- Email: [email protected]
Renal Scintigraphy in Veterinary Medicine
Renal Scintigraphy in Veterinary Medicine Reid Tyson, DVM, DACVR, and Gregory B. Daniel, DMV, MS, DACVR Renal scintigraphy is performed commonly in dogs and cats and has been used in a variety of other species. In a 2012 survey of the members of the Society of Veterinary Nuclear Medicine, 95% of the respondents indicated they perform renal scintigraphy in their practice. Renal scintigraphy is primarily used to assess renal function and to evaluate postrenal obstruction. This article reviews how renal scintigraphy is used in veterinary medicine and describes the methods of analysis. Species variation is also discussed. Semin Nucl Med 44:35-46 C 2014 Elsevier Inc. All rights reserved.
S
imilar to humans, renal disease is common in companion animals, especially the cat. Veterinarians typically rely on clinical signs and blood work for diagnosing and monitoring of renal disease in animals. Unfortunately, advanced renal disease is present long before clinical signs or evidence of blood chemistry abnormalities is seen. Animals often first present with renal disease with a history of polyuria or polydipsia or both.1 Similar to people, evidence of blood chemistry abnormalities, such as elevations in creatinine, is not detected until 65%-75% of the nephrons have been damaged.2 Diagnostic imaging is an important part of the workup of renal disease in veterinary patients. Because of its widespread availability, radiography is the most commonly used imaging modality. However, radiographs are limited to the evaluation of renal size, shape, and changes in opacity. Because of anatomical constraints, the right kidney is often poorly visualized owing to silhouetting with the renal fossa of the caudate lobe of the liver and superimposition of small intestine and colon. Intravenous pyelograms were routinely performed in veterinary medicine but are rarely carried out today. The evaluation of changes in the pattern of renal cortical opacification was once used as a method for qualitative assessment of renal function.3 Intravenous pyelography was also used to diagnose pyelonephritis, hydronephrosis, renal masses, and perinephric pseudocysts and to look for evidence of ureteral ectopia.3,4 Currently, ultrasound and computed tomography have largely replaced the need for intravenous pyelography. Ultrasound imaging has become widely available and is routinely performed at veterinary clinics, being the second
Department of Small Animal Clinical Sciences, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA. Address reprint requests to Gregory B. Daniel, DVM, MS, DACVR, Department of Small Animal Clinical Sciences, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.005
most commonly used imaging modality in veterinary medicine. In the vast majority of patients, ultrasound is performed without the use of sedation or anesthesia, as the patient is held with gentle restraint. Ultrasound imaging provides much greater detail about renal morphology than radiography and is ideal for differentiating suspected mass from cystic lesions. Ultrasound allows for a detailed examination of the renal cortex, medulla, pelvis, ureter (when dilated), and blood flow. Common abnormalities identified include small kidney, infarcts, nephroliths, cysts, pyelonephritis, hydronephrosis, acute renal failure, such as secondary to leptospirosis or toxin, and mass lesions.5,6 The modality is also ideal for ultrasoundguided procedures such as aspirates, dilated renal pelvic sampling, antegrade pyelography, and biopsies (Fig. 1). Unfortunately, radiography and ultrasound provide limited information about renal function. Computed tomography is occasionally used for renal imaging, but is only available at veterinary teaching hospitals or specialty referral clinics. Its widespread use is limited by cost and the need for heavy sedation or anesthesia to perform the procedure. Computed tomography is most often used for the evaluation of ectopic ureters and surgical planning for large mass lesions involving the retroperitoneal space, adrenal glands, or kidneys.7,8 Recently, some investigators have used dynamic renal computed tomography to estimate global and split renal function in pigs, dogs, and cats.9-15 Renal scintigraphy is performed in dogs and cats and has also been successfully performed in a variety of other species. The availability of renal scintigraphy is limited. This is largely owing to the costs of nuclear medicine equipment, the requirement for a radioactive materials license, and the lack of sufficient technical expertise. Nuclear medicine services are available at almost all of the 28 veterinary schools in the United States and in several private specialty practices. Indications for renal scintigraphy in animals are similar to that in people. However, the use of renal scintigraphy associated with 35
R. Tyson and G.B. Daniel
36
Figure 1 Evaluation of the kidneys in an iguana. The image on the left shows the placement of the ultrasound transducer to image the kidneys, which are located more caudally than most mammalian species. A biopsy needle is being directed into the left kidney via ultrasound guidance. The central image is a pulse-wave Doppler spectrum. The right image is a power Doppler image of the right kidney.
advanced treatment procedures, such as renal transplant, is far less common because of the limited number of places that offer these treatments. Renal scintigraphy is most commonly performed in dogs that are undergoing nephrectomy or nephrotomy and in patients with urolithiasis. Renal scintigraphy is most commonly performed in cats that are being evaluated for treatment of hyperthyroidism, with iodine-131, or are undergoing nephrectomy.
Incidence of Renal disease Chronic kidney disease is very common in older companion animals, in which approximately 35% of cats and 10% of dogs are affected in populations presenting to specialty referral hospitals.16,17 Chronic kidney disease is most often identified in older feline patients with a mean age of 12.6 years, but a range of 1-26 years.18,19 Certain breeds, such as Maine Coon, Abyssinian, Persian, and Burmese, have a significantly increased risk of developing chronic renal failure.20 In a previous study evaluating histopathology results from dogs and cats with renal azotemia, it was found that tubulointerstitial nephritis was present most often (58% of dogs and 70% of cats).21 Renal failure is also a major cause of illness and death in reptilian species, such as iguanas.22,23
Anatomy Just like their human counterparts, cats and dogs have paired bean-shaped kidneys that are found in the dorsal retroperitoneal space.24 Embryologically, the cat, the dog, and the horse kidneys are classified as unilobar and have a smooth exterior serosal margin.25 In dogs, the right kidney is more fixed in place and is located craniodorsal to the left kidney. In cats, the 2 kidneys are often found at a similar level in the middorsal abdomen. Cats, being more similar in size as compared with dogs, have a fairly similar kidney size with renal lengths in the range of 3.0-4.3 cm.26 Interestingly, neutered cats have statistically smaller kidneys when compared with intact cats.27 Because of the large variation in the size of dogs, a wide range of normal renal lengths exists. In both species, normal renal length
is determined by a ratio with the length of the second lumbar vertebra on radiographs.28,29 The kidney in most mammalian species receives approximately 25% of the total cardiac output through renal arteries that typically branch into dorsal and ventral rami at the renal hilus.30,31 In the dog and the cat, this equates to a renal blood flow of 4 mL/min/g of kidney weight.32,33 Anatomical variations of the renal vasculature are relatively common, and CT is often performed before renal transplant.34 The kidney is divided into 2 major anatomical regions, the cortex and the medulla. The cortex is the outer most aspect of the kidney, which primarily incorporates the proximal and distal convoluted tubules and renal corpuscles. The medulla is the inner portion of the kidney that is comprised of collecting ducts and the loop of Henle.24,30 In most domestic animals, the corticomedullary ratio is approximately 1:2 to 1:3. However, this ratio is not fixed, and in some desert animal species, it may be as high as 1:5.25
Indications In clinical veterinary medicine, renal scintigraphy is almost exclusively performed using technetium (99mTc)-diethylenetriamine pentaacetic acid (DTPA). As such, the primary goal of most studies is to determine global and split renal glomerular filtration rates (GFR). In dogs and cats, renal scintigraphy is most commonly performed for the evaluation of renal function before nephrectomy or nephrotomy.35 Surgery may be necessary to remove a mass that involves the kidney, a nidus of infection that cannot be controlled by antibiotics, a chronically hydronephrotic kidney, or for nephroliths. Renal scintigraphy is often coupled with the administration of a diuretic to evaluate the patency of the ureters from obstructive ureterolithiasis or stricture.36,37 Renal scintigraphy can also be useful for the evaluation of global renal function in cases of subclinical renal disease. This is especially important when the treatment may result in a further decrease in renal function, such as with administration of nephrotoxic drugs.38 Treatment of hyperthyroid cats with iodine-131 can result in a worsening of their renal disease.39-41 Because the prevalence of renal disease and hyperthyroidism increases in aged cats, these
Renal Scintigraphy in veterinary medicine 2 diseases often occur concurrently. Hyperthyroidism has been shown to increase blood flow to the kidneys and thus mask subclinical renal disease. After treatment with iodine131, the decrease in renal blood flow can cause some cats with underlying renal disease to go into renal failure.42 In one prior study, the mean GFR went from a mean of 2.51 mL/min/kg to a posttreatment average of 1.4 mL/min/ kg.42,43 With the high incidence of renal disease in the cat, the procedure has also been used to help detect earlyimpaired renal function that may affect the patient's longterm prognosis. 99m
Tc-DTPA
Tc-DTPA is used as a glomerular filtration agent. The suitability of 99mTc-DTPA to measure GFR varies between animal species because of in vivo protein binding. If a portion of the injected dose of 99mTc-DTPA becomes bound to plasma proteins then it would not be available for glomerular filtration and would falsely decrease the measured GFR or affect the ability to image kidney morphology. In the dog and the cat, there is minimal amount (6%-7%) of protein binding of 99mTc-DTPA, which does not significantly influence renal uptake.44,45 In the green iguana, approximately 50% of 99mTc-DTPA is protein bound, and as such, is not a good renal imaging agent in this species.46 In corn snakes, approximately 30% of 99mTc-DTPA is protein bound, and likewise, is a poor imaging agent owing to diminished renal uptake.47 In these species, the image quality of the kidney is poor and GFR cannot be quantified using 99mTc-DTPA. Although 99m Tc-DTPA would probably be suitable for most mammalian domestic species, the amount of protein binding has to be ascertained before being used in a previously untested species. 99m
37 biexponential regression analysis of the decreasing plasma radioactivity data. A least-squares approximation is used to determine the coefficients of the biexponential function. The GFR is calculated using GFR ¼
Administered Activity ðdoseÞ A=aa þ B=ab
where A and B are the y-intercept of the fast and slow compartments, and aa and ab are the slopes of the clearance from their respective compartments. The number of samples and the volume of blood removed are not significant in animals with large body weights, but can be problematic in smaller animals such as cats. As such, there has been a trend toward using a smaller number of plasma samples in the analysis and using a monoexponential model. In small animals, plasma clearance using a reduced number of plasma samples has been studied, and it shows to be a good predictor of GFR. There may be a future trend toward using plasma clearance for global renal function combined with image analysis for split renal function and clearance studies.48,54
Image Analysis
Procedure: GFR
Patients should be normally hydrated before the procedure to get the best estimation of the animal's true steady state GFR. Studies have shown the influence of hydration status, or fluid loading, on GFR quantifications.55 Doses of 99mTc-DTPA range from 1-4 and 1-3 mCi for the dog and the cat, respectively. Before and after counts of the dose syringe are used in the determination of the percent dose uptake of the radiopharmaceutical by the kidneys. Doses greater than 4 mCi are not used because of dead-time loss when counting the dose syringe on the gamma camera before injection. The dose syringe is traditionally counted at a distance of 30 cm from the center of the gamma camera. However, the exact distance is not critical, as the sensitivity of a parallel hole collimator varies little with distance if fitted with a low-energy all-purpose parallel hole collimator.56
In veterinary medicine, GFR is measured by either plasma clearance methods or image-based analysis.48-52 In general, plasma clearance methods have been used more commonly in larger species, such as horses. Image-based analysis is most frequently used for small species, such as dogs and cats. The plasma clearance methods do not have the errors associated with attenuation corrections required for image-based analysis. In large species, such as a horse, the kidney depth is quite significant and motion during a long dynamic acquisition is often problematic. Plasma clearance studies are performed using traditional techniques 52,53 Plasma samples are obtained at specific time intervals following intravenous injection of 99m Tc-DTPA. Traditionally, 6-9 plasma samples are taken out to 3-4 hours following injection of radiopharmaceutical. The plasma radioactivity is counted in a NaI well detector, and the decay corrected counts are plotted to create a plasma radioactivity curve. The area under the plasma radioactivity curve is determined by a
Figure 2 Picture showing the positioning of a cat in preparation for renal scintigraphy. Most animals tolerate positioning in lateral recumbency for the 6-8 minute acquisition. An IV catheter has been placed in the cat's left cephalic vein for the bolus injection of 3 mCi of 99m Tc-DTPA. IV, intravenous.
R. Tyson and G.B. Daniel
38
Figure 3 The plots above show the relationship between percent dose uptake of 99mTc-DTPA and inulin clearance. Linear regression analysis was used to determine the formula for predicting renal clearance from the percent dose uptake data. This is the most commonly used method in veterinary medicine for predicting GFR using renal scintigraphy. (Color version of figure is available online.)
For the examination, the patient is gently restrained in lateral recumbency. Depending on patient's demeanor and cooperativeness, the patient may have to be sedated or anesthetized, which has been demonstrated to decrease GFR, pending method used. If needed, acepromazine and butorphanol have successfully been used for sedation without negatively affecting the GFR.57 The gamma camera is positioned in a vertical
orientation along the dorsum of the patient (Fig. 2). For most procedures, a 6-minute dynamic acquisition is started simultaneously with intravenous bolus delivery of the radiopharmaceutical. After the dynamic acquisition, the gamma camera is rotated to a horizontal position, without moving the patient. A lateral static image is then obtained for measurements of individual kidney depth, for attenuation correction.
Figure 4 A typical renogram curve from a normal dog following injection of 3 mCi of 99mTc-DTPA. Note that peak renal activity occurs around 3 minutes following injection, although there is variation based on physiological influences. The recorded activity in the left kidney is usually lower than the right owing to its deeper location in the body. Attenuation correction is needed for accurate determination of splint renal function. (Color version of figure is available online.)
Figure 5 This is Patlak-Rutland plot. The y-axis is the function of kidney activity K(t) divided by plasma activity P(t). The x-axis is a plot of integral of plasma activity P(t) divided by P(t). The slope of this graph is equal or proportional to the clearance of the tracer from the blood to a tissue compartment. (Color version of figure is available online.)
Renal Scintigraphy in veterinary medicine
39
Figure 6 The images at the top are from a dynamic acquisition of a dog after injection of 99mTc-DTPA. The images were acquired at 1 frame every 6 seconds. The left kidney is small and has decreased function. Renogram curves of the left and right kidneys are shown in the bottom left, note the flat shape to the left renogram curve. The plasma clearance curve was created by counting plasma samples in a NaI well detector. The animal's global GFR was 1.86 mL/min/kg, of which 90% was derived from the right kidney. (Color version of figure is available online.)
Attenuation correction has been shown to increase the accuracy of results in the dog, because of the wide variation in breed size, but not in the cat.44,45 The estimation of GFR from dynamic renal scintigraphy can be performed by a variety of methods, but the most commonly employed method used in veterinary medicine is a modified technique originally described by Gates.44,45,51,58 GFR is predicted from a regression equation that was created from a plot of the percent dose uptakes of the 99mTc-DTPA
in the kidney to inulin clearances in a series of dogs and cats with normal and impaired renal function (Fig. 3).44,45 The best correlation to inulin clearance in the dog and the cat was obtained using percent dose uptake data from 1-3 minutes following injection. In these animals, there was a consistent upslope of the renogram curve from 1-3 minutes, with peak renal activity occurring approximately 3 minutes following injection (Fig. 4). Owing to variation in mean renal transit times, the time-to-peak renal activity
Figure 7 Renogram curves from 2 different animals. The curve on the left is a normal dog with no ureteral dilation or obstruction. The curve on the right is from a dog with a ureteral calculi obstructing the left ureter. (Color version of figure is available online.)
R. Tyson and G.B. Daniel
40
Figure 8 The images at the top from the same dog as in Figure 6. This phase of the dynamic acquisition was obtained following injection of Lasix (3 mg/kg) and the frame rate was increased to 1 frame every 3 seconds. Note the rapid clearance of the radiopharmaceutical from both kidneys. The renogram curves have been normalized to the same peak value before determining the slope of the curve by linear regression. Even though the left kidney has 10% of total renal function, the slope of the clearance phase is normal indicating no postrenal obstruction. (Color version of figure is available online.)
can differ in a variety of clinical situations. Examples would include poorly functioning kidneys (longer) or animals undergoing diuresis (shorter), which make this 1-3minute interval inappropriate.59-61 Because of the limitation of the modified Gate's technique, other methods of image analysis of dynamic renal scintigraphy have been tried in veterinary medicine. One of the more recent is the use of Patlak-Rutland plots to determine GFR. The technique assumes a 2-compartment model with the unidirectional transfer of the 99mTc-DTPA from one compartment (plasma) to the other (kidney) during the time following injection that there is no output
from the renal region of interest (ROI). The rate constant from the plasma to the kidney is the clearance rate. This clearance rate can be solved using a graphical analysis technique.62 The plot, which has as it y-axis as the function of kidney activity, is divided by plasma activity: KPððttÞÞ where K(t) represents the attenuation corrected net kidney counts at time (t) and P(t) represents plasma counts at time (t) (Fig. 5).63,64 The plasma activity is derived from an ROI drawn over the left ventricle.65 The x-axis is a plot of R the integral of plasma activity P(t) divided by P(t): PðtÞdt=PðtÞ . The points plotted are reasonably straight except for the early points that are influenced by extrarenal
Figure 9 Images of a normal dog obtained 3 hours following injection of 99mTc-DMSA. The images on the top row are from left to right (right lateral, dorsal, and left lateral images). Note most activity is located in the renal cortices. There is minimal extrarenal soft tissue or urinary bladder activity.
Renal Scintigraphy in veterinary medicine
41
Figure 10 These are right lateral images of a horse following injection of 20 mCi of 99mTc-DMSA. The image on the left is from a normal horse and the image on the right is from 1-year-old horse with severe renal dysplasia. Note the multiple photopenic voids of the dysplastic kidney. The dysplastic kidney did not develop properly and the renal cortex contained fetal glomeruli and abundant interstitial fibrosis. There were also multiple medullary cysts.
activity and late points that are influenced by the passage of the radiopharmaceutical into the lower urinary tract.64 The slope of this graph is equal, or proportional, to the clearance of the tracer from the blood to a tissue
compartment.63 The GFR value is expressed in terms of clearance per plasma volume (mL/min/L). Dynamic renal scintigraphy is not an absolute measure of GFR, and imaging GFR values have been shown to vary
Figure 11 The images at the top are from a pigeon (Columba livia domestica) following injection of 1 mCi (37 MBq) of 99mTcDTPA. The images were taken at various times during a 15-minute dynamic acquisition. You can see the radiopharmaceutical accumulating in the cloaca. The kidneys are difficult to identify owing to a low kidney to background ratio. The location of the kidneys is more easily identified following injection of 1 mCi (37 MBq) of 99mTc-DMSA. The kidneys in the second row of images are seen as elongated structures in the caudal dorsal aspect of the coelomic cavity. The liver also accumulates 99mTcDMSA and is located in the central region of the coelomic cavity. The renogram at the bottom is from a normal bird and a bird with decreased renal function. Note the lower uptake in the diseased bird.
R. Tyson and G.B. Daniel
42
Figure 12 The bottom images show the distribution of 3 common radiopharmaceutical in corn snakes (Elaphe guttata guttata). These images are from the distal aspect of the snake that includes the kidneys. Kidneys are only identified using 99mTc-MAG3. High levels of protein binding of 99mTc-DTPA prevented renal accumulations. The reason for the failure of 99mTc-DMSA to localize in the kidney is unknown. The images at the top left are part of a dynamic acquisition following the intracardiac injection of 99mTc-MAG3. Note the slow passage of the radiopharmaceutical down the aorta. The photograph in the upper right shows the intracardiac administration of the radiopharmaceutical. MAG3, mercaptoacetyltriglycine.
considerably in animals.66 Dynamic renal scintigraphy is less accurate than plasma clearance studies in determining GFR.48 This is owing in part to the fact that GFR measured from dynamic renal scintigraphy is based on a relatively short sampling of data (1-3 minutes after injection for the Gates method and 1-4 minutes for the Rutland-Patlak plot method).44,45,65 Studies that measure GFR over a longer time interval, such as 24-hour inulin clearances or 3-hour plasma clearance studies, are more likely to give an accurate measurement of the animal's true GFR.66 This is especially true in animals with a normal or near-normal renal reserve capacity. There are other factors that can influence the accuracy of GFR determination from image analysis.67 Movement, which is a problem even in small animals, would decrease the ability to obtain accurate quantification of renal activity. Measuring plasma activity by a heart or aortic ROI has errors owing to background activity. In addition, errors in ROI placement and depth attenuation can lead to inaccurate measurements.68 The GFR is also influenced by nonrenal factors such as stress, hydration status, and protein or sodium content of the diet.69-71 Still, correlation of the imaging GFR values to inulin clearance values is reasonably good in animals, and the ease and speed
with which results can be obtained makes the imaging GFR technique a useful clinical tool.
Interpretative Principles Global GFR values more than 3 mL/min/kg are considered normal in the dog and global GFR values more than 2.5 mL/ min/kg are considered normal in the cat.52,72 Animals with subclinical renal insufficiency have global values between 1.2 and 2.5 mL/min/kg. In these animals, there would be poor renal uptake of 99mTc-DTPA and the extrarenal soft tissues would be slow to clear. The renogram curve would appear flat (Fig. 6). Global GFR values less than 0.25 would have such poor renal uptake that quantitative renal scintigraphy with 99m Tc-DTPA may be difficult to perform accurately.
Evaluation for Obstructive Uropathy In cases where there is a clinical concern for ureteral obstruction, a slight modification is made to the aforementioned procedure. The acquisition is longer (at least 8 minutes)
Renal Scintigraphy in veterinary medicine
43
Figure 13 Images of a green iguana (Iquana iquana) at various times following injection of 1 mCi (37 MBq) of 99mTc-DMSA. The kidneys are the paired structures in the dorsal pelvis region. Long localization time is necessary to get a good kidney uptake. Photographs and radiographs are also shown to help with anatomical correlations.
and at 4.5 minutes after bolus injection of 99mTc-DTPA, a 3 mg/kg dose of Lasix is given intravenously.73-75 The shape of the renogram curve is then used to help diagnose obstructive uropathy.75 The injection of the diuretic is necessary to differentiate between a dilated nonobstructed vs an obstructed ureter. Without the administration of a diuretic, both of these conditions can result in a continuing rise in the renogram curve. This ureteral dilation can occur secondary to obstruction, but can also be associated with nonobstructive disorders such as vesicoureteral reflux, trauma, infection, or congenital anomalies. The rate of renal excretion can be quantified from the downslope of the renogram curves following diuretic administration. Dogs with patent ureters would have rapid clearance of the 99mTc-DTPA from the kidneys following diuretic injection, where as those with postrenal obstruction would retain the 99mTc-DTPA within the renal pelvis and would not show a downslope on the renogram curve (Fig. 7). Because the
slope of the excretion phase is dependent on the magnitude of peak renal activity, the renogram curves are normalized to the same peak value (Fig. 8). Linear regression is used to fit the downslope of the renogram curve from which the slope of the line is measured. An excretion T1/2 is derived from the slope of the fitted line. In normal dogs, the median excretion T1/2 is 4.16 minutes with a range of 3.62-5.90 minutes.74,76 This technique is useful in assessing for ureteral obstruction in dogs and cats with urolithiasis.36,37,77
Renal Morphology Scintigraphy With 99mTc-Dimercaptosuccinic Acid (DMSA) 99m
Tc-DMSA has been used to measure kidney function and morphology in veterinary medicine. Delayed imaging at 2-3
R. Tyson and G.B. Daniel
44 hours after injection is needed to allow adequate time for renal localization. By 4 hours after injection, 51.7% ⫾ 2.5% of the radiopharmaceutical would be bound to the kidney in normal dogs (Fig. 9). 99mTc-DMSA can also be used to detect space occupying masses that displace renal tubular cells. These lesions would appear as photopenic defects. As 99mTc-DMSA is a static imaging agent, it is the best radiopharmaceutical for imaging the equine kidney (Fig. 10). Motion correction software can be employed to compensate for the typical swaying motion of the horse during the 60-90 second time interval needed to acquire the images. Images can be repeated as needed. Differential estimation of functioning tubular renal mass can be made by determining the percent dose uptake of 99m Tc-DMSA by the left and right kidneys.75 It is important to note that this provides an estimate of functioning tubular renal mass and not renal function, as poor DMSA uptake in the presence of normal DTPA uptake has been seen in patients with tubulointerstitial renal disease. 99m Tc-DMSA can also be used to quantify relative (left vs right) functioning renal tubular mass.78 In a study on dogs subjected to renal tubular damage by toxic doses of gentamicin, 99m Tc-DMSA was able to detect disease earlier than either 99m Tc-DTPA or 99mTc-mercaptoacetyltriglycine.78
Other Uses of Renal Scintigraphy Renal scintigraphy has been used to evaluation variety of nontraditional pet animals. For example, in reptiles, changes in serum or plasma urea nitrogen and creatinine concentrations are not useful indicators of renal failure because they are not elevated until there is extensive renal damage and are also affected by feeding, reproductive status, and hydration.46,47 In avian species, uric acid concentrations are used for the evaluation of renal disease, but significant renal dysfunction is necessary before an increase in uric acid concentration is seen. Another factor is that uric acid secretion is primarily by the proximal tubules and is not reflective of GFR.79 As such, renal scintigraphy has been explored as a method to better evaluate renal disease in these species. 99mTc-DTPA is the method of choice for the evaluation of renal function in the bird, but 99m Tc-DMSA was better for the evaluation of renal morphology (Fig. 11). In snakes, 99mTc-mercaptoacetyltriglycine appears to be better than either 99mTc-DTPA or 99mTc-DMSA for the evaluation of kidney structure and function (Fig. 12). In iguanas, 99mTc-DMSA has been demonstrated to be useful for the evaluation of kidney structure and function (Fig. 13).
Conclusion Renal scintigraphy is the most commonly used imaging modality for the evaluation of individual and global renal function in the dog and the cat. Although less commonly used, plasma clearance studies have also been employed to determine global GFR. Diuretic renal scintigraphy is used for the evaluation of postrenal obstruction in animals with urolithiasis. Although not as commonly performed, morphologic imaging using 99mTc-DMSA has been used in the dog and may be the
best renal imaging agent for the horse. Renal scintigraphy has the potential for use in the evaluation of nontraditional pet animals and to help understand physiological differences between species.
References 1. Bartges J, Polzin DJ: Historical information and physical examination. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 2. LeFebvre HP: Renal function testing. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 3. Feeney DA, Johnson GA: The kidney and ureters. In: Thrall DE, (ed): Textbook of Veterinary Diagnostic Radiology. (ed 5). St Louis: Saunders Elsevier; 2007. pp. 693-707 4. Ackerman N: Radiology and Ultrasound of Urogential Diseases in Dogs and Cats. Ames, IA: Iowa State University Press; 1991 5. Nyland TG, Mattoon JS: Small Animal Ultrasound. (ed 2). Philadelphia, PA: WB Saunders; 2002 6. Penninck DG, d'Anjou MA: Atlas of Small Animal Ultrasonography. Ames, IA: Blackwell Publishing; 2008 7. Anders KJ, McLoughlin MA, Samii VF, et al: Ectopic ureters in male dogs: Review of 16 clinical cases (1999–2007). J Am Anim Hosp Assoc 2012;48:390-398 8. Samii VF, McLoughlin MA, Mattoon JS, et al: Digital fluoroscopic excretory urography, digital fluoroscopic urethrography, helical computed tomography, and cystoscopy in 24 dogs with suspected ureteral ectopia. J Vet Intern Med 2004;18:271-281 9. Alexander K, del Castillo JRE, Ybarra N, et al: Single-slice dynamic computed tomographic determination of glomerular filtration rate by use of Patlak plot analysis in anesthetized pigs. Am J Vet Res 2007;68:297-304 10. Alexander K, Authier S, del Castillo JRE, et al: Patlak plot analysis CT-GFR for the determination of renal function: Comparison of normal dogs with autologous kidney transplant dogs. Contrast Media Mol Imaging 2010;5:133-139 11. Chang J, Ahn S, Choi S, et al: Evaluation of glomerular filtration rate by use of dynamic computed tomography and Patlak analysis in clinically normal cats. Am J Vet Res 2011;72:1276-1282 12. Granger LA, Armbrust LJ, Rankin DC, et al: Estimation of glomerular filtration rate in healthy cats using single-slice dynamic CT and patlak plot analysis. Vet Radiol Ultrasound 2012;53:181-188 13. Alexander K, Dunn M, Carmel EN, et al: Clinical application of patlak plot CT-GFR in animals with upper urinary tract disease. Vet Radiol Ultrasound 2010;51:421-427 14. Chang J, Kim S, Jung J, et al: Assessment of glomerular filtration rate with dynamic computed tomography in normal Beagle dogs. J Vet Sci 2011;12:393-399 15. Schmidt DM, Scrivani PV, Dykes NL, et al: Comparison of glomerular filtration rate determined by use of single-slice dynamic computed tomography and scintigraphy in cats. Am J Vet Res 2012;73:463-469 16. Kirk RW: Current Veterinary Theraphy IX Small Animal Practice. (ed 9) Philadelphia, PA: WB Saunders; 1986 17. Kirk RW: Current Veterinary Therapy X: Small Animal Practice. (ed 10) Philadelphia, PA: WB Saunders; 1989 18. Elliott J, Barber PJ: Feline chronic renal failure: Clinical findings in 80 cases diagnosed between 1992 and 1995. J Small Anim Pract 1998;39:78-85 19. Dibartola SP, Rutgers HC, Zack PM, et al: Clinicopathological findings associated with chronic renal-disease in cats—74 cases (1973-1984). J Am Vet Med Assoc 1987;190:1196-1202 20. Lulich JP, Osborne CA, Obrien TD, et al: Feline renal-failure—Questions, answers, questions. Compend Contin Educ Pract Vet 1992;14:127-151 21. Minkus G, Reusch C, Horauf A, et al: Evaluation of renal biopsies in cats and dogs histopathology in comparison with clinical-data. J Small Anim Pract 1994;35:465-472 22. Hernandez-Divers SJ: Green iguana nephrology: A review of diagnostic techniques. Vet Clin North Am Exot Anim Pract 2003;6:233-250
Renal Scintigraphy in veterinary medicine 23. Hernandez-Divers SJ, Innis CJ: Renal disease in reptiles: Diagnosis and clinical management. In: Mader DR, (ed): Reptile Medicine and Surgery. (ed 2). St Louis, MO: Elsevier; 2006 24. Clarkson CE, Fletcher TF: Anatomy of the kidney and proximal ureter. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 25. Newman SJ: The urinary system. In: Zachary JF, McGavin M, (eds): Pathologic Basis of Veterinary Disease. (ed 5), St Louis, MO: Elsevier; 2012. pp 589-659 26. Walter PA, Johnston GR, Feeney DA, et al: Renal ultrasonography in healthy cats. Am J Vet Res 1987;48:600-607 27. Shiroma JT, Gabriel JK, Carter RL, et al: Effect of reproductive status on feline renal size. Vet Radiol Ultrasound 1999;40:242-245 28. Barrett RB, Kneller SK: Feline kidney mensuration. Acta Radiol Suppl 1972;319:279-280 29. Finco DR, Stiles NS, Kneller SK, et al: Radiologic estimate of kidney size of the dog. J Am Vet Med Assoc 1971;159:995-1002 30. Brown SA: Physiology of the kidney. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 31. Guyton AC, Hall JE: Urine formation by the kidneys: I. Glomerular filtration, renal blood flow and their control. In: Guyton AC, Hall JE, (eds): Textbook of Medical Physiology. 11 ed. Philadelphia, PA: Elsevier; 2006 32. Brown SA, Brown CA: Single-nephron adaptations to partial renal ablation in cats. Am J Physiol Regul Integr Comp Physiol 1995;269:R1002-R1008 33. Brown SA, Finco DR, Crowell WA, et al: Single-nephron adaptations to partial renal ablation in the dog. Am J Physiol 1990;258:F495-F503 34. Bouma JL, Aronson LR, Keith DG, et al: Use of computed tomography renal angiography for screening feline renal transplant donors. Vet Radiol Ultrasound 2003;44:636-641 35. Bolliger C, Walshaw R, Kruger JM, et al: Evaluation of the effects of nephrotomy on renal function in clinically normal cats. Am J Vet Res 2005;66:1400-1407 36. Hecht S, Lawson SM, Lane IF, et al: 99mTc-DTPA diuretic renal scintigraphy in dogs with nephroureterolithiasis. Can Vet J 2010;51: 1360-1366 37. Hecht S, Lawson SM, Lane IF, et al: 99mTc-DTPA diuretic renal scintigraphy in cats with nephroureterolithiasis. J Feline Med Surg 2010;12:423-430 38. Daniel GB, Hahn K, Bravo L: The effect of a single therapeutic dose of cisplatin on GFR in dogs. Oncol Rep 1997;4:153 39. Adams WH, Daniel GB, Legendre AM, et al: Changes in renal function in cats following treatment of hyperthyroidism using I-131. Vet Radiol Ultrasound 1997;38:231-238 40. Milner RJ, Channell CD, Levy JK, et al: Survival times for cats with hyperthyroidism treated with iodine 131, methimazole, or both: 167 cases (1996-2003). J Am Vet Med Assoc 2006;228:559-563 41. Slater MR, Geller S, Rogers K: Long-term health and predictors of survival for hyperthyroid cats treated with iodine 131. J Vet Intern Med 2001;15:47-51 42. Adams WH, Daniel GB, Legendre AM: Investigation of the effects of hyperthyroidism on renal function in the cat. Can J Vet Res 1997;61:53-56 43. Graves TK, Olivier B, Nachreiner RF, et al: Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Research 1994;55:1745-1749 44. Krawiec DR, Badertscher RR II, Twardock AR, et al: Evaluation of 99m Tc-diethylenetriaminepentaacetic acid nuclear imaging for quantitative determination of the glomerular filtration rate of dogs. Am J Vet Res 1986;47:2175-2179 45. Uribe D, Krawiec DR, Twardock AR, et al: Quantitative renal scintigraphic determination of the glomerular-filtration rate in cats with normal and abnormal kidney-function, using Tc-99m-diethylenetriaminepentaacetic acid. Am J Vet Res 1992;53:1101-1107 46. Greer LL, Daniel GB, Shearn-Bochsler VI, et al: Evaluation of the use of technetium Tc 99m diethylenetriamine pentaacetic acid and technetium Tc 99m dimercaptosuccinic acid for scintigraphic imaging of the kidneys in green iguanas (Iguana iguana). Am J Vet Res 2005;66:87-92
45 47. Sykes JMIV Schumacher J, Avenell J, et al: Preliminary evaluation Of 99m technetium diethylenetriamine pentaacetic acid, 99mtechnetium dimercaptosuccinic acid, and 99mtechnetium mercaptoacetyltriglycine for renal scintigraphy in Corn Snakes (Elaphe Guttata Guttata). Vet Radiol Ultrasound 2006;47:222-227 48. Barthez PY, Hornof WJ, Cowgill LD, et al: Comparison between the scintigraphic uptake and plasma clearance of Tc-99m-diethylenetriaminepentacetic acid (DTPA) for the evaluation of the glomerular filtration rate in dogs. Vet Radiol Ultrasound 1998;39:470-474 49. Matthews HK, Andrews FM, Daniel GB, et al: Comparison of standard and radionuclide methods for measurement of glomerular-filtration rate and effective renal blood-flow in female horses. Am J Vet Res 1992;53: 1612-1616 50. Held JP, Daniel GB: Use of nonimaging nuclear medicine techniques techniques to assess the effect of flunixin meglumine on effective renal plasma flow and effective renal blood flow in healthy horses. Am J Vet Res 1991;52:1619-1621 51. Krawiec DR, Twardock AR, Badertscher RR II, et al: Use of 99mTc diethylenetriaminepentaacetic acid for accessment of renal function in dogs with suspected renal disease. J Am Vet Med Assoc 1988;192: 1077-1080 52. Daniel GB, Mitchell SK, Mawby D, et al: Renal nuclear medicine: A review. Vet Radiol Ultrasound 1999;40:572-587 53. Cohen ML: Radionuclide clearance techniques. Semin Nucl Med 1974;4:23 54. Daniel GB, Tyson AR, Grant DC, et al: Optimal timing of blood sample collection for determining GFR in the cat using plasma clearance of 99m Tc-DTPA. Vet Radiol Ultrasound 2011;53:109 55. Tabaru H, Finco DR, Brown SA, et al: Influence of hydration state on renal functions of dogs. Am J Vet Res 1993;54:1758-1764 56. Young K, Daniel GB, Bahr A: Application of the pin-hole collimator in small animal nuclear scintigraphy: A review. Vet Radiol Ultrasound 1997;38:83-93 57. Newell SM, Ko JC, Ginn PE, et al: Effects of three sedative protocols on glomerular filtration rate in clinically normal dogs. Am J Vet Res 1997;58:446-450 58. Gates GF: Glomerular filtration rate: Estimation from fractional renal acumulation of 99mTc-DTPA (stannous). AJR Am J Roentgenol 1982;138:565 59. Barthez PY, Smeak DD, Wisner ER, et al: Ureteral obstruction after ureteroneocystostomy in dogs assessed by technetium Tc 99m diethylenetriamine pentaacetic acid (DTPA) scintigraphy. Vet Surg 2000;29: 499-506 60. Barthez PY, Smeak DD, Wisner ER, et al: Effect of partial ureteral obstruction on results of renal scintigraphy in dogs. Am J Vet Res 1999;60: 1383-1389 61. Kunze C, Bahr A, Lees GE: Evaluation of Tc-99m-diethylenetriaminepentaacetic acid renal scintigram curves in normal dogs after induction of diuresis. Vet Radiol Ultrasound 2006;47: 103-107 62. Fleming JS, Kemp PM: A comparison of deconvolution and the PatlakRutland plot in renography analysis. J Nucl Med 1999;40:1503-1507 63. Peter AM: Graphical analysis of dynamic data: The Patlak-Rutland plot. Nucl Med Commun 1994;15:669. [Editorial] 64. Piepsz A, Kinthaert M, Tondeur M, et al: The robustness of the PatlakRutland slope for the determination of split renal function. Nucl Med Commun 1996;17:817 65. Kampa N, Lord P, Maripuu ENN, et al: Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs. Vet Radiol Ultrasound 2007;48:585-593 66. Kampa N, Bostrom I, Lord P, et al: Day-to-day variability in glomerular filtration rate in normal dogs by scintigraphic technique. J Vet Med A Physiol Pathol Clin Med 2003;50:37-41 67. Kampa N: Renal Scintigraphy in Dogs. Uppsala: Swedish University of Agricultural Sciences; 2006 68. Kampa N, Wennstrom U, Lord P, et al: Effect of region of interest selection and uptake measurement on glomerular filtration rate measured by Tc-99m-DTPA scintigraphy in dogs. Vet Radiol Ultrasound 2002;43: 383-391
R. Tyson and G.B. Daniel
46 69. Singer MA: Dietary protein-induced changes in excretory function: A general animal design feature. Comp Biochem Physiol B Biochem Mol Biol 2003;136B:785-801 70. Finco DR, Cooper TL: Soy protein increases glomerular filtration rate in dogs with normal or reduced renal function. J Nutr 2000;130: 745-748 71. Greco DS, Lees GE, Dzendzel GS, et al: Effect of dietary sodium intake on glomerular filtration rate in partially nephrectomized dogs. Am J Vet Res 1994;55:152-159 72. Twardock AR, Bahr A: Renal Scintigraphy. In: Daniel GB, Berry CR, (eds): Textbook of Veterinary Nuclear Medicine. (ed 2). Harrisburg, PA: American College of Veterinary Radiology; 2006 73. Oreilly PH, Testa HJ, Lawson RS, et al: Diuresis renography in equivocal urinary-tract obstruction. Br J Urol 1978;50:76-80 74. Mitchell SK, Daniel GB, Schmidt DS: Diuresis renography in normal dogs. in: Annual Scientific Conference of the American College of Veterinary
75.
76. 77.
78.
79.
Radiology. Chicago Il, American College of Veterinary Radiology, 1998. Morton KA, Clarke PB, Boldgett TM, et al: Genitourinary. In: Morton KA, Clarke PB, (eds): Diagnostic Imaging: Nuclear Medicine. Salt Lake City: Amirsys; 2007 Hecht S, Daniel GB, Mitchell SK: Diuretic renal scintigraphy in normal dogs. Vet Radiol Ultrasound 2006;47:602-608 Hecht S, Daniel GB, Lane IF: 99mTc-DTPA diuretic renography in dogs with urolithiasis. in: 14th Meeting of the International Veterinary Radiology Association 2006. Vancouver BC, IVRA-ACVR, 2006. Lora-Michiels M, Anzola K, Amaya G, et al: Quantitative and qualitative scintigraphic measurement of renal function in dogs exposed to toxic doses gentamicin. Veterinary Radiol Ultrasound 2001;42:553-561 Marshall KL, Craig LE, Jones MP, et al: Quantitative renal scintigraphy in domestic pigeons (Columba livia domestica) exposed to toxic doses of gentamicin. Am J Vet Res 2003;64:453-462
S
imilar to humans, renal disease is common in companion animals, especially the cat. Veterinarians typically rely on clinical signs and blood work for diagnosing and monitoring of renal disease in animals. Unfortunately, advanced renal disease is present long before clinical signs or evidence of blood chemistry abnormalities is seen. Animals often first present with renal disease with a history of polyuria or polydipsia or both.1 Similar to people, evidence of blood chemistry abnormalities, such as elevations in creatinine, is not detected until 65%-75% of the nephrons have been damaged.2 Diagnostic imaging is an important part of the workup of renal disease in veterinary patients. Because of its widespread availability, radiography is the most commonly used imaging modality. However, radiographs are limited to the evaluation of renal size, shape, and changes in opacity. Because of anatomical constraints, the right kidney is often poorly visualized owing to silhouetting with the renal fossa of the caudate lobe of the liver and superimposition of small intestine and colon. Intravenous pyelograms were routinely performed in veterinary medicine but are rarely carried out today. The evaluation of changes in the pattern of renal cortical opacification was once used as a method for qualitative assessment of renal function.3 Intravenous pyelography was also used to diagnose pyelonephritis, hydronephrosis, renal masses, and perinephric pseudocysts and to look for evidence of ureteral ectopia.3,4 Currently, ultrasound and computed tomography have largely replaced the need for intravenous pyelography. Ultrasound imaging has become widely available and is routinely performed at veterinary clinics, being the second
Department of Small Animal Clinical Sciences, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA. Address reprint requests to Gregory B. Daniel, DVM, MS, DACVR, Department of Small Animal Clinical Sciences, Virginia Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060. E-mail: [email protected]
0001-2998/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semnuclmed.2013.08.005
most commonly used imaging modality in veterinary medicine. In the vast majority of patients, ultrasound is performed without the use of sedation or anesthesia, as the patient is held with gentle restraint. Ultrasound imaging provides much greater detail about renal morphology than radiography and is ideal for differentiating suspected mass from cystic lesions. Ultrasound allows for a detailed examination of the renal cortex, medulla, pelvis, ureter (when dilated), and blood flow. Common abnormalities identified include small kidney, infarcts, nephroliths, cysts, pyelonephritis, hydronephrosis, acute renal failure, such as secondary to leptospirosis or toxin, and mass lesions.5,6 The modality is also ideal for ultrasoundguided procedures such as aspirates, dilated renal pelvic sampling, antegrade pyelography, and biopsies (Fig. 1). Unfortunately, radiography and ultrasound provide limited information about renal function. Computed tomography is occasionally used for renal imaging, but is only available at veterinary teaching hospitals or specialty referral clinics. Its widespread use is limited by cost and the need for heavy sedation or anesthesia to perform the procedure. Computed tomography is most often used for the evaluation of ectopic ureters and surgical planning for large mass lesions involving the retroperitoneal space, adrenal glands, or kidneys.7,8 Recently, some investigators have used dynamic renal computed tomography to estimate global and split renal function in pigs, dogs, and cats.9-15 Renal scintigraphy is performed in dogs and cats and has also been successfully performed in a variety of other species. The availability of renal scintigraphy is limited. This is largely owing to the costs of nuclear medicine equipment, the requirement for a radioactive materials license, and the lack of sufficient technical expertise. Nuclear medicine services are available at almost all of the 28 veterinary schools in the United States and in several private specialty practices. Indications for renal scintigraphy in animals are similar to that in people. However, the use of renal scintigraphy associated with 35
R. Tyson and G.B. Daniel
36
Figure 1 Evaluation of the kidneys in an iguana. The image on the left shows the placement of the ultrasound transducer to image the kidneys, which are located more caudally than most mammalian species. A biopsy needle is being directed into the left kidney via ultrasound guidance. The central image is a pulse-wave Doppler spectrum. The right image is a power Doppler image of the right kidney.
advanced treatment procedures, such as renal transplant, is far less common because of the limited number of places that offer these treatments. Renal scintigraphy is most commonly performed in dogs that are undergoing nephrectomy or nephrotomy and in patients with urolithiasis. Renal scintigraphy is most commonly performed in cats that are being evaluated for treatment of hyperthyroidism, with iodine-131, or are undergoing nephrectomy.
Incidence of Renal disease Chronic kidney disease is very common in older companion animals, in which approximately 35% of cats and 10% of dogs are affected in populations presenting to specialty referral hospitals.16,17 Chronic kidney disease is most often identified in older feline patients with a mean age of 12.6 years, but a range of 1-26 years.18,19 Certain breeds, such as Maine Coon, Abyssinian, Persian, and Burmese, have a significantly increased risk of developing chronic renal failure.20 In a previous study evaluating histopathology results from dogs and cats with renal azotemia, it was found that tubulointerstitial nephritis was present most often (58% of dogs and 70% of cats).21 Renal failure is also a major cause of illness and death in reptilian species, such as iguanas.22,23
Anatomy Just like their human counterparts, cats and dogs have paired bean-shaped kidneys that are found in the dorsal retroperitoneal space.24 Embryologically, the cat, the dog, and the horse kidneys are classified as unilobar and have a smooth exterior serosal margin.25 In dogs, the right kidney is more fixed in place and is located craniodorsal to the left kidney. In cats, the 2 kidneys are often found at a similar level in the middorsal abdomen. Cats, being more similar in size as compared with dogs, have a fairly similar kidney size with renal lengths in the range of 3.0-4.3 cm.26 Interestingly, neutered cats have statistically smaller kidneys when compared with intact cats.27 Because of the large variation in the size of dogs, a wide range of normal renal lengths exists. In both species, normal renal length
is determined by a ratio with the length of the second lumbar vertebra on radiographs.28,29 The kidney in most mammalian species receives approximately 25% of the total cardiac output through renal arteries that typically branch into dorsal and ventral rami at the renal hilus.30,31 In the dog and the cat, this equates to a renal blood flow of 4 mL/min/g of kidney weight.32,33 Anatomical variations of the renal vasculature are relatively common, and CT is often performed before renal transplant.34 The kidney is divided into 2 major anatomical regions, the cortex and the medulla. The cortex is the outer most aspect of the kidney, which primarily incorporates the proximal and distal convoluted tubules and renal corpuscles. The medulla is the inner portion of the kidney that is comprised of collecting ducts and the loop of Henle.24,30 In most domestic animals, the corticomedullary ratio is approximately 1:2 to 1:3. However, this ratio is not fixed, and in some desert animal species, it may be as high as 1:5.25
Indications In clinical veterinary medicine, renal scintigraphy is almost exclusively performed using technetium (99mTc)-diethylenetriamine pentaacetic acid (DTPA). As such, the primary goal of most studies is to determine global and split renal glomerular filtration rates (GFR). In dogs and cats, renal scintigraphy is most commonly performed for the evaluation of renal function before nephrectomy or nephrotomy.35 Surgery may be necessary to remove a mass that involves the kidney, a nidus of infection that cannot be controlled by antibiotics, a chronically hydronephrotic kidney, or for nephroliths. Renal scintigraphy is often coupled with the administration of a diuretic to evaluate the patency of the ureters from obstructive ureterolithiasis or stricture.36,37 Renal scintigraphy can also be useful for the evaluation of global renal function in cases of subclinical renal disease. This is especially important when the treatment may result in a further decrease in renal function, such as with administration of nephrotoxic drugs.38 Treatment of hyperthyroid cats with iodine-131 can result in a worsening of their renal disease.39-41 Because the prevalence of renal disease and hyperthyroidism increases in aged cats, these
Renal Scintigraphy in veterinary medicine 2 diseases often occur concurrently. Hyperthyroidism has been shown to increase blood flow to the kidneys and thus mask subclinical renal disease. After treatment with iodine131, the decrease in renal blood flow can cause some cats with underlying renal disease to go into renal failure.42 In one prior study, the mean GFR went from a mean of 2.51 mL/min/kg to a posttreatment average of 1.4 mL/min/ kg.42,43 With the high incidence of renal disease in the cat, the procedure has also been used to help detect earlyimpaired renal function that may affect the patient's longterm prognosis. 99m
Tc-DTPA
Tc-DTPA is used as a glomerular filtration agent. The suitability of 99mTc-DTPA to measure GFR varies between animal species because of in vivo protein binding. If a portion of the injected dose of 99mTc-DTPA becomes bound to plasma proteins then it would not be available for glomerular filtration and would falsely decrease the measured GFR or affect the ability to image kidney morphology. In the dog and the cat, there is minimal amount (6%-7%) of protein binding of 99mTc-DTPA, which does not significantly influence renal uptake.44,45 In the green iguana, approximately 50% of 99mTc-DTPA is protein bound, and as such, is not a good renal imaging agent in this species.46 In corn snakes, approximately 30% of 99mTc-DTPA is protein bound, and likewise, is a poor imaging agent owing to diminished renal uptake.47 In these species, the image quality of the kidney is poor and GFR cannot be quantified using 99mTc-DTPA. Although 99m Tc-DTPA would probably be suitable for most mammalian domestic species, the amount of protein binding has to be ascertained before being used in a previously untested species. 99m
37 biexponential regression analysis of the decreasing plasma radioactivity data. A least-squares approximation is used to determine the coefficients of the biexponential function. The GFR is calculated using GFR ¼
Administered Activity ðdoseÞ A=aa þ B=ab
where A and B are the y-intercept of the fast and slow compartments, and aa and ab are the slopes of the clearance from their respective compartments. The number of samples and the volume of blood removed are not significant in animals with large body weights, but can be problematic in smaller animals such as cats. As such, there has been a trend toward using a smaller number of plasma samples in the analysis and using a monoexponential model. In small animals, plasma clearance using a reduced number of plasma samples has been studied, and it shows to be a good predictor of GFR. There may be a future trend toward using plasma clearance for global renal function combined with image analysis for split renal function and clearance studies.48,54
Image Analysis
Procedure: GFR
Patients should be normally hydrated before the procedure to get the best estimation of the animal's true steady state GFR. Studies have shown the influence of hydration status, or fluid loading, on GFR quantifications.55 Doses of 99mTc-DTPA range from 1-4 and 1-3 mCi for the dog and the cat, respectively. Before and after counts of the dose syringe are used in the determination of the percent dose uptake of the radiopharmaceutical by the kidneys. Doses greater than 4 mCi are not used because of dead-time loss when counting the dose syringe on the gamma camera before injection. The dose syringe is traditionally counted at a distance of 30 cm from the center of the gamma camera. However, the exact distance is not critical, as the sensitivity of a parallel hole collimator varies little with distance if fitted with a low-energy all-purpose parallel hole collimator.56
In veterinary medicine, GFR is measured by either plasma clearance methods or image-based analysis.48-52 In general, plasma clearance methods have been used more commonly in larger species, such as horses. Image-based analysis is most frequently used for small species, such as dogs and cats. The plasma clearance methods do not have the errors associated with attenuation corrections required for image-based analysis. In large species, such as a horse, the kidney depth is quite significant and motion during a long dynamic acquisition is often problematic. Plasma clearance studies are performed using traditional techniques 52,53 Plasma samples are obtained at specific time intervals following intravenous injection of 99m Tc-DTPA. Traditionally, 6-9 plasma samples are taken out to 3-4 hours following injection of radiopharmaceutical. The plasma radioactivity is counted in a NaI well detector, and the decay corrected counts are plotted to create a plasma radioactivity curve. The area under the plasma radioactivity curve is determined by a
Figure 2 Picture showing the positioning of a cat in preparation for renal scintigraphy. Most animals tolerate positioning in lateral recumbency for the 6-8 minute acquisition. An IV catheter has been placed in the cat's left cephalic vein for the bolus injection of 3 mCi of 99m Tc-DTPA. IV, intravenous.
R. Tyson and G.B. Daniel
38
Figure 3 The plots above show the relationship between percent dose uptake of 99mTc-DTPA and inulin clearance. Linear regression analysis was used to determine the formula for predicting renal clearance from the percent dose uptake data. This is the most commonly used method in veterinary medicine for predicting GFR using renal scintigraphy. (Color version of figure is available online.)
For the examination, the patient is gently restrained in lateral recumbency. Depending on patient's demeanor and cooperativeness, the patient may have to be sedated or anesthetized, which has been demonstrated to decrease GFR, pending method used. If needed, acepromazine and butorphanol have successfully been used for sedation without negatively affecting the GFR.57 The gamma camera is positioned in a vertical
orientation along the dorsum of the patient (Fig. 2). For most procedures, a 6-minute dynamic acquisition is started simultaneously with intravenous bolus delivery of the radiopharmaceutical. After the dynamic acquisition, the gamma camera is rotated to a horizontal position, without moving the patient. A lateral static image is then obtained for measurements of individual kidney depth, for attenuation correction.
Figure 4 A typical renogram curve from a normal dog following injection of 3 mCi of 99mTc-DTPA. Note that peak renal activity occurs around 3 minutes following injection, although there is variation based on physiological influences. The recorded activity in the left kidney is usually lower than the right owing to its deeper location in the body. Attenuation correction is needed for accurate determination of splint renal function. (Color version of figure is available online.)
Figure 5 This is Patlak-Rutland plot. The y-axis is the function of kidney activity K(t) divided by plasma activity P(t). The x-axis is a plot of integral of plasma activity P(t) divided by P(t). The slope of this graph is equal or proportional to the clearance of the tracer from the blood to a tissue compartment. (Color version of figure is available online.)
Renal Scintigraphy in veterinary medicine
39
Figure 6 The images at the top are from a dynamic acquisition of a dog after injection of 99mTc-DTPA. The images were acquired at 1 frame every 6 seconds. The left kidney is small and has decreased function. Renogram curves of the left and right kidneys are shown in the bottom left, note the flat shape to the left renogram curve. The plasma clearance curve was created by counting plasma samples in a NaI well detector. The animal's global GFR was 1.86 mL/min/kg, of which 90% was derived from the right kidney. (Color version of figure is available online.)
Attenuation correction has been shown to increase the accuracy of results in the dog, because of the wide variation in breed size, but not in the cat.44,45 The estimation of GFR from dynamic renal scintigraphy can be performed by a variety of methods, but the most commonly employed method used in veterinary medicine is a modified technique originally described by Gates.44,45,51,58 GFR is predicted from a regression equation that was created from a plot of the percent dose uptakes of the 99mTc-DTPA
in the kidney to inulin clearances in a series of dogs and cats with normal and impaired renal function (Fig. 3).44,45 The best correlation to inulin clearance in the dog and the cat was obtained using percent dose uptake data from 1-3 minutes following injection. In these animals, there was a consistent upslope of the renogram curve from 1-3 minutes, with peak renal activity occurring approximately 3 minutes following injection (Fig. 4). Owing to variation in mean renal transit times, the time-to-peak renal activity
Figure 7 Renogram curves from 2 different animals. The curve on the left is a normal dog with no ureteral dilation or obstruction. The curve on the right is from a dog with a ureteral calculi obstructing the left ureter. (Color version of figure is available online.)
R. Tyson and G.B. Daniel
40
Figure 8 The images at the top from the same dog as in Figure 6. This phase of the dynamic acquisition was obtained following injection of Lasix (3 mg/kg) and the frame rate was increased to 1 frame every 3 seconds. Note the rapid clearance of the radiopharmaceutical from both kidneys. The renogram curves have been normalized to the same peak value before determining the slope of the curve by linear regression. Even though the left kidney has 10% of total renal function, the slope of the clearance phase is normal indicating no postrenal obstruction. (Color version of figure is available online.)
can differ in a variety of clinical situations. Examples would include poorly functioning kidneys (longer) or animals undergoing diuresis (shorter), which make this 1-3minute interval inappropriate.59-61 Because of the limitation of the modified Gate's technique, other methods of image analysis of dynamic renal scintigraphy have been tried in veterinary medicine. One of the more recent is the use of Patlak-Rutland plots to determine GFR. The technique assumes a 2-compartment model with the unidirectional transfer of the 99mTc-DTPA from one compartment (plasma) to the other (kidney) during the time following injection that there is no output
from the renal region of interest (ROI). The rate constant from the plasma to the kidney is the clearance rate. This clearance rate can be solved using a graphical analysis technique.62 The plot, which has as it y-axis as the function of kidney activity, is divided by plasma activity: KPððttÞÞ where K(t) represents the attenuation corrected net kidney counts at time (t) and P(t) represents plasma counts at time (t) (Fig. 5).63,64 The plasma activity is derived from an ROI drawn over the left ventricle.65 The x-axis is a plot of R the integral of plasma activity P(t) divided by P(t): PðtÞdt=PðtÞ . The points plotted are reasonably straight except for the early points that are influenced by extrarenal
Figure 9 Images of a normal dog obtained 3 hours following injection of 99mTc-DMSA. The images on the top row are from left to right (right lateral, dorsal, and left lateral images). Note most activity is located in the renal cortices. There is minimal extrarenal soft tissue or urinary bladder activity.
Renal Scintigraphy in veterinary medicine
41
Figure 10 These are right lateral images of a horse following injection of 20 mCi of 99mTc-DMSA. The image on the left is from a normal horse and the image on the right is from 1-year-old horse with severe renal dysplasia. Note the multiple photopenic voids of the dysplastic kidney. The dysplastic kidney did not develop properly and the renal cortex contained fetal glomeruli and abundant interstitial fibrosis. There were also multiple medullary cysts.
activity and late points that are influenced by the passage of the radiopharmaceutical into the lower urinary tract.64 The slope of this graph is equal, or proportional, to the clearance of the tracer from the blood to a tissue
compartment.63 The GFR value is expressed in terms of clearance per plasma volume (mL/min/L). Dynamic renal scintigraphy is not an absolute measure of GFR, and imaging GFR values have been shown to vary
Figure 11 The images at the top are from a pigeon (Columba livia domestica) following injection of 1 mCi (37 MBq) of 99mTcDTPA. The images were taken at various times during a 15-minute dynamic acquisition. You can see the radiopharmaceutical accumulating in the cloaca. The kidneys are difficult to identify owing to a low kidney to background ratio. The location of the kidneys is more easily identified following injection of 1 mCi (37 MBq) of 99mTc-DMSA. The kidneys in the second row of images are seen as elongated structures in the caudal dorsal aspect of the coelomic cavity. The liver also accumulates 99mTcDMSA and is located in the central region of the coelomic cavity. The renogram at the bottom is from a normal bird and a bird with decreased renal function. Note the lower uptake in the diseased bird.
R. Tyson and G.B. Daniel
42
Figure 12 The bottom images show the distribution of 3 common radiopharmaceutical in corn snakes (Elaphe guttata guttata). These images are from the distal aspect of the snake that includes the kidneys. Kidneys are only identified using 99mTc-MAG3. High levels of protein binding of 99mTc-DTPA prevented renal accumulations. The reason for the failure of 99mTc-DMSA to localize in the kidney is unknown. The images at the top left are part of a dynamic acquisition following the intracardiac injection of 99mTc-MAG3. Note the slow passage of the radiopharmaceutical down the aorta. The photograph in the upper right shows the intracardiac administration of the radiopharmaceutical. MAG3, mercaptoacetyltriglycine.
considerably in animals.66 Dynamic renal scintigraphy is less accurate than plasma clearance studies in determining GFR.48 This is owing in part to the fact that GFR measured from dynamic renal scintigraphy is based on a relatively short sampling of data (1-3 minutes after injection for the Gates method and 1-4 minutes for the Rutland-Patlak plot method).44,45,65 Studies that measure GFR over a longer time interval, such as 24-hour inulin clearances or 3-hour plasma clearance studies, are more likely to give an accurate measurement of the animal's true GFR.66 This is especially true in animals with a normal or near-normal renal reserve capacity. There are other factors that can influence the accuracy of GFR determination from image analysis.67 Movement, which is a problem even in small animals, would decrease the ability to obtain accurate quantification of renal activity. Measuring plasma activity by a heart or aortic ROI has errors owing to background activity. In addition, errors in ROI placement and depth attenuation can lead to inaccurate measurements.68 The GFR is also influenced by nonrenal factors such as stress, hydration status, and protein or sodium content of the diet.69-71 Still, correlation of the imaging GFR values to inulin clearance values is reasonably good in animals, and the ease and speed
with which results can be obtained makes the imaging GFR technique a useful clinical tool.
Interpretative Principles Global GFR values more than 3 mL/min/kg are considered normal in the dog and global GFR values more than 2.5 mL/ min/kg are considered normal in the cat.52,72 Animals with subclinical renal insufficiency have global values between 1.2 and 2.5 mL/min/kg. In these animals, there would be poor renal uptake of 99mTc-DTPA and the extrarenal soft tissues would be slow to clear. The renogram curve would appear flat (Fig. 6). Global GFR values less than 0.25 would have such poor renal uptake that quantitative renal scintigraphy with 99m Tc-DTPA may be difficult to perform accurately.
Evaluation for Obstructive Uropathy In cases where there is a clinical concern for ureteral obstruction, a slight modification is made to the aforementioned procedure. The acquisition is longer (at least 8 minutes)
Renal Scintigraphy in veterinary medicine
43
Figure 13 Images of a green iguana (Iquana iquana) at various times following injection of 1 mCi (37 MBq) of 99mTc-DMSA. The kidneys are the paired structures in the dorsal pelvis region. Long localization time is necessary to get a good kidney uptake. Photographs and radiographs are also shown to help with anatomical correlations.
and at 4.5 minutes after bolus injection of 99mTc-DTPA, a 3 mg/kg dose of Lasix is given intravenously.73-75 The shape of the renogram curve is then used to help diagnose obstructive uropathy.75 The injection of the diuretic is necessary to differentiate between a dilated nonobstructed vs an obstructed ureter. Without the administration of a diuretic, both of these conditions can result in a continuing rise in the renogram curve. This ureteral dilation can occur secondary to obstruction, but can also be associated with nonobstructive disorders such as vesicoureteral reflux, trauma, infection, or congenital anomalies. The rate of renal excretion can be quantified from the downslope of the renogram curves following diuretic administration. Dogs with patent ureters would have rapid clearance of the 99mTc-DTPA from the kidneys following diuretic injection, where as those with postrenal obstruction would retain the 99mTc-DTPA within the renal pelvis and would not show a downslope on the renogram curve (Fig. 7). Because the
slope of the excretion phase is dependent on the magnitude of peak renal activity, the renogram curves are normalized to the same peak value (Fig. 8). Linear regression is used to fit the downslope of the renogram curve from which the slope of the line is measured. An excretion T1/2 is derived from the slope of the fitted line. In normal dogs, the median excretion T1/2 is 4.16 minutes with a range of 3.62-5.90 minutes.74,76 This technique is useful in assessing for ureteral obstruction in dogs and cats with urolithiasis.36,37,77
Renal Morphology Scintigraphy With 99mTc-Dimercaptosuccinic Acid (DMSA) 99m
Tc-DMSA has been used to measure kidney function and morphology in veterinary medicine. Delayed imaging at 2-3
R. Tyson and G.B. Daniel
44 hours after injection is needed to allow adequate time for renal localization. By 4 hours after injection, 51.7% ⫾ 2.5% of the radiopharmaceutical would be bound to the kidney in normal dogs (Fig. 9). 99mTc-DMSA can also be used to detect space occupying masses that displace renal tubular cells. These lesions would appear as photopenic defects. As 99mTc-DMSA is a static imaging agent, it is the best radiopharmaceutical for imaging the equine kidney (Fig. 10). Motion correction software can be employed to compensate for the typical swaying motion of the horse during the 60-90 second time interval needed to acquire the images. Images can be repeated as needed. Differential estimation of functioning tubular renal mass can be made by determining the percent dose uptake of 99m Tc-DMSA by the left and right kidneys.75 It is important to note that this provides an estimate of functioning tubular renal mass and not renal function, as poor DMSA uptake in the presence of normal DTPA uptake has been seen in patients with tubulointerstitial renal disease. 99m Tc-DMSA can also be used to quantify relative (left vs right) functioning renal tubular mass.78 In a study on dogs subjected to renal tubular damage by toxic doses of gentamicin, 99m Tc-DMSA was able to detect disease earlier than either 99m Tc-DTPA or 99mTc-mercaptoacetyltriglycine.78
Other Uses of Renal Scintigraphy Renal scintigraphy has been used to evaluation variety of nontraditional pet animals. For example, in reptiles, changes in serum or plasma urea nitrogen and creatinine concentrations are not useful indicators of renal failure because they are not elevated until there is extensive renal damage and are also affected by feeding, reproductive status, and hydration.46,47 In avian species, uric acid concentrations are used for the evaluation of renal disease, but significant renal dysfunction is necessary before an increase in uric acid concentration is seen. Another factor is that uric acid secretion is primarily by the proximal tubules and is not reflective of GFR.79 As such, renal scintigraphy has been explored as a method to better evaluate renal disease in these species. 99mTc-DTPA is the method of choice for the evaluation of renal function in the bird, but 99m Tc-DMSA was better for the evaluation of renal morphology (Fig. 11). In snakes, 99mTc-mercaptoacetyltriglycine appears to be better than either 99mTc-DTPA or 99mTc-DMSA for the evaluation of kidney structure and function (Fig. 12). In iguanas, 99mTc-DMSA has been demonstrated to be useful for the evaluation of kidney structure and function (Fig. 13).
Conclusion Renal scintigraphy is the most commonly used imaging modality for the evaluation of individual and global renal function in the dog and the cat. Although less commonly used, plasma clearance studies have also been employed to determine global GFR. Diuretic renal scintigraphy is used for the evaluation of postrenal obstruction in animals with urolithiasis. Although not as commonly performed, morphologic imaging using 99mTc-DMSA has been used in the dog and may be the
best renal imaging agent for the horse. Renal scintigraphy has the potential for use in the evaluation of nontraditional pet animals and to help understand physiological differences between species.
References 1. Bartges J, Polzin DJ: Historical information and physical examination. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 2. LeFebvre HP: Renal function testing. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 3. Feeney DA, Johnson GA: The kidney and ureters. In: Thrall DE, (ed): Textbook of Veterinary Diagnostic Radiology. (ed 5). St Louis: Saunders Elsevier; 2007. pp. 693-707 4. Ackerman N: Radiology and Ultrasound of Urogential Diseases in Dogs and Cats. Ames, IA: Iowa State University Press; 1991 5. Nyland TG, Mattoon JS: Small Animal Ultrasound. (ed 2). Philadelphia, PA: WB Saunders; 2002 6. Penninck DG, d'Anjou MA: Atlas of Small Animal Ultrasonography. Ames, IA: Blackwell Publishing; 2008 7. Anders KJ, McLoughlin MA, Samii VF, et al: Ectopic ureters in male dogs: Review of 16 clinical cases (1999–2007). J Am Anim Hosp Assoc 2012;48:390-398 8. Samii VF, McLoughlin MA, Mattoon JS, et al: Digital fluoroscopic excretory urography, digital fluoroscopic urethrography, helical computed tomography, and cystoscopy in 24 dogs with suspected ureteral ectopia. J Vet Intern Med 2004;18:271-281 9. Alexander K, del Castillo JRE, Ybarra N, et al: Single-slice dynamic computed tomographic determination of glomerular filtration rate by use of Patlak plot analysis in anesthetized pigs. Am J Vet Res 2007;68:297-304 10. Alexander K, Authier S, del Castillo JRE, et al: Patlak plot analysis CT-GFR for the determination of renal function: Comparison of normal dogs with autologous kidney transplant dogs. Contrast Media Mol Imaging 2010;5:133-139 11. Chang J, Ahn S, Choi S, et al: Evaluation of glomerular filtration rate by use of dynamic computed tomography and Patlak analysis in clinically normal cats. Am J Vet Res 2011;72:1276-1282 12. Granger LA, Armbrust LJ, Rankin DC, et al: Estimation of glomerular filtration rate in healthy cats using single-slice dynamic CT and patlak plot analysis. Vet Radiol Ultrasound 2012;53:181-188 13. Alexander K, Dunn M, Carmel EN, et al: Clinical application of patlak plot CT-GFR in animals with upper urinary tract disease. Vet Radiol Ultrasound 2010;51:421-427 14. Chang J, Kim S, Jung J, et al: Assessment of glomerular filtration rate with dynamic computed tomography in normal Beagle dogs. J Vet Sci 2011;12:393-399 15. Schmidt DM, Scrivani PV, Dykes NL, et al: Comparison of glomerular filtration rate determined by use of single-slice dynamic computed tomography and scintigraphy in cats. Am J Vet Res 2012;73:463-469 16. Kirk RW: Current Veterinary Theraphy IX Small Animal Practice. (ed 9) Philadelphia, PA: WB Saunders; 1986 17. Kirk RW: Current Veterinary Therapy X: Small Animal Practice. (ed 10) Philadelphia, PA: WB Saunders; 1989 18. Elliott J, Barber PJ: Feline chronic renal failure: Clinical findings in 80 cases diagnosed between 1992 and 1995. J Small Anim Pract 1998;39:78-85 19. Dibartola SP, Rutgers HC, Zack PM, et al: Clinicopathological findings associated with chronic renal-disease in cats—74 cases (1973-1984). J Am Vet Med Assoc 1987;190:1196-1202 20. Lulich JP, Osborne CA, Obrien TD, et al: Feline renal-failure—Questions, answers, questions. Compend Contin Educ Pract Vet 1992;14:127-151 21. Minkus G, Reusch C, Horauf A, et al: Evaluation of renal biopsies in cats and dogs histopathology in comparison with clinical-data. J Small Anim Pract 1994;35:465-472 22. Hernandez-Divers SJ: Green iguana nephrology: A review of diagnostic techniques. Vet Clin North Am Exot Anim Pract 2003;6:233-250
Renal Scintigraphy in veterinary medicine 23. Hernandez-Divers SJ, Innis CJ: Renal disease in reptiles: Diagnosis and clinical management. In: Mader DR, (ed): Reptile Medicine and Surgery. (ed 2). St Louis, MO: Elsevier; 2006 24. Clarkson CE, Fletcher TF: Anatomy of the kidney and proximal ureter. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 25. Newman SJ: The urinary system. In: Zachary JF, McGavin M, (eds): Pathologic Basis of Veterinary Disease. (ed 5), St Louis, MO: Elsevier; 2012. pp 589-659 26. Walter PA, Johnston GR, Feeney DA, et al: Renal ultrasonography in healthy cats. Am J Vet Res 1987;48:600-607 27. Shiroma JT, Gabriel JK, Carter RL, et al: Effect of reproductive status on feline renal size. Vet Radiol Ultrasound 1999;40:242-245 28. Barrett RB, Kneller SK: Feline kidney mensuration. Acta Radiol Suppl 1972;319:279-280 29. Finco DR, Stiles NS, Kneller SK, et al: Radiologic estimate of kidney size of the dog. J Am Vet Med Assoc 1971;159:995-1002 30. Brown SA: Physiology of the kidney. In: Bartges J, Polzin DJ, (eds): Nephrology and Urology of Small Animals. Ames, IA: John Wiley & Sons; 2011 31. Guyton AC, Hall JE: Urine formation by the kidneys: I. Glomerular filtration, renal blood flow and their control. In: Guyton AC, Hall JE, (eds): Textbook of Medical Physiology. 11 ed. Philadelphia, PA: Elsevier; 2006 32. Brown SA, Brown CA: Single-nephron adaptations to partial renal ablation in cats. Am J Physiol Regul Integr Comp Physiol 1995;269:R1002-R1008 33. Brown SA, Finco DR, Crowell WA, et al: Single-nephron adaptations to partial renal ablation in the dog. Am J Physiol 1990;258:F495-F503 34. Bouma JL, Aronson LR, Keith DG, et al: Use of computed tomography renal angiography for screening feline renal transplant donors. Vet Radiol Ultrasound 2003;44:636-641 35. Bolliger C, Walshaw R, Kruger JM, et al: Evaluation of the effects of nephrotomy on renal function in clinically normal cats. Am J Vet Res 2005;66:1400-1407 36. Hecht S, Lawson SM, Lane IF, et al: 99mTc-DTPA diuretic renal scintigraphy in dogs with nephroureterolithiasis. Can Vet J 2010;51: 1360-1366 37. Hecht S, Lawson SM, Lane IF, et al: 99mTc-DTPA diuretic renal scintigraphy in cats with nephroureterolithiasis. J Feline Med Surg 2010;12:423-430 38. Daniel GB, Hahn K, Bravo L: The effect of a single therapeutic dose of cisplatin on GFR in dogs. Oncol Rep 1997;4:153 39. Adams WH, Daniel GB, Legendre AM, et al: Changes in renal function in cats following treatment of hyperthyroidism using I-131. Vet Radiol Ultrasound 1997;38:231-238 40. Milner RJ, Channell CD, Levy JK, et al: Survival times for cats with hyperthyroidism treated with iodine 131, methimazole, or both: 167 cases (1996-2003). J Am Vet Med Assoc 2006;228:559-563 41. Slater MR, Geller S, Rogers K: Long-term health and predictors of survival for hyperthyroid cats treated with iodine 131. J Vet Intern Med 2001;15:47-51 42. Adams WH, Daniel GB, Legendre AM: Investigation of the effects of hyperthyroidism on renal function in the cat. Can J Vet Res 1997;61:53-56 43. Graves TK, Olivier B, Nachreiner RF, et al: Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Research 1994;55:1745-1749 44. Krawiec DR, Badertscher RR II, Twardock AR, et al: Evaluation of 99m Tc-diethylenetriaminepentaacetic acid nuclear imaging for quantitative determination of the glomerular filtration rate of dogs. Am J Vet Res 1986;47:2175-2179 45. Uribe D, Krawiec DR, Twardock AR, et al: Quantitative renal scintigraphic determination of the glomerular-filtration rate in cats with normal and abnormal kidney-function, using Tc-99m-diethylenetriaminepentaacetic acid. Am J Vet Res 1992;53:1101-1107 46. Greer LL, Daniel GB, Shearn-Bochsler VI, et al: Evaluation of the use of technetium Tc 99m diethylenetriamine pentaacetic acid and technetium Tc 99m dimercaptosuccinic acid for scintigraphic imaging of the kidneys in green iguanas (Iguana iguana). Am J Vet Res 2005;66:87-92
45 47. Sykes JMIV Schumacher J, Avenell J, et al: Preliminary evaluation Of 99m technetium diethylenetriamine pentaacetic acid, 99mtechnetium dimercaptosuccinic acid, and 99mtechnetium mercaptoacetyltriglycine for renal scintigraphy in Corn Snakes (Elaphe Guttata Guttata). Vet Radiol Ultrasound 2006;47:222-227 48. Barthez PY, Hornof WJ, Cowgill LD, et al: Comparison between the scintigraphic uptake and plasma clearance of Tc-99m-diethylenetriaminepentacetic acid (DTPA) for the evaluation of the glomerular filtration rate in dogs. Vet Radiol Ultrasound 1998;39:470-474 49. Matthews HK, Andrews FM, Daniel GB, et al: Comparison of standard and radionuclide methods for measurement of glomerular-filtration rate and effective renal blood-flow in female horses. Am J Vet Res 1992;53: 1612-1616 50. Held JP, Daniel GB: Use of nonimaging nuclear medicine techniques techniques to assess the effect of flunixin meglumine on effective renal plasma flow and effective renal blood flow in healthy horses. Am J Vet Res 1991;52:1619-1621 51. Krawiec DR, Twardock AR, Badertscher RR II, et al: Use of 99mTc diethylenetriaminepentaacetic acid for accessment of renal function in dogs with suspected renal disease. J Am Vet Med Assoc 1988;192: 1077-1080 52. Daniel GB, Mitchell SK, Mawby D, et al: Renal nuclear medicine: A review. Vet Radiol Ultrasound 1999;40:572-587 53. Cohen ML: Radionuclide clearance techniques. Semin Nucl Med 1974;4:23 54. Daniel GB, Tyson AR, Grant DC, et al: Optimal timing of blood sample collection for determining GFR in the cat using plasma clearance of 99m Tc-DTPA. Vet Radiol Ultrasound 2011;53:109 55. Tabaru H, Finco DR, Brown SA, et al: Influence of hydration state on renal functions of dogs. Am J Vet Res 1993;54:1758-1764 56. Young K, Daniel GB, Bahr A: Application of the pin-hole collimator in small animal nuclear scintigraphy: A review. Vet Radiol Ultrasound 1997;38:83-93 57. Newell SM, Ko JC, Ginn PE, et al: Effects of three sedative protocols on glomerular filtration rate in clinically normal dogs. Am J Vet Res 1997;58:446-450 58. Gates GF: Glomerular filtration rate: Estimation from fractional renal acumulation of 99mTc-DTPA (stannous). AJR Am J Roentgenol 1982;138:565 59. Barthez PY, Smeak DD, Wisner ER, et al: Ureteral obstruction after ureteroneocystostomy in dogs assessed by technetium Tc 99m diethylenetriamine pentaacetic acid (DTPA) scintigraphy. Vet Surg 2000;29: 499-506 60. Barthez PY, Smeak DD, Wisner ER, et al: Effect of partial ureteral obstruction on results of renal scintigraphy in dogs. Am J Vet Res 1999;60: 1383-1389 61. Kunze C, Bahr A, Lees GE: Evaluation of Tc-99m-diethylenetriaminepentaacetic acid renal scintigram curves in normal dogs after induction of diuresis. Vet Radiol Ultrasound 2006;47: 103-107 62. Fleming JS, Kemp PM: A comparison of deconvolution and the PatlakRutland plot in renography analysis. J Nucl Med 1999;40:1503-1507 63. Peter AM: Graphical analysis of dynamic data: The Patlak-Rutland plot. Nucl Med Commun 1994;15:669. [Editorial] 64. Piepsz A, Kinthaert M, Tondeur M, et al: The robustness of the PatlakRutland slope for the determination of split renal function. Nucl Med Commun 1996;17:817 65. Kampa N, Lord P, Maripuu ENN, et al: Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs. Vet Radiol Ultrasound 2007;48:585-593 66. Kampa N, Bostrom I, Lord P, et al: Day-to-day variability in glomerular filtration rate in normal dogs by scintigraphic technique. J Vet Med A Physiol Pathol Clin Med 2003;50:37-41 67. Kampa N: Renal Scintigraphy in Dogs. Uppsala: Swedish University of Agricultural Sciences; 2006 68. Kampa N, Wennstrom U, Lord P, et al: Effect of region of interest selection and uptake measurement on glomerular filtration rate measured by Tc-99m-DTPA scintigraphy in dogs. Vet Radiol Ultrasound 2002;43: 383-391
R. Tyson and G.B. Daniel
46 69. Singer MA: Dietary protein-induced changes in excretory function: A general animal design feature. Comp Biochem Physiol B Biochem Mol Biol 2003;136B:785-801 70. Finco DR, Cooper TL: Soy protein increases glomerular filtration rate in dogs with normal or reduced renal function. J Nutr 2000;130: 745-748 71. Greco DS, Lees GE, Dzendzel GS, et al: Effect of dietary sodium intake on glomerular filtration rate in partially nephrectomized dogs. Am J Vet Res 1994;55:152-159 72. Twardock AR, Bahr A: Renal Scintigraphy. In: Daniel GB, Berry CR, (eds): Textbook of Veterinary Nuclear Medicine. (ed 2). Harrisburg, PA: American College of Veterinary Radiology; 2006 73. Oreilly PH, Testa HJ, Lawson RS, et al: Diuresis renography in equivocal urinary-tract obstruction. Br J Urol 1978;50:76-80 74. Mitchell SK, Daniel GB, Schmidt DS: Diuresis renography in normal dogs. in: Annual Scientific Conference of the American College of Veterinary
75.
76. 77.
78.
79.
Radiology. Chicago Il, American College of Veterinary Radiology, 1998. Morton KA, Clarke PB, Boldgett TM, et al: Genitourinary. In: Morton KA, Clarke PB, (eds): Diagnostic Imaging: Nuclear Medicine. Salt Lake City: Amirsys; 2007 Hecht S, Daniel GB, Mitchell SK: Diuretic renal scintigraphy in normal dogs. Vet Radiol Ultrasound 2006;47:602-608 Hecht S, Daniel GB, Lane IF: 99mTc-DTPA diuretic renography in dogs with urolithiasis. in: 14th Meeting of the International Veterinary Radiology Association 2006. Vancouver BC, IVRA-ACVR, 2006. Lora-Michiels M, Anzola K, Amaya G, et al: Quantitative and qualitative scintigraphic measurement of renal function in dogs exposed to toxic doses gentamicin. Veterinary Radiol Ultrasound 2001;42:553-561 Marshall KL, Craig LE, Jones MP, et al: Quantitative renal scintigraphy in domestic pigeons (Columba livia domestica) exposed to toxic doses of gentamicin. Am J Vet Res 2003;64:453-462