ingestion, and after the airway is secured. AC admitted orally is contraindicated in convulsing or comatose animals.
The use of multiple doses of AC is not indicated (TA does not undergo enterohepatic circulation). It is recommended to give AC with a cathartic (such as sorbitol 1mg/kg to 2mg/kg orally using a 70% solution).
Nutrition is very important in cases of acute renal injury, even early during hospitalisation. Nutritional recommendations include:
