Introduction

Gastrointestinal (GI) complications (gastroduodenitis, enterocolitis, and associated signs of anorexia, nausea, vomiting and diarrhea) represent probably the most common cause of morbidity in dogs. Paradoxically, very few studies have been conducted to evaluate the effect of renal failure (RF) on GI physiology in dogs. Most of the data available are extrapolated from studies in humans and rodents. However, the gut of a dog is not the same as that of a human or rat! This presentation firstly describes data available on GI pathophysiology in uremic patients, and then the results of our recent study of the effect of mildly azotemic, chronic renal failure (CRF) on GI function in dogs. Finally, the main drugs used to treat GI dysfunction are discussed.

1. Gastrointestinal pathophysiology in uremic conditions

Most published data have been obtained in human patients (4, 11) and rodent models.

Vomiting/nausea/anorexia associated with uremic gastropathy-Vomiting and nausea are frequent in dogs. Uremic gastropathy is a pathological finding in acute RF or end-stage CRF. Two possible mechanisms have been proposed: i) abnormally high blood concentrations of gastrin (which increases gastric acid secretion), caused by decreased renal catabolism of gastrin and loss of inhibition of gastrin secretion. Hypergastrinemia was found in 60% of cats with CRF for example, and severity of hypergastrinemia increased with severity of renal dysfunction (5); ii) back-diffusion of HCl and pepsin into the stomach, because of reduction of function of pre-epithelial, epithelial and post-epithelial elements of the gastric mucosal barrier; this leads to inflammation and release of histamine (which also stimulates acid secretion) (10).

Gastric dysfunctions-Functional changes that may or may not be associated with uremic gastropathy have been also described: for example, gastric emptying of solids but not liquids is decreased in rats with CRF (3, 12), and gastric myoelectrical activity is decreased in human patients with CRF (7).

Intestinal dysfunctions-Diarrhea associated with uremic enterocolitis, which often is hemorrhagic, can occur in dogs, but is less common than uremic gastropathy. Constipation might be more common in cats than diarrhoea, and may result from dehydration or use of phosphate binding agent. In humans and rodents, impaired absorption of glucose, fat, magnesium, calcium and folate has been reported.

It has been shown in humans that the pathophysiology of GI complications may differ in dialysed patients or those with renal transplants.

2. Gastrointestinal alterations in subclinical moderate renal failure

There have been very few pathophysiological studies on this topic in any species, and until recently, no study has been conducted in dogs to document the effect of renal failure. The lack of canine data has been of concern because obvious interspecies differences do not allow simple extrapolation of human data to canine patients. For example, when compared to humans, GI physiology in dogs is characterized by slower gastric emptying rate in the fed state, faster small intestinal transit, and higher and more variable intestinal pH (2).

A study was therefore undertaken (6). In 12 dogs with experimentally produced azotemic, but not uremic, renal failure (66% decrease in GFR, i.e., subclinical), we examined GI electrical activity and its consequences on GI transit times, and also other aspects of GI function and morphology. No GI lesions were observed under these conditions, but GI motility indexes increased (up to 42%). A 24% decrease in the propagation velocity of the myoelectrical migrating complex in the duodenojejunal segment was observed, together with a 20%-increase in the total irregular electrical activity. Renal failure did not change xylose absorption, gastric emptying rate, or orocolonic transit time, but colonic transit time was decreased by 38%. These results show that moderate, subclinical renal failure alters duodenojejunal motility and decreases colonic transit time in the absence of GI lesions in dogs.

3. Functional pharmacology of gastrointestinal dysfunctions in the uremic patient

Currently, only curative rather than preventative, management of GI complications is proposed. Recent reviews (1, 9, 13) provide useful information for such therapies. However, no study has documented the efficacy of these drugs, under strictly controlled conditions in renal-impaired patients. Only the main drugs are presented here, but it should not be forgotten that the whole patient is being treated, not just a clinical sign or a laboratory abnormality. Fortunately, by correcting dehydration, electrolyte and acid-base disorders, one may considerably improve the patient's condition, including gastrointestinal disturbances.

Antacids, protectants and adsorbents-Sucralfate (0.5-1 g every 6-12 h), a nonabsorbable aluminium salt, is useful for medical management of uremic gastropathy. It binds to ulcerated tissue, protecting it from acid and pepsin. When other oral drugs are used concomitantly, they should be administered at least 30-60 minutes before sucralfate to avoid a decrease in bioavailability. Various other substances (magnesium- and aluminium-containing products, bismuth salicylate, kaolin-pectin, activated charcoal) are often administered in acute diarrhea to bind bacteria and their toxins and to coat and protect the intestinal mucosa. These products should be preferred to anticholinergics or antibiotics because they are safer and more efficacious. Bismuth salicylate is given at a dose of 1 mL/5 kg every 6-8 h in dogs for <5 days (use carefully in cats because they are more sensitive to salicylate). Treatment with the other agents requires at least 5-6 administrations per day, which is most often impracticable.

H₂-receptor antagonists-These agents (ranitidine 0.5-2.0 mg/kg PO, IV every 8-12h; famotidine 0.5-1.0 mg/kg PO, IM, IV every 12-24h), often given with an antiemetic, are mainly used to treat uremic gastropathy. They inhibit acid secretion by binding to the H₂-receptor sites on parietal cells. Cimetidine (5-10 mg/kg PO, IM, IV, every 4-6h (dog)) is an alternative of limited value, because it requires administrations up to 6 times per day and is less efficient than ranitine and famotidine. Ranitidine is also a prokinetic agent. Because of partial renal excretion, the dosage of H₂-receptor antagonists should be reduced 25% to 75% in end-stage CRF. No information is available about the effect of misoprostol (a prostaglandin E analog) and omeprazole (inhibits H+,K+-ATPase) on uremic gastropathy.

Antiemetics and prokinetic agents-An antiemetic may be required if vomiting is severe and/or persistent. Metoclopramide (0.2-0.5 mg/kg every 8 h orally or parenterally), a dopamine antagonist, is more effective as a centrally-acting antiemetic, than as a prokinetic agent. It should not be used in the presence of gastrointestinal hemorrhage, mechanical obstruction, perforation, or in epileptic patients. Phenothiazine derivatives are also antiemetics, but should be avoided in patients with RF because they are sedative and hypotensive. Prokinetic agents are used for treating esophagitis and delayed gastric emptying. Cisapride (0.1-0.5 mg/kg every 8-12 h), the first-choice gastric prokinetic agent, binds serotoninergic receptor on enteric postganglionic cholinergic neurons and stimulates contraction of gastrointestinal smooth muscle. The facilitation of gastric emptying could increase absorption rate of other drugs, and animals receiving drugs with low therapeutic index should be monitored closely. Concomitant treatment with cimetidine (inhibitor of cytochrome P450 enzyme systems), but not with other H₂ blockers, may lead to increased concentrations of cisapride and should thus be avoided.

Appetite stimulants-These agents should only be used in partially anorectic patients and for a limited time. Diazepam (0.2 mg/kg every 12-24h) for example has been recommended, but nutritional support by feeding tubes is the treatment of choice for anorectic patients. Glucocorticoids should be avoided in uremic patients because they worsen azotemia and had direct adverse effects on renal function.

Conclusion

GI complications remain a major problem in the medical management of canine patients with RF. We now know that GI dysfunction occurs early in the course of renal failure and that the colon may be involved first. However, further studies are required to identify the optimal nutritional and medical strategies to limit such dysfunctions and any ensuing GI lesions, and to provide firm evidence for the effectiveness of the various drugs currently used.

References

1.  Cowgill LD, Elliott DA. Acute renal failure. In: Textbook of Veterinary Internal Medicine 5^th ed., Ettinger SJ, Feldman EC, WB Saunders, Philadelphia,2000, 1615-1633.

2.  Dressman JB. Comparison of canine and human gastrointestinal physiology. Pharm Res, 1986, 3:123-131.

3.  Dumitrascu DL et al. Antral emptying of semisolid meal measured by real-time ultrasonography in chronic renal failure. Dig Dis Sci, 1995, 40:636-644.

4.  Etemad B. Gastrointestinal complications of renal failure. Gastroenterol Clin N Am, 1998, 27:875-892.

5.  Goldstein RE et al. Gastrin concentrations in plasma of cats with chronic renal failure. J Am Vet Med Assoc, 1998, 213:826-828.

6.  Lefebvre HP et al. Small bowel motility and colonic transit are altered in dogs with moderate renal failure. Am J Physiol Regulatory Integrative Comp Physiol, 2001, 281: R230-R238.

7.  Lin X et al. Impaired gastric myoelectrical activity in patients with chronic renal failure. Dig Dis Sci, 1997, 42:898-906.

8.  Polzin DJ, Osborne CA. Pathophysiology of renal failure and uremia. In Canine and Feline Nephrology and Urology, Osborne CA, Finco DR, Williams and Wilkins, Baltimore, 1995, 335-367.

9.  Polzin DJ et al. Chronic renal failure. In: Textbook of Veterinary Internal Medicine 5^th ed., Ettinger SJ, Feldman EC, WB Saunders, Philadelphia,2000, 1634-1662.

10. Quintero E et al. Uremia increases gastric mucosal permeability and acid back-diffusion injury in the rat. Gastroenterology, 1992, 103:1762-1768.

11. Ravelli AM. Gastrointestinal function in chronic renal failure. Pediatr Nephrol, 1995, 9:756-762.

12. Raybould HE et al. Gastric emptying of solids but not liquids is decreased in rats with chronic renal failure. Dig Dis Sci, 1994, 39:2301-2305.

13. Schulman RL, Krawiec DR. Gastrointestinal complications of uremia. In Kirk's Current Veterinary Therapy XIII Small Animal Practice, Bonagura JD, WB Saunders, Philadelphia, 2000, 864-866.