11 guidelines for conservatively treating chronic kidney disease

To provide optimal treatment for dogs and cats with chronic kidney disease, you'll need to thoroughly evaluate the animal and diligently monitor the natural course of the disease as well as the patient's response to intervention.1 With conservative medical management of chronic kidney disease, you're trying to attain these four general goals:

1. Provide adequate and appropriate nutritional support.

2. Correct fluid deficits and excesses, acid-base imbalance, and electrolyte abnormalities.

3. Ameliorate clinical signs of chronic kidney disease.

4. Slow the disease's progression with renoprotective therapy.

The following 11 guidelines provide a framework for achieving these treatment goals in concert with the International Renal Interest Society (IRIS) staging system for chronic kidney disease. These guidelines are for the conservative medical management of chronic kidney disease and are not intended to be provided without due consideration for identifying and specifically treating any active renal disease present, especially in patients with stages 1 and 2 chronic kidney disease in which identification and treatment of active renal disease may markedly alter the long-term outcome. See Tables 1-3 for a summary of the IRIS staging system. Because the IRIS staging system categorizes specific disease markers as they relate to kidney function, the system will help you recognize kidney disease earlier and better monitor a patient's condition. Table 4 provides an overview of the 11 guidelines.

TABLE 1: A Summary of the IRIS Staging System of Chronic Kidney Disease*

PROVIDE ADEQUATE AND APPROPRIATE NUTRITION

In many or most dogs and cats with chronic kidney disease, death or euthanasia results directly or indirectly from starvation. This devastating deterioration results from progressive hyporexia and anorexia and their associated adverse nutritional effects. It is essential that hyporexia and anorexia are recognized and responded to early in the course of chronic kidney disease. Thus, always evaluate whether the patient is maintaining a stable body weight at an acceptable nutritional status (usually measured as a body condition score and assessment of activity and strength).

TABLE 2: A Summary of Chronic Kidney Disease Substage Based on the Urine Protein/Creatinine Ratio*

#1 Recommend feeding a renal diet. Strong evidence (evidence-based medicine grade 1; see sidebar titled "The evidence-based medicine hierarchy") supports feeding a diet formulated to address the specific nutritional needs of animals with chronic kidney disease (a renal diet) to dogs and cats with serum creatinine concentrations in excess of 2 mg/dl (chronic kidney disease stages 3 and 4 in dogs and stages 2 through 4 in cats).2-4 Dietary therapy in dogs and cats slows the progression of chronic kidney disease and prevents or delays the onset of uremia and premature death due to complications of the disease. Renal diets have been shown to maintain or improve nutrition compared with maintenance diets.2-4 Patient and owner acceptance of the diets used in these studies was excellent, perhaps in large part because of gradual diet introduction over several weeks.

TABLE 3: A Summary of Chronic Kidney Disease Substage Based on Results of Blood Pressure Measurement and Signs of End-Organ Damage or Complications*

A common misconception is that renal diets are simply low-protein diets. Renal diets encompass a variety of modifications, including limited quantities of phosphorus and salt, enhanced levels of omega-3 polyunsaturated fatty acids, fiber and vitamin D, and a neutral pH effect. Indeed, the principal beneficial effects of these diets may not accrue from their low-protein content. Thus, simply replacing a renal diet with a standard manufactured diet that is lower in protein content is insufficient. Since inappropriate diets can exacerbate clinical signs of uremia and promote progression of chronic kidney disease, cats and dogs with chronic kidney disease should be fed a renal diet.

TABLE 4: Therapeutic Measures for Dogs and Cats with Chronic Kidney Disease

Re-evaluate dogs and cats receiving diet therapy every three to four months.

#2 Ensure adequate nutrition. Owners often consider food consumption to be a premier indicator of their pets' quality of life, and they are often happy when their pets show any interest in food. However, it is inappropriate to accept a pet's consumption of some food as a goal of therapy. Mal nutrition is a major cause of morbidity and mortality in dogs and cats with chronic kidney disease stages 3 and 4.5 Ideally, patients should consume sufficient calories from an appropriate diet to maintain a body condition score of 4 or 5/9.4 Increased efforts are indicated to ensure sufficient calorie intake for patients with body condition scores of 3/9 or lower or when patients fail to consume adequate calories to maintain a stable, appropriate body weight.

The evidence-based medicine hierarchy

In addition to inattention to adequate nutrition, some factors that may contribute to malnutrition in dogs and cats with chronic kidney disease include consumption of inappropriate diets and metabolic factors related to uremia (especially uremic gastrointestinal signs and metabolic acidosis). Failure to adequately address uremic gastritis, uremic stomatitis, and dental health can promote anorexia. Metabolic acidosis can promote protein catabolism and malnutrition.1 Force-feeding new diets, exposing patients to new diets while hospitalized, or administering medications or other unpleasant events during and around feeding times should all be avoided. A renal diet should be introduced to patients gradually.

Consider placing a feeding tube when patients fail to spontaneously consume adequate food. Feeding through a gastrostomy or esophagostomy tube is a simple and effective way to provide an adequate intake of calories and water. In addition, feeding tubes simplify drug administration. Although there is only weak evidence (grade 4) to support the effectiveness of feeding tubes in achieving nutritional goals in dogs and cats with chronic kidney disease, there is no proven effective alternative.

CORRECT DEFICITS AND EXCESSES IN FLUIDS, ACID-BASE BALANCE, AND ELECTROLYTES

#3 Maintain serum phosphorus concentrations below target levels. Excessive phosphorus intake and inappropriately high serum phosphorus concentrations appear to promote progressive kidney injury.4,6 Intervention is indicated in dogs and cats with chronic kidney disease stages 2 through 4 when the phosphorus concentrations rise above stage-specific therapeutic target concentrations. The targets proposed for serum phosphorus concentrations reflect a consensus of expert opinion (evidence grade 4).

Ideally, the serum phosphorus concentration should be below 4.5 mg/dl in stage 2 chronic kidney disease, below 5 mg/dl in stage 3, and below 6 mg/dl in stage 4. When the serum phosphorus concentration exceeds these target concentrations, initiate dietary phosphorus restriction by feeding a renal diet. In most dogs and cats with chronic kidney disease stages 2 and 3, dietary phosphorus restriction alone will maintain the concentration below the target concentration. However, in some patients with stage 3 chronic kidney disease and in most patients with stage 4 disease, adding an intestinal phosphate-binding agent will be necessary. If calcium-based phosphate binding agents are used, it is particularly important to monitor serum calcium concentrations. In patients with elevated serum calcium concentration or reduced serum albumin concentrations, it is desirable to measure ionized calcium concentrations.

The most commonly used intestinal phosphate-binding agents in dogs and cats contain aluminum as hydroxide, oxide, or carbonate salts.1 Aluminum-containing binding agents generally appear to be well-tolerated and safe in dogs and cats; as such, they probably represent first-choice drugs for phosphate binding. Alternative drugs include calcium carbonate, calcium acetate, sevelamer hydrochloride (Renagel —Geltex), or lanthanum carbonate (Fosrenol—Shire). Experience with these drugs in dogs and cats is limited, but hypercalcemia may be a problem with the calcium-based products, particularly when they are administered with calcitriol. An intestinal phosphate binder composed of a mixture of calcium carbonate and chitosan is marketed for use in dogs and cats (Epakitin—Vétoquinol).

Moderate evidence (grade 2) supports a phosphorus-restricted diet in dogs with chronic kidney disease6; however, the evidence in cats with chronic kidney disease is less sound (grade 4).4 While strong evidence supports feeding a renal diet to both dogs and cats with chronic kidney disease, the specific effect of phosphorus intake on clinical outcome has only been documented in dogs with induced chronic kidney disease in which dietary phosphorus restriction was shown to slow the progression of chronic kidney disease and improve survival.6

Once therapeutic targets have been attained, re-evaluate dogs and cats in stages 2 through 4 every three to four months to ensure continued compliance and therapeutic success at maintaining the target.

#4 Maintain serum potassium concentrations within the target range. Intervention to manage serum potassium concentrations is indicated in dogs and cats when the concentrations fall outside the target range of 3.5 to 5.5 mEq/L, regardless of the chronic kidney disease stage.

Hypokalemia. The goal of therapy for hypokalemia is to bring the serum potassium concentration above 4 mEq/L. Hypokalemia is primarily of concern in cats with chronic kidney disease or in patients with renal tubular disorders such as Fanconi's syndrome. Hypokalemia in cats with chronic kidney disease is presumed to result from inadequate potassium intake and enhanced urinary losses; however, recent findings suggest that increased urinary losses may also result, in part, from enhanced activation of the renin-angiotensin system in response to low sodium intake.7 The clinical effects of hypokalemia may include varying degrees of skeletal, smooth, and cardiac muscle weakness and impaired kidney function.

Enhancing food intake and administering potassium orally or parenterally may correct hypokalemia. Potassium gluconate and potassium citrate are the preferred salts for oral administration; potassium chloride is used parenterally. Descriptive studies and pathophysiologic justification (evidence grade 4) support potassium supplementation to stabilize or improve renal function in cats with chronic kidney disease. A randomized controlled clinical trial examining the effect of oral potassium supplementation on total body potassium concentrations and kidney function failed to yield conclusive findings.8

Once therapeutic targets have been attained, re-evaluate dogs and cats in stages 2 through 4 every three to four months to ensure continued compliance and therapeutic success at maintaining the target.

Hyperkalemia. Hyperkalemia has primarily been of concern in chronic kidney disease stage 4 when the kidneys are no longer able to excrete the daily potassium load. However, it may also occur in patients with less advanced chronic kidney disease in association with therapeutic blockade of the renin-angiotensin system and with hyporeninemic hypoaldosteronism. The primary clinical consequence of hyperkalemia is cardiotoxicosis. Treatment usually involves reducing potassium intake; however, hyperkalemia resulting from therapeutic blockade of the renin-angiotensin system may require lowering the drug dosage should a clinically important risk of cardiotoxicosis develop.

#5 Correct metabolic acidosis. Intervention to correct metabolic acidosis is indicated in dogs and cats with chronic kidney disease stages 1 through 4 when the blood bicarbonate concentration drops below the therapeutic target range of 18 to 24 meq/L (19 to 25 meq/L for total carbon dioxide concentration; evidence grade 4). Metabolic acidosis in chronic kidney disease results primarily from impaired renal ammoniagenesis, although impaired acid excretion and bicarbonate reabsorption may contribute as well. Metabolic acidosis also occurs in patients with renal tubular acidosis (RTA) either due to impaired bicarbonate reabsorption (proximal RTA) or impaired urine acidification (distal RTA). The clinical effects of metabolic acidosis may include progressive renal injury and increased protein catabolism with loss of lean tissue.1 Treatment involves administering an alkalinizing salt, usually sodium bicarbonate or potassium citrate, in an amount sufficient to increase the blood bicarbonate concentration into the normal range.

Oral sodium bicarbonate is the most commonly used alkalinizing agent for patients with metabolic acidosis of chronic renal insufficiency or failure. Because the effects of gastric acid on oral sodium bicarbonate are unpredictable, the dosage should be individualized for each patient. A suggested initial dose is 8 to 12 mg/kg given every eight to 12 hours. Unfortunately, many dogs and cats find sodium bicarbonate distasteful unless given as tablets. Sodium bicarbonate is available as 5-and 10-grain tablets.

Potassium citrate may offer the advantage, especially in cats, of allowing for the simultaneous treatment of both hypokalemia and acidosis with a single drug. Metabolic acidosis when accompanied by potassium or magnesium depletion may respond poorly to alkali therapy alone. However, since potassium doses required for adequate correction of hypokalemia may exceed the citrate dose required to correct acidosis, there is a risk of excessive alkalinization. Starting doses of 40 to 60 mg/kg given orally every eight to 12 hours are recommended.

Once therapeutic targets have been attained, re-evaluate dogs and cats receiving alkalinizing therapy every three to four months to ensure continued compliance and therapeutic success at maintaining the target.

#6 Maintain hydration. Intervention to correct and prevent dehydration is indicated in dogs and cats with chronic kidney disease stages 2 through 4 with clinical evidence of dehydration. Maintaining hydration in patients with chronic kidney disease depends on adequate compensatory polydipsia. Cats with chronic kidney disease appear to be particularly susceptible to chronic dehydration, perhaps because the magnitude of compensatory polydipsia is inadequate. However, lack of adequate access to good quality drinking water, certain environmental conditions, and intercurrent illnesses that limit fluid intake or promote fluid losses (e.g. pyrexia, vomiting, diarrhea) may lead to dehydration.

The clinical consequences of chronic dehydration include decreased appetite, lethargy, weakness, constipation, prerenal azotemia, and predisposition to acute kidney injury. Additional loss of kidney function due to acute kidney injury is a potentially important cause of progression of chronic kidney disease. The goal of therapy is to correct and prevent dehydration and its clinical effects.

In patients with signs consistent with chronic or recurrent dehydration, long-term subcutaneous fluid therapy may be considered (evidence grade 4). Typically, a balanced electrolyte solution (e.g. lactated Ringer's solution) is administered subcutaneously every one to three days as needed. The volume administered depends on the patient's size, with a typical cat receiving about 75 to 100 ml per dose. If the patient's clinical response is suboptimal, the dose can cautiously be increased. However, it is possible to induce fluid overload with excessive fluid administration. In addition, sodium-containing fluids used for subcutaneous therapy do not provide electrolyte-free water. A more physiologically appropriate approach is to provide water through a feeding tube. This approach may also be easier for clients. Because recent evidence suggests excessive sodium intake may harm the kidneys, recommendations for long-term sodium administration in any form should be carefully considered.9,10

AMELIORATE THE EFFECTS OF CHRONIC KIDNEY DISEASE

#7 Correct clinically apparent anemia. Treating anemia is indicated in a patient with chronic kidney disease stages 3 and 4 when the hematocrit declines below 20% and the patient has clinical signs attributable to anemia. The goal of treatment is increasing the hematocrit to about 30% to 40% in cats and 38% to 48% in dogs. Signs attributable to anemia may include impaired appetite, lethargy, weakness, and decreased social interaction. Administering erythropoietin, either as recombinant human erythropoietin (Epogen—Amgen, Procrit—Ortho Biotech) or darbepoetin alfa (Aranesp—Amgen), is the only effective means of correcting anemia of chronic kidney disease. However, other factors that may exacerbate anemia, including blood loss, iron deficiency, poor nutrition, hyperparathyroidism, and infections, should be ruled out first.

Anti-erythropoietin antibodies may develop in some patients, rendering them unresponsive to further recombinant human erythropoietin treatment. Immediately terminate therapy if antibody -associated anemia is suspected. Since canine and feline species-specific erythropoietin is not available, closely monitor patients treated with recombinant human erythropoietin for recurrence of anemia, which may herald the onset of anti-erythropoietin antibodies. A newer, longer-acting erythropoietin, darbepoetin, may be less likely to induce anti-erythropoietin antibodies, but experience with darbepoetin in dogs and cats is limited.

Monitor dogs and cats treated with erythropoietin weekly until treatment targets have been achieved. Once therapeutic targets have been attained, the packed cell volume should be monitored at least monthly to detect development of anti-erythropoietin antibodies and to adjust dosages or provide supplemental iron as needed.

#8 Ameliorate gastrointestinal signs. Dogs and cats with stage 3 or 4 chronic kidney disease may have gastrointestinal complications including reduced appetite, nausea, vomiting, uremic stomatitis and halitosis, gastrointestinal hemorrhage, diarrhea, and hemorrhagic colitis. Treatment for these gastrointestinal signs largely focuses on ameliorating uremic gastritis (evidence grade 4) by

1. Limiting gastric acidity with H2 blockers (ranitidine, famotidine)

2. Suppressing nausea and vomiting with antiemetics (metoclopramide, 5-HT3 receptor antagonists such as ondansetron hydrochloride or dolasetron mesylate, or the neurokinin-1 receptor antagonist maropitant [Cerenia—Pfizer]) or low doses of phenothiazine tranquilizers (prochlorperazine)

3. Providing mucosal protection with sucralfate.

Of these treatments, H2 blockers are most commonly used, and few adverse effects have been attributed to their use. Antiemetics are typically added when anorexia, nausea, or vomiting persist despite the use of an H2 blocker. Sucralfate is added when gastrointestinal ulcers and hemorrhage are suspected.

PROVIDE RENOPROTECTIVE THERAPY TO SLOW DISEASE PROGRESSION

#9 Reduce the magnitude of proteinuria. Glomerular proteinuria should be reduced in dogs and cats with chronic kidney disease stages 1 through 4. Intervention is indicated when the urine protein/creatinine ratio exceeds 2 in dogs and cats with stage 1 disease and when it exceeds 0.5 in dogs and 0.4 in cats with stage 2 through 4 disease.11

Proteinuria has been shown to adversely affect outcomes in people, dogs, and cats with chronic kidney disease, presumably because proteinuria itself appears to injure the renal tubules, thereby promoting progression of chronic kidney disease.11-13 In people, it is well-established that reducing proteinuria by suppressing the renin-angiotensin system ameliorates the adverse effects of proteinuria on the kidneys. Although qualitatively similar, evidence in dogs and cats is far less compelling.14,15 Studies on the long-term effects of angiotensin-converting enzyme (ACE) inhibitors on survival outcome in proteinuric dogs have not been reported, and although such studies have been reported in cats, they have failed to yield statistically significant evidence of enhanced survival. Nonetheless, an ACE inhibitor such as enalapril, benazepril, or lisinopril is recommended in patients with chronic kidney disease that meet the above criteria (evidence grade 4).11 Ideally, proteinuria should be reduced below the therapeutic target. However, this is typically difficult and may require higher doses of the ACE inhibitor or the addition of angiotensin II receptor blocking drugs (e.g. losartan or irbesartan). Losartan may be administered at a dose of 0.25 to 0.5 mg/kg/day while monitoring for any changes in serum creatinine concentration. Dosages may be increased as needed up to 1 mg/kg every 12 hours.

Initially monitor a urine protein/creatinine ratio monthly to ascertain whether the treatment target of normalizing or at least halving the urine protein/creatinine ratio has been achieved. Once therapeutic targets have been attained, monitor the urine protein/creatinine ratio every three to four months to ensure continued compliance and therapeutic success at maintaining the target.

#10 Minimize systemic hypertension. Drug therapy to lower blood pressure is indicated in dogs and cats with chronic kidney disease stages 2 through 4 when the pressure exceeds 160/100 mm Hg and in dogs and cats with chronic kidney disease stage 1 when blood pressure exceeds 180/120 mm Hg.16 Unless hypertensive retinopathy or central nervous system signs are present or the systolic blood pressure remains above 200 mm Hg, determine blood pressure values on at least three separate clinic visits before establishing the need for therapeutic intervention. The goal of therapy is to reduce blood pressure to below 160/100 mm Hg.

Amlodipine is the first-choice drug for managing elevated blood pressure in cats with chronic kidney disease (evidence grade 2).17 It is typically highly effective in reducing blood pressure in cats, often by as much as 20 to 50 mm Hg. Amlodipine is administered at a dose of 0.625 mg/cat in cats less than 11 lb (5 kg) and 1.25 mg/cat in cats 11 lb or greater. The dose may be doubled if response fails to meet treatment goals.

Hypertension in dogs appears to be more resistant to drug therapy. Because ACE inhibitors reduce intraglomerular pressure even when systemic blood pressure is not effectively ameliorated, these drugs have a therapeutic advantage as first-line drugs in dogs with chronic kidney disease in mitigating the renal effects of hypertension. However, since ACE inhibitors are often relatively ineffective antihypertensive drugs in dogs, amlodipine is typically combined with ACE inhibitor therapy to achieve the therapeutic goal. The initial dose for an ACE inhibitor is 0.25 to 0.5 mg/kg with monitoring of the serum creatinine concentration response (the dose may be cautiously increased to 3 mg/kg). The dose range for amlodipine is 0.1 to 0.6 mg/kg as needed to achieve the therapeutic goal.

Reassess patients receiving antihypertensive therapy every week or two until the treatment target (systolic blood pressure < 150 mm Hg) has been achieved. Thereafter, monitor blood pressure every three to four months.

#11 Provide calcitriol in dogs. Calcitriol is indicated in dogs with chronic kidney disease stages 3 and 4 to slow the progression of the disease and extend survival (evidence grade 1).18 However, do not begin calcitriol therapy until the patient's serum phosphorus concentration is 6 mg/dl or less. Unfortunately, evidence for or against calcitriol therapy in cats with chronic kidney disease is weak.

Calcitriol may be administered initially at a dose of 2.5 ng/kg/day. Monitor ionized calcium and parathyroid hormone (PTH) concentrations weekly until a treatment endpoint is reached. The dose of calcitriol may be adjusted to achieve a treatment endpoint of normalizing PTH concentrations without inducing hypercalcemia. Increase calcitriol doses about 0.75 to 1 ng/kg as needed to a maximum dose of 5 ng/kg. If hypercalcemia develops before PTH concentrations decline to normal, the dosage of calcitriol must be reduced to prevent adverse effects of hypercalcemia. An alternate approach is to attempt to provide two or three days total dose of calcitriol every second or third day. This dosage may mitigate the hypercalcemia and increase the effect on PTH concentrations.

Patients receiving calcitriol should have their serum calcium, ionized calcium, and phosphorus concentrations monitored at least every two to three months.

Editors' note: Dr. Polzin has received research sponsorship and speaking honoraria from Hill's Pet Nutrition, Royal Canin, and Nestlé Purina; receives support for IRIS from Novartis; and has consulted for and received honoraria from Bayer, Pfizer, and Vétoquinol.

David J. Polzin, DVM, PhD, DACVIM (small animal internal medicine)

Department of Veterinary Clinical Sciences

College of Veterinary Medicine

The University of Minnesota

St. Paul, MN 55108

Dr. Polzin lectured on this topic at the 2007 CVC Central, and this article is adapted from the conference proceedings.

REFERENCES

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