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Compendium October 2010 (Vol 32, No 10)

Glomerular Filtration Rate in General Small Animal Practice [CE]

by Eric H. Linnetz, DVM, DACVIM, Thomas K. Graves, DVM, PhD, DACVIM

    CETEST This course is approved for 3.0 CE credits

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    Abstract

    Quantitative evaluation of renal function in small animal general practice has remained essentially unchanged for decades. Glomerular filtration rate (GFR) is considered the gold standard for evaluating functional renal mass in veterinary medicine. For practical and financial reasons, GFR testing was previously available only at referral veterinary hospitals. Newer techniques for estimating GFR now allow the routine performance of this test in any small animal practice.

    For decades, quantitative evaluation of renal function in small animal, primary care practice has been limited to the measurement of serum creatinine, serum urea nitrogen, and urine specific gravity. However, these parameters are rather insensitive because they are altered only after 60% to 75% loss of renal function.1–6 They are also not specific because they may be influenced by nonrenal variables or diseases.3–5,7–9 Although abdominal ultrasonography has dramatically enhanced the ability to evaluate the kidneys in animals with renal disease, it provides no quantitative measure of renal function. The quantitative assessment of functional renal mass in general practice has remained essentially unchanged for more than 50 years.

    Measures of renal function that are sensitive to mild decreases in renal function exist. Glomerular filtration rate (GFR) has long been considered the best reflection of renal function in human and veterinary medicine1,4,6,7,10 because it is directly related to functional renal mass.3,8,9,11,12 However, practical and financial considerations have limited the use of this test to veterinary teaching hospitals, large private hospitals, and research settings. As a result, most private veterinary practitioners do not perform GFR studies, and many are unfamiliar with GFR testing techniques.

    Principles of Glomerular Filtration Rate Estimation

    Renal excretory function may be conceptually divided into glomerular function (filtration) and tubular function (secretion and absorption). Through a combination of these processes, the kidneys perform their principal physiologic role: regulation of the volume and composition of extracellular fluid.3,13,14 Although glomerular and tubular function cannot be directly measured, they can be estimated based on the principle of clearance.

    Clearance is defined as the volume of fluid completely cleared of a substance during a given period of time.10,15 This is not an actual volume. Rather, it is the conceptual volume that previously contained the amount of substance that has been removed.15 For example, if clearance is 10 mL/min, then the amount of substance removed each minute will be equal to the amount present in 10 mL of fluid. Note that clearance refers to the rate at which a fluid is cleared of a substance and not to the quantity of substance removed.

    Total plasma clearance is equal to the sum of the individual routes of plasma clearance.10,15 One potential route, renal clearance, represents the sum of the processes of glomerular filtration, tubular secretion, renal metabolism, and renal retention of the substance. Urinary clearance refers to the volume of plasma cleared of a substance that eventually appears in the urine.15 Because not all substances cleared by the kidneys necessarily appear in the urine (e.g., if renal retention or metabolism occur), urinary clearance can differ from renal clearance.

    If a substance is solely cleared by the kidneys and undergoes no renal retention or metabolism, then plasma clearance, renal clearance, and urinary clearance will be identical. In this instance, the only route of elimination from the plasma is through the kidneys, and all of the substance cleared by the kidneys appears in the urine.4,15 Furthermore, if the substance is filtered at the glomerulus and does not undergo tubular secretion, then glomerular filtration represents the only route of removal of the substance from plasma, and any of the three clearances (plasma, renal, or urinary) provides an estimate of GFR. Such a substance is called a filtration marker. The ideal filtration marker is one that5,7,10,12,15

    • is freely filtered at the glomerulus;
    • is not secreted, absorbed, or metabolized by the renal tubules;
    • is not protein bound in the plasma;
    • does not enter erythrocytes;
    • has no other routes of clearance from the plasma; and
    • does not itself alter GFR.

    Inulin is the classic ideal filtration marker.1–5,7,9–13,15

    Various techniques for estimating GFR in veterinary medicine exist. They differ by filtration marker, sampling technique, speed, cost, mathematical model, and need for specialized facilities or licensing.10,11,15

    The most obvious difference among techniques is the choice of filtration marker. Filtration markers are classified as either possessing or lacking a radionuclide (BOX 1). Because radionuclides require special facilities, licenses, and training, their use is limited in veterinary medicine. Filtration markers lacking a radionuclide are subdivided into iodinated and noniodinated agents. These markers do not require special facilities, licenses, or handling procedures. Iodinated agents are further classified as either ionic or nonionic and as either hypertonic or isotonic.

    Glomerular Filtration Rate Estimation Using Urinary Clearance

    The historical gold standard for estimating GFR in veterinary medicine is urinary clearance of inulin.2–4,7,9–12,15–17 Inulin, a fructose polymer, is eliminated from plasma exclusively by glomerular filtration, is not reabsorbed or metabolized in the kidneys, and does not itself alter GFR. Thus, inulin closely meets the criteria for the ideal filtration marker.4,7,10,15 To measure urinary inulin clearance, a constant-rate infusion of inulin is administered to establish a steady-state plasma concentration. The bladder is evacuated by urinary catheterization, a period of time is allowed to elapse, and catheterization is repeated to collect the urine formed during the interval. Urine flow (volume of urine produced per unit of time), urine concentration of inulin, and plasma concentration of inulin are measured.

    These three parameters—urine flow, urine concentration of inulin, and plasma concentration of inulin—are used to calculate urinary clearance of inulin1,3,4,10,15:

    Reported values for normal urinary inulin clearance (mean ± standard deviation) are 3.39 ± 0.7318 and 4.60 ± 0.1519 mL/min/kg for dogs and 3.51 ± 0.6020 and 2.64 ± 1.1217 mL/min/kg for cats.

    Because measurement of urinary clearance requires urine collection, this technique has several important disadvantages. Urine collection, whether performed by urinary catheterization or with a metabolic cage, is cumbersome and prone to sampling error. In addition, urinary catheterization generally necessitates sedation or anesthesia, which not only poses risk to the patient but also can alter GFR. Thus, estimation of GFR by urinary inulin clearance is impractical for routine use in general practice.

    Glomerular Filtration Rate Estimation Using Plasma Clearance

    An ideal filtration marker allows estimation of GFR by urinary, renal, or plasma clearance. Thus, an alternative to measuring urinary clearance is to measure plasma clearance. Plasma clearance is determined by measuring the rate of disappearance of a marker from plasma after bolus injection. The major advantage of this method is that only plasma samples are required, eliminating the need for urine collection.

    Mathematically, the calculation of plasma clearance is more complicated than that for urinary clearance. A plasma disappearance curve is generated by plotting the logarithm of plasma concentration of the marker versus time10 (FIGURE 1). Using mathematical models, the area under the plasma disappearance curve (AUC) is calculated.8,10 Plasma clearance is then calculated by dividing the dose of the marker administered by the AUC.8–11,15

    Plasma clearance of iohexol is particularly suitable for private small animal practice. Iohexol is a sterile, nonionic, iodinated contrast agent.2,4,5,10,21 It is commercially available (Omnipaque, GE Healthcare, Princeton, NJ), affordable, extremely stable, and allows for analysis of small sample volumes.2,10 Because iohexol is neither ionic nor hyperosmolar, adverse events with its administration are rare, even in patients with compromised renal function.2,4,5,10 Importantly, iohexol sample analysis and clearance calculation are readily available to private practitioners at the Diagnostic Center for Population and Animal Health at the Michigan State University College of Veterinary Medicine (http://www.animalhealth.msu.edu/Bin/Catalog.exe?Action=Test&Id=1578).

    Among the various protocols for plasma iohexol clearance, the most appealing require only three plasma samples drawn 2, 3, and 4 hours after injection. Using this limited sampling strategy, reported values of GFR in healthy dogs include 2.9 ± 0.3 mL/min/kg (mean ± SD)21 and 1.56 to 2.96 mL/min/kg (range; no median reported)4. Reported values in healthy cats include 3.64 ± 0.13 mL/min/kg (mean ± SD)11 and 3.22 to 6.23 mL/min/kg (range; median, 3.68)9. Adverse events were reported in only one study and were limited to transient vomiting in three of nine cats receiving simultaneous bolus injection of iohexol and inulin.1,4,8,21

    Another plasma clearance technique for estimating GFR is clearance of exogenously administered creatinine. Creatinine meets most of the criteria of an ideal filtration marker. Although intravenous injection of creatinine may seem counterintuitive, creatinine administration is safe and remarkably well tolerated. Although serum creatinine is a component of azotemia, it does not contribute to uremia, and no adverse events have been reported in dogs or cats.1,6,8,22,23 The protocol for plasma clearance of exogenous creatinine is similar to that for plasma clearance of iohexol. Various protocols have been explored in dogs and cats.1,6,8,22,23 Although these studies provided encouraging results, more work is needed to establish specific protocols and reference ranges. We know of no commercially available formulation of creatinine for injection. Reagent-grade creatinine has been used in research settings but is not recommended for clinical patients.

    Standardization of Glomerular Filtration Rate to Body Size

    The standard unit of clearance is milliliters per minute (mL/min). When estimated GFR is expressed in mL/min, however, its utility is limited because it does not account for patient size. Normal GFR in mL/min for a cat might differ greatly from that for a dog. Even within the same species, a toy-breed dog would have a GFR that differs greatly from that of a giant-breed dog when expressed in mL/min. To compensate for this variation in patient size, GFR in human and veterinary medicine is typically standardized to some measure of body size. Body surface area (human medicine) and body mass (human and veterinary medicine) are most often used. In veterinary medicine, GFR is most often expressed as mL/min/kg, allowing comparison of patients of different size.

    A third method of standardization to body size in human and veterinary medicine uses extracellular fluid volume (ECFV).7,13,14,18 One attractive feature of this method is that the primary role of the kidneys is the regulation of the size and composition of the ECFV. Thus, standardizing GFR to ECFV seems physiologically appropriate. There are techniques for estimating the GFR:ECFV ratio that require minimal patient sampling and do not require measurement of the administered dose of the filtration marker. An in-depth discussion of the principles and methods of using ECFV to standardize GFR to body size can be found in the review by Peters13 and elsewhere.7,14

    Indications for Glomerular Filtration Rate Estimation

    GFR assessment has many uses in general practice. The following are a few examples:

    • Detecting renal disease in animals with nonrenal conditions that impair urine-concentrating ability. Diabetes mellitus, hyperadrenocorticism, hypercalcemia, and diuretic therapy for congestive heart failure are all common causes of impaired urine-concentrating ability in small animals. Animals with these disorders frequently have concurrent renal disease. Detecting nonazotemic renal disease in these patients is difficult because most have polyuria and isosthenuria due to their concurrent condition. In addition, dehydration may cause mild prerenal azotemia, and urine-concentrating ability cannot be used to distinguish this condition from mild renal azotemia in these animals. Only GFR estimation can accurately identify renal disease in these patients.
    • Screening hyperthyroid cats before sodium iodide I 131 therapy. Treatment of hyperthyroidism in cats results in a decrease in GFR.24 Methimazole therapy may be used before definitive treatment with sodium iodide I 131 to ensure that the patient tolerates euthyroidism. However, some cats do not tolerate methimazole therapy, or their owners are unable to administer medication. In these cases, GFR estimation can be used to quantify the degree of renal dysfunction. Thus, the clinician could better select which patients are likely to do well with sodium iodide I 131 therapy and which patients are better managed with titrated methimazole therapy or other medical therapies.
    • Excluding renal disease as a cause of polydipsia and polyuria before water deprivation. Water deprivation (or, in some cases, gradual water restriction) is used to evaluate challenging cases of polydipsia and polyuria such as central diabetes insipidus, primary polydipsia, and some cases of hyperadrenocorticism. However, nonazotemic renal disease can manifest exclusively with polydipsia, polyuria, and isosthenuria as well. In a renal patient, deliberate induction of dehydration can precipitate an azotemic crisis.25 Thus, GFR estimation is essential to excluding renal disease before instituting water deprivation or restriction in an isosthenuric patient.5,25

    Interpretation of Estimated Glomerular Filtration Rate Results

    GFR can vary significantly between animals, whether healthy or during various clinical stages of renal disease. Similarly, reference ranges vary because different laboratories and investigators use different iohexol doses, sampling protocols, and analytic techniques. Therefore, it is difficult to define specific ranges of GFR that correlate to subclinical renal disease versus mild, moderate, or severe clinical renal disease. As illustrated by the examples in the previous section, the utility of GFR estimation at our current level of understanding is to distinguish normal from abnormal GFR states or to track changes within the same patient over time. Therefore, estimated GFR results should not be interpreted in isolation, but rather within the context of the signalment, history, clinical signs, and laboratory data for a given patient.

    Conclusion

    Plasma clearance of iohexol is a practical, affordable, and readily available test. The information gained can be invaluable to the safe and accurate diagnosis of a variety of conditions. It arguably represents the most significant advance in the quantitative assessment of renal function in general practice since the routine availability of serum creatinine and urea nitrogen assays.

    Downloadable PDF

    Dr. Graves discloses that he has received financial benefits from Abbott Laboratories, Pfizer Animal Health, and Intervet/Schering-Plough Animal Health.

    1. Finco DR, Braselton WE, Cooper TA. Relationship between plasma iohexol clearance and urinary exogenous creatinine clearance in dogs. J Vet Intern Med 2001;15:368-373.

    2. Gleadhill A, Michell AR. Evaluation of iohexol as a marker for the clinical measurement of glomerular filtration rate in dogs. Res Vet Sci 1996;60(2):117-121.

    3. Kraweic DR. Quantitative renal function tests in cats. Compend Contin Educ Pract Vet 1984;16(10):1279-1284.

    4. Moe L, Heiene R. Estimation of glomerular filtration rate in dogs with 99M-Tc-DTPA and iohexol. Res Vet Sci 1995;58:138-143.

    5. Sanderson SL. Measuring glomerular filtration rate: practical use of clearance tests. In: Bonagura JD, Twedt DC, eds. Kirk’s Current Veterinary Therapy XIV. St Louis: Saunders; 2009:868-871.

    6. Watson ADJ, Lefebvre HP, Concordet D, et al. Plasma exogenous creatinine clearance test in dogs: comparison with other methods and proposed limited sampling strategy. J Vet Intern Med 2002;16:22-33.

    7. Gleadhill A, Peters AM, Michell AR. A simple method for measuring glomerular filtration rate in dogs. Res Vet Sci 1995;59:118-123.

    8. Miyamoto K. Evaluation of single-injection method of inulin and creatinine as a renal function test in normal cats. J Vet Med Sci 1998;60(3):327-332.

    9. Miyamoto K. Clinical application of plasma clearance of iohexol on feline patients. J Feline Med Surg 2001;3:143-147.

    10. Heiene R, Moe L. Pharmacokinetic aspects of measurement of glomerular filtration rate in the dog: a review. J Vet Intern Med 1998;12:401-414.

    11. Miyamoto K. Use of plasma clearance of iohexol for estimating glomerular filtration in cats. Am J Vet Res 2001;62(4):572-575.

    12. Rogers KS, Komkov A, Brown SA, et al. Comparison of four methods of estimating glomerular filtration rate in cats. Am J Vet Res 1991;52(6):961-964.

    13. Peters AM. Expressing glomerular filtration rate in terms of extracellular fluid volume. Nephrol Dial Transplant 1992;7:205-210.

    14. White AJ, Strydom WJ. Normalisation of glomerular filtration rate measurements. Eur J Nucl Med 1991;18:385-390.

    15. Peters AM. Quantification of renal haemodynamics with radionuclides. Eur J Nucl Med 1991;18:274-286.

    16. Russell CD, Dubovsky EV. Measurement of renal function with radionuclides. J Nucl Med 1989;30:2053-2057.

    17. Uribe D, Krawiec DR, Twardock AR, Gelberg HB. Quantitative renal scintigraphic determination of the glomerular filtration rate in cats with normal and abnormal kidney function, using 99mTc-diethylenetriaminepentaacetic acid. Am J Vet Res 1991;53(7):1101-1107.

    18. Krawiec DR, Badertscher RR, Twardock AR, et al. Evaluation of 99mTc-diethylenetriaminepentaacetic acid nuclear imaging for quantitative determination of the glomerular filtration rate of dogs. Am J Vet Res 1986;47:2175-2179.

    19. Izzat NN, Rosborough JP. Renal function in conscious dogs: Potential effect of gender on measurement. Res Exp Med 1989;189:371-379.

    20. Ross LA, Finco DR. Relationship of selected clinical renal function tests to glomerular filtration rate and renal blood flow in cats. Am J Vet Res 1981;42(10):1704-1710.

    21. Laroute V, Lefebvre HP, Costes G, Toutain PL. Measurement of glomerular filtration rate and effective renal plasma flow in the conscious beagle dog by single intravenous bolus of iohexol and p-aminohippuric acid. J Pharmacol Toxicol 1999;41:17-25.

    22. Van Hoek I, Lefebvre HP, Kooistra HS, et al. Plasma clearance of exogenous creatinine, exo-iohexol, and endo-iohexol in hyperthyroid cats before and after treatment with radioiodine. J Vet Intern Med 2008;22:879-885.

    23. Van Hoek I, Vandermeulen E, Duchateau L, et al. Comparison and reproducibility of plasma clearance of exogenous creatinine, exo-iohexol, endo-iohexol, and 51Cr-EDTA in young adult and aged healthy cats. J Vet Intern Med 2007;21:950-958.

    24. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.

    25. Lunn KF. Managing the patient with polyuria and polydipsia. In: Bonagura JD, Twedt DC, eds. Kirk’s Current Veterinary Therapy XIV. St Louis: Saunders; 2009:844-850.

    References »

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