Treating Feline Renal Failure: An Evidence-Based Approach

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Treating Feline Renal Failure: An Evidence-Based Approach

Postby malernee » Thu Mar 18, 2004 2:29 pm

Treating Feline 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 cats 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 substantially increase life expectancy in cats with renal insufficiency.

Therapy with phosphate binding agents, calcitriol, antihypertensive drugs, ACE inhibitors, potassium supplementation, alkalinization agents and erythropoietin have less evidence for their routine use in cats with renal insufficiency.


Planning therapy-The role of evidence-based medicine

In planning therapy for cats 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 cats with CRF have never been examined in an appropriate and systematic fashion in cats 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 cats 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). Routine clinical practice is never "blind," and both patients and owners know when active treatment is being received. The desire of pet owners and clinicians for success, and the placebo effect, can cause both parties to overestimate efficacy.

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.

Because of the very nature of cats, over-treatment can be just as deleterious as under-treatment in sustaining an acceptable quality of life for our patients. 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 cats with CRF. However, cats are notoriously picky about their food. Clinicians are often challenged by the decision as to whether to recommend switching to a renal diet or to continue allow the cat to consume the current diet with the view that eating any food is better than risking reduced food intake by attempting a potentially unwanted diet change. One recently published clinical trial has provided support for making the change to protein/phosphorus restricted renal diets in managing cats with CRF. While this study was neither blinded nor randomized, a striking enhancement of survival time was associated with feeding a renal diet compared to not making the dietary change (Elliot et al 2000). The control group in this study was composed of cats which refused to eat the renal diet. The principal criticism of this study would be that cats electing not to consume the renal diet may have an intrinsically worse prognosis unrelated to the diet fed. However, the size of the difference in outcome (median survival time was increased nearly 2.5 times when the renal diet was fed) suggests that the clinical benefit of feeding the renal diet was likely real. Ideally, results of this study should be confirmed by a randomized controlled clinical trial to rule-out any bias in this study. Importantly, significant adverse effects of feeding the renal diet were not detected in these studies. Seemingly, the greatest problem with advocating renal diets for cats with CRF has been acceptance of the diets by cats. In most instances this can be overcome by carefully correcting metabolic complications of CRF and introducing the diet gradually over several weeks. (Evidence grade: 2)

Phosphate binding agents

Phosphorus is retained in CRF eventually resulting in hyperphosphatemia, which in turn promotes renal secondary hyperparathyroidism. Hyperphosphatemia has been reported to be a reliable clinical index of hyperparathyroidism in cats with CRF (Barber and Elliot, 2000; Barber et al 1999). Hyperphosphatemia is detected in approximately 60% of cats with CRF, with the prevalence increasing as renal function declines. In one study, the prevalence of renal secondary hyperparathyroidism in cats with CRF was reported to be 84% (Barber et al 1999). In this study, all cats with end-stage CRF, 87% of cats with some clinical signs of CRF, and 47% of clinically normal cats with only biochemical evidence of CRF were diagnosed as having renal secondary hyperparathyroidism. Hyperparathyroidism was even detected in nine cats with CRF having normal serum calcium and phosphorus concentrations.

In many cats, diet therapy alone appears to normalize hyperparathyroidism (Barber et al 1999). Phosphate binding agents may be useful in further reducing phosphate retention and hyperparathyroidism in the remaining cats, but the efficacy of such therapy has yet to be established in cats. Clinical reports and clinical impression suggest that phosphate-binding agents are useful in reducing serum phosphate concentrations, but some cats may poorly tolerate these agents.

There appears to be a consensus of opinion that phosphate retention and hyperparathyroidism is a major cause for progression in CRF in many species. However, there is no conclusive data confirming this association in cats. Mechanisms responsible for this effect remain unresolved. (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 cats receiving calcitriol therapy: 1) are brighter and more alert, 2) have improved appetites, 3) are more physically active, and 4) live longer (Nagode and Podell, 1996). These findings were based on an uncontrolled survey of veterinarians who used calcitriol in 1360 cats their practices. Unfortunately, uncontrolled studies have a notoriously high rate of false positive findings. A randomized, controlled clinical trial will be necessary to validate recommendation of this therapy for cats with CRF. (Evidence grade: 3)

Anti-hypertensive therapy

Hypertension has become a well-recognized complication of CRF in both cats and dogs. Recent data suggests that the prevalence of hypertension in cats with cats with CRF may be about 20% (Syme, 2002). The most profound clinical effect of hypertension in cats seems to be hypertensive retinopathy with retinal detachment, hemorrhage and blindness. Cats with such severe ocular manifestations reflect only a small percentage of cats with CRF and hypertension. More subtle ocular lesions of hypertension may be much more common. It has recently been shown that the calcium channel blocker amlodipine dramatically reduces the prevalence of ocular lesions attributable to hypertension in cats with an induced model of renal failure (Brown, 2002). The observations are consistent with uncontrolled clinical observations in cats with spontaneous renal failure.

While it appears that cats with hypertension and hypertensive retinopathy likely benefit from intervention with anti-hypertensive drug therapy, the touted renoprotective benefit of antihypertensive therapy in cats is largely extrapolated from observations in humans and experimental studies in animals. The potential benefits of intervention might include prolonging survival in cats with CRF and reduced the incidence of hypertensive retinopathy and hypertensive encephalopathy.

Amlodipine currently appears to be the drug of choice for managing hypertension in cats. It has been shown to be effective in at least one clinical trial in lowering blood pressure (Snyder, 1998), and in one experimental study in preventing ocular manifestations of hypertension. In contrast to amlodipine, ACE inhibitors and Beta-blocking drugs have not appeared to be as effective in lowering blood pressures in cats. (Evidence grade: 2)

ACE inhibitor therapy

Angiotensin converting enzyme inhibitors appear to be of value in limiting progression of CRF in various forms of human renal diseases. A significant clinical benefit may only accrue in proteinuric patients. One ACE inhibitor has already been licensed for use in managing CRF in cats in several countries. However, data indicating that ACE therapy influences progression of CRF or clinical outcomes of cats with CRF have yet to be published. In a recent study examining the physiological effects of ACE inhibitors in cats with induced renal disease, systemic arterial and glomerular capillary pressures were shown to be reduced by such therapy (Brown et al, 2001). However, the magnitude of reduction in systemic blood pressure was small, and a beneficial effect in reducing proteinuria was not evident. The study failed to detect any evidence that administering the ACE inhibitor resulted in structural or functional renal protection. (Evidence grade: 3)

Potassium supplementation

Although current feline renal diets are generally potassium supplemented, hypokalemia still occurs in a subset of cats with CRF. It has recently been reported that there is an inverse relationship between potassium concentrations and blood pressure in cats (Syme, 2002). It is generally accepted that potassium supplementation is warranted in CRF cats with hypokalemia; although data supporting the clinical benefits of this recommendation are limited to clinical reports. However, in addition it has been suggested that all cats with CRF should be supplemented with potassium to limit total body potassium depletion and prevent development of hypokalemia and progressive renal injury (Dow and Fettman, 1992). Although the potential benefit of potassium supplementation has been examined, the clinical benefits of such therapy remain to be proven (Theisen et al, 1997). (Evidence grade: 3)

Erythropoietin therapy

Administration of human recombinant erythropoietin has been shown to be effective in correcting anemia of CRF in cats (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 cats. 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 cats is the potential benefit of earlier intervention in management of anemia of CRF. In the future, anemia in cats with CRF may be managed using feline erythropoietin. (Evidence grade: 2-for anemic CRF cats)

Alkalization therapy

Alkalization therapy is indicated for cats with moderate to severe metabolic acidosis associated with CRF on pathophysiologic grounds and extrapolation from findings in other species. The rationale for alkalization therapy has been that acidosis: 1) can impair protein nutrition, 2) may promote progression of renal failure, and 3) can induce clinical signs similar to uremia. However, unpublished data from our laboratory indicate that acidosis of the magnitude likely to accrue from feeding a typical commercial acidifying diet does not appear to promote progressive renal injury or impair nutrition. Nonetheless, acidosis does appear to impose an unnecessary metabolic risk that can easily be corrected in cats by administration of potassium citrate or sodium bicarbonate when acidosis is appropriately confirmed. (Evidence grade: 3)


In planning therapy for cats 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 a high level of evidence for use in cats with renal insufficiency. Phosphorus binding agents, calcitriol, antihypertensive and ACE inhibitor drugs, potassium supplementation, alkalinization agents and erythropoietin have less evidence for their routine use in cats with renal insufficiency.


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3. Elliot J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000; 41: 235-242.

4. Barber PJ, Elliott J. Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between 1992 and 1995. J Small Anim Pract 1998; 39, 108-116.

5. Barber PJ, Rawlings JM, Markwell PJ, et al. Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat. J Small Anim Pract 1999; 40: 62-70.

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. Snyder PS. Amlodipine: a randomized, blinded clinical trial in 9 cats with systemic hypertension. J Vet Intern Med 1998; 12: 157-162.

8. Syme HM, Barber PJ, Markwell PJ, et al. Prevalence of systemic hypertension in cats with chronic renal failure at initial evaluation. J Am Vet Med Assoc 2002; 220: 1799-1804.

9. Brown SA, et al. Effects of amlodipine in the feline remnant kidney model of hypertensive renal insufficiency (abstract). J Vet Intern Med 2002; 16: 378A.

10. Brown SA, Brown CA, Jacobs G, et al. Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res 2001; 62: 375-383.

11. Dow SW, Fettman MJ. Renal disease in cats: the potassium connection In: Kirk RW, Bonagura JD, eds. Current Veterinary Therapy XI. Philadelphia: WB Saunders, 1992; 820-822.

12. Theisen SK, DiBartola SP, Radin MJ, et al. Muscle potassium content and potassium gluconate supplementation in normokalemic cats with naturally occurring chronic renal failure. J Vet Intern Med 1997; 11: 212-217.

13. 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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Benazepril may be an effective treatment

Postby guest » Tue Jun 15, 2004 7:26 am

Am J Vet Res. 2001 Mar;62(3):375-83. Related Articles, Links

Effects of the angiotensin converting enzyme inhibitor benazepril in cats
with induced renal insufficiency.

Brown SA, Brown CA, Jacobs G, Stiles J, Hendi RS, Wilson S.

Department of Physiology and Pharmacology, College of Veterinary Medicine,
University of Georgia, Athens 30602, USA.

OBJECTIVE: To determine effects of the angiotensin converting enzyme
inhibitor benazepril in cats with induced renal insufficiency. ANIMALS: 32
cats. PROCEDURE: Renal mass was surgically reduced, and cats were assigned
to 1 of 4 eight-cat groups. Group 1 received placebo, whereas groups 2, 3,
and 4 received benazepril hydrochloride orally once daily for approximately
6.5 months at the following doses: group 2, 0.25 to 0.50 mg/kg of body
weight; group 3, 0.50 to 1.00 mg/kg; and group 4, 1.00 to 2.00 mg/kg.
Arterial blood pressures, glomerular filtration rate (GFR), and renal plasma
flow were determined before treatment and during the treatment period. Other
determinants of renal hemodynamics were measured by use of micropuncture
techniques. Renal biopsy specimens were examined microscopically. RESULTS:
Compared with cats that received placebo, mean systolic arterial blood
pressure was significantly less and GFR significantly greater in cats that
received benazepril. Glomerular capillary pressure and the ratio of efferent
to afferent arteriolar vascular resistance were also significantly less in
treated cats. However, histologic differences in renal specimens were not
detected. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with benazepril
sustained single nephron GFR in remnant nephrons of cats with induced renal
insufficiency. Administration of benazepril was also associated with a small
but significant reduction in degree of systemic hypertension and an increase
in whole kidney GFR. Benazepril may be an effective treatment to slow the
rate of progression of renal failure in cats with renal disease.

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