CKD Early Diagnosis

Harriet Syme, London (2019)¹

Introduction

The diagnosis of CKD in dogs and cats in clinical practice is unfortunately identified quite late in the disease process, usually once the patient already presents with clinical signs. This limits the potential benefit of treatment that in many instances might be expected to delay progression rather than result in recovery of renal function, and makes identification of the underlying aetiology difficult. It is therefore a goal in veterinary and human nephrology to develop better methods for early detection of CKD.

It is often assumed that our inability to detect CKD until the canine or feline patient has lost more than three-quarters of their nephrons and developed azotaemia is because conventional diagnostic tests (urea, creatinine) are insensitive indicators of GFR. However, although it is true that the relationship between these indirect markers and GFR is curvilinear, so that when renal function is near-normal substantial changes in GFR have to occur before the increase in the markers is noticeable, the ability of the remaining nephrons to hypertrophy and hyperfiltrate is often overlooked. For example, if a patient loses 50% of its kidney function (unilateral nephrectomy), GFR will have nearly returned to its baseline (pre-surgical) value within a few weeks after surgery. Therefore, even with direct estimation of GFR (see topic 10: GFR in practice) it can be difficult to detect CKD in its incipient stages, particularly if the disease is tubulointerstitial in nature.

Identifying Patients with CKD but "normal" GFR (IRIS Stage 1)

By definition, dogs and cats with Stage 1 CKD have normal, or near-normal, GFR. This means that many of the clinical signs that are classically associated with CKD are absent; indeed, many (but not all) patients with Stage 1 disease will be asymptomatic.

Some patients are diagnosed with IRIS Stage 1 CKD due to screening because of a family- or breed-related history of a renal disorder (e.g. polycystic kidney disease in Persian cats, hereditary nephritis in cocker spaniels) for which a specific diagnostic test is available. In these patients there will be a progressive loss in GFR as the disease progresses and they will eventually develop azotaemia.

Some patients are recognized due decreased urine concentration ability manifesting as polyuria and polydipsia. When other differentials were ruled out, consideration should be given for presence of CKD.

Other dogs and cats are diagnosed with IRIS Stage 1 CKD because of the presence of structural renal lesions. In many instances these are discovered incidentally when performing abdominal ultrasonography for an unrelated problem. For example, renal infarcts, renal cysts or poor corticomedullary definition. It is often difficult to determine in these patients what the likelihood of disease progression is and whether any treatment for CKD is indicated. In addition, patients may be diagnosed with IRIS Stage 1 CKD when the renal function that is most affected is something other than GFR. Examples of this include primary glomerular disease resulting in proteinuria, aberrant blood pressure regulation resulting in hypertension, or the presence of indicators of a primary tubulopathy (glucosuria, crystalluria, acidosis). In all these dogs and cats, serial monitoring of renal function is warranted to determine whether the disease is progressive and leads to loss of functioning nephrons.

Primary glomerular disease
It is important to understand that severe proteinuria can be present, even resulting in nephrotic syndrome, without any decrease in GFR (leading to azotemia). This severe glomerular proteinuria is more frequent in dogs than in cats, and occurs due to a loss of structural integrity of the glomerular filtration barrier without an initial substantial decrease in the number of functional nephrons. The presenting clinical signs in patients with primary glomerular disease are variable. In some, signs of an underlying disease process (such as leishmaniosis) will predominate. In others, indications of a protein-losing nephropathy (PLN) are present on routine blood and urine tests; here, hypoalbuminemia, hypercholesterolemia and proteinuria are expected, but clinical signs (malaise, poor hair coat, lethargy) are very non-specific. Occasionally patients with PLN are presented with signs referable to thromboembolism (hind-limb weakness or dyspnoea) or consequences of systemic hypertension. Kidney biopsy is indicated in the diagnostic work-up of patients with primary glomerular disease without identifiable underlying cause, provided they are non-azotemic or only mildly azotemic (IRIS CKD Stages 1 or 2).

There is no finite cut-point for severity of proteinuria (quantified by UPC) that differentiates primary glomerular disease from other types of renal disease or indeed non-renal diseases. However primary glomerular disease is considered likely if the UPC is repeatedly >2.0 in the absence of urinary tract inflammation, particularly if the patient is also hypoalbuminemic. Normal UPC values are less than 0.2 in both dogs and cats but a 'grey-zone' exists above this value; many of these patients will have tubulointerstitial renal disease resulting in glomerular hypertension and secondary glomerular injury but some will have primary glomerular disease and some with borderline proteinuria (0.2-0.4 in the cat, 0.2-0.5 in the dog) will have underlying systemic disease or systemic hypertension.

Systemic hypertension
Although many cats and dogs diagnosed with systemic hypertension have azotemic CKD, some will be diagnosed before the onset of azotemia. In the absence of other identifiable causes for hypertension (e.g., hyperadrenocorticism, pheochromocytoma, aldosterone-producing adrenal tumour or hyperthyroidism), it is often presumed that these patients have underlying CKD. It has been shown that dogs with proteinuria due to leishmaniosis are at increased risk of hypertension, even when non-azotemic.1 Ideally, dogs and cats would be diagnosed with hypertension due to the pre-emptive measurement of blood pressure. Unfortunately, especially in cats, hypertension is often only diagnosed after signs of target-organ damage (particularly ocular signs such as hyphema, blindness, retinal detachment) have developed, but these seem less common in dogs.

Loss of Urine Concentrating Ability
Sometimes a dog or cat will be presented for polyuria/polydipsia, and a renal cause is suspected after other common differential diagnoses have been ruled out. Often this is because the sonographic appearance of the kidneys is abnormal. It is possible that nephron function results in interference with the medullary concentrating gradient, yet insufficient to cause azotemia. This can be an indication to assess GFR. This situation is thought to be more common in the dog than the cat, in which polyuric/polydipsic are typically indicated by the owners when the cat is usually azotemic.

As an extension of this thought process it can be tempting to assume that a patient that has sub-maximally concentrated urine (i.e. urine specific gravity >1.008 but <1.030 in the dog or <1.035 in the cat), and no other obvious alternative cause for polyuria/polydipsia, has kidney disease, even if the blood creatinine and SDMA are within the laboratory reference range. Undoubtedly some of these patients do have mild kidney disease, but not all of them. In particular, it is important to realise that there are species differences in this regard. Cats typically drink relatively little and, especially if they have been fasted, when their renal function is good they will usually make concentrated (>1.035) urine, particularly if they are eating a dry diet exclusively. In contrast, dogs drink more and do not always concentrate their urine; randomly collected urine samples quite frequently have specific gravity in the 1.020 - 1.030 range. In dogs alternative causes of polyuria/polydipsia (e.g. hyperadrenocorticism) are also relatively more common than in the cat. Therefore, non-concentrated urine in a dog without other clinical signs should not be over-interpreted as an indication of kidney disease. It is also helpful to remember that the finding of hyposthenuric urine (<1.008, in a patient that has not been receiving supplementary fluids) does not support a diagnosis of CKD.

Identifying Patients with mildly reduced GFR (IRIS CKD Stage 2)

Some dogs and cats with IRIS CKD Stage 2 disease will be easily diagnosed because blood creatinine and SDMA are increased out of the laboratory reference range. However, additional patients may be diagnosed with stage 2 CKD, including:

• Dogs and cats with independent evidence of CKD (e.g. structural changes, proteinuria, normoglycaemic glucosuria) as described in the previous section, but with creatinine and/or SDMA values that reach the threshold for stage 2

• Dogs and cats with a within-reference range increase in creatinine andr persistent SDMA concentration ³18 μg/dl.

• Dogs and cats with persistently elevated (³18μg/dl) SDMA but within reference range creatinine concentrations, especially if the patient is poorly muscled or patients that have some other evidence of CKD. This may come from the history or physical examination or diagnostic imaging.

With the last two categories there is a trade-off between sensitivity and specificity of diagnostic tests at play: there is a desire to detect CKD in as early a stage as possible because treatment is most likely to be beneficial when the number of functional nephrons is not severely reduced, while on the other hand there is the potential for misdiagnosis of CKD in some patients. Misdiagnosis of CKD is problematic, not only because of unnecessary distress and expense caused to the animal's owners, but also because of the inclusion of these patients in trials of novel therapies for CKD. For a treatment to be proven useful requires that there is a difference in the rate of disease progression in the two treatment arms, or between treatment and placebo, and if many patients that are unlikely to have progressive disease are included, this will result in erroneous conclusions regarding the efficacy of the treatment. In the future it is hoped that markers of "active" renal disease may be developed that will complement the indirect markers of GFR (creatinine, SDMA) and so help to identify canine and feline patients with active disease for which treatments should be targeted. This might include mild increases in markers of AKI.

There are some situations in which creatinine and/or SDMA is likely to be mildly increased without CKD being present. Examples of this are the greyhound dog and the Birman cat, in both cases GFR is apparently quite low, even in apparently healthy individuals without evidence of renal disease. This effect is further confounded in greyhounds due to their high muscle mass. While these examples can be considered "outliers" there are also differences in reference intervals for other breeds of dog (and possibly cat). Ultimately, whichever test (blood creatinine, SDMA or an alternative) is used as a surrogate marker of GFR in routine clinical practice, it would seem that its diagnostic accuracy for the diagnosis of CKD would be maximised by the development of breed-specific reference ranges that are narrower than those for the species as a whole.

Even if breed-specific reference ranges were to be developed there remains a great deal of inter-individual variation in GFR within breeds. It has been shown in healthy beagles that have had serial measurement of GFR that while there is significant day-to-day variation in the values, there is much greater variability between individuals (almost two-fold).⁸ This means that the best way to determine that the patient has a reduction in GFR is to use that animal as its own control, by obtaining baseline measurements of creatinine (and ideally SDMA) when the animal is a young, healthy, adult. Preferably this measurement would be performed in a reference laboratory rather than in-house and the same laboratory used for follow-up testing. However, if individual baseline values are used to monitor individual patients, care must be taken not to over-interpret small changes because day-to-day variation in blood creatinine measurements has been found to be as high as 20%.⁴

It is important to recognise that the cut-points for blood creatinine between Stages 1 and 2 are not intended to replace individual laboratory reference ranges. Identifying a blood creatinine concentration (or SDMA) that is greater than this threshold is not intended to signify in isolation that the patient has CKD. Patients must be diagnosed with CKD before the staging scheme is applied and markers of GFR alone are only sufficient to make a diagnosis of CKD if they are clearly abnormal, if mild increases are sustained or serially increasing, and the elevation is not pre- or post-renal in origin.

Although IRIS cut-offs are not intended to replace individual laboratory reference intervals it is notable that in many laboratories it is unclear how these were derived or where this is known, reference intervals are based on measurements from relatively small numbers of animals, which were not always safely confirmed to be healthy. Although differences in methodology do exist between laboratories such that it would be reasonable to expect differences in reference intervals it is not clear that the laboratories for which creatinine measurements "run high" are also those with the highest reference ranges. This is something that has also been recognised in human clinical pathology and has resulted in a movement towards harmonisation of reference ranges between laboratories with the use of shared standards and consistent adjustments to account for methodological differences. If in the future such harmonisation could be achieved between veterinary laboratories it would aid the serial monitoring of patients and establishment of breed-specific reference ranges because it would allow larger data-sets to be collated.

This article is an update of and contains material from one written by AM van Dongen, Utrecht, Netherlands and R Heiene, Oslo, Norway in 2013

References

1. Cortadellas O, del Palacio MJ, Bayon A, et al. Systemic hypertension in dogs with leishmaniasis: prevalence and clinical consequences. J Vet Intern Med 2006;20:941-947.

2. Braun J-P, Cabˇ E, Geffrˇ A, et al. Comparison of plasma creatinine values measured by different veterinary practices. Veterinary Record 2008;162:215-216.

3. Ulleberg T, Robben J, Nordahl KM, et al. Plasma creatinine in dogs: intra- and inter-laboratory variation in 10 European veterinary laboratories. Acta Vet Scand 2011;53:25.

4. Jensen AL, Aaes H. Critical differences of clinical chemical parameters in blood from dogs. Research in Veterinary Science 1993;54:10-14.

5. Reynolds BS, Concordet D, Germain CA, et al. Breed Dependency of Reference Intervals for Plasma Biochemical Values in Cats. Journal of Veterinary Internal Medicine 2010;24:809-818.

6. Dunlop MM, Sanchez-Vazquez MJ, Freeman KP, et al. Determination of serum biochemistry reference intervals in a large sample of adult greyhounds. Journal of Small Animal Practice 2011;52:4-10.

7. 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.

8. Kampa, N., et al. (2003). "Day-to-day variability in glomerular filtration rate in normal dogs by scintigraphic technique." J Vet Med A Physiol Pathol Clin Med 50(1): 37-41.