Clinical signs of nausea, vomiting and dysrexia are common in patients with chronic kidney disease (CKD). In a recent survey of owners of cats with CKD, 43% of respondents reported abnormal appetite in their cat necessitating 77% of owners to coax the pet to eat more than half the time (Markovich et al, 2015). Sufficient caloric support is crucial for chronically ill patients, and there is evidence that CKD results in an increased metabolic state making adequate nutrition even more of a challenge (Neyra et al, 2003). In humans CKD protein energy wasting and poor body condition is associated with decreased survival, even in patients receiving dialysis (Carrero et al, 2013). Poor body condition score (BCS) is also associated with a poorer prognosis in dogs and cats with CKD (Parker and Freeman, 2011; Freeman et al, 2016). A recent study documented that not only do cats commonly lose weight before CKD diagnosis and subsequently continue to lose weight during the disease process, but decreased weight is associated with a poorer prognosis (Freeman et al, 2016). Assessment of quality of life parameters in CKD cats revealed that CKD cats score significantly lower than healthy young or geriatric cats in the categories of ‘appetite’ and ‘liking food’ (Bijsmans et al, 2016). Additionally, poor appetite is perceived as a significant quality of life concern and can cause significant emotional distress to owners (Reynolds et al, 2010).
For these reasons, serial evaluations of nutritional status are a key part of CKD patient management, and should be performed for every patient at every visit (Figure 1). Awareness of these parameters and tools for assessment have been made available by the WSAVA global nutritional initiative. http://www.wsava.org/nutrition-toolkit. A nutritional assessment should include bodyweight, BCS, muscle mass score, adequacy of caloric intake (including open ended questions about how the pet is eating), and a complete dietary history (including pet food, treats, supplements and items used to give medications). In obese patients with inadequate muscle mass, BCS often does not adequately describe muscle loss. Assessment of muscle mass is particularly important in CKD patients as it can have a profound effect on serum creatinine and affect the interpretation of the severity of disease, as well as have notable implications for the potential inadequacy of the patient's caloric intake. Minimally a score of adequate muscle mass, or mild, moderate or severe muscle loss should be determined based on epaxial, skull, scapular and iliac musculature, and documented in the medical record at each visit. Such assessments will allow a determination of the need for appetite management in each individual patient.
Pathophysiology of dysrexia
Understanding the mechanisms by which patients with CKD may experience abnormal appetite helps target awareness of clinical manifestations of disease. Uraemic toxins are sensed by the chemoreceptor trigger zone of the area postrema in the brain, which subsequently stimulates emesis by the vomiting centre. Experimental ablation of the area postrema inhibits uraemic vomiting in dogs with total nephrectomy illustrating the involvement of this structure in the pathophysiology of the disease (Borison and Hebertson, 1959). It has long been thought that uraemia has effects on the intestinal tract, such as hyperacidity, uraemic gastritis and ulceration that lead to further unwillingness to eat, but our understanding of this pathophysiology in cats and dogs is incomplete. Cats with CKD have been shown to have elevated concentrations of gastrin that increase with the severity of renal failure (Goldstein et al, 1998), but it has not been demonstrated that this results in hyperacidity. Cats that have gastrin-secreting tumors with levels of hypergastrinaemia similar to those found in cats with CKD have significant gastric pathology; but this has not been demonstrated in cats with CKD (Liptak et al, 2002; McLeland et al, 2014). In human CKD the development of gastric hyperacidity appears to be inconsistent, and may be related to the presence of Helicobacter spp. infection (El Ghonaimy et al, 1985). A study evaluating the type and prevalence of histopathologic lesions in the stomach of cats with CKD found gastric fibrosis and mineralisation rather than the uraemic gastropathy lesions previously described in dogs and humans (uraemic gastritis, ulceration, vascular injury, edema) (McLeland et al, 2014). Additionally a recent study demonstrated cats with CKD do not have gastric hyperacidity compared with normal cats, calling into question whether acid suppression is appropriate (Tolbert et al, 2017). In dogs, uraemic gastropathy has been reported to be not as severe as that described in humans. Gastrointestinal haemorrhage in cats and dogs with CKD may be more attributable to factors such as uraemic thrombocytopathia rather than overt ulcerative lesions which appear to be relatively rare (Chalhoub et al, 2011). Therefore, the administration of gastric protectants, such as sucralfate, may not be justified, unless obvious clinical evidence of gastrointestinal haemorrhage, such as melaena, is appreciated.
In addition to build up of uraemic toxins and possible alterations in the gastrointestinal tract, the basic pathophysiology of appetite regulation may be significantly abnormal in animals with CKD. Appetite regulation is complex and involves a multitude of signaling compounds, but briefly regulation comprises orexigenic substances that activate the hunger center (i.e. ghrelin) and anorexigenic substances that activate the satiety centre of the brain (i.e. leptin, cholecystokinin, obestatin, des-acyl ghrelin) (Gunta and Mak, 2013). In humans, CKD is associated with an increased accumulation of anorexigenic substances secondary to decreased glomerular filtration rate without a concomitant increase in orexigenic substances such as ghrelin. Additionally anorexigenic substances have been demonstrated to be significantly higher in CKD patients with poor body condition than those with normal body condition (Gunta and Mak, 2013). Therefore CKD patients could potentially benefit from pharmacologic management of appetite.
Appetite stimulants—cyproheptadine and mirtazapine
Metabolic complications of CKD that may affect appetite such as dehydration, hypertension, anaemia, hypokalaemia, and nausea and vomiting should be identified and addressed. In addition, appetite stimulants can be used to encourage food intake, particularly in late stage patients and in patients where a feeding tube is not desirable to the owner. Cyproheptadine has been used for some time as an appetite stimulant and has anecdotal efficacy in many patients, however its efficacy has never been scientifically evaluated. It is important to ask the pet owner if both mirtazapine and cyproheptadine are present in the home as they should not be administered concurrently; cyproheptadine is used as an antidote for serotonin effects of mirtazapine overdose, and thus negates efficacy of the latter. Mirtazapine has become more commonly used, and assessment of its pharmacodynamics and pharmacokinetics have provided information for more effective use in cats and dogs (Quimby et al, 2011a, b; Giorgi and Yun, 2012). Pharmacodynamic studies in cats have illustrated that it can be a potent appetite stimulant, but higher doses are more commonly associated with side effects (hyperexcitability, vocalisation, tremors) (Ferguson et al, 2016). As side effects are typically dose related and some cats may require a decreased dose, nurses should be familiar with side effects in order to help identify patients for which dose decrease would be recommended. These side effects are typically not seen in dogs.
Pharmacokinetic studies in cats have demonstrated that the half-life is short enough that it could be administered daily in normal cats. Dose recommendations are 1.88 mg every 24 hours in cats without liver or kidney disease and 0.6–1 mg/kg once to twice daily in dogs without liver or kidney disease. Mirtazapine has been less well studied in dogs, but in one study in research dogs it was found to have a relatively short half-life (Giorgi and Yun, 2012). Therefore twice daily administration may be more effective than daily administration. Anecdotally, the efficacy of mirtazapine in dogs for appetite stimulation seems variable. No studies have looked at its efficacy in canine CKD patients, and additional work is needed to determine if this drug can be used more effectively in this species.
Mirtazapine in CKD
It is important to know the degree to which the patient may be affected by kidney disease as this may change dosing recommendations. A study was performed to determine the pharmacokinetics of mirtazapine in cats with CKD and in age-matched controls to investigate the effects of renal impairment in this species (Quimby et al, 2011a). Six CKD cats and six age-matched controls (AMC) were enrolled. Two CKD cats each from International Renal Interest Society (IRIS) stage II, III and IV were included. Blood samples were collected after a single oral dose of 1.88 mg of mirtazapine. CKD cats had significantly longer clearance and higher area under the curve (AUC) (drug exposure) than geriatric controls. In comparison to a 9.2 hour half-life in normal cats, elderly cats had a half-life of 12.1 hours and CKD cats had a half-life of 15.2 hours. Calculated accumulation factor for every 48-hour dosing of 1.88 mg in CKD cats was 1.15. It was concluded that CKD appears to delay the clearance of mirtazapine. A single low dose of mirtazapine resulted in a half-life compatible with a 48-hour dosing interval in CKD cats, unlike young normal cats where daily dosing would be appropriate.
The use of mirtazapine in cats with CKD has also been explored in a placebo-controlled, double-masked crossover clinical trial (Quimby and Lunn, 2013). In this study 11 cats with stable CKD were randomised to receive 1.88 mg mirtazapine or placebo orally every other day for 3 weeks, then crossed over to the alternate 3-week treatment. Physical examination and serum biochemistry profile were performed before and after each treatment period, and owners kept daily logs of appetite, activity, behaviour, and vomiting episodes. In comparison to placebo, mirtazapine administration to CKD cats resulted in a statistically significant increase in appetite (p=0.02) and activity (p=0.02), and a statistically significant decrease in vomiting (p=0.047) (Quimby and Lunn, 2013). Mirtazapine administration resulted in a statistically significant increase in weight (p=0.002). Median weight gain during mirtazapine administration was 0.18 kg (range 0–0.45 kg), and 91% of cats gained weight during mirtazapine administration. Median weight loss during placebo administration was 0.07 kg (range 0–0.34 kg), and 82% of cats lost weight during the placebo period. Fortyfive percent of cats experienced an increase in BCS during mirtazapine administration, all of which had a suboptimal BCS. Cats that already had optimal BCS did not experience any change. Mirtazapine also appeared to have antiemetic properties and resulted in significantly decreased vomiting in cats with CKD. It was concluded that this drug could be a useful adjunct to the nutritional management of cats with CKD.
Transdermal mirtazapine
Mirtazapine also is amenable to transdermal administration and has been demonstrated to achieve both therapeutic serum levels and appetite stimulation in healthy cats (Benson et al, 2017). Although transdermal administration is an extremely attractive method for administering medications, not all drugs are amenable to transdermal application and each requires testing for appropriate drug exposure and clinical efficacy. A study was performed assessing the use of transdermal mirtazapine compounded into Lipoderm gel in healthy cats (Benson et al, 2017). It was concluded that mirtazapine can effectively be given via the transdermal route of administration, and resulted in appetite stimulation. Doses ranging from 1.88–3.75 mg compounded into Lipoderm gel and administered every other day are currently being studied in CKD cats in placebo controlled clinical trials (Quimby et al, 2017). Side effects are seen to a lesser degree with transdermal preparations, however dose decrease for an individual patient may still be necessary if undesirable vocalisation or hyperactivity are seen. Additionally transdermal mirtazapine ointment has been recently FDA approved in the USA for use in cats for the management of unintended weight loss (Buhles et al, 2018; Poole O'Banion et al, 2018). Transdermal administration of mirtazapine has not been assessed in dogs.
Appetite stimulants—ghrelin agonist capromorelin
The ghrelin agonist capromorelin, recently FDA approved for dogs, may also provide additional opportunities to address appetite in CKD by targeting the dysregulation of appetite that occurs with disease. In both human and rodent studies administration of ghrelin has resulted in increased appetite and energy intake in patients with CKD (Gunta and Mak, 2013). In recent veterinary studies, administration of capromorelin resulted in increased appetite, food intake and weight in normal and inappetent dogs, and increased food intake and weight in laboratory cats (Zollers et al, 2015, 2016, 2017a, b; Rhodes et al, 2018). In a prospective, randomised, masked, placebo-controlled study, dogs with a reduced appetite were treated daily with capromorelin (3 mg/kg) oral solution (n = 121) or placebo oral solution (n = 56) (Zollers et al, 2016). Owners completed an evaluation of appetite at days 0 and 3 +/− 1 and success was defined as improvement in appetite at day 3. A subset of the dogs enrolled in the study were described as having IRIS Stage ≥ 2 CKD (capromorelin n=28, placebo n=17). Capromorelin administration improved appetite compared with placebo (68.6% and 44.6% respectively, p=0.008), and demonstrated it usefulness as an appetite stimulant in dogs.
Conclusions
Poor appetite and weight loss is common with CKD and nurses should have an understanding of pathophysiologic factors that result in these clinical manifestations. Nurses should be comfortable with nutritional assessment including diet history, caloric intake, bodyweight, BCS and muscle mass score, and should help ensure these are performed at every visit to identify patients that could benefit from management of appetite. Nurses should be aware of the availability of medications to manage appetite, as well as side effects that might require dose titration.