Facilitating client management of chronic kidney disease (Proceedings)

Chronic kidney disease (CKD) is a common disease in older animals. It affects 6% of cats and 1% of dogs, with the incidence increasing to 15% in cats over 15 years old. Just as there are many different causes of chronic kidney disease, there are many different levels of dysfunction.

IRIS Staging System

The International Renal Interest Society has developed a staging system for kidney disease in dogs and cats, to facilitate management recommendations and for standardization that will hopefully allow comparison in the research arena. Substages include proteinuria and hypertension.

IRIS Stages

Stage I includes non-azotemic pets, such as a Persian cat with polycystic kidney disease. Clinical signs of uremia will not be present; management involves monitoring the primary condition. Most pets with Stage II CKD are asymptomatic, with mild elevations in BUN or creatinine, are maintaining body weight and appropriate hydration, and may not need specific treatment, although routine monitoring is indicated. Pets with Stage III disease usually have some clinical signs, which may include polyuria and polydipsia, or partial anorexia, among others. More intervention is usually needed for these animals. Most pets with Stage IV CKD have significant clinical signs. Pets with CKD may develop a uremic crisis, characterized by acute decompensation with dehydration and significant clinical signs, and they will need to be hospitalized for management. Once they are stabilized, they can be sent home to continue outpatient management. About 30% of cats that present in a decompensated crisis can be stabilized at 1 or 2 stages lower than presentation.

Nutrition: Stages II, III, IV

Renal Diets: Use of a renal diet will double the survival time in dogs, compared to a maintenance diet, which makes it one of the most potent treatments we have for CKD. Similar effects are seen in cats eating a renal diet. A renal diet is formulated to have restricted protein and phosphorus. In addition to a restricted quantity of protein, the protein source should have high biologic value, which generally means animal source protein. There are several commercial options available, including Hill's K//D; Royal Canin Renal LP, Renal MP (dogs only), and Modified Formula; Purina CNM NF; Eukanuba Renal Disease Early Stage and Late Stage diets for dogs (dry only) and Multi-Stage Renal Diet for cats. Several home-cooked recipes are available but have not been rigorously evaluated.

If the pet is consuming exclusively a renal diet, the BUN:Creatinine ratio should be in the range of 10 to 15 (normal 15-20), and alterations in this ratio can indicate gastrointestinal bleeding or poor patient or client compliance with dietary recommendations.

Enhancing Dietary Compliance: Pets with stage III or IV CKD may have anorexia that makes switching to a renal diet problematic. Because of the possibility of creating a food aversion, a new diet should not be introduced in the hospital during a period of decompensation. Instead, the new diet should be introduced once the animal is home and eating its normal diet. The new diet should be offered in a separate bowl next to the regular food and removed after an hour and replaced at the next feeding time. After a few days, offer the new food at times when the pet is hungriest, and then offer the regular food if the pet does not eat the new food. Gradually decrease the amount of the regular food that is offered. It may take 4-6 weeks to completely switch a pet to the renal diet. Weekly phone calls to the client may help encourage compliance.

Appetite Stimulants: Appetite stimulants are sometimes helpful in managing pets with CKD. One dose of intravenous diazepam can induce feeding behavior in many cats. It is less dramatic in dogs. The food needs to be immediately available (onset of action is about 10 seconds), and for some cats, this one dose can "jump-start" the appetite sufficiently to result in sustained eating. If the cat eats with the valium trial, but results are short-lived, an oral valium derivative, oxazapam (Serax) can be used. Because oxazapam is a controlled drug, cyproheptidine (Periactin) is utilized more frequently. This is an antihistamine that is fairly effective at stimulating the appetite of cats, less so for dogs. Some cats may have "unusual" behavior with this drug; a decrease in dose or decrease in frequency of administration may correct this problem. Mertazapine (Remeron) seems to be gaining popularity because of its twice a week administration schedule in cats, but no data is available on its use in CKD.

Enteral Feeding: If the pet will not consume enough food voluntarily, a feeding tube can alleviate many of the obstacles in patient management. Although many people initially are resistant to the concept, most find that the ease of administering medications and removing the stress of coaxing the pet to eat enough makes a feeding tube a welcome addition. Syringe feeding a soft diet like A/D or NRF is acceptable for some patients, but it is very difficult to ensure adequate caloric intake by this method due to resistance by the patient. Nasoesophageal or nasogastric feeding tubes are temporary support methods that allow adequate caloric administration. These tubes can be placed with only a local anesthetic (a few drops of lidocaine intranasally) and a holding suture at the alar fold of the nose and one either on the side of the face or top of the head (don't forget the Elizabethan collar). Because the size of a NE tube is limited (5 French in cats, 8.5 French in medium to large dogs), only a liquid diet can be fed through them. Clinicare RF Liquid diet is formulated for this method of administration. Other liquid diets available in the grocery store or human pharmacy must be evaluated for protein content and suitability. For most animals, after an acclimation period, to allow the stomach a chance to expand to accept the volume and to avoid diarrhea from the diet change, the fluid load is helpful in maintaining hydration and diuresis. Practically speaking, however, these diets must be fed 5 to 6 times a day, which can be difficult for the owner. For animals that do not begin eating adequately within a short period of time, an esophagostomy tube or a PEG tube should be considered. By placing one of these tubes, the animal's nutritional needs can be met by 3 to 4 times a day feedings of a blenderized diet (canned K/D mixed with 1/2 to 1 part water). The esophagostomy or PEG tube will not interfere with the animal's attempts to eat on its own, and can be used to supplement animals with a fair but inadequate appetite. These tubes can remain in place for up to 6 months before needing to be replaced with a new tube, which can be done with sedation and a guide wire, without need for anesthesia or endoscopy.

Supplementation of the water-soluble vitamins (particularly B vitamins) should not be necessary in cats consuming an adequate amount of a balanced diet. However, because losses may be greater with polyuria and many of these cats have a decreased intake, multivitamins (i.e. Pet-Tinic, Favor) can be used judiciously, if care is taken to avoid oversupplementation of fat soluble vitamins.

Prevention of Progression: Stages I, II, III, IV

Proteinuria is associated with more rapid progression and shorter survival times. Assessment of proteinuria should be standard in all animals with CKD. The urine protein:creatinine ratio (UPC) could be considered the gold standard of urine protein measurement. Any positive urine dipstick should be followed with a UPC to confirm and quantify the proteinuria. Microalbuminuria can be measured semiquantatitively by an in-house test (Heska ERD HealthScreen) or quantitatively at a commercial laboratory. Microalbuminuria testing is more sensitive to smaller amounts of protein in the urine compared to the standard urine dipstick. It also will be positive before the UPC is elevated to an action level. A negative microalbumuria test indicates that significant proteinuria is not present, but a positive test should prompt measurement of a UPC in an animal with CKD (whereas monitoring to follow the trend may be appropriate in microalbuminuria positive animals without CKD).

If proteinuria is present, defined as a UPC > 0.5 in dogs or > 0.4 in cats with CKD, correction of any underlying condition (i.e., hypertension, urinary tract infection, fever, etc) should be attempted. If the proteinuria persists and is not corrected by a low protein diet, consider treating with drugs to decrease proteinuria. Angiotensin converting enzyme inhibitors (ACEi) such as enalapril or benazepril are commonly used. Benazepril is licensed to treat CKD in cats in the United Kingdom. However, it has not been proven to help cats without proteinuria (the majority of cats with CKD). I do not routinely use it unless the UPC is elevated.

Fluid Therapy: Stages III, IV

The ability to concentrate urine is destroyed with CKD, leading to an obligate polyuria. Because of the urinary water loss, polydipsia is necessary to avoid dehydration. With advancing CKD, some cats are unwilling or unable to drink a sufficient volume of water to replace the deficits, and thus they become dehydrated. Dehydration impairs the renal toxin removal capabilities, adding a prerenal azotemia to the renal azotemia. The dehydration and the azotemia can create nausea that diminishes a cat's desire to drink, exacerbating the situation. Regular fluid administration can help alleviate this problem. Encouraging water consumption in early stages may be sufficient. This can be accomplished by providing fresh cold water (or settled room temperature water, according to the individual cat's preferences), multiple water bowls, running water, or even flavored water (water from tuna, etc.) If using anything other than fresh water, pay attention to the salt and electrolyte content.

If voluntary intake is insufficient, subcutaneous fluids may be helpful. In addition to any diuresis it may provide, it can help "smooth over" any periods of stress when the animal's water intake may decrease (visitors in house, owners away, boarding, anorexia from other disease) or when there is extra fluid loss (vomiting, diarrhea). Lactated Ringer's Solution or 0.9% saline are appropriate choices, although either can lead to hypernatremia. Dextrose is irritating when given subcutaneously, so it should be avoided. There is no established dose; rather, dose is dependent on the severity of azotemia and condition of the patient. Alterations in dose are based on subjective response to treatment, as determined by the owner's perception of quality of life, activity level, appetite, and by clinical parameters such as stabilization of weight, creatinine, BUN, state of hydration, etc. For an average sized cat, a reasonable starting dose is 100-150 ml every day to every other day. Dogs larger than 20 kg usually do not benefit as much because it is harder to administer an adequate volume. Clients can learn to administer the fluids at home in most cases. Active cats may need to be restrained in an open topped box or carrier, or wrapped in a towel to allow one person to administer the dose. The occasional cat is too fractious for subcutaneous fluid therapy.

Medications: Stages III, IV

Phosphate Binders: Because the ability to excrete phosphate diminishes with decreased GFR, hyperphosphatemia is commonly seen with CKD. Because methods to increase excretion (i.e., increasing GFR by fluid therapy) are usually of limited efficiency, phosphate binders are used to prevent absorption of phosphorous that is ingested with meals. They should be administered at meal time (either shortly before or after) for maximal efficacy. They will not cause stomach upset if given between meals, but will not be effective. Dosage of phosphate binders should be titrated based on serum phosphate concentration. They can interfere with absorption of other medications. Salts of aluminum (aluminum hydroxide, aluminum carbonate, aluminum oxide), are available as over the counter antacids. Liquid forms are more effective than tablets or capsules, and Amphogel and Basalgel are two liquid antacids that are readily available. The somewhat chalky taste can be diminished by refrigeration. Powdered forms are sometimes available and can be mixed with the food. Calcium containing phosphate binders (calcium carbonate [Tums], calcium acetate [Phoslo]) should not be used in patients with an elevated calcium level. Epikitin is a combination of chitosan and calcium carbonate that is reported to be palatable. As with other phosphate binders, little data is available on its efficacy in dogs and cats.

Potassium: Hypokalemia is a consequence of polyuric CKD, especially in cats. Signs of hypokalemia are muscle weakness, which differentially affects the muscles of the head and neck first. These cats may present with profound cervical ventroflexion. The chronic hypokalemia promotes metabolic acidosis, and both the hypokalemia and acidosis promote progression of renal damage.

Potassium gluconate is the most commonly used oral potassium supplement, and it is dosed at 2 to 6 mEq/cat/day. Tumil-K is convenient for cats, and comes as powder, tablets, and gel. Potassium gluconate tablets may be purchased at many health food stores, but are not convenient for dosing small animals. Potassium citrate can be used as a potassium supplement, and comes as Polycitra-K. Potassium chloride (Lite Salt) is not recommended for oral administration because of its extreme bitterness and unpalatability.

Decreasing Gastric Acidity: Gastric ulceration is a common problem with chronic kidney disease. Histamine blockers are routinely used as anti-ulcer medications. Cimetidine (Tagamet) is the classic histamine blocker, but is associated with many drug interactions. Dosage needs to be reduced with kidney disease from q 8 hours to q 12 hours. Ranitidine (Zantac) is dosed once a day in kidney disease. Famotidine (Pepcid) also is a once a day medication. It has fewer drug interactions than cimetidine or ranitidine. All of these are over the counter medications. Proton-pump blockers decrease gastric acidity by a different mechanism and can be used instead. Omprazole is the most commonly available formulation, but dosing is complicated in that the capsules need to be given intact.

Antiemetics: Centrally acting antiemetics like metoclopramide (Reglan) can be used as needed. Ondansetron (Zofran) or dolasetron (Anzemat) have also been used with good results, although they are expensive. Meropitant (Cerenia) is a recently released injectable drug that decreased vomiting in dogs with a variety of diseases including kidney disease. It appeared to be twice as effective as metoclopramide. Limited information is available on its use in cats.

Other GI Protectants: Sucralfate (Carafate) is a gastric mucosal protectant. It works best in an acid environment, so it should be given 30-60 minutes prior to any antacid. It will interfere with absorption of other medications, so medications other than antacids should be given 30-60 minutes prior to sucralfate administration.

Systemic Acidosis: Alkalinizing therapy is indicated if the bicarbonate level is less than 16 mEq/L, or the pH is persistently below 7.2. Sodium bicarbonate is supplied as tablets (325 mg) or as baking soda, which can be mixed in water and kept in the refrigerator. Most cats do not tolerate this therapy, due to intestinal gas production, and the sodium load may be excessive. An alternative is citrate, which provides buffering for the metabolic acidosis. It is supplied as sodium citrate or potassium citrate. Using the potassium citrate formulation (Polycitra-K, Urocit-K), hypokalemia can be addressed also.

Anemia: The anemia of CKD can be treated with human recombinant DNA erythropoietin (Epogen( , Procrit( ), but only when the anemia is moderate to severe and symptomatic, due to the associated risks. I generally reserve therapy for patient with a PCV < 20%. Symptoms of anemia can include tachycardia, heart murmur, heart failure, exercise intolerance, and anorexia. If there is evidence of recent blood loss (i.e. gi bleeding) or a concurrent inflammatory process in a cat with a previously acceptable PCV, the decision to start EPO can be delayed for 2 weeks to allow control of the underlying process and improvement in the PCV. Epogen is given by subcutaneous injection up to 3 times a week. Weekly rechecks of blood pressure, PCV, and ideally, reticulocyte count are recommended during the initial loading phase (generally 4-8 weeks). A sudden decrease in PCV may signal antiEpogen antibody formation, a potentially fatal side effect that occurs in 20-25% of dogs and cats. A newer drug (darbepoeitin, Aranesp) may have a lower risk of antibody formation.

Hypertension: In dogs, hypertension (systolic blood pressure > 160 mmHg) is associated with shorter survival times. In cats, hypertension does not affect survival. In both species, catastrophic problems can arise from hypertension, and antihypertensive medications are warranted. A more complete discussion is available separately.

Monitoring

Frequency of monitoring depends on the clinical condition of the patient. If there are ever questions about the pet's stability or a change in the status, a recheck is always in order. The benefit of routine monitoring in pets that appear normal to the owners is that many conditions can be detected prior to development of clinical signs. Early treatment may be more effective, and may avoid having the pet ever exhibit those signs. For Stage II disease that is relatively asymptomatic (good appetite, maintaining weight, on minimal treatments), I recommend rechecks (physical exam, weight, chemistry panel, CBC) every 6 months. Stage III pets who are stable on therapy should be checked every 2-3 months. Stage IV pets or those receiving SQ fluids on a daily basis should be checked on a monthly basis. Urinalysis and urine culture should be performed at least twice a year in all stages. Blood pressure measurement should be performed every 3 months in hypertensive pets who are controlled on therapy.

Outcome

Dogs with CKD can live for 2 years or more. Hypertension and proteinuria are poor prognostic indicators. In cats, survival times vary by stage. Median survival of cats in Stage II CKD is 3 years, Stage III is 2 years, and Stage IV is 3 months. However, outcome is extremely difficult to predict for an individual animal because of a large amount of variability. About half of cats diagnosed at Stage II will die of a disease other than CKD, such as cancer or heart disease. The majority of cats with Stage IV CKD will die of uremia. Helping owners to have realistic expectations is an important part of case management.