Chronic Renal Failure

by Arnold Plotnick MS, DVM, ACVIM, ABVP

Long-term Medical Management of Feline Chronic Renal Failure

Introduction

            Chronic renal failure (CRF) is a common cause of illness in cats, especially in older cats, and the incidence of CRF is increasing.¹ In 1990, there were 45 cases of CRF for every 100 cats admitted to veterinary teaching hospitals. In 2000, the number increased to 96 cases per 1000 cats.

            Unless the underlying cause of the initial renal injury can be discovered and treated, CRF invariably progresses. In some instances, even after identifying the initial cause of the renal injury, a threshold or “trigger-point” has already been reached, and self-perpetuating mechanisms of kidney destruction are activated. In most cases, an underlying cause for the initial renal insult cannot be found. 

            CRF is incurable. With the exception of a kidney transplant, it is difficult or impossible to improve kidney function in cats with chronic renal failure. It is possible, however, to delay the progression of renal failure, improve the cat’s quality of life, and extend a cat’s survival time through a variety of diet and drug interventions.      

Acute management for CRF cats that are clinically ill
            Therapy for CRF can run the gamut, from a simple dietary change to a hospital stay of several days duration, depending on severity and how early the disease has been detected. For cats hospitalized with renal failure, fluid therapy remains the cornerstone of treatment. Administering fluid to cats with CRF corrects dehydration and increases urine production, reducing azotemia. Fluid therapy corrects acid/base imbalances, and helps to restore normal phosphorus and potassium levels. This is crucial, as increased levels of phosphorus and decreased levels of potassium can accelerate progression of the renal damage.^2,3  Cats with CRF may have trouble conserving water-soluble vitamins (the B vitamins and vitamin C) due to excessive loss through urine^4,5, and these vitamins can be replaced through the fluid therapy as well.
            Nutrition is an essential part of the therapy for CRF. Many cats hospitalized with CRF have decreased or absent appetite. During hospitalization, nutritional support can be achieved either through force feeding, tube feeding, or intravenous feeding, depending on the severity of the inappetance, the degree of malnutrition, and the cat’s demeanor.
            Nausea is a common occurrence for cats with CRF. The kidneys are responsible for excreting the hormone gastrin.  As such, cats with CRF often have hypergastrinemia, which leads to production of excessive amounts of gastric acid.⁶ This may contribute to the anorexia and vomiting seen in many cats with CRF. Administration of H₂-receptor antagonists such famotidine, either subcutaneously or orally, may be beneficial in this regard.
            A major objective of acute therapy is to significantly decrease the level of azotemia.  A reduction of blood urea nitrogen (BUN) and creatinine to normal levels, however, is often impossible and should not necessarily be the practitioner’s goal. During hospitalization, BUN and creatinine levels are measured every two or three days until a plateau is reached.  After several days, many cats will have improved clinically and can be released from the hospital to the owner. A typical hospital stay lasts from three to six days.
            It should be made clear to the owners of a cat with CRF that the treatment the cat received while hospitalized does not return the kidneys to normal, and that a conscientious home maintenance program will be necessary for the remainder of the cat’s life.  The focus of this article is on the long term management of CRF in cats.
Long term management and prevention of the progression of CRF
Dietary management
            The benefits of dietary modification in CRF have been well documented. Protein, when metabolized, gives rise to uremic toxins that the failing kidneys cannot properly excrete. By reducing the amount of protein in the diet, azotemia is lessened, and this helps ameliorate clinical signs such as weight loss, poor appetite, vomiting, and lethargy. In the past, choices were very limited with regard to these diets for cats. Fortunately, several companies now manufacture palatable feline “kidney failure diets” that are restricted in protein as well as phosphorus and sodium. 
            Much controversy has been generated as to whether dietary protein restriction can actually slow the progression of kidney disease in cats. Several studies in recent years, however, have confirmed that dietary modification can have a significant impact on mortality in cats. Cats with naturally occurring renal failure that were fed a veterinary renal diet lived considerably longer (median survival 633 days) than those cat that did not receive (or refused to eat) these diets (median survival 264 days).³ Another study compared 23 cats fed a maintenance food with 22 cats fed a prescription diet designed for renal failure.  Cats fed the maintenance food had a significantly greater number of uremic episodes compared to cats fed the renal diet.  Throughout the duration of the 2 year study, none of the cats fed the renal diet died from kidney-related causes, whereas five cats in the maintenance group died from renal causes.⁷ These data led the authors to recommend feeding a renal diet to cats with CRF early in the course of disease, i.e. when their serum creatinine level exceeds 2 mg/dL. More recently, a retrospective study compared 175 cats with kidney failure fed maintenance diets with 146 cats fed a special diet designed for renal failure. Survival time for cats on the conventional diet was 7 months, compared to 16 months for those fed the prescription diets.⁸ These studies confirm that cats that consume a prescription “kidney failure diet” have increased survival and good quality of life compared to cats that do not (or will not) eat this type of diet. Many manufacturers, for example, The Hill’s Company (Topeka, Kansas), Iams Company (Dayton, Ohio), Royal Canin Company (St. Charles, Missouri), and Purina Company (St. Louis, Missouri), now offer these kinds of diets. Whether or not one particular brand offers more benefit than another remains to be determined.

Monitoring potassium 
            Hypokalemia is a common finding in feline CRF. It is unclear whether hypokalemia is a cause of CRF, a consequence of CRF, or both.⁹ Most instances of hypokalemia are mild, with no apparent clinical signs. Marked hypokalemia, however, can lead to general muscle weakness.  In more severe cases, cats can develop hypokalemic polymyopathy which, if misdiagnosed, can lead to paralysis of the respiratory muscles and death by respiratory arrest if aggressive potassium supplementation is not undertaken.  Potassium depletion and hypokalemia in cats with CRF may result from inadequate consumption of potassium, dietary issues, enhanced renal loss of potassium, or a combination of these factors.¹⁰

            Hypokalemia contributes to the progression of kidney failure.² In many cats with CRF and hypokalemia, kidney function improves when low potassium levels are restored to normal using oral or parenteral potassium therapy, suggesting that hypokalemia may induce a reversible reduction in glomerular filtration rate.^9,10 Potassium supplements (usually in the form of potassium gluconate) are currently available in a variety of palatable forms (oral liquids, granules to be added to food, and flavored ointments), increasing the likelihood of successful administration in cats who tend to be finicky or difficult to medicate.

Vitamins and omega-3 fatty acids

            Cats with diseased kidneys have difficulty conserving water soluble vitamins⁵,

given the excessive amount of urine that is produced by the failing kidneys every day.  Cats with chronic renal failure, therefore, should receive a daily multivitamin. ⁴ 

            In human patients with CRF, increased free radical production and antioxidant depletion may play a role in progression of the disease¹¹, and supplementation of the diet with antioxidants such as vitamins A, C, and E has been shown to reduce oxidative stress in humans with CKD.¹²  A recent study in which cats with CRF were fed a prescription diet designed for renal failure that was supplemented with additional vitamin E (742 mg/kg), Vitamin C (84 mg/kg) and beta-carotene (2.1 mg/kg) showed a significant reduction of oxidative DNA damage in cats with spontaneous CRF.¹³

            Prescription diets that are designed for cats with renal failure are restricted in protein, phosphorus and sodium. Recently, manufacturers have been adding a larger proportion of omega-3 fatty acids to these diets, based on studies showing evidence of beneficial effects these fatty acids have in dogs¹⁴, and presumably cats, with chronic renal failure.  While it has been shown that and cats ^3,7,8 fed prescription diets designed for renal failure live longer and have improved quality of life than cats fed a conventional diet, it is not possible to say which single nutrient alteration (or combination of alterations) is responsible for the benefit. In a retrospective study that evaluated the median survival time of cats fed a variety of “renal failure diets” vs. maintenance diets, not only did the cats fed the modified diets live longer (median survival: 7 months vs. 16 months), the diet associated with the longest survival time (23 months) had particularly high levels of eicosapentaenoic acid.⁸ The ideal ratio of omega-6: omega-3 fatty acids in diets designed for renal failure has yet to be determined.           

Controlling excessive urinary protein loss

            In humans, proteinuria is a risk factor for the progression of chronic renal failure, and controlling proteinuria has been shown to increase survival times in humans with CRF.  A recent study has shown that the severity of proteinuria is related to survival in cats with chronic renal failure.¹⁵

            When the kidneys start to fail and nephrons are lost, hemodynamic adaptations occur in some of the remaining nephrons, causing increased single nephron GFR, glomerular plasma flow, and increased hydraulic pressure across the glomerulus.¹⁶ 

Angiotensin converting enzyme (ACE) catalyzes the generation of angiotensin-II from angiotensin-I within the kidney, causing vasoconstriction of glomerular arterioles. The efferent arteriole is preferentially constricted.  Vasoconstriction of the efferent arteriole increases intraglomerular capillary pressure.  Initially, this is adaptive, allowing for maintenance of excretory function and total kidney GFR.  Ongoing intraglomerular hypertension, however, is ultimately maladaptive, leading to increased trafficking of macromolecules into the mesangium, resulting in proliferation of mesangial cells and increased production of mesangial matrix, i.e. glomerulosclerosis, resulting in further kidney damage. 

            Measuring the intraglomerular pressure is not possible in a clinical setting, however, proteinuria can be an indicator of elevated glomerular pressure. Proteinuria can be detected and quantified by determining the urine protein/creatinine ratio (UPC). In cats, a UPC ≥ 0.5 is indicative of persistent renal proteinuria.¹⁷   In a study that looked at the relationship between survival time and proteinuria in cats with CRF, the UPC was shown to be a significant predictor of survival time.  Median survival time for cats with a UPC < 0.43 was 766 days compared to only 281 days for cats with UPC > 0.43. ¹⁵ Although cats with chronic renal failure typically have low concentrations of protein in their urine, the degree of proteinuria is of prognostic significance.

            ACE inhibitors are ideally suited to treat elevated intraglomerular pressure because they selectively dilate the efferent arteriole of the glomerulus.  The ACE inhibitor benazepril has been shown to prolong survival time and reduce proteinuria in a large clinical trial in humans ¹⁸ and to have beneficial hemodynamic effects (normalization of glomerular hypertension with maintained or increased glomerular filtration rate) in a model of CRF in cats.¹⁹ Benazepril has been studied in cats.  A clinical trial of 201 cats with CRF showed that cats that received benazepril had improved appetite, quality of life, weight gain, and longer lifespan, particularly those cats whose renal failure was deemed severe (401 day survival, compared to 126 days for cats that received placebo). ²⁰ Benazepril appears to decrease proteinuria, and in doing so increases survival times and slows progression of renal disease in cats diagnosed with CRF.  Veterinarians should view the results of this study cautiously, however, as the results have not been published in a peer-reviewed veterinary journal.

Phosphorus restriction, Renal Secondary Hyperparathyroidism, and Calcitriol
            Renal secondary hyperparathyroidism occurs when the parathyroid glands secrete excessive parathyroid hormone as a result of chronic renal failure.  This is due to several factors, the primary factor being an impaired ability of cats with CRF to synthesize calcitriol. 

            The kidneys are responsible for the final step in the synthesis of calcitriol from its precursor, 25-hydroxyvitamin D.  As the kidneys fail, there are fewer healthy proximal tubule cells with the enzyme system necessary to catalyze this synthesis. Another contributing factor is the inhibition of calcitriol synthesis due to rising phosphorus levels.  Phosphorus inhibits the enzyme system involved in the synthesis of calcitriol. 

            Phosphorus is filtered from the bloodstream by the kidneys. When the kidneys begin to fail, the phosphorus levels begin to rise. When serum phosphorus levels are high, phosphorus can combine with calcium in the bloodstream.  This is known as the law of mass action.  The formation and deposition of calcium phosphate in the soft tissues, including the kidneys, can cause further renal damage.  Serum phosphorus levels in excess of 7 or 8 mg/dL will decrease the serum ionized calcium level approximately 0.1 mg/dL, which is enough to stimulate PTH secretion.  This is yet another factor in which hyperphosphatemia promotes the development of renal secondary hyperparathyroidism.

            Calcitriol plays a role in maintaining normal levels of calcium in the bloodstream, since calcitriol is necessary for the intestines to properly absorb dietary calcium.  As the kidneys fail and become incapable of producing adequate amounts of calcitriol, the serum calcium level begins to fall. To maintain adequate levels of calcium in the bloodstream, the parathyroid glands release PTH, restoring and maintaining normal calcium levels.

            Although production of PTH is physiologically appropriate, excessive amounts of PTH are toxic to the kidneys and other organs. Toxic effects of PTH on the brain likely contribute to the depression and stupor seen in cats with renal failure.²¹ In experimental animals, excessive PTH also slows nerve conduction, contributes to the anemia often seen with CRF, and enhances the progression of kidney failure.²¹  This likely occurs in cats as well.

            Calcitriol is the natural, biologically active form of Vitamin D. When administered to animals with renal secondary hyperparathyroidism, calcitriol causes a reduction in PTH production by the parathyroid glands. ¹⁸ Reducing PTH levels through control of dietary phosphorus intake has been shown to improve survival in cats³ with CRF. Although data demonstrating improved survival as a result of administration of calcitriol to cats with CRF is lacking, calcitriol has many direct beneficial effects in uremic animals independent of its PTH-lowering properties²¹, and administration of calcitriol to supplement cats in the early stages of chronic renal disease appears safe, effective, and advisable. ²²      

            Limiting phosphorus consumption appears to slow the progression of CRF in humans and dogs, and there is evidence that dietary phosphorus restriction also limits renal injury in cats with CRF.³

            Prescription diets designed for cats with kidney failure contain reduced levels of phosphorus. However, the level may not be restricted enough to prevent hyperphosphatemia. Orally administered phosphorus binders, such as aluminum salts (e.g. aluminum hydroxide) and calcium salts (e.g. calcium carbonate) are the most commonly used phosphate binders. Aluminum salts have been removed from the human market over concern for aluminum toxicity.

            Sevelamer hydrocholoride (Renalgel) is an organic polymer that is a non-calcium, non-aluminum containing compound that binds phosphorus in the intestinal tract. It has been used safely in cats, but has the potential to bind vitamins in the intestinal tract. Animals receiving this drug should receive a vitamin supplement as a precaution. Lanthanum carbonate (Fosrenol) is a new intestinal phosphate binder in human medicine that does not contain calcium or aluminum. Reports of its clinical use in dogs or cats are lacking.  Epakitin (Vetoquinol USA, Buena NJ) is a phosphate binder consisting of calcium carbonate and chitosan. Most cats dislike the taste of liquid phosphorus binders, and the tablets are often difficult to administer due to their large size. Epakitin is a palatable powder that can be mixed into canned food.  Because they are calcium-based, there is some concern that the use of calcium salts could raise the blood calcium level, especially if given in conjunction with calcitriol.  Phosphorus binders are most effective when given at the time of feeding or shortly thereafter (within 2 hours).           

            Traditionally, phosphorus restriction was initiated when high phosphorus levels were detected on blood tests.  However, phosphorus restriction may have benefit when initiated before the onset of overtly high levels of phosphorus, because renal secondary hyperparathyroidism occurs before serum phosphorus concentrations exceed the normal range, and because fasting serum phosphorus concentration may not accurately reflect overall phosphorus metabolism.¹⁰  Return of serum phosphorus to normal levels does not guarantee that PTH levels will return to normal, since phosphorus restriction is effective only in those animals that have an adequate number of healthy proximal tubule cells to synthesize calcitriol once the inhibitory effects of excessive phosphorus are controlled.  For those patients whose PTH levels remain high despite a seemingly well-controlled phosphorus level, administration of calcitriol may be necessary to control PTH levels.
            Calcitriol should not be given to cats until hyperphosphatemia has been controlled.  If the Ca x P product exceeds 70, or if the serum phosphorus remains higher than 6.0 mg/dl, calcitriol should not be administered, as soft tissue mineralization, including renal mineralization, is a risk.

Fluid therapy
            While there are ways to encourage additional water intake in the home setting (e.g., feeding canned food rather than dry food, adding water or broth to the food), the fluid intake for cats with CRF is often inadequate, and some cats require subcutaneous fluid administration. Most cats tolerate this well, and clients can easily be taught how to perform this procedure. Fluids are initially administered every day, and may be tapered to every other day or even less frequently, depending on how the cat is feeling at home. There is no consensus among veterinarians regarding when subcutaneous fluid therapy should be initiated in any given feline patient. In the author’s experience, cats are clinically more sensitive to changes in hydration status compared to dogs and will often show dramatic improvement in appetite and activity when given subcutaneous fluids, with no clear correlation to their level of azotemia. 

Controlling high blood pressure
            High blood pressure is seen in almost 20% of cats with CRF presenting to primary care facilities²³.  In referral practices, the incidence has been reported to be as high as 65%.²⁴ CRF, perfusion pressure in remnant glomeruli tends to be increased.  Increased systemic blood pressure may be transmitted to the glomeruli, causing further damage. Hypertension can also cause damage to the brain, eyes, and heart if uncontrolled.

            High blood pressure is a major risk factor for the progression of chronic renal failure in humans and rats, and evidence has shown this to be true for dogs²⁵ , and presumably for cats as well. Cats with CRF should have their blood pressure evaluated. Hypertension in cats is defined as an indirect systolic pressure greater than 160 or 170 mm Hg, and a diastolic blood pressure greater than 100 mm Hg.^26,24 

            If hypertension is detected, treatment with amlodipine is recommended. Hypertensive cats need life-long therapy to keep their blood pressure under control.
Nausea and vomiting.
            Gastrin is a digestive hormone that causes the stomach to produce acid. The kidneys are responsible for excreting much of the gastrin produced in the body. As the kidneys fail, gastrin levels begin to rise, the degree of hypergastrinemia increasing with the severity of the renal insufficiency.⁶ This results in increased gastric acidity, nausea, vomiting, poor appetite, and possible gastric ulceration and justifies the use of appropriate treatments, such as histamine-₂ receptor antagonists or proton pump inhibitors to suppress gastric acid secretion. Cimetidine, ranitidine, and famotidine are effective at decreasing gastric acidity in cats. Famotidine may offer an advantage in that it may be administered only once daily, compared to the others. For cats suspected of having gastric ulcers, sucralfate helps form a protective coating over the ulcer, reducing symptoms such as pain, nausea, and vomiting. The use of a compounding pharmacy may be necessary, as sucralfate tablets cannot be divided accurately to achieve the proper dose for most cats.
Anemia
            As the kidneys fail, they produce inadequate amounts of erythropoietin, and many cats with CRF become progressively anemic. Anemia contributes to the lethargy and poor appetite seen in cats with CRF. Recombinant human erythropoietin, when given to cats dramatically reverses the anemia. However, because the hormone is not of feline origin, approximately 25% of cats will develop antibodies against it. These antibodies not only bind the human erythropoietin being administered, but will also bind whatever remaining feline erythropoietin is present. Cats develop sudden, severe anemia as a result, and become transfusion dependent.  It is usually at this point that owners elect euthanasia.

Intraintestinal Bacteriotherapy (“Enteric Dialysis”)

            The concept of “enteric dialysis” is based on the premise that the intestinal wall functions as a semi-permeable membrane; solutes that are in high concentration in the bloodstream readily diffuse from plasma into the intestinal lumen.  The use of live bacteria that catabolize uremic solutes in the gut when ingested would create a gradient favorable for the uremic toxins to diffuse from the plasma into the gut. Azodyl^® (Vetoquinol USA, Buena, NJ) is a recently introduced nutritional supplement that contains the bacteria Enterococcus thermophilus, Bifidobacterium longum, and Lactobacillus acidophilus, in capsule form, for this purpose. However, there are no controlled clinical trials of the use of these probiotics for azotemia and chronic renal failure in cats.

Conclusion
            Many advances have been achieved regarding the treatment of chronic renal failure. Although CRF is not curable, cats can live for many years after diagnosis if treated appropriately.

Updated 2/19/08