Managing Gastrointestinal Complications of Uremia

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MANAGING GASTROINTESTINAL COMPLICATIONS OF UREMIA Donald R. Krawiec, DVM, MS, PhD

Dogs and cats with uremia may display abnormalities of essentially all parts of the gastrointestinal (GI) tract. Gast.rointestinal complications of uremia include Uremic breath Stomatitis Oral ulceration Parotiditis Anorexia Nausea Vomiting Oral or gastrointestinal hemorrhage Gastrointestinal perforation Diarrhea Constipation Intestinal obstruction Pseudomembranous colitis Abnormalities may be mild or severe. They may result from inflammation, edema, erosions, ulceration and/ or necrosis. Clinical signs of GI complications of uremia may include anorexia, nausea, vomiting, abdominal pain, diarrhea, and GI bleeding. Uremic patients may also have preexisting GI disease. Gastroin~ testinal side effects of various therapeutic agents may be accentuated in uremic patients and therapeutic agents used to treat renal failure may have GI side effects. No data exists indicating the number of uremic animals that exhibit GI signs of disease, but 40% of people with renal failure reportedly have .GI complications. Mucosal lesions of gastritis and duodenitis are most commonly seen on endoscopic evaluation of human patients with renal failure. As common

From the Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, Illinois VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 6 • NOVEMBER 1996

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as GI complications of uremia appear to be their pathogenesis is still poorly understood. One theory is that elevated blood gastrin levels lead to gastric hyperacidity and uremic gastritis. Gastrin is cleared from the blood by the kidney and levels are therefore increased in direct proportion to the level of renal insufficiency and failure. Levels of gastrin, however, are inversely proportional to gastric acidity and may therefore represent a response to hypochlorhydria instead of being a direct cause of GI lesions. Some uremia-induced abnormality in gastric mucosal cytoprotection has been proposed but not proven. This article discusses the GI manifestations of uremia according to anatomic sites and also describes the management of common clinical problems as they relate to uremic GI abnormalities. UREMIC EFFECTS ON GASTROINTESTINAL TRACT STRUCTURE AND FUNCTION Oropharynx

Common oral signs of uremia include uremic fetor or uriniferous I ammoniacal breath, stomatitis, and mouth ulcers. The conversion of salivary urea into ammonia by urease-producing bacteria may be responsible for the mouth lesions.3 Uremic stomatitis is characterized by brownish discoloration of the ~orsal surface of the tongue and buccal mucosa. In its worst manifestation, necrosis and sloughing of the anterior tongue may be seen. Ulcerative stomatitis is less common in uremic patients, but may be painful and is often associated with gingival bleeding. Xerostomia (dryness of the mouth) and sialorrhea (increased secretion of saliva) are also seen in uremic dogs and cats." Parotiditis may also be seen." Increased oral bacteria associated with dental disease and/ or gingivitis may potentiate the severity of uremic stomatitis? Esophagus

Metabolic and electrolyte abnormalities that occur with uremia may promote abnormal esophageal motility and reflux esophagitis. Esophageal ulceration and bleeding may also occur in uremic patients but are rare." Esophageal motility disorders may be identified by contrast radiographic studies. Esophageal ulcers are best diagnosed by endoscopy. Stomach

Anatomic and functional abnormalities have been identified at all levels of the GI tract in uremic animals. Gross anatomic abnormalities include gastritis, ulceration, and hemorrhage. 5 Microscopic changes include glandular atrophy, edema of the lamina propria, mast cell infiltration, fibroplasia, mineralization, and submucosal arteritis. 7 Functional abnormalities include abnormalities in acid-pepsin secretion, gastric emptying, mucosal permeability, and serum gastrin levels. 3 The clinical significance of these functional abnormalities remains uncertain. Dietary protein restriction is a fundamental therapeutic recommendation for the amelioration of GI uremic signs including anorexia, nausea, and vomiting.

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However, little information correlates the improvement of these signs with actual changes in structure or function of the stomach and/ or duodenum. 3 Human patients with renal failure show delayed gastric emptying that improves with dialysis. 3 Causes of delayed gastric emptying include electrolyte disturbance, alterations in GI hormones, and dysfunction of the autonomic nervous system. People with uremia who are not receiving dialysis also have increased gastric mucosal permeability that is reversible with dialysis. 3 Little information exists concerning gastric motility and mucosal permeability in uremic dogs and cats. A number of GI hormones including gastrin, cholecysto~inin, gastric inhibitory polypeptide, glucagon, vasoactive intestinal peptide, and motilin have been found elevated in uremic patients? The significance of these hormone elevations remains uncertain. Gastrin increases were thought to be due to decreased renal catabolism. Investigators proposed that increased gastrin resulted in increased gastric acidity, which resulted in gastric mucosal hypertrophy, inflammation, ulceration, and hemorrhage. Other investigators believe the increase in gastrin . is due to the hypochlorhydria seen in some uremic patients. The significance of elevated serum gastrin levels thus remains uncertain. Gastritis and gastric acid hypoacidity were originally thought to be due to increased ammonia levels that both neutralized gastric acid and irritated the stomach: While this view has been challenged, hypoacidity does seem to be associated with atrophic or nonspecific gastritis. Gastric acid hyperacidity seems to occur more commonly in patients receiving dialysis. Individual uremic animals may have normal, increased, or decreased gastric acid levels. This fact may be the reason that formulating a unifying theory for the effect of increased serum gastrin levels in uremic patients is difficult. Hyperacidity causes gastric irritation. Chronic hyperacidity results in the backflow of gastric acid into the stomach wall leading to hemorrhage, inflammation, and release of histamine from mast cells? Animals with normal or reduced gastric acid may still be susceptible to gastric acid injury because of the effect of uremia on the epithelial elements of the gastric mucosal barrier. Renal failure may increase proton permeability and enhance susceptibility to acid injury? Other causes of uremic gastritis ·have been suggested: disease-related stress, increased proton backdiffusion associated with high urea levels, irritation and inflammation caused by increased ammonia levels, vascular lesions with resultant ischemia, alterations in the gastric mucous barrier, and pyloric incompetence with resultant biliary reflux? The hemorrhagic nature of the gastritis may be enhanced as a result of uremia-induced platelet defects? Angiodysplasia, which has been associated with both upper and lower intestinal bleeding, can be seen in the stomach, duodenum, jejunum, and large intestine. 10 Angiodysplasia is characterized by clusters of small arteries in cherry red or fernlike tufts! Why this lesion occurs in renal failure is not understood.

Small Bowel

Uremic changes in the small bowel may range in severity from edema and hemorrhage to severe necrotizing, pseudomembranous, or ulcerative lesions. 3 These lesions likely result from several causes. Small bowel lesions may result from uremic coagulopathy, bacterial infection, toxic effects of ammonia, or severe arterial hypertension. Small bowel lesions are rare in humans receiving

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dialysis indicating that severity of the small bowel lesion correlates well with severity of azotemia and uremia. Functional small bowel abnormalities that have been associated with uremia in various species include alterations in enzyme activity; absorption, bile acid content, and microbial flora. Specific abnormalities have not been well characterized in the dog and cat. Amino acid absorption seems to be dependent on the degree of uremia with increased absorption occurring with severe uremia. 3 Impaired absorption of glucose, fat, calcium, and folate has been reported? Intestinal loss of albumin has also been reported. Vitamin D supplementation has been reported to return absorption of calcium, phosphate, and magnesium to normal. Bacterial overgrowth has been identified in uremic patients and may be responsible in part for impaired absorption. 3 Peptic ulcer disease has been reported in human patients with renal failure.U Treatment for ulcers in patients with renal failure is the same as in patients without renal failure. Large Bowel

Colon disorders are seen more commonly in uremic patients than in nonuremic patients. 7• 11 Uremia-induced large bowel syndromes include colonic ulceration, spontaneous colonic perforation, pseudomembranous colitis, and adynamic ileus. 5 Chronic dehydration in cats has been associated with constipation. Antacid therapy for hyperphosphatemia may also cause constipation or in severe cases colonic obstruction. 7• 11 MANAGEMENT OF COMMON CLINICAL PROBLEMS Anorexia

Anorexia has been reported in a large percentage of dogs and cats with chronic renal failure. 8 In fact many animals are initially diagnosed with renal failure after their owners present them to a veterinarian with the problem of anorexia. Anorexia of renal failure is thought to result from accumulation of toxic metabolic waste products that are normally excreted by the kidney. Other causes of uremic anorexia may include uremic gastritis, hypokalemia, metabolic acidosis, dehydration, anemia, and hyperparathyroidism. Uremic anorexia may be exacerbated when the palatability of renal failure diets is poor. By-products of protein catabolism are commonly incriminated as uremic toxins. Although unlikely to be the sole or primary uremic toxin, urea nitrogen has been found to induce anorexia as well as weakness and decreased attentiveness in dogs.u Dietary protein restriction reduces serum urea nitrogen levels and reduces the systemic signs of uremia including anorexia. Other uremic toxins include skatoles, trace elements, guanidine compounds, hippurate esters, phenols, hormones, serum proteases, j32-microglobulins, middle molecules, indoles, polyamines, pyridine derivatives, aliphatic amines, and aromatic amines. What specific effect each of these has on clinical signs of uremia is not known. Many suggestions have been made to increase the palatability of renal failure diets. Gradually introducing the diet to an animal in renal failure over 2 weeks or longer may improve compliance. If the animal totally refuses the new diet, mixing it with something the pet likes may at least result in partial compliance. Trying different types of food may be of some benefit. Warming

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moist foods or adding warm water to dry foods improves acceptance in some patients. Renal failure diets may be made more palatable by adding a condiment to the diet. Agents that have been suggested include liquid enteral diets, fat, butter, dehydrated cottage cheese, garlic, bouillon, clam juice, brewer's yeast, and carnitine. Feeding small amounts of freshly prepared foods also may help in certain patients. Nutritional support is of paramount importance to the well being of patients with renal failure. 2 Renal failure patients who are in a catabolic state begin to metabolize endogenous protein for energy. ·catabolism of endogenous protein has a serious detrimental effect on the overall well being of the animal via promoting uremia and malnutrition. My view is that eating something is always better than eating nothing. If an animal is totally anorectic and will simply not eat the appropriate diet, it should be allowed to eat whatever it wants. If an animal remains anorectic and is not vomiting, a percutaneous gastrotomy tube can be placed. The animal can then be permanently or temporally fed an appropriate diet. Vomiting

Vomiting is another common sign of uremia. Vomiting may be caused by systemic effects of uremic toxins or it may be caused by a more direct effect of gastritis. Nausea and vomiting in uremic patients may be caused by Metabolic disturbances due to uremia Medications Primary gastrointestinal disease unrelated to uremia Secondary gastrointestinal disease unrelated to uremia Medications that animals in renal failure are receiving should be evaluated very closely for their ability to induce anorexia and vomiting. A medication's ability to induce nausea may be enhanced by the uremic state. The approach to uremic patients with chronic nausea or vomiting is similar to that for nonuremic patients. Nonrenal causes of vomiting should be evaluated and pursued. 9 Prior history of GI disease, concurrent use of medications, and other underlying disease processes should be evaluated. Patients with no history of underlying GI disorder who have no other likely cause for their nausea or vomiting may be assumed to have uremic gastritis. Anorexia, nausea, and vomiting due to uremic gastropathy may be treated with H 2-receptor antagonists like cimetidine or ranitidine. These agents reduce gastric acid and therefore are ineffective in uremic animals with gastric hypoacidity. Cimetidine may be used at a dose of 5 mg/kg every 8 to 12 hours in dogs and 2.5 to 5 mg/kg every 12 hours in cats. Ranitidine may be used at a · dose of 2 to 4 mg/kg every 12 hours. The prokinetic and antiemetic drug metaclopramide has been used to ameliorate severe vomiting in dogs and cats. The normal dose of metaclopramide is often reduced in animals with renal failure because it is excreted by the kidney. Reported oral dose of metoclopramide is 0.2 to 0.4 mg/kg every 6 to 8 hours. In severe cases of vomiting metoclopramide may be given via continuous intravenous infusion at a dose of 1 to 2 mg/kg every 24 hours. 8 Metaclopramide may be particularly helpful in patients with gastroparesis or disordered gastric motility.• Domperidone, cisapride, and erythromycin have also been used in human patients with renal failure for their prokinetic effects. Erythromycin is

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the only one of these three that comes in an intravenous form. Dose of cisapride does not appear to need altering in human patients with renal failure.• Gastrointestinal Bleeding

Patients with GI bleeding should be thoroughly evaluated just as should vomiting patients. Uremic patients must be assessed for nonrenal causes of GI bleeding. Gastrointestinal bleeding may be caused by foreign body, carcinoma, inflammatory bowel disease, and/ or ulceration. Coagulation abnormalities should be considered in any uremic animal with GI bleeding. Treatment for GI bleeding includes an H 2 blocker like cimetidine or ranitidine as described above as well as sucralfate. Sucralfate acts as a protectant on the gastric mucosal surface. It minimizes the back diffusion of acid and pepsin into the stomach wall. Reported dosage of sucralfate in the dog is 0.25 to 1 g every 8 to 12 hours. References 1. Amerling R, Levin NW: Uremia. In Massry SG, Glassock RJ (eds): Textbook of Nephrology, ed 3. Baltimore, Williams & Wilkins, 1995, p 611 2. Bergstrom J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329, 1995 3. Doherty CC: Gastrointestinal effects of chronic renal failure. In Cameron S, Davison AM, Grunfeld JP, et a! (eds): Oxford Textbook of Clinical Nephrology. New York, Oxford University Press, 1992, p 1278 4. Jamidar R, Kendall B: Gastrointestinal disease in patients with chronic renal failure. In Nissenson AR, Fine RN, Gentile DE (eds): Clinical Dialysis. Norwalk, CT, Appleton & Lange, 1995, p 607 5. Lazarus H: Medical aspects of hemodialysis. In Brenner BM, Rector FC (eds): The Kidney. Philadelphia, WB Saunders, 1991, p 2254 6. May RC, Kelly RA, Mitch WE: Pathophysiology of uremia. In Brenner BM, Rector FC (eds): The Kidney. Philadelphia, WB Saunders, 1991, p 1997 7. Osborne CA, Polzin DJ: Pathophysiology of renal failure and uremia. In Osborne CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Williams & Wilkins, Baltimore, 1996, p 335 8. Osborne CA, Polzin DJ: Conservative medical management of chronic renal failure. In Osborne CA, Finco DR (eds): Canine and Feline Nephrology and Urology. Williams & Wilkins, Baltimore, 1996, p 508 9. Ritz E: Gastrointestinal problems. In Cameron S, Davison AM, Grunfeld JP, eta! (eds): Oxford Textbook of Clinical Nephrology. New York, Oxford University Press, 1992, p 2310 10. Salem M, Mujais SK: Gastrointestinal tract in uremia. In Massry SG, Glassock RJ (eds): Textbook of Nephrology, ed 3. Baltimore, Williams & Wilkins, 1995, p 1379 11. Valenzuela J: Gastrointestinal abnormalities. In Massry SG, Glassock RJ (eds): Textbook of Nephrology. Baltimore, Williams & Wilkins, 1983, p 7.59

Address reprint requests to Donald R. Krawiec, DVM, MS, PhD Department of Veterinary Clinical Medicine University of Illinois 1008 W. Hazelwood Drive Urbana, IL 61801