Felipedia

Kidney disease is one of the most common diseases seen in older cats. It commonly occurs in cats over ten years of age, although it can occur at younger ages. Although there are many causes to kidney disease, such as genetic ( polycystic kidney disease, amyloidosis), potassium depletion neuropathy and lymphosarcoma, many times it occurs as a result of age, and in some cats because of their reluctance to drink much water. The kidneys are vital for cat health. They maintain the water balance, excrete bodily toxins and regulate blood hormone levels. When the kidneys begin to fail, the amount of urea, hormones and electrolytes (especially potassium) rise sharply. Also, renal secondary hyperparathyroidism is an important complication of chronic renal insufficiency.

The common symptoms in early kidney disease (as shown in stage 2 in the diagram) are very subtle, and can include weight loss, a fish/urine breath (because of increased urea in blood), reduced appetite (finicky eater), vocalising (meowing a lot) and increased restlessness, such as wandering around the house at night. Thirst is not a good indicator of kidney disease as some cats will drink more and some won't, but increased thirst is a common sign in many cats with this disease. Some cats will take to drinking from the shower cubicle or bath, or even from the goldfish bowl!

Blood tests at this stage can be inconclusive since more than 70% of kidney function has to be lost before any increases in urea and creatinine are seen in a blood test. At this stage, an ultrasound may be helpful, and many cats at this stage of kidney disease show reduced kidney mass, reduced tissue density or the presence of cysts in the kidney on ultrasound. A blood test using Azostix® (which can be done during a consultation) can detect subtle rises in blood urea and may be the only suggestion of kidney disease in the earlier stages. Testing of urine for protein ( proteinuria) and comparison of urine protein:creatinine ratios are a reliable clinical tool to assess renal function.

As kidney disease progresses (see above diagram), appetite becomes significantly reduced. The cat begins to show dramatic weight loss, and because of increased blood levels of urea, may become more vocal, follow the owner more closely and be more restless at night. Vomiting during or after meals is also a common symptom.

At this stage, blood levels of urea and creatinine are usually elevated above normal and a diagnosis by your veterinarian is not difficult to make.

Recently, the International Renal Interest Society (IRIS) developed a four stage system for gauging the continuum of progressive renal disease. Staging is based on the level of blood creatine as a function of renal competence.

Stage	1 - Non-azotaemic renal disease	2 - Mild renal azotaemia	3 - Moderate renal azotaemia	4 - Severe renal azotaemia

Creatinine (mmol/L)	<140	140 - 250	251-440	440
Clinical signs	None	+/- inappetence, weight loss, PU/PD	inappetence, weight loss, PU/PD	uraemia, clinically ill
Progression	Stable for long periods	Stable for long periods	May progress	Fragile
Therapeutic goals	Identify any disease, e.g. pyelonephritis, nephrolithiasis	Identify any disease, e.g. pyelonephritis, nephrolithiasis	phosphorus restriction, omega-3 fatty acids supplements	protein restriction, anti-emetics, erythropoietin, appetite stimulants, SQ fluid supplements, peritoneal dialysis

Blood pressure monitoring is also a crucial monitor of renal function. As renal function deteriorates, clearance of vasopressin from the plasma is reduced with consequent increase in circulating levels of this hormone, causing elevations in blood pressure.

Classification of blood pressure

NH - non-hypertensive - <150 mm Hg - no clinical complications

BH - borderline hypertension - 150-160 mm Hg - no clinical complications

Hnc - hypertensive, no complications - >160 mm Hg

Hc - hypertensive with non-renal complications - >160 mm Hg

As the disease becomes advanced, vomiting becomes more regular and the vomit itself may be dark red (claret coloured), suggesting the presence of minor stomach ulcers (a common secondary complaint with kidney disease). At this stage, your cat usually requires fluids because dehydration is a common problem and aggravates the symptoms. Normally fluids are given intravenously by the vet, but some cats can be given fluids subcutaneously (under the skin) as a cheaper alternative.

In experimental renal disease in rats, dietary protein restriction decreases intraglomerular pressure and retards the decline of renal function. Clinical trials of protein restriction in humans, however, have yielded variable results. Some studies have shown no benefit with regard to the rate of loss of renal function, whereas others have found that progression of renal disease is ameliorated by a low-protein diet.

Three studies have evaluated the effects of restriction of dietary protein and/or phosphorus in cats with induced kidney disease. Although Ross et al found significantly more renal morphological changes and greater serum phosphorus levels in cats with 5/6 nephrectomy fed a high-phosphorus diet compared with a low-phosphorus diet a corresponding decrease in glomerular filtration rate (GFR) was not correlated with these changes. In cats with 5/6 nephrectomy, Adams et al found that restricting dietary protein (to approximately 2.7 g/kg/day) and energy intake (to approximately 56 kcal/day) resulted in a significant decrease in morphological lesions compared with consumption of approximately 6.8 g protein/kg/day and 75 kcal/day. The GFR of the cats in this study was not significantly different between groups nor within groups. The study by Finco et al did not demonstrate morphological differences or changes in GFR between cats with 11/12 nephrectomy consuming different dietary protein levels (approximately 5.3 or 9.0 g/kg/day) and only minor differences in morphology when different caloric intakes were examined. Although evidence of morphological changes were observed in some cats in these studies, the GFRs in all groups remained stable over the 12-month period of study.

Beneficial effects of dietary modifications were observed in a nonrandomised, open clinical trial of 50 cats with naturally occurring CRI. Renal-related mortality in 29 cats fed a diet restricted in protein and phosphorus was approximately 33 per cent compared with 52 per cent mortality in cats fed an unrestricted diet. Overall, this dietary clinical trial identified a median survival time of 264 days for cats without dietary intervention, and a median survival time of 633 days for cats fed a diet modified for renal failure. A 24-month, randomised, double-masked, controlled clinical trial that evaluated the effects of dietary modifications on 45 cats with spontaneous CRI was completed recently at the University of Minnesota. Renal-related mortality in 23 cats fed an adult maintenance diet was 17.4%, although no deaths were observed in 22 cats fed a diet restricted in protein and phosphorus.

The results of these clinical trials support the early intervention with dietary modification in cats with spontaneous CRI. The question of timing of dietary intervention also is important. Traditionally, dietary intervention has been recommended based on haematological or biochemical values, or biochemical evidence of progression of the renal disease. Early dietary intervention may be particularly beneficial in cats with a long period of clinical quiescence during which minimal detectable progression is followed by abrupt deterioration in renal function. Given this pattern of disease progression, early dietary intervention before the onset of signs of uraemia may minimise progression of renal disease.

Elevated serum phosphorus concentrations are common is CRI and play a critical role in the pathogenesis of renal secondary hyperparathyroidism. A recent clinical trial demonstrated that control of serum phosphorus concentration, using dietary modification and oral phosphate binders, increased survival times in cats with CRI. Hyperphosphatemia inhibits the conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). This inhibition may be either a direct inhibition by the effect of elevated phosphorus of reduced renal mass and subsequent decrease in production of 1-alpha hydroxylase (enzyme responsible for conversion of vitamin D to calcitriol). The decreased levels of calcitriol lead to a decreased circulating ionised calcium concentration, which stimulates production of parathyroid hormone (PTH). High levels of PTH has a toxic effect on many systemic functions.

Dietary phosphorus restriction is indicated in all patients with an elevated serum phosphorus concentration. Dietary phosphorus restriction may be implemented in the early stages of CRI, because phosphorus retention and hyperparathyroidism likely are present even when the serum phosphorus concentration is within the normal range. The majority of commercial diets formulated for the treatment of CRI in cats have a restricted phosphorus content (<0.6% dry matter basis).

If hyperphosphatemia persists despite dietary phosphorus restriction, oral phosphate binding agents should be considered. The most commonly use phosphorus-binding agents are aluminium-based or calcium-based compounds that bind intestinal phosphorus in exchange for their cation. The phosphorus-binding agents should be administered at the time of feeding so that they may minimise absorption or ingested phosphorus.

Aluminium-based compounds (aluminium hydroxide, aluminium carbonate) are inexpensive, efficient phosphorus binders with minimal side effects in cats; however, declining use in human medicine because of neurological and bone toxicity with extended use is making them more difficult to find. Readily available calcium-based phosphorus-binding agents include calcium acetate, calcium carbonate, or calcium citrate. Calcium-based drugs have the potential to promote significant hypercalcaemia in cats, particularly when administered between meals or used in combination with calcitriol.

Dosages vary among patients and should be adjusted according to the target serum phosphorus concentration. The goal of dietary restriction and use of phosphate-binding agents is to keep serum phosphorus within the normal laboratory range. Recent studies in human beings indicate that maintaining serum phosphorus concentrations at the lower end of the reference range was superior to reducing serum phosphorus concentrations to the high end of the reference range. Furthermore, to prevent soft tissue deposition of calcium-phosphorus complexes, the product of calcium and phosphorus must be kept below 70.

Recently, polyallylamine hydrochloride (RenaGel, Geltex Pharmaceuticals, Waltham, MA), an aluminium-free and calcium-free phosphate-binding polymer, has been shown to bind dietary phosphorus effectively in human patients with CRI on maintenance hemodialysis. This polymer was comparable to calcium carbonate and calcium acetate in binding phosphorus without any changes in serum calcium concentrations. Preclinical studies in rats and dogs using several times the recommended dose resulted in reduced vitamin D, E, K and folic acid levels. Safety and efficacy information was not available for its use in cats. Polyallylamine hydrochloride may prove to be a safe and effective alternative to calcium salts for the managements of hyperphosphatemia in cats with CRI; however, controlled clinical trials are needed to prove its efficacy.

Systemic hypertension has been recognised commonly in association with many disease and has been implicated as a major determinant in the progression of CRI in human beings and dogs. A recent study of the prevalence of systolic hypertension in cats with CRI indicated that 20% of cats with CRI were hypertensive at initial evaluation. The general consensus among veterinary nephrologists is that systolic blood pressures exceeding 160 mm Hg may lead to end-organ injury and progression of underlying kidney damage. Hypertension therefore warrants detection and treatment.

Hypertension usually is a consequence rather than a cause of CRI in dogs and cats. Although microscopic renal lesions suggestive of hypertensive injury have been identified in the kidneys of dogs and cats, they do not develop the syndrome of hypertensive nephropathy encountered commonly in human patients. However, occasionally patients are presented with profound hypertension (<220 mmHg) in combination with rapidly deteriorating renal function. Although the hypertension may not be the underlying cause of the renal disease, it may contribute to a rapid decline in renal function and thus aggressive therapy is warranted.

Diagnosis of systemic hypertension should be based on arterial blood pressure determination using either direct or indirect methods. In the absence of end-organ damage, systolic blood pressure less than 200 mmHg generally do not require immediate therapy and should be confirmed on two to three successive clinic visits to ensure that the observed elevations in blood pressure are not the result of the transient 'white coat effect'. Cats with systolic blood pressures repeatedly greater than 160 mmHg should be treated to minimise the development of end-organ damage (e.g. retinal lesions) and progression of renal disease.

Because of its effectiveness, lack of side effects, and once-daily oral administration, the calcium channel blocker amlodipine currently is the antihypertensive drug of choice in cats. Amlodipine initially is prescribed at a dose of 0.625 mg/cat and may be increased to 1.25 mg/cat in larger patients or if the desired effect is not obtained at the lower dosage. If the blood pressure cannot be controlled with amlodipine, the addition of an angiotensin-converting enzyme (ACE) inhibitor should be considered.

In human beings, proteinuria has been identified as an independent risk factor for the progression of CRI. The magnitude of proteinuria is related inversely to median survival times, Proteinuria also appears to be a risk factor for progression of CRI in cats and may be associated therefore with decreased survival times. Therapy for proteinuria in human beings traditionally has involved ACE inhibitors, which have been shown to reduce the magnitude of proteinuria and increase survival times.

A recent 3-year clinical trial demonstrated that treatment with an ACE inhibitor did reduce the quantity of protein significantly in the urine of cats with spontaneous CRI. However, this reduction in protein was not associated with a significant increase in median survival times, In another study, urine protein:creatinine (UPC) ratios were useful as a predictor of survival times in cats with spontaneous CRI. In this study, median survival times for cats with UPC less than 0.43 was 766 days, whereas median survival times for cats with UPC greater than 0.43 was only 281 days.

Treatment of kidney disease can prolong the life of your cat, but the disease usually continues. Low protein diets, antibiotics and blood pressure tablets help slow the progress of disease. A cat that has been diagnosed with kidney disease lives on average between three and twelve months, depending on how severe the disease is at the time it is diagnosed.

In acute renal insufficiency and in mild to moderate renal insufficiency, restriction of dietary protein may limit the kidney's compensatory response to injury. Protein restriction may also lead to protein malnutrition, which impairs immunological responses, decreases haemoglobin production (thus promoting anaemia), decreases plasma protein levels and promotes muscle wasting. Inadequate protein also decreases urinary excretion of magnesium; this may result in CaPO₄ precipitation in the kidneys. It is important for cats with mild to moderate renal insufficiency to maintain caloric intake in order to avoid protein-calorie malnutrition. Monitoring for protein-calorie malnutrition should include monitoring for weight loss, hypoalbuminaemia, poor coat quality and muscle wasting.

Cats are metabolically adapted to use protein and fat for energy production and for maintenance of blood glucose concentration even when sources of protein in the diet are limited. As a result, the protein requirement of cats is more than twice that of dogs.

Restriction of protein and phosphorus are required in order to avoid uraemic complications. Benefits of protein restriction are related to non-renal effects (toxins affecting other organs). Using protein sources of high biological value is important. Protein restriction may be especially harmful in renal patients who are inappetant, as sustained calorie deficit causes body proteins to be catabolized to supply caloric needs and nitrogenous end products of this process will further accentuate uraemic signs. Inappetence is an indication for avoiding protein-restricted diets. Uraemia is associated with variable dietary intake, intestinal malabsorption, metabolic acidosis and co-morbid conditions, which independently influence nitrogen balance. Reliance on BUN as predictor may fail to adequately define nutritional status.

Phosphorus intake should be restricted in moderately azotemic patients; this is more important than protein restriction to survival and has been shown to produce less severe renal lesions. The literature dose of phosphate binders may be too low; increase as necessary to produce consistent serum phosphorus levels within normal ranges. If using calcium based phosphate binders, watch the serum calcium levels carefully and switch to or combine aluminium based phosphate binders if necessary. For these agents to be effective, they must be given with food. They act by binding the phosphorus in the ingested food, making it unavailable for absorption into the body. Epakitin™ (containing chitosan) is a new product designed as an alternative to feeding renal diets as a method to reduce serum phosphorus.

Calcitriol use is still controversial in that some researchers feel that its use is more urgent than other workers do. Advocates of calcitriol suggest that it should be started at 2.5-3.5 ng/kg/day in early renal insufficiency when serum Calcium is 2-3 mg/dL. In these patients, the PTH (parathyroid hormone) levels are often normal and the calcitriol is used to prevent PTH increase to slow progression of the renal insufficiency and prevent symptoms related to PTH toxicity. In patients with a serum creatinine of >3 mg/dL and serum phosphorus <6 mg/dL, the dose of calcitriol is 3.5 ng/kg/day PO. The baseline PTH in these patients is useful since the levels are commonly elevated and may require higher doses of calcitriol. The Ca X P product must be <60. If hypercalcemia is detected, a week of discontinued calcitriol will allow determination of whether or not the medication is the cause. Hypercalcemia may be due to inadequate calcitriol rather than too much. This relates to the control calcitriol exerts on the 'set point' for PTH secretion. Serum creatinine should be monitored on a regular basis (q 1-3 months)

Erythropoietin (EPO) will cause rapid correction of anaemia by stimulating marrow progenitor cells. Consider using EPO when PCV is <20%: dose with 75-100 U/kg SQ three times per week until PCV is low normal (35%), then reduce dose and frequency to 50-75 U/kg SQ two times per week. It is important to monitor PCV and blood pressure, due to the direct vasoactive effects of EPO, every two weeks for the first 60-90 days to detect development of anti-EPO antibodies should they occur. If they do, cease EPO immediately. The cat may be transfusion-dependant for 2-4 months until antibody levels decrease. It is also important to administer iron at the start of the regime and until appetite is good. While there is a risk of antibodies to EPO developing, the majority of cats will enjoy the benefits of an improved hemogram.

Metabolic acidosis promotes severe catabolism of endogenous proteins, exacerbates azotemia regardless of diet, promotes wasting (degradation of protein), inhibits protein synthesis, causes a negative nitrogen balance and enhances hypokalemia, Acidosis should be aggressively corrected through fluid therapy and H₂ receptor antagonist use.

Potassium loss is due to polyuria. i.e polyuria -> increased K loss in urine. Dietary acidification -> acidosis -> shifts K out of cells into extracellular compartment (including serum) thus giving a falsely elevated/normal serum K. It is critical to eliminate acidosis. If total CO₂is < normal, treat with NaHCO₃ 8-12 mg/kg PO bid or K citrate 15-30 mg/kg (2.5 mEq) PO bid. Potassium supplementation (K gluconate 2-4 mEq PO bid) may be considered after acidosis is corrected.

Uraemic gastritis in many cats shows as partial anorexia, or nausea rather than outright vomiting. H₂ receptor antagonists are under-utilised; they function by preventing gastric HCl acid production. Famotidine 0.5mg/kg PO q 24-48 hrs or ranitidine 2-3 mg/kg q12 hrs PO may be considered whether cats seem nauseous or not.

Blood pressure should be closely monitored in CRI cats. Cats with CRI lose normal auto-regulatory capacity of the glomerular arterioles. This may not only cause systemic hypertension (50% of cats with CRI) but also promote progression of renal insufficiency through glomerular injury. Treatment of hypertension should be considered in cats whose systolic BP is consistently > 80 mm Hg. Amlodipine (Norvasc) is the most efficacious agent (0.625mg/cat PO q12-24 hrs) as it has direct effect on the calcium channels of the peripheral vasculature. Angiotensin-converting enzyme (ACE) inhibitors will have overall effect of reduced vasoconstriction of efferent arterioles that can increase overall renal flow, reduce glomerular hypertension (beneficial in the case of renal protein loss) but can at the same time reduce driving force for GFR by which we may create, in essence, a pre-renal azotemia. If ACE inhibitors are used, monitor BUN and creatinine after 1 or 2 doses and respond accordingly. Beta-blockers reduce renin secretion, which will have the same net effect.

Ace inhibitors, particularly benazepril have undergone a large multi-institutional study to assess its effects on CRI in cats. Results of this and other smaller studies show that using benazepril or placebo didn't make any significant difference in survival time for all CRI cats. For cats with urinary protein loss (urine protein: creatine >0.4), benazepril-treated cats had longer survival times and better appetite than placebo treated urinary protein-losing cats. Cats without a protein-losing glomerulonephropathy may potentially be harmed by using this agent as its action is to divert renal blood resulting in a beneficially increased renal blood flow rate but a potentially deleterious reduction in glomerular filtration rate. Cats with an increased urine protein:creatinine ratio (>0.4) who are started on this medication should be rechecked within 3-7 days and have their renal parameters, hydration, body weight, appetite and overall health monitored. Thereafter, re-evaluation should occur every 2-4 months in a stable patient.

Azodyl™ is a probiotic/prebiotic combination similar to a probiotic/prebiotic combination marketed for human patients under the brand name of Kibow Biotics. According to the company literature, these agents are generally recognised as safe. Azodyl is used to reduce azotemia and uraemia in human patients with CRI. It is composed of bacteria predisposed to metabolising urea, creatinine, phosphate, uric acid, various carcinogenic amines, guanidine and indole metabolites. The bacteria are selected or possible genetically modified to display these characteristics. The specific bacterial species are Enterococcus thermophilus, Lactobacillus acidophilus and Bifidobacterium longum. The prebiotic component comprises various small sugars (oligosaccharides) that selectively stimulate growth of specific bacteria in the colon - namely bifidobacteria. Azodyl is claimed to work by enteric dialysis; a process of extracting urea and other substances from the enteric circulation or from the intestinal tissues. This reduces the concentration of circulating urea. What must be remembered is that while azotemia is defined as the increase in serum levels of urea and creatinine, these substances are markers for a decrease in renal function, but are not responsible for the cat feeling poorly.

The company suggests the following dosing protocol: 1 tab / 2.5 kg PO oid. The company recommends concurrent use of Epakitin in cats with azotemia and hyperphosphatemia.