Chronic progressive renal disease in the cat: Recognition and management (Proceedings)

Renal insufficiency/failure is the most common cause of morbidity and mortality in older cats. There are some specific degenerative renal diseases (e.g. polycystic kidney disease of Persians and Persian-crossbreds, amyloidosis of Abyssinians), infectious causes (e.g. FIP, chronic pyelonephritis), and neoplastic renal disease (most commonly LSA) that may lead to renal failure in cats. However the most common cause of eventual renal failure is referred to as Chronic Progressive Renal Disease (CPRD). By the time this condition is recognized, renal histopathology usually reflects end-stage renal disease and any initiating insult usually cannot be identified. The most common histologic findings are those of chronic interstitial nephritis and lymphoplasmacytic nephritis.

Recognition

The first step in managing feline patients with CPRD is identification of affected individuals. All middle-aged to older cats should receive at least once yearly historical assessment, thorough physical examination, and appropriate laboratory screening for patient age. Lethargy and decreased appetite may be important owner observations. Owners should be asked about changes in water consumption and urinary habits although these signs may not be noticed by some owners, particularly if cats spend significant time outside. Subtle weight loss is often one of the first physical findings in CPRD. Other physical findings might include reduced renal size, changes in renal consistency, renal irregularity or disparity in renal sizes, halitosis, stomatitis, and constipation. Retinal examination may reveal hemorrhages or retinal detachment secondary to renal-associated systemic hypertension.

We encourage "senior cat" profiling after the age of 8 years. However, the decision to perform laboratory testing should not be based on age alone. Our minimum baseline laboratory evaluation includes a complete blood count, serum biochemistry profile and electrolytes, total T4, and urinalysis (by cysto). Beware of over- or under-interpretation of marginal elevations of BUN and creatinine levels and remember that these measures of renal function must always be assessed with respect to patient hydration status and urine specific gravity. Cats do not follow the 66% (isosthenuria) - 75% (azotemia) rule of dogs. That is, cats do not become isosthenuric when they lose 2/3 of their renal mass and they can be in overt renal failure without isosthenuria. Because cats are descended from desert animals, they have much better normal renal concentration abilities than do dogs. A normally hydrated cat can produce urine with a specific gravity of 1.095 or greater. Therefore, in order to be considered to have adequate urine concentration abilities, a cat should have a USG of > 1.035.

If abnormalities are recognized that indicate the presence of CPRD, additional studies are performed including abdominal radiography and ultrasonography, and blood pressure measurement (Doppler). The earliest change seen on US examination is lack of corticomedullary differentiation. Because cats with CPRD do not concentrate urine well, they are more prone to developing true urinary tract infection. For whatever reason, inflammatory sediment is often not seen in the urine sediment on UA in these patients. We submit a urine culture in all cats with CPRD to detect those with occult infection. Cats with protein-losing nephropathy have a poor prognosis and additional interventional steps may be important in their management. Dipstick assessment of urine protein is often misleading and the ERD test is not sufficiently quantitative to critically assess the true severity of protein loss. We perform a urine protein/creatinine ratio in all cats with CPRD. Kidney biopsy is rarely performed if CPRD is suspected because there is no specific therapy other than to address the changes associated with the disease that are identical regardless of the underlying etiology of the renal damage.

Early management

Increase water consumption/maintain hydration

Older cats have a decreased thirst drive and a decreased thirst response to dehydration compared to younger cats. This will contribute to and aggravate the impact of CPRD-associated azotemia. In addition, these cats will be doubly prone to developing significant azotemia if water intake is restricted for any reason. Efforts to increase voluntary water consumption include providing clean, fresh water at all times, feeding a canned food diet (with added water if possible), offering beef or chicken broth (low sodium), bottled clam juice, or "tuna juice". Many cats enjoy drinking the water squeezed from cans of tuna. I have owners use a blender to mix a can of tuna with water, pour the mixture into ice cube trays and freeze, then pop cubes out into a plastic bag for freezer storage. These tuna juice cubes can be thawed out one at a time for the cat to enjoy. Cats that like to drink from running water sources (faucets, etc) may drink more enthusiastically from a recirculating water fountain than a water bowl. These drinking fountains are available at many pet stores.

Diet

There is no question that dietary protein and phosphorus restriction are important aspects in the management of advanced renal insufficiency. However, there are many opinions about when in the course of the disease a "renal diet" (protein and phosphorus restricted) should be given to cats with CPRD. A recent study does show improved longevity and fewer uremic crises when a low protein diet is started early in the course of azotemia. Because renal diets tend to be less palatable to cats than their "regular" food and because cats have a high dietary protein requirement, I usually wait to institute a special diet until the BUN > 35 mg/dl and creatinine is > 2.0 mg/dl. A good early choice is g/d (Hill's) which is slightly protein/phosphorus restricted compared to regular adult diets but less restricted than the renal diets. There are several excellent feline renal diets now available and generally one can be found that the patient will eat. I send owners home with baggies of different dry formulas and cans of different foods to try. Ideally, canned formulas are better because of their higher fluid content. For some cats, the diet cannot be changed for other reasons such as concurrent disease (e.g. hypoallergenic diet for IBD, etc). In those cases, we just have to work around the diet as best we can. Some cats would rather starve rather than eat the prescription renal diet. In that case, it is better to keep the cat eating a food he/she likes than to attempt to force a change to one he/she will not eat. It may not be ideal, but a cat that is eating a little bit of something is better off than one eating a whole lot of nothing.

Calcitriol

I am a proponent of the initiation of calcitriol therapy early in the course of CPRD, in fact, even before azotemia becomes apparent. I have been impressed with the improvement in attitude, appetite, and sense of well-being in many of my patients with these subtle signs of early disease. A complete discussion of the many effects of calcitriol is beyond the scope of this discussion. In brief, it acts to lower PTH levels and helps to prevent the development of renal secondary hyperparathyroidism with its attendant negative effects. In order to use calcitriol, the serum calcium value should be normal and the serum phosphorus value < 6.0 mg/dl. I start at a calcitriol dose of 2.5 to 3.5 ng/kg PO q24h. Our pharmacy makes a suspension of calcitriol in a concentration of 25 ng/ml so it can be measured accurately and the volume administered is not excessive. Cats receiving calcitriol should have serum calcium/phosphorus levels monitored periodically to assure that the agent is working and that hypercalcemia has not occurred. If hypercalcemia is a concern, the daily dose can be multiplied by 3.5 and given twice weekly on Wed PM and Sunday AM. This regimen will have the same beneficial effect on managing PTH but with less potential for hypercalcemia. If hypercalcemia persists or serum phosphorus levels rise above the normal range and cannot be managed with diet/phosphate binders, calcitriol treatment must be discontinued.

Selected additional therapy

Hypertension

About 10-15% of cats with CPRD will be hypertensive at the time of diagnosis and another similar number will become hypertensive during the progression of the disease. If hypertension (MSP = > 160 mmHg) is present, the treatment of choice is amlodipine. The usual starting dose for amlodipine is 0.625 mg/cat PO q24h. The blood pressure (BP) should be checked after a week of therapy and the dose may be increased if the desired effect is not observed. Reassessment of BP should be part of the patient assessment on each subsequent follow up visit to assure that the BP remains under good control and to adjust medications as needed.

Hypokalemia

Hypokalemia can lead to muscle weakness, gastrointestinal hypomotility, and other problems. Hypokalemic patients should receive potassium gluconate supplementation, 2-4 mEq PO q12h. There is no clear evidence that hypokalemia contributes to the progression of renal insufficiency but renal insufficiency definitely can lead to renal potassium wasting and hypokalemia. Many forms of potassium supplement are available including flavored powders to add to food, tablets (chewable and non-chewable), and oral gel. Potassium levels should be checked at subsequent follow up visits. If the cat is significantly acidemic, potassium citrate (15-30 mg/kg or 2.5 mEq q12h) can be used as both a potassium supplement and alkalinizing agent for initial therapy. Cats with persistent hypokalemia in spite of aggressive K supplementation, particularly if also hypertensive, should be checked for hyperaldosteronism.

Proteinuria

Although most laboratories set the normal value for the feline urine protein/creatinine (UPC) ratio at < 1.0, recent studies have shown that normal cats should have a ratio of < 0.4. Cats with CPRD and an elevated UPC may benefit from treatment with an ACE inhibitor such as benazepril (Lotensin) – 0.5 – 1.0 mg/kg PO q24h). There is presently no evidence that ACE inhibitors improve survival or slow the progression of non-proteinuric renal disease in cats. The ERD test is a reasonable screening test for proteinuria but high level results should be followed with a UPC because this is more quantitative and sensitive to smaller changes in urinary protein excretion.

Other adjunctive therapies

There has been a lot of advertising and interest in adjunctive therapies with agents such as epakitin and Azodyl. I agree with Dr. Larry Nagode's comments about these agents

"Azodyl use is intended to modify the intestinal bacterial population into species of bacteria that will metabolize urea and creatinine thus lowering their blood levels as certain amounts are circulating through the gut and normally getting reabsorbed to blood. This is at least part of the supposedly beneficial role they play but of course it would only be so if other "true" uremic toxins were similarly metabolized by the new population of gut bacteria as again neither urea nor creatinine are toxins in any way. They are just handy "markers" of extent of deficit of GFR and use of Azodyl in my view ruins their normal utility as markers of GFR deficit.

Epakitin in some of the company literature one can find is touted as a Pi binder (only the calcium carbonate contained in Epakitin could do this and I've been told there is so little calcium carbonate that it would not produce hypercalcemia if used together with calcitriol)—therefore since it takes a LOT of calcium carbonate to be anywhere near as effective as the much superior binder Al-hydroxide, I have to conclude Epakitin is a VERY POOR gut Pi binder(and the chitin which binds urea and creatinine does not bind Pi at all by any literature I can find). A poor binder that is in comparison to much lower doses of Al-hydroxide thats very cheap and very available.

The chitin in Epakitin in some of the literature I have seen is touted to bind urea and creatinine thus improving CRF patients status. This again is a "false" improvement in my view again as neither of these chemicals is toxic. I feel both Epakitin and Azodyl are best considered as masterpieces of marketing of possibly questionable real use in therapy of CRF in dogs and cats—although veterinary users through a profit sharing arrangement with Vetoquinol involving a retail "markup" can turn a tidy profit by prescribing them for clients. I say this in part because of lack of data I am aware of that Azodyl removes "real" uremic toxins from patients guts and "word of mouth" I have heard that this perturbation of the normal intestinal bacterial flora in these patients has often led to significant diarrheal and other intestinal "upset" problems—how often this has been so I have no idea. Vetoquinol marketed Epakitin first and Azodyl more recently so that the "urea and creatinine lowering" capacity originally being part of the justification for use of Epakitin is now the rationale for added use of Azodyl. Why sell clients one product when you can sell them two??. My cynicism with respect to these products may well be misplaced and they may well be outstanding wonderful products for our dogs and cats—but until I can find data that solidly supports this view I remain skeptical."-Larry Nagode

Later stage management

Subcutaneous fluid administration

As renal insufficiency progresses, oral fluid intake cannot keep pace with fluid losses. Many cats will benefit from intermittent subcutaneous fluid administration. We recommend 100-150 ml of balanced electrolyte solution given once daily. The frequency of administration per week depends on the level of azotemia and clinical signs being shown by the cat. While the implantable subcutaneous catheter advertised for SQ fluid administration looks attractive, in practice many clinicians have found that it clogs easily and that abscess/infection associated with the tube limits its usefulness. We find that most dedicated owners can easily administer SQ fluids with a drip set and fluid bag with a large bore needle (18 or 20 ga) with very few problems or complications.

Anorexia/nausea/vomiting

Increased gastrin accumulation due to reduced clearance associated with CPRD can lead to gastric hyperacidity, gastric irritation, and ulceration. H-2 receptor blockers such as cimetidine, ranitidine (2-3 mg/kg PO q12h), or famotidine (Pepcid 1 mg/kg PO q24h) will reduce gastric acid secretion and can help improve appetite and food intake. Sucralfate (Carafate - 500 mg PO q12h) is reserved for those patients with significant evidence of gastric ulceration. Metoclopramide (Reglan - 0.2 – 0.4 mg/kg PO q8h) may be helpful in patients with signs of nausea (vomiting, lip smacking, ptyalism). This drug should be given 30 minutes prior to feeding for best results.

Hyperphosphatemia

Eventually, renal function will fall to the point that serum phosphorus levels cannot be managed with dietary restriction alone. In general, cats do not enjoy our attempts to administer large volumes of mint flavored human liquid phosphate binders. More of the product usually ends up on the cat and the owner rather than inside the cat. To circumvent this problem we use aluminum hydroxide (30-90 mg/kg/day) compounded into capsules or available as tablets. An excellent preparation if the desiccated AlOH gel. This is a virtually tasteless powder and is accepted readily by most cats when mixed with canned food. More information about this binder and information about sources and dosing can be found at: http://www.zzcat.com/CRF/supplies/binders.htm. Phosphate binders should be given prior to a meal for maximum beneficial effect.

Anemia

Anemia develops in later stage CPRD as a result of decreased erythropoietin production by the failing kidneys. Human recombinant erythropoietin (EPO) has been shown to be very effective in increasing red cell mass in cats. However, most cats treated with EPO will develop antibodies against it at some point with the result that EPO treatment must be discontinued. Therefore, we wait until as late in the course as possible before using this therapy. There is no magic PCV value that should trigger initiation of EPO therapy in a cat with CPRD. In addition to the PCV, you should decide whether the cats clinical signs should be attributed to anemia (e.g. lethargy, anorexia, etc) and if so, use this as a guide to initiate therapy. The initial dose for EPO is 100 Units/kg SC 3 times weekly until the PCV reaches 30%. The frequency of administration should then be reduced gradually to twice weekly, once weekly, every other week or the least frequent interval that will maintain an adequate PCV in the cat. Darbepoetin is a newer synthetic EPO that is given less frequently. The recommended dose for Darbe in cats is: 6.25 mcg/CAT SQ or IV once weekly. Give iron dextran IM with the first dose. As packed cell volume (PCV) comes up, you can extend dosing interval to q2-4 weeks to maintain PCV. Darbe comes in 1 ml vials at 25 mcg/vial so that's 4 cat doses. Shop the big chains for the best price. Whether antibody formation against this compound will develop, we do not yet know.

Renal transplantation

There are some clients who may be interested in renal transplantation. Discussion of the specifics of these procedures and programs is beyond the scope of this presentation. However, it is best to introduce this idea early in your conversations with an owner of a cat with CPRD. If renal transplantation is to be performed, it is best done before the cat becomes seriously ill and debilitated. An excellent website for information for your clients about CPRD in general and links to renal transplant centers is: http://www.felinecrf.com/.

Frequent reassessment

Cats with CPRD should be scheduled for regular reevaluation. Close attention should be paid to body weight because subtle weight loss can indicate continuing deterioration of renal function or the presence of a new concurrent problem in these older cats such as hyperthyroidism or IBD. Oral cavity health is very important and dental prophylaxis should be performed as needed. Hypertension may be present initially or can develop at any point during the progression of CPRD. Blood pressure should be reassessed at each follow up visit to detect the development of this complication of renal disease if it is not already present and to assess the efficacy of anti-hypertensive therapy if this is being given. Repeat laboratory studies are performed on an as needed basis which is determined by the severity of CPRD, complicating factors such as recurring UTI, and the type of therapy the cat is receiving (e.g. potassium supplementation or calcitriol). Feline CPRD can be successfully managed for years in many cats if it is detected early and managed appropriately.