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Current Guidelines for Managing Feline Renal Failure

David Polzin United States

Ideally, management guidelines for feline renal failure should be based on randomized, controlled clinical trials that document the efficacy and safety of therapeutic recommendations. However, many forms of therapy recommended for cats with chronic renal failure have never been examined in an appropriate and systematic fashion in cats with spontaneous disease. Often, these treatments are recommended based on expert opinion, pathophysiologic rationale, or studies performed in other species or in cats with artificial disease. In deciding which treatment to recommend, as clinicians, we must examine the quality of data supporting a recommendation to use (or not use) a given form of therapy. 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.

Diet therapy

Dietary protein and phosphorus restriction is among the most commonly prescribed therapies for cats with chronic renal failure.(1) However, 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 unwelcome diet change. A recently published clinical trial has provided support for making the change to protein/phosphorus restricted renal diets in managing cats with chronic renal failure. 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.(2) The principal criticism of this study would have to be that cats which resisted a change in diet, were assigned to the “control” diet group. Obviously, if the reason they resisted change was related to severity of their disease, the outcome of the study could be questioned. 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 chronic renal failure has been acceptance of the diets by cats. In most instances, this can be overcome by introducing the diet slowly over one or more weeks.

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.(3,4) Hyperphosphatemia has been detected in approximately 60% of cats with CRF with the prevalence increasing as renal function declines.(4,5) In one study, the prevalence of renal secondary hyperparathyroidism in cats with CRF has been reported to be 84%.(4) 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 had 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.(4) Phosphate binding agents may be useful in 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 poorly.

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. There is no conclusive data confirming this association in cats. In dogs, dietary phosphate restriction, when combined with protein restriction, has been shown to improve survival.(6) 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.(7) 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. Mechanisms responsible for the effect of hyperphosphatemia on mortality remain unresolved.

Calcitriol therapy

The kidneys are responsible for converting 25-hydroxycholecalciferol to its most active metabolite, 1,25-dihydroxycholecalciferol, or calcitriol. Calcitriol is a major renal hormone responsible for calcium metabolism. Among its important functions is modulation of parathyroid hormone activity at the transcriptional level. Because calcitriol production may be impaired in patients with renal failure, calcitriol deficiency may be one factor promoting renal secondary hyperparathyroidism. Calcitriol supplementation has been advocated as a means of normalizing hyperparathyroidism. Because PTH may act as a “uremic toxin,” clinical benefits of calcitriol therapy may accrue from ameliorating the supposed toxic effects of PTH in renal failure. 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.(8) These findings were based on an uncontrolled survey of veterinarians who use calcitriol in their practice. 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 chronic renal failure. Concern has been raised concerning the potential for calcitriol therapy to result in hypercalcemia and renal injury.

Anti-hypertensive therapy

Hypertension is a well-recognized complication of feline renal failure. The most profound clinical effect of hypertension seems to be hypertensive retinopathy with retinal detachment, hemorrhage, and blindness. Cats with such severe ocular manifestations reflect only a tiny percentage of cats with renal failure and hypertension. Studies in our laboratory have suggested that hypertension is a risk factor for shortened survival times in dogs with renal failure. Similar data has not been reported in cats. While it is clear that cats with hypertension and hypertensive retinopathy likely benefit from intervention with anti-hypertensive drug therapy, justification for therapy in cats without retinopathy 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.

Amlodipine 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.(9) In contrast to amlodipine, ACE inhibitors and beta-blocking drugs do not appear to be as effective in lowering blood pressures in cats. However, the indications for and benefits of therapeutic intervention for hypertension in cats remain to be elucidated.

ACE inhibitor therapy

Angiotensin converting enzyme inhibitors appear to be of value in limiting progression of renal failure in various forms of human renal diseases.(10) One ACE inhibitor has been licensed for use in managing renal failure in cats in several countries. However, convincing data that ACE therapy influences progression of renal failure or clinical outcomes of cats with chronic renal failure 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.(11) 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.

Potassium supplementation

Although current feline renal diets are generally potassium supplemented, hypokalemia still occurs in a subset of cats with renal failure. It is generally accepted that potassium supplementation is warranted in cats with hypokalemia. However, it has been suggested that all cats with renal failure should be supplemented with potassium to limit total body potassium depletion and prevent development of hypokalemia and progressive renal injury.(12) Although the potential benefit of potassium supplementation has been examined, the clinical benefits of such therapy remain to be proven.(13)

Erythropoietin therapy

Administration of human recombinant erythropoietin has been shown to correct the anemia of chronic renal failure in cats.(14) 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. Consequently, 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 renal failure. In the future, anemia in cats with renal failure may be managed using gene therapy in preference to administration of erythropoietin.(15)

Alkalization therapy

Alkalization therapy is clearly indicated for cats with moderate to severe metabolic acidosis associated with renal failure. 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.

References

1.  Polzin DJ, Osborne CA, Ross S, and Jacob F: Dietary management of feline renal failure: Where are we now? In what direction are we headed? J Fel Med Surg 2:75-82, 2000.

2.  Elliot J, Rawlings JM, Markwell PJ, and Barber PJ: Survival of cats with naturally occurring chronic renal failure: Effect of dietary management. J Small An Pract 41:235-42, 2000.

3.  Barber PJ and Elliott J: Feline chronic renal failure: calcium homeostasis in 80 cases diagnosed between 1992 and 1995. J Small Animal Practice 39, 108-116, 1998.

4.  Barber PJ, Rawlings JM, Markwell PJ, and Elliott J: Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat. J Small Animal Practice 40, 62-70, 1999.

5.  DiBartola SP, Rutgers HC, Zack PM, and Tarr MJ: Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973-1984). Journal of the American Veterinary Medical Association 190:1196-1202, 1987.

6.  Brown SA, Crowell WA, Barsanti JA, White JV, Finco DR: Beneficial effects of dietary mineral restriction in dogs with marked reduction of functional renal mass. Journal of the American Society of Nephrology 1:1169-1179, 1991.

7.  Block GA H-ST, Levin NW, Port FK. Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Diseases 31:607-617, 1998.

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

9.  Snyder P. Amlodipine: A randomized, blinded clinical trial in nine cats with systemic hypertension. J Vet Int Med 12:157-162, 1998.

10. Kshirsagar AV, Joy MS, Hogan, Falk RJ and Colindres RE: Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic review overview of randomized placebo-controlled trials. Am J Kidney Diseases 35:695-707, 2000.

11. Brown SA, Brown CA, Jacobs G, Stiles J, Hendi RS, and Wilson S: Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res 62:375-383, 2001.

12. Dow S, Fettman M. Renal disease in cats: The potassium connection In: R. Kirk and J. Bonagura, eds. Current Veterinary Therapy XI. Philadelphia: WB Saunders, 1992;820-822.

13. Theisen S DS, Radin MJ, Chew DJ, Buffington CAT, and Dow SW. Muscle potassium content and potassium gluconate supplementation in normokalemic cats with naturally occurring chronic renal failure. J Vet Int Med 11:212-217, 1997.

14. Cowgill LD, James KM, Levy JK, Browne JK, Miller A; Lobingier RT, Egrie JC: Use of Recombinant Human Erythropoietin for Management of Anemia in Dogs and Cats with Renal Failure. J Am Vet Med Assoc 212:521-528, 1998.

15. Beall CJ, Phipps AJ, Mathes LE, Stromberg P, Johnson PR: Transfer of the feline erythropoietin gene to cats using a recombinant adeno-associated virus vector.Gene Ther 7:534-9, 2000.


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