Chronic renal failure (CRF) is a common and important cause of morbidity and mortality in cats. The hallmark of CRF is a chronic decline in the population of functional nephrons to a point where the glomerular filtration rate (GFR) is no longer adequate to maintain normal excretory function. This leads to azotaemia (elevation in plasma urea and/or creatinine concentrations) and the retention of other plasma solutes and protein catabolic products normally eliminated via the kidneys. Ultimately, renal dysfunction and the retention of these products results in a spectrum of clinical signs associated with CRF, commonly referred to as the 'uraemic syndrome'.

Aetiology of Feline CRF

The underlying aetiology of feline CRF is often obscure although a variety of causes have been documented. Histological evaluation of kidneys from affected cats most commonly reveals the presence of chronic interstitial nephritis (CIN) characterised by the presence of progressive fibrosis, loss of nephrons and the presence of sterile inflammation, but the cause of this uncertain. It has been speculated that chronic pyelonephritis or glomerulonephritis may account for at least some of these 'end stage' cases of chronic renal failure, but whatever the underlying cause, unlike many cases of human renal failure, this is not predominantly a glomerular disease in cats, but rather a tubulointerstitial disease (with glomerular involvement) that results in nephron loss.

Clinicopathological Changes and Diagnosis

The diagnosis of CRF is usually based on the presence of appropriate clinical signs (although these are often vague and non-specific) together with the demonstration of azotaemia and inappropriately concentrated urine. Because cats often retain some concentrating ability during CRF, isosthenuria is not necessarily observed and indeed studies suggest that isosthenuria (urine SG <1.015) may only be seen in around 50-60% of cases of feline CRF, with the remaining having various degrees of hypersthenuria. However, the ability of the kidneys to concentrate urine will depend to some extent on the severity of the renal failure, and few cats with advanced or well established CRF can concentrate urine above 1.035.

Because factors other than CRF can cause azotaemia (in particular dehydration), the finding of azotaemia alone is not sufficient to make a diagnosis of CRF. In all cases, the presence of azotaemia should be interpreted together with a concomitant urine sample for measurement of urine SG. Thus the presence of azotaemia with a urine SG <1.035-1.040 is usually considered evidence of primary renal failure as if the azotaemia were associated with dehydration, in the presence of normal renal function active water conservation would lead to a much higher urine SG. However, as some cats with early renal failure ar still able to concentrate urine well, the presence of azotaemia and a urine SG >1.040 does not rule out the possibility of CRF. Although in most cases the diagnosis of CRF is relatively straightforward, there may be some where this is difficult, and additional investigations of renal function may be required (see below).

Stages of Feline CRF

The IRIS (International Renal Interest Society) group has defined four stages of renal failure in cats and these may help to some extent in targeting therapy for the disease. Absolute cut-off values of creatinine values for the different stages cannot be applied as these are affected by numerous variables other than renal function itself (hydration status, lean body mass etc.):

Stages of feline chronic renal failure (IRIS).

Although renal failure cannot generally be diagnosed until cats have developed azotaemia, many cats present with diseases where there is clearly renal damage even though they have not progressed to overt renal failure. Thus cats that present with pyelonephritis, glomerulonephritis, renal lymphoma etc., although they may not necessarily be azotaemic at the time of the diagnosis of their primary disease, there will be renal damage and loss of functioning nephrons. In these cases, the clear priority is specific therapy for the underlying disease, and preventing further renal damage through adequate disease diagnosis and management.

By the time azotaemia has developed, it can be assumed that around 75% of functioning nephrons have been lost, but even at this stage, clinical signs will be relatively mild or even non-existent early on. If an underlying disease can be diagnosed and specific treatment instituted this will again provide significant benefits in preventing further progression of disease, but in many (if not all) cats, the CRF will progress, although often at a slow rate. Attention is focused on therapeutic interventions that will help to slow down the rate of progressive nephron loss.

As cats progress though the period of moderate azotaemia, there is an increasing likelihood of clinical signs developing relating to the CRF (development of uraemic signs), and thus as cats progress through stage III disease and on into stage IV disease there is an increasing need to provide symptomatic and supportive therapy to address the manifestations of the uraemic syndrome and to some extent a lesser emphasis on therapies to slow progression of disease as this becomes more difficult in advanced renal failure.

Medical Management of CRF

Treatment of Underlying Cause

Identifying and treating reversible causes or contributory factors to CRF is important, although in many cases these may not be present. However, searching for conditions such as pyelonephritis, glomerulonephritis and urinary tract obstruction, or iatrogenic renal damage through administration of non-steroidal anti-inflammatory drugs or aminoglycoside antibiotics, may allow intervention to arrest further renal damage, and as such this part of the patient assessment should not be overlooked. Full urinalysis including urine sediment analysis, urine protein:creatinine ratio and urine culture (especially if there is evidence of inflammation on urine sediment analysis) should be performed as part of the initial assessment whenever possible.

Maintaining Fluid Balance

Inadequate water intake in CRF is associated with dehydration, reduced renal perfusion and further impairment of renal function. Some cats are presented in acute decompensation of CRF due to sudden volume depletion, whereas others, particularly as CRF progresses, may experience chronic or recurrent dehydration and renal hypoperfusion. Acutely decompensated cats require intravenous fluid therapy and reassessment of azotaemia after correction of the dehydration to permit accurate assessment of renal function.

Maintaining adequate fluid intake is of prime importance in CRF, and owners should be made aware of the obligatory polyuria that frequently accompanies renal failure and, therefore the consequent need for free access to water. Additional water intake can be achieved in a variety of ways

 Feeding moist rather than dry foods (this is a priority in cases of CRF, and cats that have been accustomed to dry food should be encouraged to slowly switch to a moist (tinned/sachet) food

 Supplementing the diet with water or broths

 Providing running water (pet fountains) and flavoured water, etc.

 Sub-cutaneous administration of fluids at home by owners

Delaying Progression, and Managing Complications of CRF

Dietary Protein Restriction

The benefits of protein restriction in dogs and cats with established CRF are not in doubt, and the positive impact that this can have on the quality of life and clinical disease is unquestioned. Accumulated evidence suggests that it is likely (though not certain) that protein restriction does have a positive impact on the progression of renal failure in these species, but it is generally accepted that this effect is likely to be relatively small, and the major benefit is through amelioration of signs of the uraemic syndrome.

Dietary Phosphorus Restriction

Both findings in cat studies, and also extrapolation from studies in dogs and other species, suggest that dietary phosphorus restriction is an important goal in the management of CRF. As much dietary phosphorus is associated with protein, the use of a protein restricted diet will reduce phosphate intake, and commercial renal diets are specifically phosphate restricted. It is now generally accepted that the combined effects of dietary phosphate restriction (direct reduction in circulating phosphate levels, indirect reduction in circulating PTH levels) is likely to have a very important renoprotective effect and can significantly help to slow the progression of renal failure. In addition, as PTH has been implicated as a uraemic toxin, control of dietary phosphate may also help to improve quality of life and relieve other uraemic manifestations.

Use of Phosphate Binders

If hyperphosphataemia persists (fasting serum phosphorus >2 mmol/l) despite dietary restriction, oral phosphate binders are indicated to control this and are best administered along with meals. Aluminium hydroxide was the traditional product of choice, and although very effective as a phosphate binder (30-90 mg/kg/day), this was always associated with palatability issues. In recent years, this product has been withdrawn from the market due to concerns over aluminium toxicity in humans. Two newer products have become available on the human market, and although relatively little is known about their use in dogs and cats, anecdotally they appear to be both safe and effective. Sevelamer (Renagel®) has been used in cats at a dose of 200mg 2-3 times daily and lanthanum carbonate (Fosrenal®) has been used at a similar dose.

Control of Hypokalaemia

Hypokalaemia, probably mainly from inappropriate kaliuresis, is a common finding in feline CRF with a reported prevalence of around 15-20% of cats with CRF. Overt clinical signs are generally not seen until the serum concentration falls below around 3.0 mmol/l. However, although polymyopathy is often regarded as the major clinical manifestation of hypokalaemia, there are other significant consequences that are of particular importance in cats with CRF and may occur with less severe hypokalaemia. Hypokalaemia can directly contribute renal damage (hypokalaemic nephropathy) and the advancement of renal failure. The renal compromise induced by hypokalaemia has a number of facets but includes hypokalaemia-induced renal vasoconstriction, reduced responsiveness of the kidneys to vasopressin and increased renal ammoniagenesis which directly contributes to interstitial nephritis. There is also evidence that the presence of hypokalaemia will contribute to both the metabolic acidosis and hypertension that can occur in CRF. Potassium concentrations should be monitored regularly in cats with CRF and if they fall below 4 mmol/l, supplementation with potassium salts is recommended.

Hypertension and Chronic Renal Failure

Although primary hypertension is recognised, many cases of feline hypertension are secondary to other diseases, and the association with renal failure is the most important of these. There is a great degree of individual variation in response to therapy, but in cats monotherapy with amlodipine (a calcium channel blocker) is generally regarded as the treatment of choice for systemic hypertension.

ACE-inhibitor Therapy in Humans

At present there is too little data available to know whether ACE-inhibitor therapy slows progression of feline CRF, although there is rationale and some data to suggest that cats with elevated (and especially markedly elevated) proteinuria levels do benefit from therapy (especially cats with a UPC ratio >1.0). If human data is applicable to the cat, then in hypertensive renal failure, the first priority is to control the hypertension, and ACEI may not adequately do this in cats. However, a second priority could be control of the degree of proteinuria and it could be argued that these two objectives might best be achieved by a combination of an ACEI and a calcium channel blocker, but evidence to support this as a first line therapy is lacking.