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INFLUENCE OF RENAL ULTRASONOGRAPHIC FINDINGS ON GFR DURING CHRONIC UNILATERAL OBSTRUCTION IN DOGS.

Byline: S. G. Bokhari, J. Hou, M. Iqbal, Y. Wu and Y. Wang

ABSTRACT

Renal sonographic findings can now be implicated for prediction of changes in Glomerular filtration rate, and estimation of the degree of renal dysfunction in pets. This was successfully determined during a 20-day chronic unilateral ureteral obstruction in experimental dogs. GFR was quantitatively measured following a single intravenous bolus of inulin. The total clearance of the marker was calculated from the decrease in serum concentrations using a two-compartment model. Changes in renal architecture (i.e. length, width, depth, cortex, pelvis and ureteral dilation) were simultaneously assessed using B-mode ultrasonography.

The results showed significant changes in GFR and renal architecture. Statistical analysis revealed minimum intragroup variance in renal length, width and depth. Linear regression analysis indicated a highly significant average correlation coefficient (r) with low standard error of estimates (SEE) and greater predictability between GFR and left renal dimensions of length (r=0.9454, SEE= 2.64), width (r= 0.8632, SEE= 1.69), depth (r= 0.9461, SEE= 2.11), pelvis (r= 0.9035, SEE= 3.91) and left ureter (r= 0.9714, SEE= 2.07). The prediction error was about 9-12%. Conclusively, ultrasonographic changes in renal dimensions, particularly renal length, width and depth may successfully be used in dogs for prediction of changes in GFR, without the need to perform complicated laboratory procedures in future.

Keywords: ureteral obstruction; GFR; ultrasonography; dogs.

INTRODUCTION

Urine outflow obstruction, due to calculi, inflammatory disease, neoplasia, stricture or accidental ureteral ligation during ovariohysterectomy, is the common presenting complaint in face of a currently increasing frequency of urinary tract disorders in pets (Brown, 2003). Undiagnosed, neglected, or untreated cases can lead to renal hydronephrosis, and hence, progression of an acute reversible condition to a chronic irreversible malady.

In unilateral ureteral obstruction, compensatory renal responses mask the injury and its effect on the renal patient during the first phase of renal damage. The animal is not azotemic but may only have some reduced urine concentrating ability (Klahr et al., 1988; Watson et al.,2002a; Brown, 2003). Furthermore, as reported by Braun and Lefebvre (2008), and Brown (2003), the large renal functional reserve ensures maximal compensation, so that clinical signs and routine laboratory indices generally do not indicate severity of the renal disease, until 75% of renal mass is destroyed. The results of this experimental study correlated exactly well with all these findings mentioned above. Hence, this necessitates the implementation of additional and precise diagnostic aids for early assessment of the degree of renal damage and successful monitoring for follow-up patients.

The glomerular filtration rate (GFR) is currently considered the best parameter for direct quantitative assessment of overall renal function (Brown, 2003; Laroute et al, 1999). The single-injection clearance of Inulin is an attractive, cheap, precise and effective alternative to the other more complicated and expensive methods; however the set-back lies in the method being time-consuming and hence, less commonly applied in routine veterinary practice, making the clinician ultimately rely upon routine laboratory indices. For qualitative assessment of renal architecture, B-mode ultrasonography is currently one of the most sensitive, least-invasive diagnostic modality, providing additional benefits of direct visualization of normal structure of internal organs, characterization and location of lesions and collection of biopsy samples. (DiBartola, 2005; Hager et al, 1985; Konde et al., 1984).

Recent studies conducted in humans negate the misconception that sonography is unable to provide information on renal function. It has now been proved by some scientists that renal sonography provides useful information about renal function. Similar data in animals has not yet been researched.

The present study was thus conducted to evaluate the architectural and functional changes in renal tissue in experimental models mimicking unilateral obstructive uropathy; and thus to ascertain the best correlation and degree of predictability of GFR values using gray-scale sonographic changes observed in the affected kidney, for futuristic convenience and success in monitoring progressive renal disease in dogs.

MATERIALS AND METHODS

Dogs: Twenty-four healthy mongrel dogs of either sex, aged from 6 months to 6 years and weighing 6 to 11 kg were selected in this study. The study protocol was approved by the Animal Ethics Committee of the Nanjing Police Dog Research Institute of Public Security Ministry. After acclimatization and complete health check-up, jugular catheterization was performed using a 16 gauge indwelling catheter, for convenient blood sampling (Bright, 2003). Just a day before the launching of the experimental study, the left ureter was ligated in each dog through a midline laparotomy, to create experimental models of obstructive uropathy.

Test substances: For the direct quantitative assessment of renal function, Inulin (50g equivalent to 173.7g) was purchased from China National Medicines Corporation Ltd., Beijing, and used as test marker.

For each kinetic study, Inulin was reconstituted aseptically with 0.9% saline solution to obtain a final concentration of 250mg. mL-1 (Miyamoto, K, 1998; Laroute et al., 1999).

Real-time ultrasonographic scans of all dogs were performed after the kinetic studies, using a small animal ultrasound unit granted by Keen Trade Co., Wuxi, China.

Experimental design: The dogs were randomly assigned to four groups of six animals each. In all experimental dogs, direct measurement of renal function was carried out to quantitate the degree of damage, using Inulin plasma clearance assays.

For precise functional assessment of the various stages of renal dysfunction, each kinetic study was carried out on 0, 1, 3, 5, 7, 11, 15 and 20 days after the left ureteral ligation. Day 0 dogs served as control (i.e. before ureteral ligation).

Prior to the clearance studies, food was withheld for at least 12 hours, however, the dogs were providedfree access to water before and during the procedure (Haller et al., 1998; Laroute et al., 1999).

Inulin clearance: On each day of the kinetic study, Inulin was administered, as a single intravenous injection, at a dose rate of 100 mg/kg, via an indwelling catheter placed in the cephalic vein of either limb (Laroute et al.,1999). The catheter was flushed with 4 mL of saline solution (0.9% NaCl) after the injection. The total duration of administration of Inulin was 20 seconds. Blood samples were obtained from the jugular vein via the indwelling jugular catheter. For Inulin assays, blood samples were obtained at time 0 (i.e. before injection), and at one, three, 10, 20, 40, 80 and 120 min after injection. The samples were allowed to clot and were centrifuged at 3000 rpm for 10-15 min; the serum thus collected was frozen at 20 degC until analysis.

Laboratory analysis: The concentration of Inulin was measured with an optimized colorimetric method.

Inulin assay: The concentration of Inulin in each serum test sample was determined by a chemical method using anthrone reagent (Wright and Gann, 1966; Jung et al.,1990) and spectrophotometric readings were taken at an absorbance value of 636 nm.

The concentration profile following bolus injection of Inulin showed a biphasic behavior pattern: the initial rapid decrease in the plasma level was followed by a phase of gradual decline. Such a time curve can be described by the sum of two exponential functions (Jung et al., 1992). For this reason, a two-compartment model was considered to suitably fit the curve, and used to calculate the glomerular filtration rate with the aid of the computer software 3P97, using the formula (Sapirstein et al., 1955):

GFR = dose

A/a + B/b

Where

GFR = glomerular filtration rate

A = intercept of the rapid phase

B = intercept of the terminal phase a = first-order rate constant of the

Rapid phase

b = first-order rate constant of the terminal phase.

Ultrasonography: B-mode ultrasound assessment was performed on the same day as the kinetic studies, in order to assess the qualitative changes in renal tissue, during progression of the renal dysfunction in experimental dogs.

After appropriate patient preparation (i.e. hair clipping from ventral abdomen, thorough cleaning of the skin with surgical spirit, and application of acoustic gel) (Mattoon, et al., 2002), both right and left kidneys were scanned in standard sagittal and transverse planes (Nyland et al., 2002; Holt, 2008), using a 5.0 MHz convex-array curvilinear transducer. Length, width, depth, thickness of cortex, distance of pelves of each kidney and opening of the left ureter were recorded.

Statistical Analysis: The results were analyzed by application of ANOVA for calculation of the means. Correlations of GFR with left renal dimensions were assessed through linear regression analysis. All statistical analyses were performed with SAS statistical software (SAS Institute Inc., USA).

RESULTS

Changes in Renal Function assessed through calculated Mean GFR values: In the experimental dogs, the GFR value decreased gradually with progression of renal disease after ureteral ligation. Hence, from a normal recorded mean value of 2.585+- 0.225 mL. min-1. kg-1 on Day 0, GFR showed a highly significant decrease on Days 3, 8 and 11 (P less than 0.01); the least recorded mean value of GFR was 0.754+-0.063 mL. min-1. kg-1 on Day 20 (P less than 0.05)- Table 1.

Changes in Renal Architecture assessed through Ultrasonographic findings: During the 20-day ureteral ligation, left renal length, width and depth showed enormous increases (Table 1). When compared with Day 0, the changes in left renal length, width and depth on each day were highly significant (P less than 0.01).

Left renal pelvis, likewise, showed significant increase in size from 7.37+- 0.32 on Day 0, to 26.14+-3.40 mm on Day 20 (Fig. 1C). When compared with Day 0, the changes were significant (P less than 0.05 on Days 2 and 3, and P less than 0.01 on Days 4, 6, 8, 10, 12, 14, 17 and 20, respectively). Similarly, when compared with Day 0 findings, a significant decrease in left renal cortical thickness was observed on Days 10 and 12 (P less than 0.05); thereafter, the decrease in cortical thickness due to pressure atrophy of renal tissue, was highly significant i.e. P less than 0.01 on Days 14, 17 and 20, respectively (Fig.1E).

Table 1. Quantitative Changes in GFR and Left Renal Length, Width, Depth, Pelvis, Cortex and Left Ureteral Opening During the 20-Day Experimental Period

Day###GFR###Left Renal###Left Renal###Left Renal###Left Renal###Left Renal###Left Upper

###(ml/min/kg)###Length (mm)###Width (mm)###Depth (mm)###Pelvis (mm)###Cortex###Ureteral

###(mm)###Opening

###(mm)

0###2.58+-0.23###51.58+-0.76###27.87+-0.58###25.87+-0.43###7.37+-0.18###5.52+-0.22###1.17+-0.08

1###1.96+-0.1P###59.92+-0.9###34.58+-0.64a###31.75+-0.55a###9.87+-0.37a###535+-0.22a###6.62+-0.29a

3###1.48+-0.09a###61.58+-o.82a###34.16+-O.99a###31.87+-0.49a###11.79+-0.32a###5.17+-0.27a###933+-0.27a

5###1.324+-0.09a###61.37+-0.96a###34.83+-0.65a###34 54+-0 4a###15.67+-0.39a###4.61+-0.21a###13.83+-0.59a

8###1.32+-0.09a###63.25+-o.85a###33.08+-0.60a###34.21+-0.49a###16.25+-0.43a###3.82+-0.23a###14.67+-0.52a

11###1.21+-0.12a###66.50+-0.76a###34 37+-0 41a###38.54+-0.47a###22.12+-0.55a###3.48+-0.18a###17.12+-0.49a

15###1.37+-0.15a###68.46+-1.06a###35.92+-0.82a###39.17+-0.63a###24.08+-0.78a###4.0+-0.24a###17.83+-0.88a

20###0.75+-0.13a###67.25+-1.07###36.33+-0.80a###40.29+-0.87a###26.17+-1.00a###3.74+-0.22a###23.29+-0.92a

Table 2. Average Coefficient of Variation of GFR and Renal Dimensions

Variables###Average Mean+-S.D###Average Coefficient of Variation (CV/ %)

GFR###1.462+-0.20###39.086

Length###62.49+-1.90###8.608

Width###33.89+-0.93###7.773

Depth###34.53+-1.69###13.870

Pelvis###16.67+-2.44###41.349

Cortex###4.46+-0.34###21.775

Ureter###12.98+-2.48###53.979

DISCUSSION

The objectives of this study were aimed towards quantitative and qualitative determination of the degree of renal dysfunction produced as a result of experimental unilateral ureteral obstruction; and the interrelationship and prediction of changes in GFR with ultrasonographically observed changes in the dimensions of the affected kidney, for futuristic convenience in GFR calculation in clinically ill renal patients.

In clinical situations, obstructive uropathy in pets can lead to profound hydronephrosis, which if left untreated or undiagnosed, can cause permanent renal damage and chronic renal failure, as a result of pressure atrophy of the kidney tissue (Kahn et al., 2005; Vegad and Katiyar, 1998). Although in early stages of renal disease in dogs, the routinely-used indices do not indicate an ongoing disease process, however, the direct functional markers and ultrasonographic assessment enable the clinician to detect minute changes in GFR and renal architecture, earlier in the course of a progressive renal disorder, thus holding importance as regards treatment protocols and monitoring of follow-up patients.

However, since the routine calculation of GFR is a time- consuming procedure and alternative formulae used in human medicine for GFR calculation are not popular in veterinary practice, hence we have predicted significant correlation of the functional GFR changes with morphological changes in affected renal tissues, which can successfully be applied to routine veterinary practice in future.

For determination of the glomerular filtration rate, Inulin is still the accepted "gold standard" amongst all indicator substances; toxicity for this compound is very low (Brown, 1994), and no side effects were observed in this study, either (Haller et al., 1998). Furthermore, the strategy of determining the total plasma clearance of the test marker after a single bolus injection with repeated blood sampling over a limited period of time (Laroute et al., 1999), proved a time-saving, precise and better alternative to continuous infusion or urine sampling techniques. One striking result of this study was that Inulin concentration could successfully be determined by application of the two-compartment model (Haller et al.,1998; Laroute et al., 1999).

Immediately after left ureteral ligation, a highly significant decrease in GFR was evidenced on Days 3, 5, 8 and 11 (P less than 0.01). With progression of time, most experimental dogs showed a reduced renal function, as compared to the normal dogs (P less than 0.05 on Days 15 and 20). In some dogs, however, there were observable fluctuations in the GFR value with a tendency to rebound towards improvement at various times; this could be attributed to the early stage of renal disease (because the experimental study lasted less than three months); early renal disease usually does not cause loss of the whole nephron, and hence the GFR can be observed to be close to normal at various times, because of the hyperfiltration of other nephrons and other compensatory mechanisms of the contralateral kidney. This observation of GFR returning towards a normal value, despite slight insignificant proteinuria, was hence not surprising (Grauer and DiBartola, 1995).

However, it was simultaneously observed that the compensatory changes in the body occurring alongside the inflammatory process were not consistent or supportive to repair the hydronephrotic lesion completely. As a result, GFR value decreased consistently (Klahr, et al., 1988), with an overall aggravated compromising condition of the experimental animals, towards the end of the experimental study.

Qualitative assessment of renal dysfunction through sonograms obtained post-ligation, revealed that longer the duration of urinary obstruction, greater is the degree of dilatation (and hence, pressure atrophy) of the renal pelvis (Canpolat et al., 1996; Cartee, et al., 1980; D'Anjou et al., 2011). After two weeks of the experimental study, the size of the renal pelvis increased to about 3.54 times its normal size; the increase in renal length and width were approximately 1.3 times the normal value, and renal depth increased to about 1.5 times the normal. After about 3 weeks post-operatively, the left ureter showed 23 times increase in its size from normal (Table 1); in some dogs such immense increase in size made it a bit difficult to discriminate between the pressure-atrophied, enlarged pelvis, from the hydroureter.

In humans, the presence of a close correlation between kidney size and function is reported to be helpful in the diagnosis of renal diseases (Adibi et al., 2007; Kariyanna et al., 2004; Paleologo et al., 2007; Widjaja et al., 2010). For our experimental study in canines, the relationship between GFR and affected kidney morphology investigated through simple linear regression analysis yielded a highly significant (inverse) correlation, low standard error of estimate and greater predictability between GFR and left renal length, depth and ureteral size (Table 2). Furthermore, the results in Table 2 showed a significantly smaller coefficient of variation for renal length, width and depth, as compared to the GFR, thus emphasizing smaller group variability and greater predictability.

The group variability of cortex, pelvis and ureteral size was higher than other renal parameters, and hence we infer that these parameters may not be considered as reliable for prediction of GFR, as renal length, width and depth. It can however, be hypothesized that sonographic measurements proved to be highly specific, while GFR measurements showed high sensitivity and lower specificity. Additionally, in contrast to studies in humans emphasizing greater predictability of GFR solely through renal length, we propose that sonographic renal length, width and depth measurements in canine patients may prove to be highly prognostic of GFR changes in renal disease.

It can thus be concluded that despite immense structural damage to the renal architecture, in cases of prolonged urine outflow obstruction, the kidneys compromise for the functional changes by compensatory responses which minimize the total loss in GFR. Furthermore, sonographic measurements of affected kidneys not only prove as a non-invasive method, rather, renal length, width and depth correlate well with GFR values in canines. Hence, they can importantly be employed, successfully and conveniently, in routine veterinary clinical settings in future, for precise measurement of renal function, assessment of the degree of renal dysfunction in affected animals, and as an alternative to expensive, complicated and time- consuming methods. (Total words: 2, 715).

Acknowledgements: This study was part of a broader research project, and was accomplished through a collaborative international research scholarship grant for the PhD scholar, Dr. Shehla G. Bokhari, funded by the Government of Pakistan-Higher Education Commission (through Chinese Scholarship Council, P.R. China); additional funding resources include Nanjing Agricultural University PhD Students' Research Funds, Keen Trade Ltd., Wuxi, China (ultrasound machine manufacturers), and funds drawn from projects running under China National Fund.

The author would like to thank her devoted teachers who guided her at each step during accomplishment of this research work, and co-authors and fellow workers, the integrated team-work of whom made this study successful.

Ethical Standards: The authors hereby declare that the experiments comply with the current laws of the country in which they were performed and International Standards. Furthermore, animal use ethics were adopted as permitted by the Animal Ethics Committee of the Nanjing Police Dog Research Institute of Public Security Ministry, P. R. China and as guided under International legislation.

Conflict of Interest Statement: This research work was conducted through a scholarship grant. None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.

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Author:Bokhari, S.G.; Hou, J.; Iqbal, M.; Wu, Y.; Wang, Y.
Publication:Journal of Animal and Plant Sciences
Article Type:Report
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Date:Sep 30, 2012
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