Proceeding of the NAVC North American Veterinary Conference Jan. 8-12, 2005, Orlando, Florida

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1 Proceeding of the NAVC North American Veterinary Conference Jan. 8-12, 2005, Orlando, Florida Reprinted in the IVIS website with the permission of the NAVC

2 P and Published in IVIS with the permission of the NAVC The North American Veterinary Conference 2005 Proceedings THE PROBLEM WITH PEE CHRONIC URINARY TRACT DISEASE Joe Bartges, BS, DVM, PhD, DiplACVIM, DiplACVN The University of Tennessee Knoxville, TN INTRODUCTION Chronic renal failure is the most common form of renal disease in older dogs and cats, but it can occur in any aged animal. Although many things can cause chronic renal failure, by the time chronic renal failure is diagnosed the cause(s) is/are not present and not treatable. Chronic renal failure is irreversible, stable for some period of time, but ultimately progressive. Clinical signs include: (1) alteration in water balance polyuria/polydipsia; (2) those related to the gastrointestinal tract vomiting, anorexia, gastroenteritis, halitosis; and (3) general body condition weight loss, unkempt appearance, loss of body condition. Some animals have no clinical signs Laboratory findings often, but not always, include: azotemia with inappropriately dilute urine, hypokalemia, metabolic acidosis, hyperphosphatemia, non-regenerative anemia, and bacterial urinary tract infection. Kidneys are often small and irregular on palpation, abdominal radiography, and abdominal ultrasonography. Systemic arterial hypertension occurs in 65-80% of dogs and cats in chronic renal failure The kidneys are involved with whole body homeostasis; therefore, chronic renal failure affects general well-being. Excesses and deficiencies occurring because of chronic renal failure that must be addressed therapeutically can be summarized using the acronym NEPHRONS. NUTRITION Maintain adequate to optimum body condition. Estimates of daily caloric requirements are approximately: dogs BWBkgPB cats 100BWBkgPB P. Adjust caloric intake as needed. Anorexia and nausea occur commonly with chronic renal failure. Treatment includes: (1) Minimizing excesses and deficiencies; (2) Feeding a highly palatable diet or increasing palatability of diet add water to dog food, use flavoring agents, warm food to near body temperature; (3) Modifying feeding patterns feed frequent small meals, offer rewards, prevent food aversion; (4) Treat uremic gastroenteritis; (5) Antacids/anti-emetics I usually use a histamine 2 receptor blocking agent; and (6) Mucosal protectant agents use sucralfate with active ulcer disease. Feeding diets containing omega-3 fatty acids may be beneficial, at least in dogs. Omega-3 fatty acids decrease intraglomerular hypertension, maintain GFR, and prolong survival. An omega-6 to omega-3 fatty acid ratio of 3:1 to 5:1 appears to be a reasonable intake and is present in many renal failure diets ELECTROLYTES Hypokalemia may occur especially in cats due to anorexia, excessive urinary and fecal losses, and chronic metabolic acidosis. Clinical signs of hypokalemia include: (1) Polymyopathy classic sign is an animal that cannot lift its head while sitting sternally; however, generalized weakness may occur more commonly. Figure 1: Hypokalemic polymyopathy in a cat with chronic renal failure. (2) Worsening renal failure, and (3) Anorexia. Serum potassium concentrations should be maintained over 4.5 meq/l. The treatment for hypokalemia involves supplementation if diet alone cannot maintain an adequate serum concentration. Potassium (as potassium chloride) may be added to IV or SQ fluids. Potassium is often present in renal failure diets as potassium citrate. Potassium may be supplemented orally using potassium gluconate or potassium citrate. Potassium chloride (lite or substitute salt) can be used, but cats will not often eat it. ph OF BLOOD (ACID-BASE STATUS) Metabolic acidosis occurs commonly with chronic renal failure. Metabolic acidosis may cause anorexia, hypokalemia, and muscle weakness; however, it does not appear to directly influence progression of chronic renal failure. Serum bicarbonate or total carbon dioxide concentration can be used to estimate blood bicarbonate levels. Try to maintain a normal concentration. Many renal failure diets contain potassium citrate, an alkalinizing agent. Because metabolism of dietary protein results in production of organic acids, dietary protein restriction decreases amount of organic acid that must be excreted by kidneys. Additional alkalinizing agents (potassium citrate or sodium bicarbonate) may be administered if needed. Potassium citrate may be preferred because it provides potassium in addition to its alkalinizing properties. Sodium bicarbonate administration results in a large sodium load that may worsen hypertension and fluid retention HYDRATION Polyuria associated with chronic renal failure is offset by a compensatory polydipsia. Dehydration occurs if water intake does not equal water loss (as urine or in vomitus). Because water requirements are higher than maintenance, supplementation may be required. Clean fresh water should be available at all times. Water may be added to food or a canned formulated diet may be fed. Flavoring agents, such as broth, may be added to food. In a dehydrated animal, intravenous fluid therapy should be undertaken. it is necessary to address 3 parts of fluid therapy: (1) Amount needed for rehydration: %dehydrated x BWBkgB = liters needed for rehydration; (2) Maintenance: for healthy animals: ml/kg/day; (3) Amount necessary to replace fluid lost as vomitus, diarrhea, or third-spaced fluid. Animals with chronic 512

3 Published in IVIS with the permission of the NAVC Small Animal Nephrology - Urology renal failure, especially cats, may require subcutaneously administered fluids to maintain hydration and prevent dehydration. Usually ml are administered q12-72hr. Use a non-glucose containing electrolyte solution such as lactated Ringer s solution, Ringer s solution, etc. An implantable device is available for long term subcutaneous fluid administration. Figure 2: Subcutaneus fluid catheter. RETENTION OF WASTES Elimination of wastes particularly nitrogen-containing compounds is an important function of the kidneys. Therefore, reduction of dietary protein seems logical. Dietary protein restriction may be associated with: decreased degree of azotemia, decreased serum phosphorous concentration (meat-based protein is also high in phosphorous), decreased metabolic acids, and decreased gastric acidity (protein digestion occurs in stomach and gastric acid secretion is stimulated, in part, by dietary protein). Two studies, one in cats and one in dogs, of spontaneously occurring renal failure, demonstrated a beneficial effect from feeding a renal failure diet when compared with feeding a maintenance diet to dogs and cats with chronic renal failure. The animals consuming a renal failure diet lived longer, episodes of uremia were less frequent and time to onset of first episode was longer, and owners perceived quality of life for their pet was better. Renal failure diets, however, differ from maintenance in more ways than protein. The level of dietary protein found in renal failure diets is adequate for maintenance of adult animals is not likely to be associated with protein malnutrition. Feeding diets that contain soluble fiber may redistribute a small amount of nitrogen into the gut for elimination thus decreasing the amount required by the kidneys to eliminate. Soluble fiber promotes bacterial proliferation in the colon, which requires nitrogen. The major source of nitrogen is blood urea nitrogen. Thus, promoting colonic bacterial proliferation may decrease blood urea nitrogen concentration. The effect is small and studies are lacking to demonstrate an effect on survival or quality of life OTHER RENAL INSULTS AVOID Dehydration may precipitate an acute renal failure episode making the chronic renal failure worse. Certain drugs may be directly nephrotoxic or may worsen renal failure such as gentamicin, amphotericin, urinary acidifiers, catabolic drugs (e.g. glucocorticoids, chemotherapeutic agents, and immunosuppressive drugs) and non-steroidal antinflammatory drugs. NSAID s may be nephrotoxic if given in high enough doses, but are not nephrotoxic when given at recommended dosages. They are a risk factor for renal failure. By decreasing production of prostaglandins, vasodilatory prostaglandins may also be decreased. If the animal becomes hypotensive or hypovolemic, blood flow to renal medulla will be compromised due to decreased activity of vasodilatory prostaglandins resulting in ischemia and renal tubular necrosis. The risk of bacterial urinary tract infection is increased in animals with chronic renal failure. Concentrated urine is a defense against bacterial urinary tract infection, and dilute urine occurs with chronic renal failure. Animals with chronic renal failure and a bacterial urinary tract infection may not show clinical signs. Bacterial urinary tract infections may worsen chronic renal failure if the infection involves one or both kidneys. However, prophylactic antibiotics should be avoided because they may select for resistant organism and some antibiotics are nephrotoxic. Most antibiotics are renally excreted and so their kinetics are altered by chronic renal failure. Thus, their administration may have side effects, such as anorexia, vomiting, diarrhea. Only use antibiotics if a bacterial infection occurs and is documented NEUROENDOCRINE FUNCTION RENAL HYPERPARATHYROIDISM occurs, in part, because of phosphorous retention and decreased calcitriol (vitamin D3) metabolism by the failing kidneys. Hyperphosphatemia is associated with progression of chronic renal failure and of shortened survival. Serum phosphorous concentration may be decreased by: (1) Feeding a low phosphorous diet (often found in renal failure diets), (2) Administering phosphate binders, and (3) Vitamin D replacement therapy. Hypovitaminosis D has a role in renal hyperparathyroidism. The kidneys metabolize 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D (calcitriol) by enzyme, 1-alpha-hydroxylase. Calcitriol decreases parathyroid hormone concentration and activity. Parathyroid hormone may have a role in clinical signs and of progression of chronic renal failure, but this is controversial. Dietary phosphorous restriction decreases parathyroid hormone levels. Additionally, oral administration of low doses of calcitriol may decrease parathyroid hormone. Serum phosphorous concentration should be normalized before administering calcitriol because of risk of hypercalcemia and increasing the calcium x phosphorous solubility product HYPOPROLIFERATIVE ANEMIA, characterized by being normocytic, normochromic, and non-regenerative anemia occurs in many animals with chronic renal failure. Anemia occurs because of decreased erythropoietin production, nutritional imbalances, and blood loss due to uremic gastroenteritis. The anemia is treated by maintaining a good nutritional plane and minimizing gastrointestinal blood los. Additionally, red blood cell production by bone marrow can be stimulated. Anabolic steroids have a minimal effect in promoting red blood cell production, and although they may stimulate appetite, their use has been associated with hepatopathy. Recombinant human erythropoietin (rhuepo) has been used successfully in dogs and cats with chronic renal failure that are severely anemic. Many animals receiving rhuepo feel better even if their anemia does not improve. It is indicated when the packed cell volume is less than 15-20%, and/or the animal does not feel well because of the anemia. Because uremic gastroenteritis is common, iron 513

4 Published in IVIS with the permission of the NAVC The North American Veterinary Conference 2005 Proceedings should be supplemented to offset the iron deficiency associated with blood loss. In addition, infections should also be treated to minimize iron sequestration. Target of treatment is to achieve a packed cell volume of 25-30%. Once the target is reached, the frequency and amount of dosage can be slowly decreased to find lowest amount necessary to control anemia. Complications include: Irritation at injection site, systemic arterial hypertension, and polycythemia. In some patients, the anemia may worsen after an initial response. This is usually, but not always, related to antibody production against rhuepo. This occurs in 20-40% of dogs and cats Anti-rHuEPO antibodies may cross-react with native erythropoietin resulting in more severe anemia than initial. Discontinuing rhuepo usually results in improvement of packed cell volume to value at start of rhuepo treatment. If an animal initially responds to rhuepo, but the packed cell volume begins to decline, it may be due to: cross-reacting antibodies or iron deficiency. If it has not been done, you should treat for uremic gastroenteritis and evaluate and treat for infections (especially a bacterial urinary tract infection). If the dog or cat is not already receiving iron supplementation, they should receive it. A recombinant feline erythropoietin (rfelepo) is available, but not yet commercially SYSTEMIC ARTERIAL HYPERTENSION occurs in 65-75% of dogs and cats with chronic renal failure and has been associated with a poorer prognosis in dogs. Results in diseases associated with organs where small vessels are present: Eyes retinal vessel tortuosity hemorrhage Kidneys proteinuria, progression of renal failure. Heart left ventricular hypertrophy, possible congestive heart failure (left sided) Brain ischemic encephalopathy, seizures, death Figure 3: Retinal vessel tortuosity, hyphema Figure 4: Hyphema, blindness Diagnosis is made by measuring arterial blood pressure. Usually arterial pressure is measured indirectly using a Doppler monitor or by oscillometry. There are several strategies that can be used to treat systemic arterial hypertension. Restricting dietary sodium is important because of the role of sodium in fluid retention and hypertension, and because this potentiates the antihypertensive effects of pharmacologic therapy. Angiotensin converting enzyme (ACE) inhibitors decrease metabolism of angiotensin I to angiotensin II resulting in vasodilation and decreased aldosterone production. They are an effective first line treatment for systemic arterial hypertension in dogs and cats. However, they may worsen azotemia. Benazepril has been reported to slow progression of chronic renal failure in cats. But only 1 study of induced chronic renal failure has been reported. In this study, GFR values were not different between benazepril and placebo groups. Calcium channel blockers are another class of anti-hypertensive agents. They decreases blood pressure by vasodilation and are an effective first line treatment for systemic arterial hypertension in dogs and cats. In addition, they appear to have fewer complications than with ACE inhibitors. Other drugs are not as effective and are only used if multiple drugs are required to lower systemic arterial blood pressure. These include beta-blockers (propranolol, atenolol), alpha-blockers (prazosin), direct arteriolar vasodilators (hydralazine), and diuretics (furosemide, thiazides, and spironolactone) SERIAL MONITORING Chronic renal failure is progressive and thus a dynamic disease. Serial monitoring of body condition, body weight, thoracic auscultation, blood pressure, CBC and serum biochemical profile, urinalysis, and urine culture are necessary to adjust treatment. How often an animal should be examined depends on: How rapidly the chronic renal failure is progressing Any non-renal influences that affect renal function Owner satisfaction and finances 514

5 P Edition. Published in IVIS with the permission of the NAVC Small Animal Nephrology - Urology HOW CAN MEDICAL TREATMENT OF CHRONIC RENAL FAILURE BE IMPROVED? Early detection and intervention this may include detection of microalbuminuria Chronic renal failure is more common in older animals; therefore, geriatric screening blood work may identify animals in early chronic renal failure Minimize or eliminate non-renal influences on renal function Individualize treatment Avoid over-treatment Serial monitoring WHEN SHOULD DIET BE CHANGED IN AN ANIMAL WITH CHRONIC RENAL FAILURE? Dietary modification can offset many deficiencies and excesses that occur with chronic renal failure Dietary modification includes more than just dietary protein restriction as renal failure diets are more calorically dense, may contain omega-3 fatty acids, may contain soluble fiber, low phosphorous, low sodium, potassium replete, alkalinizing, and water soluble vitamin replete I believe diet should be changed when an animal is diagnosed with chronic renal failure Renal failure diets are usually indicated at some point in management of dogs and cats with chronic renal failure Renal failure diets are not associated with deficiencies Renal failure diets may be tolerated better if introduced while the animal feels good and is willing to accept a dietary change Renal failure diets may decease uremic episodes and prolong survival REFERENCES/SUGGESTED READING 1. Allen TA, Polzin DJ, Adams LG. Renal disease. In: Hand MS, Thatcher CD, Remillard RL, Roudebush P th (eds.). Small Animal Clinical Nutrition, 4P Marceline: Wadsworth Publishing Company. 2000: Barber PJ, Rawlings JM, Markwell PJ, Elliott J. Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat J Small Anim Pract 1999;40: Bartges JW, Willis AM, Polzin DJ. Hypertension and renal disease. Vet Clin North Amer Small Anim Pract 1996;26: Brown SA, Brown CA, Crowell WA, et al. Effects of dietary polyunsaturated fatty acid supplementation in early renal insufficiency in dogs J Lab Clin Med. 2000;135: Brown SA, Finco DR, Brown CA, et al. Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced chronic renal insufficiency Am J Vet Res. 2003;64: Brown SA, Finco DR, Brown CA, et al. Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced chronic renal insufficiency Am J Vet Res 2003; Chew D, Nagode L. Calcitriol in treatment of chronic renal failure. In: Kirk RW, Bonagura JD (eds.). Current Veterinary Therapy XI. Philadelphia:WB Saunders, 1992: Cowgill L. Pathophysiology and management of anemia in chronic progressive renal failure. Semin Vet Med Surg 1992;7: Dow SW, Fettman MJ, LeCouteur RA, et al. Potassium depletion in cats: renal and dietary influences. J Am Vet Med Assoc 1987;191: Elliott DA, Riel DL, Rogers QR. Complications and outcomes associated with use of gastrostomy tubes for nutritional management of dogs with renal failure: 56 cases ( ) J Am Vet Med Assoc 2000;217: Elliott J, Rawlings JM, Markwell PJ, Barber PJ. Survival of cats with naturally occurring chronic renal failure: effect of dietary management J Small Anim Pract 2000;41: Jacob F, Polzin DJ, Osborne CA, et al. Association between initial systolic blood pressure and risk of developing a uremic crisis or of dying in dogs with chronic renal failure J Am Vet Med Assoc 2003;222: Jacob F, Polzin DJ, Osborne CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogsj Am Vet Med Assoc 2002;220: