Treating Canine Renal Failure: An Evidence-Based Approach

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Treating Canine Renal Failure: An Evidence-Based Approach

Postby malernee » Thu Mar 18, 2004 2:33 pm

Treating Canine Renal Failure: An Evidence-Based Approach
Western Veterinary Conference 2003
David Polzin, DVM, PhD, Diplomate ACVIM (Small Animal Internal Medicine)
College of Veterinary Medicine, University of Minnesota
St Paul, MN, USA


Planning therapy for dogs with chronic renal failure based on published evidence.

Key Points

Veterinarians deciding which treatments to recommend should consider the quality of data supporting a recommendation to use (or not use) a given form of therapy in prioritizing therapeutic recommendations.

Whenever possible, therapeutic recommendations should be based on results of rigorous, controlled scientific studies.

Dietary therapy with a commercial renal food has been shown to improve quality of life and substantially increase life expectancy in dogs with renal insufficiency.

Phosphorus binding agents, calcitriol, antihypertensive drugs and erythropoietin currently have less evidence for their routine use in dogs with renal insufficiency.


Planning therapy-The role of evidence-based medicine

In planning therapy for dogs with chronic renal failure (CRF), recommendations should ideally be based on results of randomized, controlled clinical trials (RCCT), which document the efficacy and safety of therapeutic recommendations. Unfortunately, many therapies recommended for dogs with CRF have never been examined in an appropriate and systematic fashion in dogs with spontaneous disease. Often, treatments are recommended on the basis of less convincing evidence such as clinical experience, expert opinion, pathophysiologic rationale, or studies performed in other species or in dogs with artificial disease. Evidence from the recalled experiences of clinicians and other experts tend to overestimate the efficacy of a therapy or other interventions for several reasons (Sackett, 1993).

In examining evidence supporting or refuting a therapeutic claim is whether the evidence is clinically relevant. Treatments are indicated when they provide important clinical benefits. Unfortunately, studies often focus on outcomes that may or may not have any clinical relevance to pets and their owners. For example, a study linking calcitriol therapy to correcting hyperparathyroidism does not necessarily provide sufficient reason for recommending such therapy. PTH activities, or other physiologic or laboratory measurements, are often used as "substitute end points" in studies because they are more easily obtained. Such results only provide a pathophysiologic rationale for applying the treatment to patients. It is of primary importance to provide evidence that the treatment influences outcomes that are important to pets and their owners, such as increased activity or appetite, decreased vomiting, decreased incidence of uremic crises, or prolonged good-quality life-span.

Clinicians deciding which treatments to recommend should consider the quality of data supporting a recommendation to use (or not use) a given form of therapy in prioritizing therapeutic recommendations. Whenever possible, recommendations should be based on results of rigorous, controlled scientific studies. Of course, not all recommendations can or will be based on such studies. Nonetheless, it is important to recognize the inherent limitations of recommendations based on less secure forms of evidence. One suggested method of accommodating concerns regarding these limitations is to assign a score defining the strength and quality of the recommendation. Grade "I" evidence, the highest quality evidence, is that obtained from at least one properly randomized controlled clinical trial. Grade "II" evidence may be data obtained: 1) from at least one well-designed clinical trial without randomization, 2) from cohort or case-controlled analytic studies, 3) from studies utilizing acceptable laboratory models or simulations in the target species, preferably from more than one center, 4) from multiple time series, or 5) from dramatic results in uncontrolled experiments. Grade "III" evidence, the weakest form of evidence, is that from: 1) opinions of respected authorities on the basis of clinical experience, 2) descriptive studies, 3) studies in other species, 4) pathophysiological justification, or 5) reports of expert committees (McGowan, 1992). This scoring system recognizes that the quality of the evidence supporting a recommendation is an important consideration when making therapeutic decisions.

Diet therapy

Dietary protein and phosphorus restriction is among the most commonly prescribed therapies for canine patients with CRF. However, renal patients often have selective appetites. Clinicians are often challenged by the decision as to whether to recommend switching to a renal diet or to continue the current diet with the view that eating any food is better than risking reduced food intake by attempting a potentially unwanted diet change. We recently completed a randomized, controlled clinical trial designed to address the question of effectiveness of manufactured renal diets (Jacob et al, 2002). Essentially, we asked whether there were clinically important benefits to recommending a diet change from a typical canine maintenance diet to a "renal diet" in dogs with spontaneously occurring chronic renal failure. Other than being randomly assigned to either the renal diet or the maintenance diet, dogs were managed in an identical manner with respect to other treatment interventions.

We found that feeding a manufactured renal diet results in a better quality of life and a substantially longer life in dogs with renal insufficiency. Compared to dogs fed the maintenance diet, feeding the renal diet reduced incidences of uremic crises and renal-related mortality. Feeding the renal diet reduced the relative risk of a dog having a uremic crisis by over 70%. In fact, dogs fed the renal diet remained free of uremic signs almost 2.5 times longer than dogs fed the maintenance diet. In addition, dogs fed the renal diet had a median survival time over three times loner than dogs fed the maintenance diet. Renal-related death was the primary cause for the higher rate of premature mortality among dogs fed the maintenance diet. An important reason for the longer survival times observed among dogs fed the renal diet appeared to be that renal function declined more slowly in dogs fed the renal diet. (Evidence grade: 1)

Dietary phosphorus restriction and Phosphate binding agents

Phosphorus is retained in CRF eventually resulting in hyperphosphatemia, which in turn promotes renal secondary hyperparathyroidism. There appears to be a consensus of opinion that phosphate retention and hyperparathyroidism is a major cause for progression in renal failure in many species. In humans with CRF receiving hemodialysis therapy, the adjusted relative risk of mortality was stable in patients with serum phosphate concentrations below 6.5 mg/dl, but increased significantly above this level (Block et al, 1998). Patients with serum phosphate in the 6.6 to 7.8 mg/dl range had 13% higher mortality than patients in the reference range (4.6 to 5.5 mg/dl); patients in the 7.9 to 16.9 mg/dl range had a relative mortality risk 34% higher than patients in the reference range. Mild hyperphosphatemia (5.0 to 6.5 mg/dl) was not associated with an elevated mortality risk. The overall mortality risk associated with hyperphosphatemia was 1.06 per 1 mg/dl higher serum phosphorus. In a model of induced chronic renal failure in dogs, dietary phosphate restriction, when combined with protein restriction, has been shown to slow progression of renal failure and improve survival (Brown et al, 1991). Mechanisms responsible for the effect of hyperphosphatemia on mortality remain unresolved. Clinical or experimental studies establishing the value of adding phosphate binding agents to dietary phosphate restriction in dogs have not been reported. (For dietary phosphorus restriction, Evidence grade: 2; for phosphorus binding agents, Evidence grade: 3)

Calcitriol therapy

The kidneys are responsible for converting 25-hydroxycholecalciferol to its most active metabolite, 1,25-dihydroxycholecalciferol, or calcitriol. Calcitriol is the major renal hormone responsible for calcium metabolism. Among its important functions is modulation of parathyroid hormone activity at the transcriptional level. Because CRF may impair production of calcitriol, calcitriol deficiency may be one factor promoting renal secondary hyperparathyroidism. Calcitriol supplementation has been advocated as a means of normalizing hyperparathyroidism. PTH has been proposed to act as a "uremic toxin." Thus, supplementing calcitriol may ameliorate a variety of supposed toxic effects of PTH in CRF. Nagode and colleagues have reported that in 570 dogs receiving calcitriol therapy, patients: 1) were brighter and more alert, 2) had improved appetites, 3) were more physically active, and 4) lived longer (Nagode and Podell, 1996). These findings were based on an uncontrolled survey of veterinarians who used calcitriol in their practice. The safety of wide-spread use of calcitriol has been questioned because of the risk of inducing hypercalcemia and renal injury. Further, studies in dogs with induced renal failure have thus far failed to document the value of suppressing hyperparathyroidism on progressive renal injury. However, these studies failed to directly address the value of calcitriol therapy. (Evidence grade: 3)

Anti-hypertensive therapy

Hypertension is a well-recognized complication of chronic renal failure. The most profound clinical effect of hypertension seems to be hypertensive retinopathy with retinal detachment, hemorrhage and blindness. Hypertension-related CNS disorders (e.g., seizures, loss of balanced, abrupt changes in personality, obtundation, etc) have also been observed. Studies in our laboratory have suggested that hypertension is also a risk factor for shortened survival times in dogs with renal failure. The justification for treating hypertension in dogs is largely extrapolated from observations in humans and experimental animals. The likely benefits of intervention might include retarding progression of renal failure and reduced incidences of hypertensive retinopathy and hypertensive encephalopathy. Well controlled clinical trials on the effectiveness of antihypertensive agents in hypertensive dogs with CRF have not been reported; however, one study did demonstrate enalapril at doses up to 0.5 mg/kg daily can produce a moderate reduction in blood pressure. (Evidence grade: 3)

ACE inhibitor therapy

Angiotensin converting enzyme inhibitors appear to be of value in limiting progression of renal failure in proteinuric renal diseases in humans. A recently reported prospective clinical trial performed in dogs with spontaneous idiopathic glomerulonephritis confirmed that enalapril reduced proteinuria and may have been of benefit in stabilizing the progression of renal failure (Grauer et al, 2000). (For reducing Proteinuria-Evidence grade: 1)

Erythropoietin therapy

Administration of human recombinant erythropoietin has been shown to be effective in correcting anemia of CRF in dogs (Cowgill et al, 1998). Uncontrolled clinical trials have also indicated a substantial improvement in appetite and quality of life associated with this treatment. Unfortunately, development of antibodies directed against the drug has limited usefulness of this therapy in a substantial number of dogs. As a consequence, it is best to carefully select those cases most likely to benefit from erythropoietin for treatment. An interesting concept that has not received adequate examination in dogs is the potential benefit of earlier intervention in management of anemia of CRF. In the future, anemia in dogs with CRF may be managed using canine erythropoietin. (Evidence grade: 2-for anemic CRF dogs)


In planning therapy for dogs with chronic renal failure, recommendations should ideally be based on results of controlled clinical trials, which document the efficacy and safety of therapeutic recommendations. Dietary therapy with renal foods has the highest level of evidence for use in dogs with renal insufficiency. Phosphorus binding agents, calcitriol, antihypertensive drugs and erythropoietin currently have less evidence for their routine use in dogs with renal insufficiency.


1. Sackett D. Rules of evidence and clinical recommendations. Can J Cardiol 1993; 9: 487-489.

2. McGowan J, Chesney K, LaForce F. Guidelines for the use of systemic glucocorticoids in the management of selected infections. J Infecti Dis 1992; 165: 1-13.

3. Jacob F, Polzin DJ, Osborne CA, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs. J Am Vet Med Assoc 2002; 220:1163-1170.

4. Brown SA, Crowell WA, Barsanti JA, et al. Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass. J Am Soc Nephrol 1991; 1: 1169-1179.

5. Block GA, Hulbert-Shearon TE, Levin NW, et al. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 1998; 31: 607-617.

6. Nagode LA, Chew DJ, Podell M. Benefits of calcitriol therapy and serum phosphorus control in dogs and cats with chronic renal failure. Vet Clin North Amer 1996; 26: 1293-1330.

7. Grauer G, Greco DS, Getzy DM, et al. Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 2000; 14: 526-533

8. Cowgill LD, James KM, Levy JK, et al. Use of recombinant human erythropoietin for management of anemia in dogs and cats with renal failure. J Am Vet Med Assoc 1998; 212:521-528.

Speaker Information
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David J. Polzin, DVM, PhD, Dipl. ACVIM
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