Relationship of Serum Creatinine and Glomerular Filtration Rate by 99mTc-DTPA Scintigraphy in Dogs with Renal Failure
Rajeev Vasantrao Gaikwad,
Glomerular Filtration Rate (GFR) is considered as the best single parameter for assessing renal function because it is directly proportional to the number of functioning nephrons. Serum creatinine is the most frequently measured analyze in clinical biochemistry as an indirect indicator of glomerular Filtration Rate (GFR). Renal scintigraphy has been used as direct measurement of the glomerular Filtration Rate (GFR) either of individual kidney or global (both kidneys). By this technique, the GFR is calculated by a regression equation relating the percent of the injected dose of radiopharmaceutical, technetium-99m Diethylene-Triaminepentaacetic acid (DTPA), taken up and filtered by the kidneys. This communication reports the relationship of direct (scintigraphy) and indirect (creatinine) methods of GFR measurement. Scintigraphy is a quick, noninvasive diagnostic technique in which a two-dimensional picture of internal body tissue is produced through the detection of the gamma radiation emitted by radioactive substances injected into the body within 15 min with a gamma camera. Serum creatinine increases in renal failure correlating with a decrease in GFR forming a curvilinear relationship. Based on the study undertaken in 44 dogs with renal failure, it was found that 86.36% dogs suffering from renal failure showed a conventional pattern of curvilinear relationship between creatinine and GFR. Inter-individual variations were observed in 11.36% of dogs. False positive results were obtained in 9% of total dogs, where creatinine was within normal reference range but GFR decreased on scintigraphic analysis. False negative observations were seen in 4.5% of dogs, where normal GFR with marginally high creatinine values was reported.
Received: August 27, 2011;
Accepted: November 18, 2011;
Published: December 01, 2011
Incidence of renal disease increases with age due to progressive loss of nephron
mass in every mammalian species, except horses (Grauer,
1992). Renal failure is a common clinical problem occurring in 2-5% of dogs
(Lora-Michiels et al., 2001) and third leading
cause of death in canines. Robertson (2001) reported that
by the age of 5 years, nearly 60% of dogs show renal lesions and decrements
in renal function which approaches 90% by ten years. Management of renal failure
is most successful if initiated early which (Grauer and Lane,
1995). Early recognition of renal dysfunction is also essential for monitoring
of patients receiving nephrotoxic drugs. GFR is considered as best single parameter
for assessing renal function (Heiene and Moe, 1998),
because it is directly proportional to the number of functioning nephron. Renal
dysfunction is routinely identified by elevations in Blood Urea Nitrogen (BUN)
and serum creatinine, but azotemia is usually not present until an animal has
lost which approximately 75% of its total renal function (Ross,
1995).Under steady state conditions, the rate of creatinine excretion is
equal to the rate of its production in skeletal muscles which (Guyton
and Hall, 1998), so its measurement indirectly reflects the GFR. The determination
of GFR is especially valuable as it can detect renal dysfunction in patients
(Ettinger et al., 2000). Scintigraphy is a quick,
noninvasive diagnostic technique in which a two-dimensional picture of internal
body tissue is produced through the detection of the gamma radiation emitted
by radioactive substances injected into the body within 15 min with a gamma
camera. Gamma camera technique is the only method to determine GFR, both as
a global value of enal function and as an individual function of each kidney
(Kampa, 2007). The 99 mTc-DTPA is the radiopharmaceutical
of choice for GFR study by scintigraphy, because DTPA meets the criteria for
GFR measurement and energy of the emitted radiation of 99 mTc is at 140 Kev
is ideal for effective detection by the gamma camera. This agent is excreted
principally by kidney and can be used to measure GFR; accumulation by the kidneys
reflects reduced renal function. The agent can also be used to assess renal
blood flow, suspected renovascular hypertension and obstructive uropathy (ACR
practice guideline, ACR (2006). Present communication
reports a relationship between serum creatinine and glomerular filtration rate
in dogs suffering from renal failure.
MATERIALS AND METHODS
The present research was carried out at the Veterinary Nuclear Medicine Center of the Department of Medicine, Bombay Veterinary College in 2006 to 2008. The study was performed on 44 canine patients with renal disorder referred from Bai Sakarabai Dinshaw Pettit Hospital for Animals (affiliated from Bombay Veterinary college). The kits of DTPA (TCK-7*) and molybdenum (Mo-99) were obtained from Board of Radiation and Isotope Technology, Mumbai.
A total of 44 dogs of either sex, breed weighing about 21.11±2 kg, height
40.13±2.32 cm and age about 7.56±0.92 year were selected. The
inclusive criterion for the dogs was serum creatinine level more than 2.0 mg
dL-1. All the dogs underwent routine hematology and serum biochemistry
analysis along with electrolyte analysis as per standard procedure suggested
by Benjamin (1978). Based on clinical examination and
findings of Packed Cell Volume and urine specific gravity, best possible oral
hydration done approximately 2 h prior to the study as state of hydration has
been reported to affect the Glomerular Filteration Rate (Kampa,
2007). After oral rehydration, if required, intravenous hydration was also
done using normal saline @ 15 mL kg-1 body weight over a period of
30 min before the study.
Scintigraphy was performed using 6.44 Mbq kg-1 (174 μCi kg-1)
of 99 mTc-Diethylene-triaminepentaacetic acid injected through a cephalic vein
(Kampa et al., 2006).
|| Curvilinear relationship between GFR and serum creatinine
Counting of activity in front of the gamma camera before and after injection
and correction for radioactive decay during the time interval was done. The
dog was laid down in sternal recumbency and camera positioned with the collimator
facing down, gantry 0° without any tilt, to include the kidneys, bladder
and the thorax including heart whenever possible (Fig. 1).
A dynamic acquisition was started of six frames per minute for 20 min. Immediately
after starting acquisition, 99m Tc-DTPA was injected intravenously as a bolus.
A low energy all purpose (LEGP) collimator on a gamma camera was used and 64x64
pixel matrix for the dynamic study and 128x128 matrix was selected for static
study. Immediately after the dynamic acquisition period, the camera was rotated
90 degree above the dog and a static lateral 30 sec image was made to measure
the kidney depth. The camera was then returned to its original position and
the activity in the syringe was counted to exclude it from injected dose. All
data were kept in the computer and calculated using eNTEGRA work station.
Gates Analysis programming was used to generate time activity curve. Manual
drawing of kidney ROI was done with the background (Region of Interest) ROI
at 2 pixels out from the kidney (Kampa et al., 2006).
For correction of background activity, small crescent shape areas were manually
drawn at the caudal pole of the kidneys (Liedtke and Duarte,
1980). Correction for soft tissue attenuation was done using the known attenuation
coefficient for 99m Tc in soft tissue [linear absorption coefficient in soft
tissue = 0.153 cm-1 (Gates, 1982).
Based on the creatinine level which ranging from 1.8 to 5.5 mg dL-1,
total 44 dogs suffering from renal disorders were divided in 6 groups ( Table
1). Serum creatinine is used as screening test of renal function as it is
handled primarily by glomerular filtration and essentially reflects GFR. All
the dogs underwent 99mTc-DTPA scintigraphy for estimation of GFR by using Gates
protocol. Maximum observed GFR was 4.0 mL min-1 kg-1 at
creatinine level 1.8 mg dL-1, while minimum was 1.1 mL min-1
kg-1 at creatinine concentration of 5 mg dL-1 (Table
1) and a curve was plotted between mean serum creatinine and mean GFR (Fig.
1). In our study 38 dogs (86.36%) out of 44, showed a conventional pattern
of curvilinear relationship between creatinine and GFR.
|| Distribution of animal on basis of creatinine range and mean
GFR and mean serum creatinine
||Statistical analysis of the creatinine and GFR relationship
Interindividual variations was observed in 5 (11.36%) dogs where at the same
creatinine concentration (2.3 mg dL-1), different GFR values were
obtained ranging from normal (4.0 mL min-1 kg-1) in 2
dogs to reduced ( 2.2 to 3.2 mL min-1 kg-1) in 3 dogs.
False positive results were obtained in 4 (9%) dogs), where on scintigraphic
analysis, creatinine was within normal reference range but GFR decreased (3.2
to 3.5 mL min kg). False negative observations were seen in two (4.5%) of the
dogs, where normal GFR with marginally high creatinine values (2.3 mg dL-1)
were observed (Table 2).
The shape of the curve plotted between serum creatinine and GFR is not a straight
line but more or less curvilinear (Fig. 1) which is in agreement
with Toutain et al. (2000). The pattern of curve
has several consequences. At both ends, a large variation of one parameter corresponds
to a very small change in the other which means that a reduction of GFR has
modest effect on serum creatinine and a huge decrease of creatinine corresponds
to only a minor increase in GFR, therefore in early stages of renal disease,
these tests could create a false sense of security. These which observations
are in agreement with Finco et al. (1994) who
reported that 50% reduction of renal mass produced no change in creatinine for
4 years in dogs. Serum creatinine is also an unreliable indicator of renal function
and often overestimates GFR in chronic renal failure. Interindividual variations
were observed in 11.36% of dogs where at the same creatinine concentration (2.3
mg dL-1) there were different GFR values ranging from normal in 2
dogs to reduced in 3 dogs. In such dogs creatinine was found a poor predictor
of change in GFR. The findings are in agreement with Finco
et al. (1999) who reported that at same creatinine concentration
there may be normal or reduced GFR.
In two dogs, creatinine was within normal range but there was decrease in GFR
on scintigraphic analysis, the suggested reason for this observation is presentation
of dogs in phase of early renal failure, this observation is in accordance with
Bauer et al. (1982) who stated that in the early
stages of renal disease, creatinine could create a false sense of security.
Ross (1995) also reported similar findings in dogs and
stated that biochemical markers like creatinine and blood urea nitrogen are
relatively insensitive in detecting renal dysfunction because about 70-75% of
the nephrons should be nonfunctional before these values rise above the normal
range. In four dogs, normal GFR with marginally high creatinine values was observed,
the possible cause for this may be the diet of dogs as reported by Watson
et al. (1981), who suggested that creatinine is increased for the
first few h and remains up for almost 12 h after meals of raw or cooked meat
or following ingestion of commercial food (Evans, 1987).
In this study both kenneled dogs and stray dogs were included, that may be another
possible cause of interindividual variation as reported by Rautenbach
and Joubert (1988) who found a higher creatinine in dogs living outside
than in kenneled dogs, although their weight and food intake were similar.
Based on the present study, it is concluded that biochemical markers like serum creatinine are not too sensitive in detection of early renal damage. Also usefulness of creatinine estimation is limited in early renal failure when marked reduction of GFR may be associated with little change in creatinine concentration, therefore serum creatinine should only be used for screening of animal for renal diseases, monitoring the progression of renal disease or the efficiency of a treatment. In contrast, scintigraphy has the advantage of physiological imaging and can be used in early diagnosis of renal failure in dogs to enable timely application of therapeutic intervention. This imaging technique has added advantage of estimating global and individual kidney function which can not be obtained by creatinine estimation.
1: ACR, 2006. ACR Practice Guideline for the Performance of Adult and Pediatric Renal Scintigraphy. ACR Practice Guideline Renal Scintigraphy, pp: 1-7.
2: Bauer, J.H., C.S. Brooks and R.N. Burch, 1982. Renal function studies in man with advanced renal insufficiency. Am. J. Kidney Dis., 2: 30-35.
3: Benjamin, M.M., 1978. Outline of Veterinary Clinical Pathology. 2nd Edn., The Iowa State University Press, Ames, Iowa, USA.
4: Ettinger, S.J., E.C. Feldman and S. Renal, 2000. Disease. In: Textbook of Veterinary Internal Medicine, Ettinger S.J. and E.C. Feldman (Eds.). 5th Edn. W.B. Saunders Co., Philadelphia, PA., USA.
5: Evans, G.O., 1987. Post-prandial changes in canine plasma creatinine. J. Small Anim. Pract., 28: 311-315.
6: Finco, D.R., S.A. Brown, C.A. Brown, W.A. Crowell, T.A. Cooper and J.A. Barsanti, 1999. Progression of chronic renal disease in the dog. J. Vet. Internal Med., 13: 516-528.
7: Finco, D.R., S.A. Brown, W.A. Crowell, C.A. Brown, J.A. Barsanti, D.P. Carey and D.A. Hirakawa, 1994. Effects of aging and dietary protein intake on uninephrectomized geriatric dogs. Am. J. Vet. Res., 55: 1282-1290.
8: Gates, G.F., 1982. Glomerular filtration rate: Estimation from fractional renal accumulation of 99mTc-DTPA (stannous). Am. J. Roentgenol., 138: 565-570.
9: Grauer, G.F., 1992. Glomerulonephritis. Semin. Vet. Med. Surg. Small Anim., 7: 187-197.
10: Grauer, G.F. and I.F. Lane, 1995. Acute Renal Failure. In: Textbook of Veterinary Internal Medicine, Ettinger, S.J. and E.C. Feldman (Eds.). 4th Edn. WB Saunders Co., Philadelphia, PA., USA., pp: 851-855.
11: Guyton, A. and J.E. Hall, 1998. Urine Formation by the Kidneys: I. Glomerular Filtration and Renal Blood Flow. In: Textbook of Medical Physiology, Guyton, A.C. and J.E. Hall (Eds.). W.B. Saunders Co., Philadelphia, PA., USA., pp: 315-358.
12: Heiene, R. and L. Moe, 1998. Pharmacokinetic aspects of measurement of glomerular filtration rate in the dog: A review. J. Vet. Int. Med., 12: 401-414.
13: Kampa, N., P. Lord and E. Maripuu, 2006. Effect of observer variability on glomerular filtration rate measurement by renal scintigraphy in dogs. Vet. Radiol. Ultrasound, 47: 212-221.
14: Liedtke, R. and C. Duarte, 1980. Laboratory Protocols and Methods for Measurement of Glomerular Filtration Rate and Renal Plasma Flow. In: Renal Function Test, Duarte, C.G. (Eds.). Little, Brown and Co., Boston, pp: 49-63.
15: Lora-Michiels, M., K. Anzola, G. Amaya and M. Solano, 2001. Quantitative and qualitative scintigraphic measurement of renal function in dogs exposed to toxic doses of Gentamicin. Vet. Radiol. Ultrasound, 42: 553-561.
16: Rautenbach, G.H. and H.F. Joubert, 1988. A comparison of health parameters in two different canine populations. Part II: Chemical pathology data. J. Sci. Afr. Vet. Assoc., 59: 135-138.
17: Robertson, J., 2001. The Kidney in the Aging Dog: Pathobiology of the Aging Dog. Iowa State University Press, Blacksburg, Virginia, USA.
18: Ross, L.A., 1995. Assessment of Renal Function in the Dog and Cat. In: Current Veterinary Therapy, Kirk, R.W. (Ed.). W.B. Saunders, Philadelphia.
19: Kampa, N., 2007. The effect of fluid administration on Glomerular Filtration Rate (GFR) measured by scintigraphy in dog. KKU Vet. J., 17: 22-32.
20: Toutain, P.L., H.P. Lefebvre and V. Laroute, 2000. New insights on effects on kidney insufficiency on disposition of angiotensin-converting enzyme inhibitors: case of enalapril and benazepril in dogs. J. Pharmacol. Exp. Ther., 292: 1094-1103.
21: Watson, A.D., D.B. Church and A.J. Fairburn, 1981. Postprandial changes in plasma urea and creatinine concentrations in dogs. Am. J. Vet. Res., 42: 1878-1880.