Early detection of chronic kidney disease in cats

Chronic kidney disease (CKD) is a common disease in cats, particularly as they get older. A recent study analysing electronic health records of cats found the prevalence of CKD to be 17 percent, with a mean age at diagnosis of around 13 years (Bradley et al., 2019). The cause remains unclear in many patients, but histology of the kidneys of affected cats often shows chronic interstitial nephritis and renal fibrosis, the severity of which is dependent on the stage of disease (McLeland et al., 2015). One of the most important and challenging aspects of CKD management is early diagnosis in order to implement effective treatments and management strategies to slow the progression of the disease and monitor it effectively.

What are the benefits of detecting CKD early?

Detecting CKD in the earlier stages is beneficial for enabling the prompt implementation of therapeutic interventions. These interventions are likely to be most effective earlier on in the course of the disease (Lees, 2004). The International Renal Interest Society (IRIS) has described a staging method for CKD in cats (Table 1), incorporating multiple factors including serum creatinine and symmetric dimethylarginine (SDMA), and can be further staged using the urine protein to creatinine ratio (UPC) and blood pressure. Nutrition is one of the most important aspects of management, as it has been shown to significantly impact the survival time of cats with CKD, particularly with respect to phosphorous restriction (Elliot et al., 2000). Recent guidelines from the International Society of Feline Medicine have recommended starting a renal diet for cats with CKD as early as possible in stage 2 (Sparkes et al., 2016). Whilst they acknowledge that there has been no determined point at which diet starts to produce benefits, ensuring that the cat accepts the diet and will eat it consistently is important, and acceptance of a new diet is more likely to occur before the cat’s appetite starts to become affected as a consequence of uraemic toxins. Renal diets should be gradually introduced over four to eight weeks to increase the likelihood of acceptance.

One of the benefits of starting a phosphorous-restricted diet early on is the addressing of hyperphosphataemia, which in turn can cause secondary renal hyperparathy­roidism. As the number of functioning nephrons decreases so does glomerular filtration rate (GFR), in turn leading to a reduction in the excretion of phosphate ions. Para­thyroid hormone (PTH) is secreted in response to hyper­phosphataemia to inhibit phosphate ion reabsorption in the kidney but also increases calcium and phosphate ion efflux from bone, in addition to stimulating renal calcitriol production. This increases calcium ion concentrations, and decreases phosphorous concentrations, but as phos­phorous is ultimately excreted by the kidney, hyperphos­phataemia occurs if dietary intake is not controlled (Ged­des et al., 2013).

Hyperphosphataemia also inhibits the production of calcitriol, which is an important inhibitor of PTH synthesis and is involved in phosphorous and calcium absorption from the intestine (Kidder and Chew, 2009). One study found that 84 percent of cats with CKD have an increased PTH (Barber and Elliot, 1998). Furthermore, some cats in that study were found to have normal concentrations of ionised calcium and serum phosphorous with elevated levels of PTH. Feeding renal diets with restricted phosphorous is associated with suppression of phosphate and PTH concentrations (Elliot et al., 2000). Secondary renal hyperparathyroidism is usually seen in cats with CKD at stages 3 and 4, given the severity is seen to increase with increasing azotaemia (Barber and Elliot, 1998). However, hyperphosphataemia and secondary renal hyperparathyroidism can be identified in cats with CKD as early as IRIS stage 2 (Kidder and Chew, 2009) which suggests the importance of starting dietary modification promptly in these cases.

How can CKD be diagnosed earlier?

Investigations to rule CKD in or out are often started in response to the cat being presented with clinical signs that the owner has noticed, or after abnormalities are detected on routine monitoring tests. Routine “wellness checks” are encouraged for senior cats once they reach between 7 and 10 years of age at intervals of six months, and it is recommended that a physical examination and haematology, biochemistry, urinalysis, total thyroxine (T4) and blood pressure measurement is included (Pittari et al., 2009). This may help to detect CKD at an earlier stage for many cats, as they often appear well despite suffering from underlying diseases. In addition, owners may attribute clinical signs in older cats solely to ageing. Clinical signs in these patients include polyuria, polydipsia, weight loss, anorexia and lethargy among others (Reynolds and Lefebvre, 2013).

Clinical signs are important factors when considering the likelihood of a patient having CKD. A study by Green et al. (2014) found that the likelihood of a patient having CKD increased when cats had lost 10 percent or more of their body weight in the previous 6 to 12 months. The same study found that periodontal disease, cystitis, dehydration or anaesthesia occurring in the previous year were also associated with an increased likelihood of CKD, which should prompt investigation to rule CKD in or out in those patients.

When considering investigations for these patients, the diagnosis of early CKD is difficult; there is no accurate biomarker that exists for renal function. Methods that directly measure glomerular filtration rate are not widely available and a diagnosis is usually achieved using a combination of blood testing and urinalysis. Even then, interpretation of these tests can be challenging (Sparkes et al., 2016).

Creatinine is widely used to aid diagnosis of renal disease in cats alongside other diagnostic tools including urinalysis. It is produced by muscle and filtered by the glomerulus, although not reabsorbed. This means it is not as affected by pre-renal causes, such as dehydration, unlike urea. However, the interpretation of creatinine is not without challenge. Because creatinine is produced by muscle, muscle mass can affect creatinine levels and should be considered when interpreting creatinine values (Braun et al., 2003). In addition, approximately 75 percent of renal filtering capacity can be lost before elevations in creatinine and urea are seen on serum biochemistry (Finco et al., 1995), so detecting CKD early on is challenging. Indeed, the IRIS staging criteria (2019) indicates that a cat with stage 1 or 2 CKD may have a normal serum creatinine, and to diagnose these earlier stages of renal disease other diagnostics should be considered.

Identifying an SDMA that is persistently elevated above 14 μg/dl, proteinuria or other findings including abnormal histopathology results from a renal biopsy may raise suspicion of underlying CKD. Measuring SDMA is a relatively new test that has become available over the last few years and shows promise in identifying CKD in cats at an earlier stage. Concentrations of SDMA have been shown to increase up to 17 months before serum creatinine (Hall et al., 2014), therefore it has a place in aiding diagnosis in cases where creatinine is not elevated but CKD is suspected. SDMA can also be of use in Birman cats, which have been shown to have physiologically high creatinine levels, to avoid over-diagnosing CKD in this breed (Paltrinieri et al., 2018).

Urinalysis is of great importance in the diagnosis of CKD and is recommended for use alongside biochemical tests during investigation of these patients. Detecting the presence of proteinuria is also useful in the early diagnosis of CKD in cats, and the UPC has been shown to be associated with survival in cats (Syme et al., 2006; King et al., 2007).

Conclusion

The early detection of CKD in cats can be difficult, although advancements have been made recently that increase the likelihood of detecting CKD at earlier stages, including the availability of SDMA analysis. A thorough clinical history, along with regular assessments of those cats most at risk of developing CKD, is recommended. Once diagnosis is achieved, CKD should be staged and substaged to appropriately tailor treatment, and appropriate therapeutic interventions should be instigated early in the course of CKD.