Diagnosis and Staging
Any discussion of the management of feline CKD tends to focus on the treatments that can be given to these patients. It is, however, essential to ensure at the outset that the patient does not have a pre- or post-renal component to their azotaemia and, if possible, to identify any underlying identifiable cause for the CKD.
Unfortunately, in cats it is not often possible to determine this; if the patients were to have a renal biopsy (although this is not advocated) it is likely that tubulo-interstitial inflammation and fibrosis would be identified but this gives limited insight into disease pathogenesis.1 Having ensured that there is no underlying, treatable cause for the patient's CKD it can then also be helpful to stage the disease severity using the IRIS Staging Scheme (http://iris-kidney.com/) as this can be used as a guide for the further management of the patient.
Broadly speaking treatments for CKD can be divided into those therapies that might delay progression of the kidney disease and those that just treat the symptoms. Treatments aimed at delaying disease progression are likely to be most effective in patients with Stage 2 & 3 CKD (mild-moderate azotaemia). Some symptomatic therapies (anti-emetics, fluid therapy, erythropoiesis-stimulating agents) will only be required in more severely azotaemic patients (Stage 3 & 4) while the need for others (antibiotics for UTIs, anti-hypertensive agents) is related to factors other than the severity of azotaemia.
Delaying Progression of CKD Dietary Therapy
The best example of a treatment that delays progression of CKD is dietary therapy (primarily phosphate restriction). This ameliorates CKD-mineral bone disorder (CKD-MBD) and is proven to be associated with increased survival time. The term CKD-MBD is preferred to that of renal-secondary hyperparathyroidism because it reflects that the problem is multi-faceted with mineral imbalance (primarily calcium and phosphate), multiple hormone derangements (PTH, calcitriol and fibroblast growth factor-23; FGF-23) and abnormalities of soft tissue mineralisation and bone loss all occurring simultaneously. All of these abnormalities are highly inter-related. Recent work has shown that increases in FGF-23 concentration may be one of the first changes to occur in cats with CKD and that this may be detectable even before patients are azotaemic. The concentration of FGF-23 at the time of diagnosis of CKD in cats is related to survival time2 and the concentration of this hormone (and of PTH) can be reduced by feeding of a phosphate-restricted, renal-care diets.3
Renal-care diets have been shown in numerous studies, conducted in different countries and by different research groups, to improve survival of cats with azotaemic CKD.4,5 What has still to be established is whether these treatments can also be of benefit in selected patients with non-azotaemic CKD or if additional benefit can be gained by the use of target-driven therapy (for example normalisation of phosphate, PTH or FGF-23) in management of CKD. The potential role for phosphate-binding agents is also an area that warrants further study; when given to patients consuming an unrestricted diet they may be of little benefit because there is just so much phosphate in the gut to bind, but they are likely to be of more use when given in combination with a renal-care diet in patients where this is not enough, in isolation, to ameliorate CKD-MBD.
Drugs Acting on the Renin-Angiotensin System
The evidence for the use of angiotensin converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) in management of feline patients with CKD is less strong than for dietary therapy. These agents have been shown to reduce proteinuria6,7 but have not been proven to extend survival in feline patients with tubulo-interstitial renal disease.
Proteinuria has been shown in many species, including the cat, to be associated with shorter survival times. This could be due to injurious effects of the proteins themselves, some of which get reabsorbed following filtration and passage through the tubulo-interstitium, or it could relate to the fact that proteinuria is considered to be a surrogate marker for glomerular hypertension. In either situation treatment with ACE-inhibitors (such as benazepril) or ARBs (such as telmisartan) could be beneficial because they reduce either the production of angiotensin II (ACE-inhibitors) or its receptor binding (ARBs); angiotensin II has a preferential constrictive effect in the efferent arteriole, blocking its actions reduces pressure across the glomerular capillaries and so decreases proteinuria.
Symptomatic Therapies
Monitoring and Treating Urinary Tract Infections
Urinary tract infections (UTIs) are common in cats with CKD. Infection may in some instances ascend to the patient's kidneys resulting in pyelonephritis and then the patient may become systemically unwell.
Pyelonephritis is difficult to definitively diagnose so specific data on its incidence are lacking. Cats with CKD have traditionally been considered likely to have 'complicated' UTIs and have been treated with relatively long courses of antibacterials when these have been diagnosed. Whether this is really necessary is unknown especially since most cats with CKD that develop UTIs are asymptomatic. In humans asymptomatic bacteriuria (ASB) is common and it is not recommended that ASB is treated since this has not been found to reduce the incidence of subsequent symptomatic UTIs, incidence of pyelonephritis, patient morbidity, or mortality. One study found no difference in survival of cats with CKD with and without UTI.8
Treatment of Anaemia
Anaemia is common in cats with CKD but it is not usually severe until azotaemia is relatively marked; IRIS stage 4 is typical once the patient is symptomatic. Treatment is usually only considered once the PCV is <20%. The cause of the anaemia is multifactorial with a lack of erythropoietin being an important factor. Recombinant human erythropoietin has been used to treat anaemia although cross-reacting antibodies may develop in some patients. Darbepoetin is a modified molecule with a long half-life and it is postulated that this results in a lower incidence of cross-reacting antibody formation.9 The recommended starting dose for darbepoetin is 1 µg/kg (SQ or IV) weekly with a tapering of the dose and/or frequency of administration once the PCV rises. Iron supplementation should also be given initially.
Fluid Therapy and Feeding Tubes
Some patients with CKD have a tendency to become dehydrated causing a pre-renal component to their azotaemia and clinical deterioration. This can result in a patient that responds to intravenous fluids when hospitalised but decompensates after a few days at home. In these patients subcutaneous administration of fluids by the owner at home may be beneficial.
Alternatively if the patient has a feeding tube placed then additional water can be given via this route. Feeding tubes can be very well tolerated by patients and have the advantage that as well as allowing optimal nutrition to be delivered, medications can also be given by the tube in a stress-free manner.
Potassium Supplementation
About 20–30% of cats with CKD are hypokalaemic. Chronic hypokalaemia induces histological lesions in the kidneys of experimental animals and the concept of hypokalaemic nephropathy emerged from these observations. Whether or not this phenomenon plays a role in the primary insult to the feline kidney or as a factor perpetuating progression of renal damage remains to be proven in clinical cases of feline CKD. Nevertheless, treatment of significant hypokalaemia does lead to a clinical improvement in the cats' appetite and level of muscle strength and activity.
Laxatives
Constipation is quite common in patients with CKD and may contribute to anorexia. Judicious use of stool-softening agents can be helpful but it is important to ensure the patient does not develop diarrhoea which may exacerbate dehydration. Liquid paraffin (in the form of palatable paste e.g., katalax) and lactulose have traditionally been used but while dogs are quite accepting of the sweet taste of lactulose this is not well accepted by cats. Miralax (polyethylene glycol 3350) is much better accepted and can be dosed at ¼ teaspoon per meal, either mixed in the food or dissolved in water.
Appetite Stimulants
Recent work has been done to evaluate the most suitable appetite stimulants for use in cats with CKD. Maropitant was found to reduce vomiting but there was no increase in appetite compared with the placebo group and no weight gain. Mirtazapine, has been evaluated in several studies; firstly to determine the appropriate dosing strategies (1.88 mg [1/8 tablet] per cat every other day appears optimal) and then to assess its efficacy as an appetite stimulant.10 Mirtazapine was found to increase appetite, with weight gain and a reduction in vomiting. At present this appears to be the preferred treatment in cats with CKD although it should be noted that all these studies were very small.
Anti-Hypertensive Therapy
This will be the focus of an accompanying lecture.
References
1. Chakrabarti S, Syme HM, Brown CA, Elliott J. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Veterinary Pathology Online. 2013;50(1):147–155.
2. Geddes RF, Elliott J, Syme HM. Relationship between plasma fibroblast growth factor-23 concentration and survival time in cats with chronic kidney disease. J Vet Intern Med. 2015;29(6):1494–1501.
3. Geddes RF, Elliott J, Syme HM. The effect of feeding a renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease. J Vet Intern Med. 2013;27(6):1354–1361.
4. Elliott J, Rawlings JM, Markwell PJ, Barber PJ. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract. 2000;41(6):235–242.
5. Ross SJ, Osborne CA, Kirk CA, Lowry SR, Koehler LA, Polzin DJ. Clinical evaluation of dietary modification for treatment of spontaneous chronic kidney disease in cats. J Am Vet Med Assoc. 2006;229(6):949–957.
6. King JN, Gunn-Moore DA, Tasker S, Gleadhill A, Strehlau G. Tolerability and efficacy of benazepril in cats with chronic kidney disease. J Vet Intern Med. 2006;20(5):1054–1064.
7. Sent U, Gossl R, Elliott J, Syme HM, Zimmering T. Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in cats with chronic kidney disease. J Vet Intern Med. 2015;29(6):1479–1487.
8. White JD, Stevenson M, Malik R, Snow D, Norris JM. Urinary tract infections in cats with chronic kidney disease. J Feline Med Surg. 2013;15(6):459–465.
9. Chalhoub S, Langston CE, Farrelly J. The use of darbepoetin to stimulate erythropoiesis in anemia of chronic kidney disease in cats: 25 cases. J Vet Intern Med. 2012;26(2):363–369.
10. Quimby JM, Lunn KF. Mirtazapine as an appetite stimulant and anti-emetic in cats with chronic kidney disease: a masked placebo-controlled crossover clinical trial. Vet J. 2013;197(3):651–655.