Chronic kidney disease in cats

Transcription

1 Vet Times The website for the veterinary profession Chronic kidney disease in cats Author : Julien Bazelle, Penny Watson Categories : Vets Date : October 15, 2012 ABSTRACT Chronic kidney disease is a common disease in cats with an increasing prevalence with age. Causes of renal damage are variable and include inflammatory, infectious, neoplastic or mechanical lesions. Eventually, any patient will progress to severe chronic kidney disease with irreversible loss of renal function. The severity of chronic kidney disease is now classified according to the degree of elevation of serum creatinine and the presence or absence of systemic hypertension and proteinuria following the IRIS classification scheme. Management aims to decrease the systemic consequences and reduce progression of the renal disease. Dietary management and maintenance of hydration are important in the treatment of chronic kidney disease. Drugs can be used in combination with diet to improve the control of hyperphosphataemia, hypertension, proteinuria, nausea, urinary tract infection or anorexia. Negative prognostic factors recognised in the cat with CKD are presence of proteinuria, increasing IRIS stage, anaemia and hyperphosphataemia. Key words: cat, chronic kidney disease, treatment, prognostic, staging CHRONIC kidney disease (CKD) is a common clinical problem, with a prevalence of one per cent to three per cent out of the feline patients presented to veterinarians (DiBartola, 1987; Polzin, 2011). CKD is defined by the presence of functional and/or structural abnormalities of the kidneys for more than three months (Polzin, 2010). CKD is a progressive and most often irreversible disease that eventually leads to severe systemic complications. 1 / 8

2 Recent research has mainly focused on the factors influencing progression of the disease, and on the developing therapies notably dietary management of CKD patients. This article reviews the knowledge on causes, pathophysiology and treating feline CKD. Epidemiology After exclusion of congenital causes, multiple studies show a greater prevalence of CKD in geriatric cats. In a prospective study in 1998, the mean age for feline CKD was found to be 12.6 years, with a range of one to 26 years (Elliot, 1998). In a retrospective study, prevalence of CKD was 1.6 per cent for cats of all ages, 7.7 per cent for cats more than 10 years old and 15.3 per cent for cats more than 15 years old (DiBartola, 1987). In a more recent prospective study performed in Australia, 71 per cent of the cats with CKD were more than 12 years old (White, 2006). The same study reported male cats with CKD were significantly younger than female cats with the condition (White, 2006). Previous studies failed to show similar predisposition (DiBartola, 1987; Elliot, 1998; Ross, 2006). Breed predispositions were suggested by some authors with Maine coon, Abyssinian, Siamese, Russian blue, Burmese, British shorthair, Birman, Somali and Angora cats being overrepresented (DiBartola, 1987; Ross, 2006), although CKD is also common in domestic shorthairs. Initiating factors and progression A variety of initiating factors can induce renal lesions with loss of functional nephrons. Due to the persistent effects of the initiating factors or factors independent of initial damage, the number of functional nephrons can decrease under a critical threshold. Under this threshold, renal adaptive responses, while initially advantageous, become deleterious and induce further nephron loss. This is called spontaneous progression of CKD (Polzin, 2011). With time, recruitment of inflammatory cells and induction of endothelial-mesothelial differentiation with transformation of tubular endothelial cells into myofibroblasts initiate glomerulosclerosis, interstitial nephritis and fibrosis (DiBartola, 1987; Arata, 2005; Yabuki, 2010). Initiating factors are diverse, but it is rare to be able to diagnose the origin of CKD, as patients are presented in a late stage of the disease. Amyloidosis is probably the most common familial cause of CKD in cats, accounting for two per cent of biopsy results in azotaemic cats (Minkus, 1994). Abyssinian, Siamese and Oriental shorthair are significantly more affected (Boyce, 1984; Godfrey, 1998; Greco, 2001). Polycystic kidney disease can uncommonly be associated with CKD if residual functional renal tissue is affected by the presence of the cysts (Greco, 2001; Volta, 2010). With 2 / 8

3 development of genetic testing and improvement in ultrasonography technique, polycystic kidney disease is likely to become less common in practice, and most frequent ultrasound findings include loss of corticomedullary definition, small and irregular kidneys and mineralisations ( Figure 1 ). Renal dysplasia is a rare condition, leading to CKD in cats (Greco, 2001; Aresu, 2009). Renal lymphoma is still a major cause of feline CKD, representing 11 per cent of the biopsy results in azotaemic cats (Minkus, 1994). Other primary renal tumours are reported in cats (Henry, 1999). Infectious diseases have been investigated as potential causes of CKD in cats. In a recent study, young patients with CKD were more likely to have positive results for serum antibodies against feline immunodeficiency virus (FIV; White, 2010). However, the direct role of FIV in the development of CKD was unclear. Another study failed to find an association between CKD and seropositivity for Encephalitozoon cuniculi and Toxoplasma gondii (Hsu, 2011). Leptospira species infection is another possible cause. Although serology studies report a seroprevalence of 10 to 30 per cent, cats are resistant to leptospirosis, and it is unknown if Leptospira species infection is associated with significant renal damage in cats (Mylonakis, 2005). Chronic pyelonephritis is described as a common cause of CKD progression, but evidence is lacking to prove it is a common cause of CKD (Ross, 2006; Mayer-Roenne, 2007). It is not uncommon to diagnose CKD and hyperthyroidism concurrently in a geriatric cat. The comcomitant presence of hyperthyroidism can complicate the diagnosis of CKD, as hyperthyroidism is associated with increased glomerular filtration rate (GFR). This can mask CKD, which may be revealed after treating for hyperthyroidism (Becker, 2000). This is seen in 15 per cent to 20 per cent of treated hyperthyroid cats, with medical treatment as well as surgical or radioiodine therapy. Medical treatment is reversible and is, therefore, recommended before any definitive treatment to monitor the evolution of the renal function. Ureteroliths are an increasingly recognised cause of CKD in cats. Even if bilateral ureterolithiasis is more frequently associated with renal failure, 76 per cent of cats with unilateral ureteral calculi are azotaemic, indicating impairment of the renal function of the controlateral kidney or prerenal azotaemia (Kyles, 2005). Most often, these ureteroliths contain calcium oxalate, but dried solidified blood ureteroliths are now frequently recognised (Westropp, 2006). Interestingly, a retrospective study on cats with mild or moderate CKD found no association between the presence of nephrolithiasis and decreased survival or CKD progression (Ross, 2007). Use of NSAIDs has been incriminated as the cause of acute renal failure in cats (Khan, 2012). However, their use in stable CKD cats to control concomitant painful conditions has not been associated with decreased survival (Gowan, 2011). This list of potential causes for CKD is not exhaustive. Despite that, it is important to remember the original cause for CKD remains unknown in most of the cases. 3 / 8

4 Diagnosis and clinical staging The International Renal Interest Society (IRIS) has introduced a staging system for classifying the severity of feline CKD, based on the serum creatinine in a stable patient ( Table 1 ). CKD cats are further classified according to their systolic blood pressure ( Table 2 ) and presence or absence of proteinuria ( Table 3 ). In stage one (non-azotaemic cats), evaluation of GFR may help detect early kidney damage. Recently, determination of GFR by evaluation of exogenous creatinine clearance has been simplified using only two blood samples at 30 minutes and between 198 and 222 minutes after injection (Vandermeulen, 2010). Iohexol clearance measurement is another way to determine GFR in cats, and reference ranges for both creatinine and iohexol clearance have been published (Heiene, 2009). However, a study suggests a significant difference in the GFR results between clearance techniques exists and this variability must be taken into account (Van Hoek, 2009). Other diagnostic investigations required for a CKD patient in addition to assessment of blood pressure and proteinuria include investigations for the initial causes of CKD and the systemic complications associated with CKD, including anaemia and electrolyte imbalances and ruling out urinary tract infections. Clinical and clinicopathological consequences The most frequent signs of CKD in cats include polyuria and polydipsia, weight loss and lethargy (Elliot, 1998; Ross, 2006). Other signs frequently described include gastrointestinal disease, anorexia, halitosis and signs of hypertension. Loss of renal function is first associated with impaired water reabsorption, which leads to polyuria and compensatory polydipsia. Frequently, at the time of diagnosis, dehydration is detected. Systemic hypertension is observed in 20 per cent to 60 per cent of CKD cats at any stage of the disease (Kobayashi, 1990; Syme, 2002). Hypertensive damage can be observed in extrarenal end organs, such as the retina, central nervous system or heart, and hypertension may worsen the progression of the renal disease. Renal secondary hyperparathyroidism occurs early in the course of CKD and is reported in 84 per cent of cats with CKD. As might be expected, the degree of elevation of parathyroid hormone increases with the severity of renal disease and correlates with the elevation of phosphate (Barber, 1998). Systemic implications of renal secondary hyperparathyroidism include mental dullness, muscle weakness and immunodeficiency (Polzin, 2010). It is also thought to be an important contributor to the progression of CKD (Elliott, 2000). 4 / 8

5 Anaemia is detected in 30 per cent to 65 per cent of cats with CKD (Chalhoub, 2011). The origin of anaemia in CKD patients is multifactorial, with a combination of decreased erythropoiesis due to a lack of erythropoietin (EPO), shortened red blood cell survival due to uraemic toxins and increased red blood cell loss from gastrointestinal bleeding, which can also induce iron deficiency. Anaemia is a frequent cause of weakness in severe CKD patients, and can be associated with haemodynamic compensatory mechanisms, resulting in volume overload and secondary cardiac hypertrophy (Wilson, 2010). Metabolic acidosis is a frequent complication of severe CKD (stage four), and is relatively less common in earlier stages. A study reported a frequency of 52.6 per cent in cats with stage four, 15 per cent for cats in stage three, and zero per cent in stages one and two (Elliott, 2003). Metabolic acidosis results in anorexia, nausea, vomiting, lethargy and protein catabolism. Hypokalaemia is relatively prevalent in cats with CKD, with 20 per cent to 30 per cent of patients affected (DiBartola, 1987; Elliot, 1998). Muscle weakness and neck ventroflexion have been described in cases of severe hypokalaemia (Polzin, 2010). Less common complications of feline CKD include peripheral neuropathy, encephalopathy and platelet dysfunction. Treatment CKD treatment should aim to control the causal disease, to prevent or treat the complications of CKD and to reduce the rate of progression of the renal lesions. Whenever possible, specific treatment should be prescribed to limit further renal damage (Polzin, 2011). Unfortunately, at the time of diagnosis, it is uncommon to detect a cause for the CKD. Moreover, extensive and irreversible lesions are likely to be present and spontaneous progression is expected independently of the successful treatment of a specific aetiologic disease. Maintaining a correct hydration status is recommended for cats with stage two to four CKD (Polzin, 2009). If dehydration is noticed, intravenous fluid therapy with balanced electrolyte solution is preferred, to limit additional renal injury. Replacement should consider water lost by severe polyuria and vomiting. Serial measurements of potassium are required during intravenous fluid therapy, and supplementation should be adjusted as necessary ( Table 4 ). Correction of the dehydration most often resolves, and administration of bicarbonates or potassium citrate should be used cautiously, as their use can be associated with electrolyte imbalance as a result of rapid changes in ph. For stable and mildly dehydrated patients, improvement of the hydration status can be achieved by 75ml to 100ml of subcutaneous fluid administration at home daily or every other day (Grauer, 1998). For every patient, constant access to fresh water must be offered and causes that limit fluid intake should be controlled whenever possible, for example: nausea (see Figure 2 ), vomiting, diarrhoea and hot environmental conditions. 5 / 8

6 Providing adequate nutritional support is one of the most important components of managing of CKD in cats. Use of a specific renal diet has been demonstrated in different studies to more than double the survival time in cats with CKD and to decrease uraemic episodes (Elliott, 2000; Ross, 2006). The main modifications in these renal diets are protein and phosphorus restriction and use of high-quality proteins to reduce the amount of uraemic waste. A retrospective study comparing seven different commercial feline renal diets found that the diet associated with the longest survival had the highest omega 3 polyunsaturated fatty acid content, which may indicate some beneficial effects of these fatty acids (Plantinga, 2005). Home-made diets are variable in their nutritional adequacy. This often results in inappropriate coverage of the nutritional needs of CKD cats. It is not recommended to use home-made diets for long-term feeding of CKD cats unless they have been carefully formulated by a veterinary nutritionist to ensure phosphate restriction (Larsen, 2012). Optimal nutritional and hydration support can be achieved via placing a feeding tube in some animals. Oesophagostomy or, preferably, gastrostomy tube feeding are the most commonly used feeding tubes, allowing longterm management with good acceptance by the animal (Elliott, 2009). Phosphorus-binding agents can be given to cats where phosphorus levels cannot be controlled only by renal diet. The serum phosphate concentration should be measured about four weeks after the diet has been started, and phosphate binders added at this time if necessary (Barber, 1999). These agents trap phosphorus in the intestinal lumen and limit its absorption. Aluminium salts are efficient in reducing phosphorus serum levels, but can be associated with aluminium toxicity. New intestinal binding agents (sevelamer, chitosan and lanthanum) are more expensive but promising for treating unresponsive patients (Kidder, 2009). Consumption of food can be reduced due to the gastrointestinal signs experienced by cats with CKD: nausea ( Figures 2 and 3 ), vomiting, uraemic stomatitis and gastrointestinal bleeding. Treatment includes limiting gastric acidity using antacids (cimetidine, ranitidine or omeprazole), suppressing nausea (metoclopramide or maropitant) or providing mucosal protection (sucralfate). Administering appetite stimulants (such as mirtazepine) has been reported as safe in cats with CKD at a dose of 1.88mg every other day (Quimby, 2011) Anaemia is mainly caused by impaired erythropoietin production as a result of loss of functional kidney tissue. Use of erythrocyte-stimulating agents has been proven to be efficient in treating anaemia of renal disease and may improve the cat s quality of life. Recombinant human EPO was the first agent used in cats (Cowgill, 1998). However, anti-epo antibodies may develop after the use of recombinant human EPO, and these antibodies may crossreact with the endogenous EPO, leading to worsening of the anaemia. It is, therefore, recommended to use recombinant human EPO only in the late stage of the disease, when anaemia is associated with significant deterioration of the quality of life (Polzin, 2011). A recent retrospective study of the use of 1.0ìg/ kg/week of darbopoeitin, a recombinant EPO analogue, in CKD cats showed this treatment was efficient in increasing haematocrit and suggested a decreased risk of anti-epo antibodies formation, though more studies are required to confirm this (Chalhoub, 2012). Other causes of anaemia, such as gastrointestinal bleeding, must be investigated and treated accordingly. 6 / 8

7 Systemic hypertension must be identified and treated, if present, to avoid further renal damage and lesions to other organs. There is no evidence that dietary sodium restriction has an effect on hypertension in cats with CKD (Buranakarl, 2004; Xu, 2009). The calciumchannel blocker amlodipine is considered a safe and efficient monotherapy in cats (Mathur, 2002). If normotension is not achieved after treatment with amlodipine, it can be combined with an angiotensin-converting enzyme inhibitor (ACEi). ACEi should not be used as a monotherapy agent in CKD cats with hypertension, as the response is usually too small to be clinically beneficial (Brown, 2001). Recent recommendations indicate treatment of proteinuria must be started for every patient in stage one with a urinary protein-creatinine ratio (UPC) exceeding 2.0, and for every cat with stage two to four CKD with a UPC exceeding 0.4 (Lees, 2005). Benazepril has been associated with improved clinical signs and decreased UPC in cats, with initial UPC > 1.0 (King, 2006). In other studies of cats with CKD, the use of benazepril was associated with a delay in the progression of the disease and reduced renal hypertension (Watanabe, 2007; Mizutani, 2006). However, it is unclear if these beneficial effects do not concern only proteinuric cats, and serial measurement of serum creatinine is required during treatment with an ACEi as these drugs can decrease the GFR and induce acute renal failure (Lefebvre, 2004). If an increase in creatinine is noted after started ACEi, they should be stopped immediately or the dose lowered. Calcitriol therapy has been used to reduce renal secondary hyperparathyroidism in human and canine CKD patients. To date, several studies failed to show significant benefit in the use of calcitriol in cats, and the optimal dose for this species is still unknown (Hostutler, 2006; Polzin, 2009). Its use remains controversial. Some authors do not advocate it because of the potential for precipitation of calcium salts in the face of a high serum phosphate, and argue that control of serum phosphate alone is enough to reduce hyperparathyroidism (Barbe, 1999). Urinary tract infections occur relatively frequently in cats with CKD, with a reported prevalence of 22 per cent (Mayer-Roanne, 2007). Diagnosis and control of secondary infections should be based on urinary culture and sensitivity. It has been proven that antibiotic sensitivity varies markedly over time, even in cases of persistent or relapsing urinary tract infections, and it is, therefore, recommended to regularly request culture and sensitivity of the urine. A review of the use of the drugs used in managing feline renal patients is shown in Table 5. For drugs excreted by urine, doses may be decreased, or the interval between two doses should be increased to avoid significant drug accumulation and toxicity. Prognosis CKD in cats is usually a slowly progressive disease, and some patients may die from another 7 / 8

8 Powered by TCPDF ( disease before showing signs of progression (Chakrabarti, 2012). Despite appropriate treatment, most of the patients will eventually progress to higher CKD stages. Some laboratory findings have been associated with decreased survival or increased rate of progression of the disease in cats. Survival time depends on the severity of the CKD, and increasing the IRIS stage is associated with decreased survival: cats with stage two have a median survival time of three years, two years for cats in stage three and four months for cats in stage four (Kuwahara, 2006; Boyd, 2008). Presence of proteinuria is a strong and independent negative prognostic factor (Syme, 2006; King, 2007; Chakrabarti, 2012). Other negative factors include increased blood leukocyte count (King, 2007), anaemia and hyperphosphataemia (Chakrabarti, 2012), and urinary tract infections (Mayer Roanne, 2007). Therapeutic management of these negative factors may increase survival in CKD patients. Conclusions CKD is a common disease in geriatric cats. Treatment is mainly based on dietary modifications and maintenance of a correct hydration status. Management of systemic complications and recognised negative prognostic factors has increased the survival of cats with CKD. More studies are needed to improve our detection of early CKD and to validate the use of new therapeutic agents. References for this article are available upon request. // 8 / 8