CHRONIC RENAL FAILURE IN CATS

Chronic renal failure (CRF) is a condition characterized by inability of the kidneys to perform excretion, regulate electrolyte and water balance, perform biosynthetic endocrine functions, and perform metabolic degratory functions adequately due to a loss of nephrons over a period of time. The loss of kidney function usually results in abnormal filtration of blood and retention of waste materials, failure to produce the hormones erythropoietin and calcitriol, and derangement of fluid, electrolyte and acid-base balance. Chronic renal failure causes many changes throughout the body affecting almost every body system.

It is important to differentiate between acute renal failure (ARF) and CRF. The causes and treatment can be very different. ARF is a potentially reversible disease, whereas CRF is not. An acute kidney problem can turn into a chronic problem. It is usually possible to differentiate between acute and chronic disease based on history, physical examination, urinary tract imaging, and routine laboratory testing.

DIAGNOSIS OF CHRONIC RENAL FAILURE

ETIOLOGY AND RISK FACTORS

• Causes
• Chronic interstitial nephritis of unknown cause (most common)
• Amyloidosis (familial in Abyssinian cats and Oriental shorthair cats)
• Chronic glomerulonephritis
• Chronic obstructive uropathy (hydronephrosis)
• Chronic pyelonephritis
• Feline infectious peritonitis
• Polycystic disease (PPD - Persians)
• Chronic kaliopenia (with or without hypokalemia)
• Chronic hypercalcemia (especially idiopathic but also primary hyperparathyroidism)
• Neoplasia (renal lymphoma)
• Hypokalemia can both initiate and perpetuate chronic renal damage.
• Hypokalemia can both initiate and perpetuate chronic renal damage. Hypokalemia is much more common in cats than in dogs in general, especially for cats with CRF.
  
  Acute renal failure can progress to chronic renal failure. Some causes of acute renal failure include:
• Toxins (ethylene glycol, Easter lily, NSAIDs, aminoglycosides)
• Acute hypercalcemic nephropathy (vitamin D toxicosis)
• Risk factors
• Age - Older pets are commonly affected as the prevalence increases with age. There is a dramatic increase in risk for cats over 15 years of age. The average age of diagnosis in cats is nine years.
• Breed/genetics - Breeds thought to be more susceptible include the Abyssinian and Persian.
• Sex - CRF equally affects males and females
• Geographic/environmental - No known risk
• Other medical disorders - ARF can develop into CRF. Other medical disorders as listed above can lead to CRF.

• Prevention - There are no specific recommendations for prevention of CRF. There is no evidence that the feeding of lower protein diets prevents CRF. General suggestions include providing frequent opportunity to urinate and free access to fresh clean water. Avoid exposure to ethylene glycol and toxic plants such as Easter lily (uniquely toxic to cats) that can cause acute kidney damage.

HISTORY AND CLINICAL SIGNS

• Species affected - Dog and cat
• Presenting signs and historical problems - The primary presenting complaint in CRF is anorexia, vomiting and lethargy. Other signs include polyuria, polydipsia, halitosis, weakness, ataxia and depression. Constipation is a common finding in cats. Be aware that polyuria and polydipsia are not commonly noted by owners unless specifically questioned as to the weight of the litter box or to the size of urine clumps in cats using clumpable litter.

PHYSICAL EXAMINATION FINDINGS

Physical examination findings will vary widely depending on the stage of the chronic renal disease and the animal's ability to adapt to the uremic environment. Signs may be minimal in those with compensated CRF versus those that are in decompensated CRF.

• General
• Attitude - The mental status can range from lethargic to comatose.
• Body condition - Advanced renal failure often results in a thin, unkempt and even emaciated animal with a poor body condition score.
• Vital signs - Normal body temperature is maintained unless the cat is in an advanced state of uremic crisis. Heart rate and respiratory rate are usually normal.
• Mucous membranes - Due to dehydration, the mucous membranes are often tacky. If anemia is present, the mucous membranes may be pale.
• Hydration status - Dehydration is a common finding in animals with CRF.
• Head and neck - The thyroid glands should be carefully examined for tumors in cats over 7 years of age.
• Eyes - A thorough ophthalmic exam is recommended since hypertension is common in cat with CRF. The retina should be examined for retinal hemorrhage, detachments or tortuous vessels.
• Oral cavity - Malodorous breath and uremic ulcers may be present. Gingivitis is common.
• Thorax (cardio-pulmonary) - Usually unremarkable though murmur secondary to effects of systemic hypertension may be ausculted.
• Abdomen (gastrointestinal/urinary) - The kidneys may be small, firm or irregular. Swollen, painful kidneys usually indicate acute renal failure. About 1/3 of cats with CRF have normal size kidneys on palpation, while 1/3 are enlarged, and 1/3 are small.
• Reproductive system - Unremarkable
• Lymph nodes - Unremarkable
• Integumentary system - Many cats with CRF appear unkempt.
• Neurologic examination - Neurologic signs are not common, but uremic seizures can occur in cases of severe renal failure. Depression may be a manifestation of uremic encephalopathy.
• Musculoskeletal examination - Muscle wasting and atrophy may be present and can be quite marked in some cats. Marked musculoskeletal weakness and myopathy following rhabdomyolysis can be observed in animals with significant hypokalemia. Some cats with profound hypokalemia exhibit a weakening of the neck muscles with inability to lift the head.

DIAGNOSTIC STUDIES

• Special examination techniques - Arterial blood pressure is recommended since 50 to 90 percent of cats with CRF have hypertension. Blood gas analysis allows evaluation of acid base disturbances.
• Clinical laboratory tests
• CBC - A complete blood count is recommended to evaluate for signs of infection, inflammation or anemia. Non-regenerative anemia is a common finding, often due to a lack of erythropoietin from the kidneys.
• Serum biochemical tests - Biochemical profile tests are very important in diagnosing renal failure. Common findings include:
  ↑ Serum creatinine
  ↑ BUN
  ↑ Phosphorus
  ↓ Potassium is a much more common finding in cats than in dogs and is commonly associated with renal disease in cats.
  
  Normal calcium is present in most. Decreased calcium may be a result of secondary renal hyperparathyroidism due to a lack of calcitriol. Increased calcium may be present in some and seems to be increasing in importance.
  
  T4 may be elevated in cats with complicating hyperthyroidism.
• Urinalysis - Urinalysis usually shows a low specific gravity less than 1.040 or 1.045 with CRF. The presence of isosthenuria (1.007 to 1.017) is common in those with advanced renal failure but is not required for diagnosis. The combination of submaximally concentrated urine simultaneously with the finding of azotemia is the hallmark of primary renal disease. Some cats with chronic generalized renal disease retain the ability to concentrate urine to a specific gravity greater than 1.045, which makes definitive diagnosis difficult in these instances. Increased urine protein may indicate glomerular disease if the urinary sediment is inactive. Pyuria with or without bacteriuria may indicate urinary infection. A urine protein/creatinine ratio is another useful test to evaluate urinary protein loss in pets suspected to have glomerular disease. Fractional excretion of electrolytes (sodium, potassium, chloride, and phosphorus) is occasionally useful in evaluation of animals with suspected generalized renal disease in cases with mild azotemia in which it is not entirely clear if the azotemia is renal or pre-renal.
• Serology/immunologic tests - Feline leukemia and feline immunodeficiency virus testing should be performed on all ill cats if status is unknown. These viruses can be associated with glomerulonephritis directly or following opportunistic infections.
• Microbiology - Urine culture should be performed to evaluate for the presence of upper or lower urinary tract infection. As many as 30 to 50 percent of cats can be expected to develop a positive urine culture at some point during their CRF. This figure is much higher than that which happens in dogs. Urine should be obtained via cystocentesis.
• Diagnostic imaging
• Radiographs (thoracic/abdominal) - Abdominal radiographs may show small kidney size, which is common with CRF, but normal renal size does not rule out CRF. Some chronic kidney diseases can be associated with enlarged kidneys, such as polycystic renal disease and renal lymphoma. Survey radiography is important to perform in all cats with CRF since an increasing number of these cats have renal and ureteral stones that can be contributing to the renal failure.
• Contrast radiography - Excretory urography may be useful in the evaluation of abnormalities in renal size, shape or location. It may also be valuable in the detection of obstruction, cancer or stones. This method is not recommended for routine evaluation since it is more invasive than ultrasound and does carry some risk for nephrotoxicity.
• Ultrasound (abdominal) - Renal ultrasonography can provide additional information about the kidneys. Kidneys with chronic disease are typically small and sometimes irregularly shaped. Large kidneys may indicate polycystic renal disease, cancer or acute kidney disease. It is important to follow up CRF cats that are found to have a mineral density in the region of the ureters on survey radiography to assess the degree of ureteral obstruction (hydronephrosis) if any. Some pets can have a normal ultrasound with CRF.
• Nuclear imaging - Radioisotope clearances may be used to determine kidney filtration and blood flow but is not needed in those with obvious azotemia and submaximally concentrated urine.
• Pathology
• Biopsy/histopathology - A fine needle aspirate or biopsy of the kidney may be useful in some cats with renal diseases like renal lymphoma and granulomatous interstitial nephritis due to FIP.

DIAGNOSIS AND PROGNOSIS

• Differential diagnosis - Differential diagnosis for conditions that create dilute urine and azotemia
• Acute renal failure
• Diuretic phase of acute renal failure (ARF)
• Diabetes mellitus with pre-renal azotemia
• Diuretics with pre-renal azotemia
• Chronic hypercalcemia
• Hyperthyroidism
• Chronic hypokalemia
• Partial urinary tract obstruction
• Post-obstructive diuresis
• Pyelonephritis
• Pyometra - with pre and primary renal possibilities
• Recommended tests
• CBC
• Serum biochemistry
• Urinalysis
• Summary of diagnostic criteria - Elevated BUN, creatinine, phosphorus, submaximal urinary concentration
• Prognosis - The prognosis for recovery of renal function depends on the severity of the renal lesions and the cause of CRF.

TREATMENT OF CHRONIC RENAL FAILURE

TREATMENT PRINCIPLES

Treatment of chronic renal failure must be individualized based on the severity of the condition, the cause, secondary diseases or conditions and other factors that must be analyzed. A search for reversible causes of kidney failure should be completed. The ultimate goal of the management of CRF is to provide supportive care while trying to treat/eliminate secondary factors aggravating kidney failure, such as: infections, dehydration, malnutrition and anemia.

INITIAL/HOSPITAL THERAPY

Not all CRF cats will need hospitalization for treatment depending on how well compensated they are. Below are treatments for those that are quite ill and need hospitalization. It is important to remember knee-jerk fluid diuresis based on a level of azotemia may not be needed in compensated CRF cats.

• Fluid therapy is important to correct dehydration and abnormalities in serum electrolytes. Care must be taken to avoid over-hydrating the patient, because the kidneys may not be able to excrete a sudden fluid volume quickly. Most CRF cats are in a state of polyuric renal failure and can handle reasonable IV fluid volumes if cardiovascular status is adequate.
• Hypokalemia in cats can be treated with potassium gluconate at a dose of 2 to 6 mEq/cat once or twice daily, depending on the size of the cat and the severity of hypokalemia. If parenteral potassium is needed, add the appropriate amount of potassium to the intravenous fluids. Cats are known to suffer paradoxical lowering of serum potassium following IV fluid treatments designed to correct hypokalemia. This effect seems to be most profound in those with a serum potassium less than 2.5 mEq/L but can also be seen at higher levels. In these instances, a combination of oral and subcutaneous potassium repletion is a better idea before more vigorous IV fluid treatments are implemented.
• Correction of metabolic acidosis is recommended if the blood pH is less than 7.2 or the total carbon dioxide is less than 12 mEq/L. Sodium bicarbonate can be administered at a dose of 1 to 4 mEq/kg as needed by slow infusion. Too much alkali infusion can result in associated sodium retention and alkalosis, which are effects secondary to lowering of ionized calcium.
• Elevated phosphorus may be treated with intestinal phosphorus binders such as aluminum hydroxide (dosed at 100 mg/kg/day) and calcium carbonate (dosed at 100 mg/kg/day). These drugs should be divided into three to four doses per day. The effect of binding is greatest in animals that are eating, but there is still an effect to bind phosphorus in gut water in those that do not eat.
• Control of vomiting may be treated with antacid drugs, including: cimetidine (Tagamet®), ranitidine (Zantac®) or famotidine (Pepcid®) and the proton pump blockers such as omeprazole. These products may be useful in those that are not vomiting also as they may increase food intake in those with gastric ulcers. Metoclopramide may be needed to control vomiting in some. Chlorpromazine may be considered for treatment of those that have failed the above treatments to control vomiting.
• Anabolic steroids are available, but there are no long-term studies demonstrating their efficacy. Winstrol® (stanazolol) is not presently recommended for use in CRF cats (or in normal cats) due to the frequent development of severe hepatotoxicity following treatment in normal and diseased cats.
• Anemia may be treated with recombinant human erythropoietin if the PCV drops below 25 percent or when clinical signs warrant. Animals treated with Epogen (dosed at 75 to 100 U/kg subcutaneously three times weekly) have demonstrated resolution of anemia, weight gain, improved appetite, improved hair coat and improved sociability with their owners. Treatment is usually continued until the PCV reaches 30 to 40 percent, which often takes 8 to 12 weeks. Monitoring is important since 50 percent or more of cats on erythropoietin therapy develop antibodies against the drug. If this occurs, the hematocrit can rapidly fall and administration of the drug should be discontinued. It appears that the anti-EPO antibodies also cross react with whatever little native EPO is circulating in the cat's body. This means that the anemia could be considerably worse than before the EPO treatments were started. An alternate treatment for anemia is transfusion with either whole blood or packed red blood cells. This is reserved for severe anemia. Routine use of human recombinant forms of EPO cannot be recommended for all anemic CRF cats. This treatment is recommended ONLY for cats that are already transfusion dependent.
• During treatment with erythropoietin, iron supplementation is recommended. Oral ferrous sulfate (50 to 100 mg per cat per day) can be administered. Be aware that many cats do not like the taste of ferrous sulfate. It is advisable to measure the iron blood level prior to starting erythropoietin therapy and correct any deficiency before initiating treatment. Parenteral intramuscular iron may be better at correcting iron deficiency but injections are painful.
• Hypertension can be treated with atenolol (0.25 to 1 mg/kg BID to TID PO), enalapril (0.2 to 0.5 mg/kg SID to BID PO), diltiazem (1 to 2.25 mg/kg BID to TID PO) or amlodipine (0.625 mg per cat once daily). Amlodipine appears to be the antihypertensive agent of choice for cats.
• Calcitriol (1,25-dihydroxycholecalciferol is the most active metabolite of vitamin D) may be supplemented. Calcitriol synthesis is impaired with CRF and this contributes to hypocalcemia and to secondary hyperparathyroidism. Whether or not calcitriol supplementation reduces the rate of progression of chronic renal failure is controversial; there is no controversy that PTH levels are reversible during calcitriol treatments. Calcitriol must only be used after hyperphosphatemia has been adequately controlled otherwise there is undue risk for soft tissue mineralization.
• Aggressive in-hospital treatment has traditionally been given for three to five days, depending on the response and secondary causes. Some cases do benefit from considerably longer medical support before failure of a successful outcome. If treatment fails, dialysis or kidney transplant may be a treatment possibility. Referral is required for dialysis treatment. Dialysis is not usually considered as an option to maintain chronic renal patients unless transplantation is planned. Only a few veterinary colleges and referral practices perform renal transplantation. The required immunosuppression regimen is reasonable for cats though the surgery requires microvascular technique and a specialty team of internists and surgeons to allow long term successful outcome in selected cases.

LONG-TERM/HOME THERAPY

After being discharged, treatments will vary depending on the response to hospitalized therapy. Home administration of subcutaneous fluids can be helpful to correct mild dehydration and to provide a mild excretory boost from volume expansion. Doses will depend on the clinical signs and level of dehydration. Many cats do well on 100 ml of LRS or 0.9% saline 1 to 2 timed weekly; greater frequency is needed in some cats. Long-term drug therapy may include phosphate binders, potassium supplementation or antiemetic drugs for some patients. Dosage needs may change with the progression of the underlying renal disease. Epogen may be given for anemia two to three times weekly in those with severe and transfusion dependent anemia. Calcitriol can be considered for use in patients that are stable on dietary change and phosphorus binders.

The use of ACE-inhibition can be considered for use in cats with CRF that are otherwise stable. Specific studies as to beneficial effects have not been published as they have for dogs with protein-losing nephropathy. Benazepril is licensed for use in cats with CRF with or without primary glomerular disease in the European Union (results not published in peer-reviewed literature). Any benefits to the kidneys are thought to arise from decreases in intrarenal hemodynamics following efferent arteriolar dilatation. It is important to recheck the BUN and serum creatinine about one week after starting therapy to ensure that too much glomerular afterload has not been excessively reduced.

Dietary therapy may include a "kidney-friendly" diet that is low in protein, phosphorus, sodium and calcium as well as supplemented with potassium, alkali precursor and, in many instances, dietary lipids. Special diets are formulated for pets with chronic renal failure such as Hill's Prescription diet k/d, Purina's CNM NF-FORMULA, Iams Eukanuba Nutritional Kidney Formula/Early Stage, Eukanuba Nutritional Kidney Formula/Advanced Stage, Waltham's Low Protein and IVD Modified.

Nasogastric tube feedings can be useful in uremic cats during initial in-hospital stabilization. Longer-term management of anorexia and poor body condition can be successfully employed in many cats using PEG tubes for months or even years in some cats.

FOLLOW-UP CARE

Patient monitoring is an important part of continuing optimal treatment. Monitoring may include the following: serial body weight to facilitate proper fluid therapy and to evaluate nutritional adequacy (in addition to body and muscle condition scores); packed cell volume (PCV) and total plasma proteins to help monitor fluid load; and serial determinations of serum biochemistry are necessary to determine if the animal is responding to treatment. These will help determine proper fluid, nutrition, and drug therapy.

After discharge, biochemical analysis and urinalysis should be repeated within five to seven days to monitor status. If present, hypokalemia should be monitored weekly initially to decide on the appropriate long-term dose of potassium supplementation. CRF is variably progressive despite treatment. Euthanasia may be considered for pets that do not respond to treatment.

In those with systemic hypertension, blood pressure should be monitored every one to two weeks until under control. Then, the blood pressure should be monitored every two to three months.