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IRIS CKD Guidelines Updates 2014 - 2015
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The IRIS Board made three significant changes to CKD Guidelines during 2014 and 2015. A summary of these new recommendations is presented here. The full version of 2015 Guidelines will be uploaded during our website relaunch by the end of 2015.

Substaging by Arterial Blood Pressure

We recommend replacement of the existing abbreviations for blood pressure substages (AP0-AP1) with descriptive terms as follows:

Systolic blood pressure
(mm Hg)
Diastolic blood pressure
(mm Hg)
Risk of future target organ
damage
BP substage
OriginalNew
<150 <95 Minimal AP0 Normotension
150 - 159 95 - 99 Mild AP1 Borderline hypertension
160 - 179 100 - 119 Moderate AP2 Hypertension
>180 >120 Severe AP3 Severe hypertension

Treatment of Proteinuria

We recommend that IRIS CKD Stage 1 patients with persistent proteinuria (UPC ≥ 0.5 for dogs or 0.4 for cats) are not only monitored and thoroughly investigated but also receive standard treatment for proteinuria as currently recommended for IRIS CKD Stages 2 to 4. This parallels the IRIS consensus statement on standard treatment for glomerulonephritis (J Vet Intern Med 2013;27:S27–S43).

Interpreting Blood Concentrations of Symmetric Dimethylarginine (SDMA) in CKD

SDMA concentrations in blood (plasma or serum) may be a more sensitive biomarker of renal function than blood creatinine concentrations. A persistent increase in SDMA above 14 µg/dl suggests reduced renal function and may be a reason to consider a dog or cat with creatinine values <1.4 or <1.6 mg/dl, respectively, as IRIS CKD Stage 1.

In IRIS CKD Stage 2 patients with low body condition scores, SDMA ≥25 µg/dl may indicate the degree of renal dysfunction has been underestimated. Consider treatment recommendations listed under IRIS CKD Stage 3 for this patient.

In IRIS CKD Stage 3 patients with low body condition scores, SDMA ≥45 µg/dl may indicate the degree of renal dysfunction has been underestimated. Consider treatment recommendations listed under IRIS CKD Stage 4 for this patient.

These comments are preliminary and based on early data from the use of SDMA in veterinary patients. We expect them to be updated as the veterinary profession gains further experience using SDMA alongside creatinine, the long-established marker in diagnosis and monitoring of canine and feline CKD.

CKD Early Diagnosis

Harriet Syme, London (2016)1

Introduction

One of the unfortunate things about managing CKD in dogs and cats in clinical practice is that the problem may only be 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 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 markers increase, the ability of the remaining nephrons to hypertrophy and hyperfiltrate is often overlooked: for example, if a patient has a 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 IRIS Stage 1 CKD

By definition, patients 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 develop azotaemia.

Other patients 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, a patient may have 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).

Primary glomerular disease
It is important to understand that severe proteinuria can be present, even resulting in nephrotic syndrome, without azotaemia. This severe glomerular proteinuria 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 very 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, hypoalbuminaemia, 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-azotaemic or only mildly azotaemic.

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 infection, particularly if the patient is also hypoalbuminaemic. 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 hypertension.

Systemic hypertension
Although many cats and dogs diagnosed with systemic hypertension have azotaemic CKD, some will be diagnosed before the advent of azotaemia. 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 they are non-azotaemic.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 end-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 patient will be presented for polyuria/polydipsia, and a renal cause is suspected after other common differential diagnoses have been ruled out, and the sonographic appearance of the kidneys is abnormal even though the patient is non-azotaemic. It is possible for there to be loss of nephron function sufficient to interfere with the medullary concentrating gradient yet insufficient to cause azotaemia. This can be an indication to assess GFR. This situation is thought to be more common in the dog than the cat; by the time owners complain that a cat is polyuric/polydipsic it is usually also azotaemic.

As an extension of this thought process it can be tempting to assume that any 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 is within the laboratory reference range. Undoubtedly some of these patients do have 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. 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. 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 Non-Azotaemic IRIS CKD Stage 22

Many, but not all non-azotaemic patients with IRIS Stage 2 CKD are thought to have reduced GFR compared to their individual baseline (pre-CKD) value. This deterioration in renal function results in a within-reference-range increase in blood creatinine concentration. Thus, while many patients are diagnosed with non-azotaemic IRIS CKD Stage 2 with the same methods as patients with Stage 1 disease as described above, additional patients may be identified by the serial monitoring of blood creatinine. With this in mind, it can be advantageous to obtain a baseline value for blood creatinine in an adult patient while the animal remains healthy, preferably using a reference laboratory rather than an in-house laboratory for consistency.2 This is valuable because it is clear that there are quite marked breed, size and inter-individual differences in GFR/serum creatinine which mean that evaluating trends in measurements within individual patients facilitates earlier detection of CKD. Additionally, substantial differences have been demonstrated in reference ranges for blood creatinine values between laboratories, so that a patient considered azotaemic in one laboratory might be reported as non- azotaemic by another.3 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 that is greater than this threshold is not intended to signify in isolation that the patient has CKD. In fact, Birman cats and some large or well-muscled breeds of dog cats will have blood creatinine values that are higher than these values, even sometimes falling outside the laboratory's reference range, while remaining healthy.5,6 Patients must be diagnosed with CKD before the staging scheme is applied and blood creatinine measurement alone is only sufficient to make a diagnosis of CKD if it exceeds the laboratory reference range, is sustained, and is not pre- or post-renal in origin.

A current area of active research and development within the veterinary nephrology community is in the development and evaluation of indirect measures of GFR (for example serum cystatin C and SDMA concentrations) that may have higher sensitivity than blood creatinine in the detection of patients with mildly reduced renal function.7 It remains to be determined whether these markers can provide increased sensitivity for detection of renal dysfunction without resulting loss of specificity. For now, the interpretation of discordant results (for example where blood creatinine is normal and SDMA is increased) will be context-specific; for example, if the patient is extremely poorly muscled and the blood creatinine is high-normal but serum SDMA is increased this is likely to support a diagnosis of CKD. Following the current IRIS guidelines, CKD must be diagnosed before applying the IRIS CKD staging system (based on blood creatinine) in the usual way.

Ultimately, whichever test (blood creatinine 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 will be maximised by the development of breed-specific reference ranges that are narrower than those for the species as a whole.

1 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

2 Stage 2 CKD starts with serum creatinine above 1.4 mg/dl (125 µmol/l) in dogs and 1.6 mg/dl (140 µmol/l) in cats which is below the laboratory reference range for many laboratories, hence the term 'non-azotaemic'

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, Cabé E, Geffré 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.