Practical Matters: Practical ways to measure GFR in your patients

Serum creatinine concentration is a commonly used marker of renal function because of its simplicity, availability, and cost. Unfortunately, it is an insensitive marker of renal function, in that the glomerular filtration rate (GFR) must be 75% below normal for the creatinine concentration to be elevated.

Cathy E. Langston, DVM, DACVIM

As an alternative, measuring the GFR can be useful in numerous situations commonly encountered in practice, such as

• Evaluating patients with polyuria without azotemia to definitively exclude or diagnose kidney disease as the underlying cause

• Monitoring renal function in patients with early kidney disease (i.e. annual testing) to evaluate the efficacy of therapy

• Monitoring for further kidney injury in patients with suspected nonazotemic kidney disease that must receive nephrotoxic drugs (e.g. chemotherapeutics, aminoglycoside antibiotics)

• Evaluating patients in which nephrectomy is being considered (i.e. renal neoplasia).

Not all methods of GFR measurement are practical for private practice. Tests that require urine collection over a specified time are prone to error from incomplete recovery of urine because of urinary catheterization problems. However, plasma clearance techniques involve obtaining multiple blood samples without urine sampling. The basic premise behind these tests involves an intravenous injection of a substance that is freely filtered by the glomerulus and is not further excreted or reabsorbed by the renal tubules or cleared or metabolized by other organs. The rate of disappearance from the bloodstream indicates the plasma clearance. Multiple plasma markers and test protocols have been investigated, and no optimal protocol has been identified, but some methods of GFR measurement such as iohexol clearance and exogenous creatinine clearance can be readily performed in private practice with sufficient accuracy for clinical decision-making. In addition, patients in which nephrectomy is being considered may be referred for renal scintigraphy to measure the GFR of each kidney.

IOHEXOL CLEARANCE

In this test, 300 mg/kg of iohexol, a commonly used radiographic contrast agent, is administered intravenously, and blood samples are typically drawn two, three, and four hours later.1,2 The timing of sample collection is flexible, but the exact time the samples were drawn needs to be accurately recorded so the precise time elapsed since injection can be calculated. The most commonly used veterinary diagnostic laboratory that offers measurement of iohexol concentrations and calculated GFR is Michigan State University's Diagnostic Center for Population & Animal Health (animalhealth.msu.edu/Submittal_Forms/AD.ADM.FORM.017.pdf), and results are generally available within a week. Other radiographic contrast agents such as iothalamate cannot be substituted for iohexol because the assay specifically measures iohexol and does not detect iothalamate. Although iodine allergic reaction or development of mild reversible acute kidney failure has been reported in people undergoing this type of test, the risk in animals appears to be low.3

Case examples: Iohexol clearance

The next four brief case examples reveal how measuring GFR with the iohexol clearance test was a valuable tool in patient management.

A senior Rhodesian ridgeback with PU/PD. Sheba, a 10-year-old spayed female Rhodesian ridgeback, was evaluated because of polyuria and polydipsia. Her blood urea nitrogen concentration (BUN) was 15 mg/dl (reference range = 7 to 27 mg/dl), creatinine concentration was 1.5 mg/dl (reference range = 0.4 to 1.8 mg/dl), and urine specific gravity was 1.005. Urine bacterial culture results were negative, the urine cortisol:creatinine ratio was normal, and the urine protein:creatinine ratio was 0.1 (reference range < 0.5). No abnormalities were seen on an abdominal ultrasonographic examination.

Her GFR was measured by iohexol clearance, with a result of 1.635 ml/kg/min, which is a 70% reduction from the expected mean of 5.48 ml/kg/min, confirming IRIS Stage I chronic kidney disease (iris-kidney.com/pdf/IRIS2009_Staging_CKD.pdf). Inadequate urine concentration tends to occur with over 66% reduction in GFR, whereas azotemia occurs with over 75% reduction.

A renal diet was initiated. One month later, hypertension was diagnosed, so benazepril and amlodipine were prescribed. Nine months later, Sheba remains clinically stable.

A senior dog with PU/PD and cystic calculi. Belle, an 11-year-old spayed female mixed-breed dog, was presented for evaluation of polyuria and polydipsia. Her BUN concentration was 12 mg/dl, creatinine concentration was 1 mg/dl, and urine specific gravity was 1.018. ACTH stimulation test results were normal, as were fasting and postprandial bile acid concentrations. An abdominal ultrasonographic examination revealed cystic calculi. The owner was unsure if there had been a partial improvement in the polydipsia after a course of antibiotics.

GFR was measured by iohexol clearance, with a result of 3.1 ml/kg/min (reference range = 2.89 to 8.07 ml/kg/min). Based on these normal results, a water deprivation test was performed. Belle's urine specific gravity increased to 1.031 within 10 hours, and psychogenic polydipsia was diagnosed. The owner was instructed on behavior modification techniques to decrease stress and advised that some water restriction would be safe. The owners declined therapy for the cystic calculi. Two years later, Belle presented for an unrelated problem and was noted to have a urine specific gravity of 1.050.

A boxer with chronic PU/PD. Ali, a 10-year-old spayed female boxer, presented for evaluation of polyuria and polydipsia of 12 months' duration that had gotten progressively worse over the previous three months. Her BUN concentration was 11 mg/dl, creatinine concentration was 0.8 mg/dl, and urine specific gravity was 1.004.

ACTH stimulation test results and fasting and postprandial bile acid concentrations were normal. No abnormalities were seen on an abdominal ultrasonographic examination. During a water deprivation test, when Ali had lost 5% of her body weight, her urine specific gravity was still 1.020. Urine concentration did not increase after administration of antidiuretic hormone.

GFR was measured by iohexol clearance to exclude renal insufficiency. The result was 4.932 ml/kg/min, well within the reference range. Nephrogenic diabetes insipidus was diagnosed, and chlorothiazide therapy was initiated.

A Westie with a history of acute renal failure. Nico, a 6-year-old castrated male West Highland white terrier, was presented for a follow-up evaluation. He had a history of acute renal failure associated with pyuria two years previously. His azotemia had resolved completely. He remained polyuric since that episode, with urine specific gravity measurements ranging between 1.010 and 1.027.

On a routine recheck, microalbuminuria was noted, and the owner requested testing to determine if Nico had chronic kidney disease. The benefits of renal biopsy to determine if structural changes were present were discussed with the owner as well as GFR measurement to determine whether functional changes were present. The result of GFR measurement by iohexol clearance was 6.95 ml/kg/min and indicated that renal function had returned to normal after the pyelonephritis episode. No renal therapy was prescribed. Biannual urinalysis, urine protein concentration determination, and serum chemistry profile testing and annual GFR measurement were recommended to monitor Nico for renal disease progression.

EXOGENOUS CREATININE CLEARANCE

While the exogenous creatinine clearance test is generally less accurate than iohexol clearance in animals with reduced GFR or with fewer than six sampling points, it has the advantage of providing results rapidly after completion of the test.2 In this test, exogenous creatinine (60 mg/kg) is administered intravenously. Many different protocols exist for the timing of obtaining the blood samples after injection, but, in general, at least three samples are needed, and the last sample should be at least six hours after the injection. The protocol I use includes blood sampling immediately before creatinine administration and 10, 60, 240, 360, and 600 minutes after administration. The serum creatinine concentration results, which can be obtained through standard laboratories, are used to calculate the GFR.

Creatinine is safe to administer intravenously and does not induce signs of uremia. Injectable-grade creatinine is not readily available commercially but can be obtained through some specialty pharmacies that will custom-formulate preparations from chemical-grade creatinine. Royal Canin has developed a software program to calculate the GFR for creatinine clearance.4,5 (For a copy, e-mail the author at Cathy.langston@amcny.org.)

Case example: Exogenous creatinine clearance in a young Mastiff with renal dysplasia

Exogenous creatinine clearance was performed in Annie, a 1-year-old female Mastiff with renal dysplasia. Because the 10-hour sample had such a high creatinine concentration (Table 1), Annie was presented again the next day for a 24-hour sample. Creatinine clearance was 0.6 ml/kg/min, which is markedly below the reference range of 2 to 4.5 ml/kg/min. By the following week, the serum creatinine concentration had decreased to the baseline at 7.2 mg/dl. Annie was enrolled in a drug study at that time. Three months later, her baseline serum creatinine concentration was 9.9 mg/dl and her GFR measured by creatinine clearance had dropped to half of the initial value—0.3 ml/kg/min. She was euthanized two months later because of progressive signs of uremia.

Table 1: Annie's Exogenous Creatinine Clearance Results

RENAL SCINTIGRAPHY

Radiolabeled marker clearance (i.e. renal scintigraphy) can measure the GFR of each kidney individually, which is important if nephrectomy is being considered. This test requires referral to a facility with the necessary equipment and quarantine facilities (i.e. most veterinary schools and some larger specialty practices with a veterinary radiologist on staff). The radioisotope technetium 99m diethylenetriamine pentaacetic acid (Tc-99m-DTPA) is administered intravenously, and radioisotope uptake in the kidney is quantified with a gamma camera over three minutes.6 Patients are quarantined for 24 hours afterward to allow the radioactive marker to be cleared.

Case example: Renal scintigraphy in a senior cat with a renal mass

Lobelia, a 13-year-old spayed female domestic shorthaired cat, was presented for evaluation of polycythemia (PCV 61%) and was found to have a right renal mass. She was not azotemic. Renal scintigraphy was performed. The global GFR of 2.3 ml/min/kg was within the reference range, and function was almost equally split between the two kidneys. The GFR of the left kidney was 1.3 ml/kg/min, which was deemed insufficient to maintain normal homeostasis. Chronic kidney failure seemed a likely outcome if the right kidney was removed. So a subcutaneous vascular access port was placed to facilitate phlebotomy every one to two months. Lobelia lived for another three years before she succumbed to an abrupt cerebrovascular event.

Cathy E. Langston, DVM, DACVIM

Animal Medical Center

510 East 62nd St.

New York, NY

REFERENCES

1. Heiene R, Eliassen KA, Risoen U, et al. Glomerular filtration rate in dogs as estimated via plasma clearance of inulin and iohexol and use of limited-sample methods. Am J Vet Res 2010;71(9):1100-1107.

2. van Hoek IM, Lefebvre HP, Paepe D, et al. Comparison of plasma clearance of exogenous creatinine, exo-iohexol, and endo-iohexol over a range of glomerular filtration rates expected in cats. J Feline Med Surg 2009;11(12):1028-1030.

3. Pollard RE, Pasco PJ. Severe reaction to intravenous administration of an ionic iodinated contrast agent in two anesthetized dogs. J Am Vet Med Assoc 2008;233(2):274-278.

4. Lefebvre HP, Watson ADJ. Royal Canin Creatinine Clearance Calculator CD in Early Diagnosis of Chronic Renal Failure. Waltham Focus Special Edition, October 2003.

5. Watson AD, 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(1):22-33.

6. Kerl ME, Cook CR. Glomerular filtration rate and renal scintigraphy. Clin Tech Small Anim Pract 2005;20(1):31-38.