Feline CKD

Abstract

Practical relevance:

Chronic kidney disease (CKD) is common in humans as well as in cats, and is a significant human health problem. In feline medicine, despite recent research and improvements in our understanding of the condition, management remains limited by late diagnosis and an inadequate ability to prevent progression of disease. Investigation of future treatments that both delay the progression of CKD and manage clinical signs, and that are also easy and cost effective to administer, is desirable. To this end, we may learn from our colleagues in the medical profession.

Audience:

CKD is commonly encountered in general practice and so all practitioners dealing with cats will benefit from understanding future treatment possibilities and interventions in the management of CKD.

Evidence base:

Large-scale medical studies have been performed to provide an evidence base for treatment decisions in human CKD. Several studies in cats have looked at various aspects of treatment and prognosis, but large-scale studies are needed to assess the benefits of treatments such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Clinical challenges:

Providing treatment that is effective, easy to administer and not cost-prohibitive is the challenge currently faced by clinicians in the management of feline CKD.

Limitations of current management of CKD in cats

Despite research into the management and progression of chronic kidney disease (CKD) in cats, as practitioners we still face many challenges when diagnosing and treating CKD in this species.

The first is late diagnosis. Our counterparts in the human medical profession face similar challenges but humans tend to present at earlier stages of the disease, providing more opportunity to intervene. Feline patients with CKD, given the tendency of cats to hide signs of illness, are often not identified until the later stages of the condition. Screening high-risk patients may enable earlier diagnosis – for example, human diabetic or hypertensive patients have a higher risk of CKD and, therefore, are regularly screened for the presence of microalbuminuria.¹ Screening may, similarly, be appropriate for certain cat populations such as mature to geriatric cats, hypertensive cats and as part of a pre-anaesthestic assessment; the use of nursing clinics with simple assessments of urine specific gravity (USG) and proteinuria may help identify early-stage CKD in such patients. Routine use of estimated glomerular filtration rate (eGFR) in humans (using a formula derived from serum creatinine concentration) also facilitates earlier diagnosis of CKD given the insensitivity of serum creatinine measurement alone in early stages of the disease (see later).^2–4

Of course, if cats are to benefit from earlier diagnosis of CKD, we need to investigate interventions that will slow, arrest or, ideally, reverse the progression of the disease.

Therefore, currently a further challenge in cats is the lack of reversibility of feline CKD coupled with limited interventions that are known to slow progression. Regardless of the initial insult, a common pathway of progression to end-stage renal disease (ie, the need for dialysis or transplantation in humans), involving compensatory glomerular haemodynamic changes as a result of nephron loss, is recognised in both humans^4–6 and animals.⁷ However, in human medicine, arrest of progression and even reversal of damage is possible (see later).⁸

Current treatment strategies for feline CKD consist largely of supportive and symptomatic treatment of the consequences of the disease – the initial renal injury often being unknown (with some exceptions, as reviewed in the first article in this JFMS supplement). Despite the desirability of early detection of feline CKD and treatment to modify progression, only one therapeutic intervention has been shown to significantly improve survival time, and that is the use of a therapeutic kidney diet.^9–12 Further studies are urgently required to investigate the ability of other treatments to arrest the progression of CKD, or even reverse renal damage, and thereby lengthen survival for cats with CKD. Such studies should encompass both conventional and newly licensed treatments for feline CKD, as well as appropriate investigations of drugs used in humans.

Additional issues faced by veterinarians and owners relate both to the administration and the cost of medications. Prescribing multiple medications, especially if unpalatable and/or requiring frequent administration, will potentially lead to non-compliance, a possible reduction in the quality of life of the cat, and damage to the cat–human bond at an important time in the cat’s life. Equally, a prescription kidney diet must be carefully introduced to avoid aversion to the new food and any associated loss of confidence in the veterinarian by the owner.

Costs are also clearly important because, despite the increased availability of pet insurance in many markets, older cats will frequently not be insured and owners may not be able to fund costly treatments; for some, the cost of a therapeutic diet, let alone expensive medications, is prohibitive. Therefore, palatable, easy to administer, cost-effective medical treatments with known efficacy should be the goal of management of feline CKD.

To overcome these challenges further research and development of drugs specifically designed for cats, with palatability/administration in mind, is required. A closer look at human nephrology may also aid our understanding of feline CKD and prompt further developments.

Progression of CKD – what do we know?

In human medicine, a common pathway for the progression of renal disease is accepted, with the central theme being that increased intraglomerular capillary pressure leads to glomerular cell injury and impairment of the permselective function of the capillary. This damage to glomerular function can also occur under circumstances of normal glomerular capillary pressure in various conditions such as immune-complex glomerular disease. Whatever the cause, this damage to podocyte, capillary and glomerular function allows excessive filtration of plasma proteins. Glomerular cell damage may also result in angiotensin II (Ang II) release and increased expression of angiotensin type 1 receptors in podocytes. The excessive filtration of proteins induces tubular cells to produce various inflammatory mediators (cytokines, chemokines, growth factors and vasoactive molecules), resulting in tissue injury, fibrosis and, ultimately, progressive renal injury,⁵ as illustrated in the box on page 46.

In feline medicine, is it reasonable to assume that proteinuria results in a similar pathway of progression? Studies have demonstrated that proteinuria is predictive of survival in cats, with the hazard ratios (for death or euthanasia) 2.9 (1.4–6.3) and 4.0 (2.0–8.0) for urine protein:creatinine ratios (UPCs) of 0.2–0.4 and >0.4, respectively.¹³ It is noteworthy that UPC values of up to 0.4–0.6 have in the past been considered to be within the normal reference range in cats, and uncertainty remains about what should be considered the reference interval in this species.^14,15

Whether proteinuria is a surrogate marker for more rapidly progressive CKD or a cause of progression in cats remains unknown, but measurement of proteinuria in cats with CKD and its control following the International Renal Interest Society (IRIS, www.iris-kidney.com) and American College of Veterinary Internal Medicine (ACVIM) consensus guidelines¹⁵ should form part of the standard management of the condition (see second article in this JFMS supplement).

In human medicine, hypertension is a direct cause of CKD as well as a consequence, and strict control of blood pressure is vital to avoid progression of CKD and adverse cardiovascular events.¹⁶ In cats, one study of 141 hypertensive patients failed to demonstrate an independent association between blood pressure and survival but again demonstrated that the most proteinuric cats had a shorter survival, that these tended to be cats with the highest blood pressure, and that treatment with amlodipine lowered both blood pressure and proteinuria.¹⁷ Certainly, given the prevalence of hypertension in azotaemic cats (19–65%),^18–20 blood pressure should be routinely measured and hypertension both treated and monitored, along with any associated proteinuria.

Other factors associated with progression of CKD in humans include dyslipidaemia, anaemia, oxidative stress and disorders of calcium–phosphate balance.⁶ Such factors remain poorly studied in cats but may represent potential treatment targets.^21–25

Comparative aspects – what is the approach to CKD in humans?

CKD in humans is a worldwide public health problem, the extent of which is likely underestimated due to underdiagnosis. Causes include diabetes, hypertension, polycystic kidney disease and glomerular diseases. Diabetic nephropathy is a major complication of diabetes, and CKD is a major risk factor for cardiovascular morbidity. The prevalence of CKD in humans increases with age, as it does in cats, with approximately 17% of people over 60 having a reduced glomerular filtration rate (GFR).²⁶ Human CKD is thus a syndrome caused by various renal diseases, the biggest group being glomerular diseases including diabetic and hypertensive nephropathies. This is in contrast to cats, where the most common histopathological diagnosis is tubulointerstitial nephritis (ie, tubular disease) rather than predominantly glomerular disease.

This difference may be important in relation to treatment effects, and is one reason why we cannot necessarily transpose information found in human studies directly to feline patients.

Diagnosis and staging

Early diagnosis and management of CKD in humans is desirable to allow prompt intervention and to minimise progression of CKD, thereby reducing the risk of end-stage renal disease and cardiovascular disease.²⁷ Screening of ‘at-risk’ patients such as diabetics and hypertensive patients often starts with urinalysis for albuminuria, which has been shown to have a greater sensitivity for detection of low level proteinuria than urine protein measurement. Microalbuminuria screening has been shown to identify patients at risk of adverse renal and cardiac outcomes, and intervention can prevent progression to macroalbuminuria and associated morbidities.⁵ In cats, measurement of albuminuria is not known to have advantages over UPC measurement and hence is not the preferred test in this species.^13,15

In 2002, the National Kidney Foundation published a staging scheme to clarify ambiguities in the classification and use of terms such as ‘chronic renal failure’ and ‘renal insufficiency’ and to standardise management of human CKD.²⁸ Similarly, in the veterinary field, IRIS has developed a staging system for cats and dogs.^29,30 In humans, staging is based on measurement of GFR, as this is the most accurate method of assessing kidney function. However, it is expensive and time consuming to use clearance methods (as in our patients); therefore, GFR is routinely measured using a formula-based estimation from serum creatinine (eGFR), using body surface area with adjustments for age, race and sex.³¹ In animals no such equivalent equation exists for routine use,³² but its development would be an important step forward in the diagnosis and staging of feline CKD.

Table 1 outlines the human classification system for CKD.²⁸ Note that stage 1 is allocated similarly to the IRIS system used in dogs and cats – the GFR is normal but there is ‘other evidence of kidney damage’ (eg, persistent proteinuria, haematuria, renal biopsy abnormalities or structural renal abnormalities). Importantly, the use of eGFR measurements allows earlier detection of CKD, prior to serum creatinine being elevated, meaning our feline IRIS stage 2 patients³⁰ would be stage 3–4 human CKD patients, while a whole subset of feline CKD patients are undetected at what would be in (the lower) human stage 2 classification.

Table 1

Stages of human CKD

Stage	Description	GFR (ml/min/1.73 m2)
1	Kidney damage with normal or increased GFR	≥90
2	Kidney damage with mild reduction in GFR	60–89
3	Moderate reduction in GFR	30–59
4	Severe reduction in GFR	15–29
5	Kidney failure	<15 or dialysis

From NICE guidelines³¹

Treatment via modification of the RAAS

Much research in human medicine has focused on the effect of modification of the renin– angiotensin–aldosterone system (RAAS) in the treatment of CKD. It has been demonstrated in clinical trials over the past 20 years that blocking the action of Ang II induces restoration of glomerular permselective properties, prevents or reduces proteinuria, and has beneficial effects on the progression of kidney disease by lowering the protein load of tubular cells and, in turn, reducing the production of inflammatory mediators and profibrotic agents by these cells (see box on page 46).^33,34

The effects of Ang II can be blocked by angiotensin-converting enzyme (ACE) inhibitors or by antagonising the effects of Ang II at the receptor with Ang II receptor antagonists/blockers (ARBs). Further modification of the RAAS system has also been attempted with the renin inhibitor aliskiren (Table 2),³⁵ although this treatment requires further research.

Table 2

Novel therapies under investigation for the treatment of CKD in humans

Drug	Mechanism of action/effect
Aliskiren	Renin blockade
Vitamin D receptor agonist (paricalcitol)	Inhibition of renin and reduction of proteinuria
Aldosterone antagonists (spironolactone)	Reduction of proteinuria when used with an ACE inhibitor
Endothelin receptor blockers	Inhibition of endothelin-mediated vasoconstriction, glomerular hypertension and interstitial fibrosis
Pirfenidone	Inhibition of TGF-β-mediated fibrosis

Modified from Ruggenenti et al⁵

TGF-β = transforming growth factor

ACE inhibitors

Numerous studies have demonstrated the benefit of ACE inhibitors in human CKD, most notably the Ramipril Efficiency in Nephropathy (REIN) study,³⁶ in which proteinuric CKD patients treated with ramipril (compared with placebo) showed a marked reduction in progression to end-stage renal disease, an effect largely explained by the reduction in proteinuria. Importantly, this beneficial effect of ACE inhibitor treatment is not seen in non-proteinuric, non-diabetic patients;³⁷ therefore, treatment with an ACE inhibitor is not generally recommended for non-diabetic and non-proteinuric CKD patients, although this remains an area of research and clinical uncertainty.³⁸ Even where proteinuria is present, RAAS blockade may not always have survival benefits, as appears to be the case in humans with polycystic kidney disease.³⁹

ARBs

ARBs are, as mentioned, an alternative method of RAAS blockade used in human medicine. The advantages of RAAS blockade by other means are the avoidance of side effects of ACE inhibitor treatment (a cough can be a significant side effect in humans, due to the blockade of other roles of the Ang II enzyme) and avoidance of so-called ‘ACE escape’ or ‘angiotensin breakthrough’, where levels of Ang II and aldosterone rise to pre-treatment levels despite ACE inhibition, due to alternative enzyme pathways.^40,41 In addition, ARBs selectively block the AT₁ receptor and do not interact with the AT₂ receptor, which may exert some counter-regulatory activity and lead to enhanced vasodilation and reduced blood pressure.^42,43

Despite some potential advantages of the use of ARBs in human CKD, their efficacy appears to be similar to that of ACE inhibitors, effected via a reduction in glomerular capillary pressure and improvement in permselectivity of the glomerular capillary barrier, and hence a reduction in proteinuria and arrest of progression in proteinuric renal diseases.^5,8,44 The use of ACE inhibitors and ARBs in human CKD thus appears largely to be interchangeable, with NICE guidelines in the UK not indicating a preferred treatment.³¹

Other drugs

In humans with CKD the renin inhibitor aliskiren is a further way of influencing RAAS activation,^35,44 and it has been shown that aldosterone antagonists may also have the ability to further reduce proteinuria and slow progression of disease.⁵³ Certain other drugs may additionally be beneficial in modifying the inflammatory process (Table 2), but no data are available on the use of these agents in feline CKD.

Other approaches to management

Lifestyle changes are considered important in the management of CKD in humans, including cessation of smoking, management of obesity and general improvement in fitness.³¹

Dietary modification with a low protein, low phosphate diet has been shown to reduce disease progression in human CKD,⁵⁴ as it has in cats.^9–11 However, protein restriction in CKD remains controversial, with a large study failing to support any benefit of severe restriction in human patients.^55,56 Protein malnutrition and inadequate iron intake is a common concern in human CKD, and compliance with a low protein diet is often poor due to palatability issues as well as reluctance by patients to weigh food and follow a strict and restrictive diet.^57–59 Therefore, recommendations include specialist dietary advice for patients with progressive or later stage CKD (stages 4 and 5) that may include protein, potassium, sodium and phosphate restriction.⁶⁰

Other priorities in the management of human CKD include:^60–63

Tight control of blood pressure, if indicated.

Use of statins to reduce the risk of cardiovascular disease (and possibly lower proteinuria and slow progression of renal disease).⁴³

Management of anaemia with erythropoietin (EPO) therapy and iron supplementation (iron deficiency being common in late-stage CKD).⁶²

Management of metabolic derangements in parathyroid hormone, phosphate, calcium and vitamin D, with vitamin D supplementation and the use of bisphosphonates in patients with osteoporosis.⁶¹

It is notable that these interventions are usually recommended for higher stage human CKD patients and may have an effect on progression of the disease.

Future developments in feline CKD

Research into treatments for feline CKD should be a priority, as, clearly, improving our ability to achieve early diagnosis in patients will only be of benefit when we have good knowledge of what therapies are of real value at different stages and with different types of feline CKD. The box above highlights just some of the areas that we need to focus on, with particular effort to undertake larger, collaborative well-conducted trials to determine clinical benefits.

Many unanswered questions remain in human CKD, too, but we have much to learn about CKD in cats to even approach the level of understanding of the disease in human medicine, particularly with regard to prevention of progression. Whatever future research tells us, cost, palatability and ease of administration of medications will remain major concerns when managing the feline CKD patient, so future therapies must also consider these factors.

Footnotes

Funding

The preparation of this article was supported by an educational grant from Boehringer Ingelheim.

Conflict of interest

Samantha Taylor is Distance Education Coordinator for the ISFM and this position is partially funded by a grant from Boehringer Ingelheim.

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