Dennis J. Chew, DVM, DACVIM (Internal Medicine); Stephen P. DiBartola, DVM, DACVIM (Internal Medicine)
Cats are more often diagnosed with IRIS (International Renal Interest Society) Stage 1 (not azotemic) & 2 (minimally azotemic) chronic kidney disease (CKD) compared to dogs, though the serum creatinine at the time of diagnosis is quite variable. Many cats live for a long time (years) compared to dogs with CKD.
A surprising number of cats with recently diagnosed CRF in North America have been discovered to have simultaneous renal and/or ureteral urolithiasis. It is not clear whether the stone formation is causing renal failure, the renal failure is leading to stone formation, or they are independent processes (the same thing that is leading to the stone formation could also be creating renal failure directly). All cats with recently diagnosed CRF should have an abdominal radiograph to determine if upper urinary tract urolithiasis is part of the problem. Obstruction from these stones adds an element of post-renal azotemia on top of chronic primary renal azotemia. In these instances, often one kidney is big and one is small (so-called "big kidney little kidney syndrome"). Renal ultrasonography is very helpful in determining whether these stones are causing obstruction or not.
Differential Diagnosis of Chronic Renal Failure
Tubulo-interstitial nephritis of unknown origin is the most common cause of CRF in the cat, as in the dog. However, cats have several renal diseases that deserve additional consideration as compared to dogs, especially that for renal lymphoma, polycystic kidney disease, and chronic pyelonephritis.
Glomerulonephritis and Renal Amyloidosis
Primary glomerular disease appears to be less common in cats than in dogs as a cause for endstage renal disease. Chronic antigenemia from FeLV or FIV should be considered as a possible underlying cause in cats with glomerulonephritis. Amyloidosis is most common in Abyssinians, Oriental Shorthairs, and Siamese. Renal amyloid occurs sporadically in other breeds of cats, and there is great variability in the age of onset and severity of renal involvement. Amyloid is preferentially deposited in the renal medulla and to some degree, in glomeruli in 75% of affected cats. Proteinuria is a less reliable indicator of renal amyloidosis in cats than in dogs due to variable glomerular involvement. Since renal biopsies sample tissue from the cortex, medullary amyloid deposits are often missed, and glomeruli may not contain amyloid, which obscures the diagnosis. Biopsy may reveal changes of chronic interstitial nephritis and fibrosis associated with amyloid deposits.
Polycystic Kidney Disease
Polycystic kidney disease (PKD) is an important consideration in Persians and other longhair cats, whereas this is extremely uncommon in dogs. Cortical and medullary cysts continue to increase in number and size with age, leading to progressive loss of functional renal mass occupied by the cysts. All cats with PKD have at least one parent also affected with PKD (autosomal dominant inheritance). Renal ultrasonography is the imaging method of choice, and renal biopsy is not necessary. Renal cysts may be detected as early as 7 weeks of age; the absence of detectable cysts by 6 months of age usually indicates that the cat is not affected with PKD, though further evaluation at 1 year is recommended before entry into a breeding program.
Bilateral renal lymphoma is much more common in cats than in dogs. Renal lymphosarcoma (LSA) is a major differential for smooth or irregular enlarged kidneys in the cat. The kidneys may be the only organs affected with lymphoma, and FeLV status is often negative when the kidney is the only organ affected. Fine needle aspiration of renal tissue and cytology is usually adequate to diagnose LSA.
Hyperthyroid cats may develop azotemia, or display a worsening of azotemia following therapy to induce euthyroidism. Thyroid hormones have a supportive role for glomerular filtration rate (GFR) by increasing renal blood flow. Lessening the degree of hyperthyroidism results in decreased renal blood flow (RBF) and GFR, which unmasks azotemia in cats with marginal renal function. Some increase in serum creatinine concentration is expected following the development of euthyroidism, due to increased muscle mass.
If clinical signs related to hyperthyroidism are severe, an attempt at treatment is warranted. Cats with obvious azotemia, and those suspected of having renal disease, should be challenged with methimazole. An initial dose of 2.5 mg BID is given for 2 weeks, and serum biochemistry repeated to evaluate renal function and T4 levels. If renal function is stable, the dose is gradually increased every two weeks as needed, until T4 levels have entered the normal range. The dose can be increased to 2.5 mg TID, then 5 mg BID, and 5 mg TID, if needed. Methimazole is discontinued if renal function deteriorates during the methimazole challenge. If renal function remains stable, then long term methimazole can be considered, or more definitive treatment of hyperthyroidism provided by I-131 treatment or surgery.
Other Considerations for CRF in Cats
An estimated 20 to 30% of cats with CRF have positive urine cultures in large numbers with or without classical signs of urinary tract infection. Whether this occurrence of UTI is likely the cause for the chronic renal damage or is now a threat to create more upper urinary tract infection is not known. We take the position that a UTI poses a threat to kidney function should the infection be active in the kidneys and so should be treated. It has been assumed that bacterial UTI occurs in this setting because the kidneys no longer elaborate maximally concentrated urine that previously protected the urinary tract from infection.
Vaccines developed against feline herpesvirus, calicivirus and panleukopenia virus are often raised in a feline kidney cell line. Parenteral, but not intranasal or intraocular, inoculation with these vaccines has been shown to result in the production of antibodies against this cell line and feline renal cell lysates in cats. No evidence for the development of renal disease was found in initial studies. Interstitial nephritis was documented, however, in cats following sensitization and booster injections with renal cell line lysates. It is not known how important the role, if any, for vaccine-induced antibodies directed toward renal cell antigens and development of chronic renal injury in cats.
Food associated renal failure (FARF) can be a cause for CKD/CRF but we are not certain how commonly this occurs. Kaliopenic nephropathy is still occasionally the cause for CRF in cats but less so since the pet food industry added additional potassium salts to commercial pet foods. Acute renal failure related to contaminated foods was reported in cats and dogs of North America during early 2007, apparently related to dynamics of melamine and cyanuric acid from supplements. Though acute renal failure was dramatic in some of these cats, similar processes could create subacute or chronic renal injury. The degree of vitamin D supplementation in many commercial cat foods is worrisome as to a potential role for chronic renal injury remembering that hypercalciuria is an early toxic effect of too much supplementation. One epidemiological study discovered increased risk for CRF in cats with ad libitum feeding--increased dietary fiber, magnesium, protein and sodium were associated with decreased risk for CRF in cats.
Treatment of Chronic Renal Failure
General goals for management of CRF are the same as for dogs (reduce uremic signs, provide optimal nutrition, retard the progression of CRF, and provide endocrine replacement when possible). Dietary management of CRF in cats is somewhat different in that cats require a higher level of dietary protein intake and seem more prone to malnutrition during use of diets that are restricted in dietary protein.
The feeding of "renal-friendly" veterinary diets has been shown in several studies of clinical cats to exert a positive effect on survival times and fewer numbers of uremic crises. The survival times was 16 months for cats with CRF that were eating any of 7 renal kidney diets compared to 7 months when maintenance foods were fed. What exactly in these renal diets confers the extension in life is not known. Traditionally, benefits of such diets are attributed to the well-known protective effects of dietary phosphorus restriction (with or without lowering of PTH). Recent support has developed that those diets with higher eicosapentaenoic acid content confer further protection.
Renal diets may provide sufficient dietary phosphate restriction during early stages of CKD but often dietary phosphate binders are needed. Diet and binders should be prescribed to effect of serum phosphorus and PTH levels. Normal serum phosphorus concentrations are desirable but do not guarantee that PTH is normal. Chitosan in combination with calcium carbonate has been marketed as a phosphate binder for cats in recent years (Epakatin, Vetoquinol)--one study in chronic renal failure cats has shown an effect of this product to lower serum phosphorus in those eating a normal diet after 35 days. Lanthanum carbonate is a potent phosphate binder that appears to be an emerging favorite phosphate binder in human nephrology, but there are no reports of its use in cats yet.
Management of Systemic Arterial Hypertension
Systemic hypertension occurs in 20 to 65% of cats with chronic renal failure when determined by methods that indirectly measure blood pressure. Levels of serum potassium have been negatively correlated with the development of hypertension in cats with CRF. The correlation of unregulated arterial hypertension to the progression of CRF has not been established in cats, but there are some preliminary studies in dogs and humans that suggest a positive relationship. It is likely that high systemic blood pressure is transmitted to the glomerular vessels, which promotes their injury. Cats that have systemic hypertension from a variety of causes have been shown to survive longest when their blood pressure is well controlled based on a recent study.
Candidates for antihypertensive therapy include those with systolic blood pressure readings consistently above 170 mm Hg, and those with abnormally high blood pressure readings that also have fundic lesions consistent with hypertensive retinopathy (retinal edema, intraretinal serous exudation, retinal hemorrhages, arterial tortuosity, retinal detachment). The calcium channel blocker, amlodipine, has been used orally at a dosage of 0.018 mg/kg, or 0.625 to 1.25 mg per cat per day. Side effects from antihypertensives include hypotension and reduced blood flow to the kidneys. Hypertension should not be treated unless access to serial measurement of blood pressure is available.
ACE-Inhibition and Anti-Proteinuric Treatments
The detection of proteinuria is a diagnostic index in cats with CRF. Based on the theories of glomerular hypertension that occur in "super nephrons" of the adapted kidney, protein gaining access to tubular fluid and the mesangium is also a creator of further renal injury. The magnitude of proteinuria is a function of the integrity of the glomerular barrier, GFR, tubular reabsorptive capacity, and effects from elevated systemic and intraglomerular blood pressure.
Cats with CRF increased their risk for death or euthanasia when the UPC was 0.2 to 0.4 compared to <0.2 and was further increased in cats with UPC of >0.4. The prognosis for survival is influenced by the UPC despite what has traditionally been thought to be low-level proteinuria. The effect of treatments that lower proteinuria on survival have not been specifically studied.
Since even low-level proteinuria is a risk factor to not survive, it is prudent to consider treatments that lower the amount of proteinuria in those with CKD and CRF. Benazepril has been shown in two recent clinical studies to reduce the UPC in cats with CRF. Cats treated with benazepril in one study did not progress from IRIS stage 2 or 3 to the next stage as rapidly as those treated with placebo but over 6 months. CRF cats of another study that had a UPC of 1.0 or greater survived much longer when treated with benazepril than with placebo; no difference in survival was seen in those cats with a UPC less than 1.0.
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