Introduction

The major role of the kidneys is to maintain the volume and balanced composition of the extracellular fluid. Blood is filtered through the glomerulus, and the composition of the filtrate is adjusted, as it passes along the tubules, according to the body's requirements. Assessment of renal function [especially direct and indirect evaluation of glomerular filtration rate (GFR)] has been carried out for several decades in small animal patients. Paradoxically, the physiological factors of variations of kidney function in small animals are poorly documented even though this knowledge is clearly a prerequisite for appropriate interpretation of renal variables in clinical settings. Only dogs will be considered here as limited information is available for cats. Body weight (or more generally body size) is one relevant physiological factor that potentially affects renal function in dogs, for the following reasons: i) during puppy growth, the body weight changes rapidly over a limited period of time, ii) obesity is frequent in dogs, iii) canine breeds may show large differences in body weight, and iv) body weight is generally used for indexation of functional renal parameters.

Within-Individual Variations of Body Weight and Renal Function

Effect of Growth

The effect of growth on normal kidney function includes an age and a size effect. Both effects are clearly confounded, but, for a given individual, the hugest variations in body weight are observed during this period of life. For instance, a miniature Poodle reaches its adult weight around 8 months of age by which time it has multiplied its birth weight (150-200 g) by 20. A Newfoundland dog is still growing at 18 to 24 months of age, until its birth weight (600-700 g) has multiplied by approximately 100.¹ During the exponential phase of growth, the approximate rate of increase in body weight per week, for most breeds, is 13-17%.² In other words, the body weight doubles in 6-8 weeks.

In growing Beagle puppies, the mean GFR decreases by ~40% (from 4.1 to 2.5 mL/min/kg) and the fractional excretion of sodium increases by ~2.3 (from 0.18 to 0.42%) between the age of 9 and 27 weeks.³ The most striking differences in 2-month-old Beagle puppies compared to 6-9 year-old Beagle dogs were a higher daily urinary volume (+65%), GFR (+87%), free water reabsorption (+159%), lower daily protein excretion (-88%), and fractional excretion of phosphorus (-35%) and plasma creatinine (-30%).⁴ Such differences might be explained by other factors, such as diet, but need to be considered for appropriate interpretation of renal variables in the growing animal. Ideally, measurements of renal variables in puppies should be compared with age-matched results.

Effect of Obesity

Although obesity should not be considered as a physiological condition, its prevalence with that of overweight is relatively high in canine populations. In a model of obesity in dogs (body weight increased by ~60%), the mean arterial pressure was increased by 12 mm Hg, and the GFR (mL/min) and renal plasma flow (mL/min) were increased by 38 and 61%, respectively, compared with lean dogs.⁵ Such increases in renal functional parameters could lead to kidney injury as structural changes were also observed.

Between-Individual Differences in Body Weight and Renal Function

Most of the available information focuses on the direct and indirect assessment of GFR.

Plasma Creatinine

Plasma creatinine (Pl-Cr), the most frequently assayed plasma constituent, is routinely used as an indirect marker of GFR.⁶ Reference intervals (RI) should be established by taking into account the size of the dogs, as shown in a previous study.⁷ 317 clinically healthy, purebred dogs from 32 breeds (2-37 dogs per breed), aged from 0.5 to 16 years, were divided into four body weight (BW) categories: Mini: <10kg (n=36); Medium: 11-25kg (n=130); Maxi: 26-45kg (n=127); and Giant: >45kg (n=24). Mean Pl-Cr and RI for the whole population were 0.93 ± 0.24 mg/dl and 0.45-1.40 mg/dl, respectively (1.4 mg/dL=124 µmol/L). The Pl-Cr (mg/dl) for each BW category were significantly different (P<0.001) (Mini: 0.70 ± 0.12, range 0.48-1.02; Medium: 0.85 ± 0.16, range: 0.55-1.24; Maxi: 1.01 ± 0.26, range: 0.60-2.01; and Giant: 1.19 ± 0.24, range: 0.88-1.82). Using the same reference interval, irrespective of dog size, would lead to false positive and false negative results.

Glomerular Filtration Rate

The first evidence of the effect of body weight on GFR in a large healthy canine population was reported in 2004.⁸ GFR was estimated in 113 dogs using plasma clearance of exogenous creatinine. The animals were divided into 4 body weight categories (Mini, Medium, Maxi and Giant; see above). The corresponding GFR values (mean ± SD) were 3.66 ± 0.47, 3.04 ± 0.52, 2.53 ± 0.42, and 2.35 ± 0.56 mL/min/kg, respectively. Accepting the hypothesis of a normal distribution of GFR values, the corresponding lower limits of the reference range would be 2.7, 2.0, 1.7 and 1.3 mL/min/kg.

Other authors obtained similar results in 118 adult healthy dogs using plasma iohexol clearance to estimate GFR. A significant negative linear relationship was also detected between body weight and estimated GFR. Reference ranges in different weight quartiles were 1.54-4.25, 1.29-3.50, 0.95-3.36, and 1.12-3.39 mL/min/kg, respectively, for body weight quartiles of 1.8-12.4, 13.2-25.5, 25.7-31.6, and 32.0-70.3 kg.⁹

In conclusion, it can be stated that the higher the body weight, the lower the GFR (expressed in mL/min/kg).

Interactions Between the Size and the Breed

The size (body weight) not only has a direct effect on renal function; it may also interact with the effects of other covariables, such as the breed.⁷ In other words, the effect of body weight on plasma creatinine or GFR may vary according to the breed. Large between-individual variations in body weight may be observed within a given breed, according to the national kennel standards [e.g., from 4.5 kg (miniature) to 45 kg (Giant) in Schnauzers]. We recently assessed glomerular filtration rate and plasma creatinine in 16 adult Schnauzers with body weights ranging from 5.6 to 30.0 kg. A significant effect of body weight on GFR and plasma creatinine was observed. The corresponding equations were GFR = 4.64 - 0.093BW (P<0.001, R²=0.835) and Pl-Cr= 47.5 + 1.88BW (P<0.001, R²=0.853). Inversely, no significant effect of body weight on GFR was evidenced in a group of 19 Dachshunds with body weights ranging from 3.4 to 10 kg.¹⁰

Future Directions

One of the consequences resulting from these studies is that the indexation of GFR values (mL/min) to body weight does not allow for similar GFR values (mL/min/kg) in dogs with different body weights. Therefore, the definition of a "unique" cut-off value for clinical use in the overall canine population is not possible as this value will depend on the body weight of the patient. As described above, a simplified alternative approach consists of stratifying the canine population into body weight categories and defining "averaged" cut-offs for the GFR estimates in each category. The main limitation of this approach is that the larger the range of body weights for a given category, the more inaccurate the corresponding cut-off values.

Thus, the main current challenge is to define the most appropriate way of scaling GFR. Body surface area (BSA) has been proposed as the reference for indexing physiological variables. However, the abandoning of such an indexation for GFR has been recommended¹¹ and the formulae used to estimate BSA in dogs are probably inaccurate.¹² Due to the limitations of correcting GFR for BSA, an indexation to ECFV has been proposed because one of the major roles of the kidney is to regulate body fluid composition.^13,14 Nevertheless, standardization to ECFV rather than kilogram body weight did not produce substantial changes in the relationships between GFR estimates and body weight in adult dogs.⁹ Moreover, when this indexation was used, differences between puppies and adult dogs were still observed, but were inversed.⁴

Therefore, a need to establish an equation in canine species for the standardization of GFR measurements according to body weight exists. The only way is to use regression analysis on a large representative population of adult dogs of different breeds, body weight, age and sex. This is clearly a prerequisite before the use of GFR measurements can be recommended in clinical settings.

References

1.  Royal Canin. http://eng.royalcanin.com/the-puppy-and-the-dog/the-puppy/growth-a-key-stage/weaning-period

2.  Hawthorne AJ, et al. J Nutrition 2004 ;134: 2027S.

3.  Lane IF, et al, Am J Vet Res 2000;61:577.

4.  Laroute V, et al. Res Vet Sci 2005;79:161.

5.  Henegar JR, et al. J Am Soc Nephrol 2001 ;12: 1211.

6.  Braun JP, et al. Vet Clin Pathol 2003 ;32 :162.

7.  Craig AJ, et al. J Vet Intern Med 2006 ;20:766.

8.  Lefebvre HP, et al. J Vet Intern Med 2004 ; 18:415.

9.  Bexfield NH, et al. J Vet Intern Med 2008;22:66.

10. Unpublished data.

11. Turner ST, et al. Am J Physiol 1995;268:R978.

12. Price GS, et al. J Vet Intern Med 1998;12:267.

13. Gleadhill, et al. Res Vet Sci 1995 ;59 :118.

14. Peters AM, et al. Eur J Nucl Med Mol Imaging 2004;31:137.