Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
Importance of Early Detection of Chronic Kidney Disease (CKD)
Feline CKD is an irreversible and variably progressive disease. The main factors associated with progressive renal injury are glomerular hyperfiltration in remaining nephrons, proteinuria, hyperphosphatemia, renal hypoxia and likely systemic hypertension. Correcting these factors, in order to retard disease progression, is a major goal of current therapeutic guidelines. Unfortunately, the diagnosis is often made late in the disease course (IRIS stage 3–4), limiting therapeutic options largely to supportive care. Early disease detection is important because more timely control of the factors associated with disease progression might lead to improved survival rates and quality of life.
Screening is regarded as an important public health tool for the early detection of CKD in people. General population screening is not recommended, instead screening is advised in patient groups at risk for CKD. Similarly, veterinarians are strongly encouraged to take efforts to diagnose CKD in earlier, preferably non-azotemic, stages (IRIS stage 1–2). In order to achieve this, screening of at-risk feline populations for CKD is fundamental.
Which Cats Should Be Screened for CKD?
The prevalence of CKD increases with age and CKD affects at least one third of geriatric cats (>15 years). Thus, screening for feline CKD is mandatory in apparently healthy aged cats. Ideally, screening of geriatric cats for CKD must be part of a more extensive health-screening program in order to also detect other chronic conditions.1 In addition, kidney function should be evaluated in aging cats whenever they present with acute or chronic illness or prior to anesthesia.
Endocrine diseases may affect kidney function. There is a strong link between thyroid and kidney function which becomes important in cats if hyperthyroidism develops. The increased GFR and muscle atrophy in untreated hyperthyroid cats may mask concurrent CKD by diminishing serum creatinine concentration, which may reverse after normalization of the hyperthyroid state. It is therefore important to closely evaluate kidney function in hyperthyroid cats before, during and after treatment.2 Diabetic kidney disease is a common and serious complication in people, but appears to be less important in feline diabetics. Recent data suggest monitoring of all diabetic cats for proteinuria.3
Pre-breeding screening for CKD is advised for cat breeds predisposed for polycystic kidney disease, namely Persian and related breeds, and may also be warranted for amyloidosis, mainly in Abyssinian cats. Other breeds, such as Ragdoll cats or Maine Coons, undergo pre-breeding screening, at least in some European countries, because recent studies revealed a predisposition for juvenile nephropathy.4,5
Evaluation of kidney function is also recommended in cats with diseases that might lead to CKD (e.g., infectious diseases, metabolic conditions, renal neoplasia, urolithiasis, conditions associated with renal ischemia and diseases potentially associated with glomerulopathy), in cats with unexplained weight loss, polyuria/polydipsia or hypertension, and in cats that require treatment with potentially nephrotoxic agents. Finally, after an episode of acute kidney injury, cats must be closely monitored for CKD.
Screening for CKD Using Routine Diagnostic Tests
In early CKD, clinical signs and physical examination abnormalities may be absent or remain unnoticed by cat owners. Therefore, veterinarians should improve owner awareness for these early signs (e.g., polyuria/polydipsia, weight loss, poor body condition), should perform a thorough nutritional assessment at each examination and compare physical findings with previous health examinations.
Until recently, the minimum laboratory database for CKD screening consisted of measuring serum creatinine, urine specific gravity (USG) and urinary protein:creatinine ratio (UPC). Unfortunately, serum creatinine and USG are insensitive markers for CKD and become abnormal only with advanced disease. Indeed, cats with early CKD often retain their urine concentrating ability (USG 1.015–1.035). In contrast, the majority of healthy cats, including aged cats, have USG>1.040, which makes CKD less likely in cats with USG>1.040. Additional problems for the interpretation of serum creatinine are the potential influence of muscle atrophy and the reference interval. Muscle wasting may lower serum creatinine concentrations and thus overestimate kidney function. Further, serum creatinine reference intervals can widely differ between laboratories and may be inappropriate, potentially leading to misclassification of samples. Also, the interpretation of UPC has recently been questioned because of frequent borderline proteinuria in juvenile healthy cats.6
Serial assessments of these routine variables may improve their sensitivity. Increasing serum creatinine concentrations, even within the reference interval, may indicate early kidney dysfunction, particularly in cats with weight loss, muscle wasting or USG consistently <1.035. To more objectively evaluate the clinical relevance of changes on serial laboratory measurements, subject-based reference intervals may be considered, by calculating reference change values or critical differences. Recent findings indicate that persistent increases of serum creatinine, 15–20% higher than baseline, may be consistent with reduced renal function.7
All the limitations of routine diagnostic tests for CKD imply that non-azotemic CKD is challenging to diagnose. An important progress has been made in veterinary medicine since symmetric dimethylarginine (SDMA) became available. Compared to serum creatinine, SDMA is more sensitive to detect CKD and increases earlier in the disease process.8 Moreover, SDMA is not influenced by muscle mass and might more accurately estimate kidney dysfunction in cats with muscle wasting.9 CKD IRIS stage 1 can be diagnosed if SDMA persistently exceeds the upper reference limit (14 µg/dL). Though current data support that SDMA becomes part of the minimum database for CKD screening, further studies are still warranted.
Advanced Diagnostic Tests for Early CKD Detection
More advanced diagnostic tests might be considered in cats with risk factor(s) or clinical sign(s) indicative for CKD that have questionable routine blood and urine tests. Unfortunately, currently only few advanced diagnostic tests are widely available that are both convenient and cost-effective.
Determination of glomerular filtration rate is considered to be the gold standard to evaluate kidney function. Both multi-sample and limited sampling approaches have been published in feline medicine, but all have practical limitations. Because the actual GFR value is not of major importance in daily practice, our research group recently developed two simple methods to identify cats with borderline or low GFR.10
Urinary biomarkers for tubular or glomerular damage might be helpful to better characterize feline kidney disease. However, many of these assays are not widely available and whether these biomarkers have benefit over routine variables in cats is currently unknown.
Finally, kidney biopsies may be considered where knowledge of morphologic alterations in renal structure will substantially influence patient management. However, this is not true for most cats with CKD that typically suffer from generalized tubulointerstitial nephritis. The diagnostic value of kidney biopsies in the management of feline CKD is currently poorly studied.
Conclusion
Veterinarians play a major role in the detection of early feline CKD. Through educating cat owners, regular thorough physical examinations and performing routine laboratory tests in cats with increased risk for CKD, kidney dysfunction may be diagnosed at earlier stages. The recent availability of SDMA is an important step forward for early detection of CKD. In cats with equivocal routine tests, close follow-up or advanced diagnostic tests should be considered.
These proceedings were adapted from "Paepe D. Early recognition of feline chronic kidney disease. Eur J Comp An Pract. 2015;25(3):61–77".
References
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2. van Hoek I, Daminet S. Interactions between thyroid and kidney function in pathological conditions of these organ systems: a review. Gen Comp Endocrinol. 2009;160:205–215.
3. Paepe D, Ghys LFE, Smets P, et al. Routine kidney variables, glomerular filtration rate and urinary cystatin C in cats with diabetes mellitus, cats with chronic kidney disease and healthy cats. J Feline Med Surg. 2015;17:880–888.
4. Paepe D, Bavegems V, Combes A, et al. Prospective evaluation of healthy ragdoll and control cats for chronic kidney disease by routine laboratory parameters and ultrasonography. J Feline Med Surg. 2013;15:849–857.
5. Gendron K, Owczarek-Lipska M, Lang J, Leeb T. Maine Coon renal screening: ultrasonographical characterization and preliminary genetic analysis for common genes in cats with renal cysts. J Feline Med Surg. 2013;15:1079–1085.
6. Paepe D. Screening for early feline chronic kidney disease. Limitations of currently available tests and possible solutions. PhD Thesis, Ghent University, Belgium; 2014.
7. Baral RM, Dhand NK, Freeman KP, et al. Biological variation and reference change values of feline plasma biochemistry analytes. J Feline Med Surg. 2014;16:317–325.
8. Hall JA, Yerramilli M, Obare E, et al. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28:1676–1683.
9. Hall JA, Yerramilli M, Obare E, et al. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine and medium-chain triglycerides. Vet J. 2014;202:588–596.
10. Paepe D, Lefebvre HP, Concordet D, et al. Simplified methods for estimating glomerular filtration rate in cats and for detection of cats with low or borderline glomerular filtration rate. J Feline Med Surg. 2015;17:889–900.