Chronic renal disease
From Felipedia
Chronic renal disease (CRD) is one of the most common diseases seen in older cats, reportedly affecting one in three cats over the age of 12 years[1].
CRD can appear as acute renal failure or as an insidious chronic renal insuficiency, which is more common. CRD 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[2].
Glomerular capillary hypertension, hyperfiltration and mild proteinuria have been reported in cats following mass renal reduction. This leakage of protein into the glomerular filtrate has been implicated in causing renal pathology[3].
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Causes
The most common cause of chronic renal disease in cats is the slow and insidious age-related syndrome of nephritis. Although there are a multitude of possible etiologies, improper diets and over-vaccination are incriminated as insults that hasten the end result, renal failure.
1.Congenital
- - Polycystic kidney disease in Persian and Himalayan cats
- - Amyloidosis in Abyssinian and Oriental shorthair cats
- - Fanconi syndrome
2. Acquired
- - Degenerative (age-related - most common; due to chronic interstitial nephritis)
- - Secondary to acute renal failure
- - Immune complex glomerulonephropathy
- - Feline leukemia virus
- - Mycoplasma spp polyarthritis
- - Neoplasia associated
- - Lymphosarcoma
- - Renal cell carcinoma
- - Nephroblastoma
- - Others
- - Infectious
- - Bacterial
- - Chronic pyelonephritis
- - Leptospirosis
- - Viral
- - Fungal
- - Bacterial
- - Mechanical
- - Nephrolithiasis
- - Spey granuloma
- - Perinephric pseudocysts
- - Idiopathic renal disease
Clinical signs
The common symptoms in early kidney disease are very subtle, and can include weight loss, intermittent anorexia, vomiting and halitosis. There may be psychological effects referable to uraemia, including increased vocalising (uremic encephalopathy) and increased restlessness, such as wandering around the house at night. Polydipsia is not a hallmark sign, since many cats are poor drinkers. Vomiting may be regular (daily) and contents may be blood-tinged or coffee-colored due to low grade uraemic gastritis[4].
Blood tests at this stage can be inconclusive since more than 70% of kidney function has to be lost before any changes in urea, creatinine or phosphate levels is seen. Hypokalemia occurs in about 20% of cats with chronic renal disease.
Testing of urine for protein ( proteinuria) and comparison of urine protein:creatinine ratios are a reliable clinical tool to assess renal function. Studies suggest that a urine protein:creatinine ratio of <0.4 is the upper reference range and cats with UPC values greater than 0.4 have a four times higher risk of death[5].
Recently, the International Renal Interest Society (IRIS staging system) has developed a standard 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 azotemia | 3 - Moderate renal azotemia | 4 - Severe renal azotemia |
| 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 CRD 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.
Diseases which need to be considered in any differential diagnosis of chronic renal disease include ureteral calculi, Feline lower urinary tract disease (FLUTD), Feline upper urinary tract disease (FUUTD), renal lymphosarcoma, renal carcinoma, acute pyelonephritis (immune-mediated, bacterial, viral, fungal), ureteral neoplasia and Leptospirosis.
Treatment
- Diet
The effect of a modified protein, low-phosphate diet on cats with stable, naturally occurring stage II/III CRD have been reported as beneficial[6], with survival rates nearly double that of standard diet-fed cats (633 days on low-protein diet versus 264 days with normal diet-fed cats).
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[7].
2. Hyperphosphatemia
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), and Lantharenol (lanthanum carbonate; Bayer Health Care), which are aluminium-free and calcium-free phosphate-binding polymers, have 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.
3. Hypertension
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 besylate 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.
4. Proteinuria
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
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.
i) Acute renal insufficiency / mild - moderate renal insufficiency
- Dietary considerations
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.
- Fluid replacement.
Cats with mild renal insufficiency often present with dehydration. Replacement of fluids by subcutaneous injection of fluids are sufficient to maintain fluid balance in the short term (months). Wekkly or twice weekly doses of approximately 100ml saline of sodium glucose solutions work well in rehydration of cats and is relatively quick and inexpensive to perform.
ii) Moderate to severe renal insufficiency
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 CO2 is < 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.
See also...
Further Reading
1. Feline Chronic Renal Failure Information Centre
2. Tanya's Chronic Renal Failure UK.
3. Technical veterinary information on chronic renal failure
References
- ↑ Lulich, JP et al (1992) Feline renal failure: questions, answers, questions. Compend Contin Educ Pract Vet 12:127
- ↑ August, JR (2006) Consultations in Feline Internal Medicine, Vol 5. Elsevier Saunders
- ↑ Brown, SA & Brown, CA (1995) Single-nephron adaptations to partial renal ablation in cats. Am J Physiol 269:R1002
- ↑ Elliott, J & Barber, PJ (1998) Feline chronic renal failure: clinical findings in 80 cases diagnosed between 1992 and 1995. J Small Anim Pract 39:78
- ↑ Syme, HM et al (2006) Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Int Med 20:528
- ↑ Elliott, J et al (2000) Survival of cats with naturally occurring renal failure: effect ofconventional dietary management. J Small Anim Pract 41:235
- ↑ Elliott, DA (2010) Nutritional management of chronic kidney disease. In August, JR (Ed): Consultations in feline internal medicine. Vol 6. pp:137
