CHAPTER 47 Linking Treatment to Staging in Chronic Kidney Disease
The International Renal Interest Society (IRIS) has proposed that the terms chronic renal failure and chronic renal insufficiency be replaced by chronic kidney disease (CKD) and that a staging system be used to facilitate the management of feline patients with CKD.1 This classification scheme is based on a two-step process: (1) establish a diagnosis of CKD and (2) establish the stage of the disease. Stage of disease also can be linked to prognosis,2 diagnostic approach, and treatment recommendations (Figure 47-1).1
Figure 47-1 Diagnostic and therapeutic emphases in different stages of feline chronic kidney disease (CKD). Once a diagnosis of CKD is established, the International Renal Interest Society (IRIS) recommends staging the disease on the basis of a measurement of serum creatinine concentration (Cr) in a cat that is hydrated with stable renal function. There are three sets of linked diagnostic and therapeutic considerations, with the importance of each set reflected by the thickness of the corresponding arrow in the diagram. See text for further details.
The term CKD refers to any disease process in which there is a loss of renal function due to a prolonged (generally >2 months in duration) and, usually, progressive process. CKD generally will produce dramatic changes in renal structure as well, although the correlation between structural and functional changes in the kidney is imprecise. This is partly because of the tremendous renal functional reserve that allows cats to appear healthy for long periods of time with only a small fraction of initial renal tissue, perhaps less than 10 per cent. Thus a CKD often “smolders” for many months or years before becoming clinically apparent.
Most feline CKD is not reversible, and once acquired, rarely resolves. Although congenital disease causes a transient increase in incidence of CKD in cats less than 3 years of age, the prevalence of CKD increases with advancing age from 5 to 6 years upward. In aged populations at referral institutions, CKD affects up to 35 per cent of cats.3,4 A reasonable estimate of the prevalence of CKD in the general feline population is 1 to 3 per cent.
The first step in the IRIS staging scheme is to establish a diagnosis of CKD. Any disease that affects the kidney of a cat is likely to alter both renal structure and function. It is the adequacy of renal function, however, that dictates the impact of this disease on the patient. Although the kidney has many biological functions of importance to a cat, the most basic and central renal function is filtration; the glomerular filtration rate (GFR) serves as the “gold standard” for assessment of kidney function in cats. It is generally fair to assume that changes in the level of most renal functions parallel changes in GFR in a clinical patient.
Confirmation of a reduced GFR is a highly reliable indicator of renal dysfunction, although it must be remembered that reductions of GFR (and elevations of serum creatinine) can be caused by renal, prerenal, and postrenal factors and that renal function may be lost due to acute kidney injury (also known as acute renal failure) or CKD. In the research laboratory, GFR is assessed as urinary clearance of marker substances, such as inulin or creatinine. In clinical patients, urinary clearance tests generally are not practical; however, the measurement of the disappearance from plasma of renally cleared marker substances such as creatinine, inulin, iohexol, or diethylenetriamine pentaacetic acid (DTPA), following intravenous administration, can provide an approximation of GFR.5–9
The IRIS recommendations recognize that in most clinical patients, GFR is assessed by the measurement of plasma or serum concentrations of creatinine (Cr) and/or blood urea nitrogen (BUN). The BUN is affected by several nonrenal factors, such as protein intake, liver function, and urine flow rate, making Cr a better index of GFR. Classically, CKD in cats was diagnosed (Box 47-1) as the presence of renal azotemia (elevated Cr) accompanied by low urine specific gravity (USG) (<1.035). The wide reference range for Cr has led to the oversimplified assertion that 75 per cent of nephrons must be destroyed before Cr (and BUN) rises out of the range. Unfortunately, although valid, these diagnostic criteria are insensitive, often failing to identify CKD until dramatic loss of functional renal mass has occurred. However, any structural damage that reduces GFR almost always will be reflected as an increase in Cr (or BUN), initially within the normal range. The IRIS recommends that serial measurements of Cr be interpreted with this relationship in mind, noting that increases in Cr, even within the normal range, suggest a declining GFR and the presence of a renal disease.
Structural changes appreciated by palpation, radiography, ultrasonography, or histopathological examination generally are diagnostic of renal disease. In early feline CKD, when azotemia and clinical signs are absent, renal disease sometimes is discovered inadvertently as a result of imaging studies, laparotomy, or urinalyses conducted for other purposes.
The urinalysis may provide clues to the presence of a renal disease. A urinary tract infection localized to the kidney is one example. A potentially useful early indicator of the presence of CKD is a USG lower than 1.035 despite dehydration. Cats with early CKD often have a USG lower than 1.020. However, cats with early CKD, and some with CKD of any severity, may retain the ability to concentrate urine to a specific gravity greater than 1.035. Although USG is a simple and readily available test, interpretation of a low USG can be complicated by the presence of conditions that lead to retention of solute in tubular fluid (e.g., diuretic administration and diabetes mellitus), central diabetes insipidus, and nephrogenic diabetes insipidus (e.g., hyperadrenocorticism, hypercalcemia, and diseases causing septicemia).
Recently, tests for identification of proteinuria in cats that are both sensitive and specific have been developed.10 These include the protein-creatinine ratio (UPC) and feline-specific albuminuria tests. The ability to identify persistent renal proteinuria with these tests offers promise for identifying early CKD.10 The presence of persistent renal proteinuria in a cat is suggestive of renal disease.
Distinguishing acute kidney injury (AKI) from CKD is, in ideal circumstances, based on knowledge of disease duration, with CKD generally being defined as any renal disease that is present for 2 months or longer. History, physical examination, complete blood count, and renal imaging studies also are useful in distinguishing AKI and CKD. Although AKI may progress to CKD, it is generally identified soon (less than 2 weeks) after the insult. Staging and management of AKI and CKD differ; this chapter addresses the latter. Some findings that are suggestive of CKD, such as the presence of renal osteodystrophy and anemia, may assist in establishing a diagnosis of CKD but generally are not useful for identifying the presence of an otherwise masked case of CKD.
For all patients with CKD, a thorough history and physical examination should be accompanied by complete clinical pathology testing, which includes a serum biochemical panel, hematology, and urinalysis with specific proteinuria tests and aerobic bacterial culture. Survey radiography, abdominal ultrasonography when available, and blood pressure measurements also should be performed (see Chapter 49). This initial battery of tests (best conducted while the disease is stable) allows the veterinarian to stage the disease and to choose proper therapeutic and diagnostic strategies.
CKD in cats often progresses along a continuum from an initial nonazotemic stage to end-stage uremia. In many cats with CKD, the rate of progression is remarkably slow. As veterinarians, we are obligated to address the specific problems and patient needs that characterize the animal’s disease, and these vary from stage to stage. Staging of an animal with an established diagnosis of CKD is based on measurement of Cr in a well-hydrated patient with stable renal function (Table 47-1).1 This classification system employs four stages: Stage I: nonazotemic CKD disease; Stage II: mild renal azotemia; Stage III: moderate renal azotemia; and Stage IV: severe renal azotemia.
Cats with CKD frequently exhibit elevations of systemic arterial blood pressure (BP)11 (see Chapter 49). The American College of Veterinary Internal Medicine Consensus Statement11 and IRIS1 define systemic hypertension as any elevation of BP that leads to target-organ damage (TOD) and defined blood pressure ranges associated with minimal, low, moderate, and severe risk of TOD (Table 47-2). The target organs of concern in cats are the kidneys (TOD: progression of CKD, proteinuria); eyes (TOD: blindness, intraocular hemorrhage, retinal detachment, retinal vessel tortuosity); brain (TOD: seizures, depression); and cardiovascular system (TOD: congestive heart failure, vessel rupture). Left ventricular hypertrophy (LVH) is observed commonly in hypertensive cats, although there is controversy as to whether this constitutes true TOD or is simply an adaptive change. Nonetheless, the presence of LVH in a cat with CKD should be taken as presumptive evidence of clinically significant hypertension unless proven otherwise. The IRIS recommends that BP be measured using a device and method individualized for each clinical practice in every cat with CKD and that target organs be evaluated carefully for the presence of TOD, which is referred to as a complication. Although some devices provide both systolic and diastolic BP, staging most often is done on the basis of systolic BP measurements; recent evidence suggests that systolic hypertension is the most important determinant of TOD in other species.11 Additional information about blood pressure measurement and feline hypertension can be found in Chapter 49.