Urinary inulin clearance for estimating glomerular filtration rate (GFR) provides the most accepted measurement of renal function. However, application of the standard inulin method to feline medicine is cumbersome and difficult. For example, this procedure relies on accurately timed repeated blood and urine samplings and usually involves bladder catheterization to achieve accurate urine collection. The nonionic monomeric X-ray contrast medium iohexol has been used extensively for GFR assessment in cats,[2, 3] but using multiple (n ≥ 3) blood sampling strategies. Moreover, it has been reported that there is concern regarding the deteriorating potential of iohexol on impaired kidney function in humans.[4, 5] Use of radiolabeled compounds required specific equipment and considerations.
The concentration of a tracer in a single plasma sample taken a few hours after injection was previously reported to be well correlated with renal clearance in humans. On the basis of this information, Jacobsson devised a formula derived from a simple 1-compartment model combined with the volume of distribution (Vd) and optimum time for taking plasma using a radio-labeled tracer and accurately determined the GFR. Because the Vd is dependent on the elimination kinetics of each tracer and animal size, one must obtain it in the respective species. The objective of the present study was to establish a simplified procedure to estimate GFR in cats based on Jacobsson's formula and using a single serum inulin concentration.
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- Supporting Information
We assessed the validity of a single-blood-sample method using a bolus injection of inulin for estimating the feline GFR, in comparison with the conventional 3-sample method.
In healthy cats given 50 mg/kg inulin, a linear semilogarithmic plot of serum inulin concentrations versus time demonstrated the suitability of using a 1-compartment model for GFR calculation (3-sample method). Although the 1-compartment model was a simplification and only applied after an equilibration period (30–120 minutes after inulin injection), it was thought to underestimate AUC, compared with the 2-compartment model. Thus, the difference between GFR values estimated from the 1-compartment model using 4 blood-sample points and the 2-compartment model using 7 blood-sample points was considered to be caused by a difference in calculated AUC. Briefly, the AUC from the 1-compartment model was approximately 15% lower than that from the 2-compartment model, indicative of higher GFR in the former. However, no significant difference was detected between the GFR values estimated from 4 versus 3 blood sample collection times in the 1-compartment model. Based on these results, the approach involving 3 blood sample collection times (60, 90, and 120 minutes later) was chosen because of a minimum SD of difference in GFR values.
Under the conditions of this study, the Vd values ranged from 60 to 250 mL/kg and from 10 to 70 mL/kg in clinically healthy and CKD cats, respectively, although there was no report dealing with the Vd of inulin in the diseased states of cats so far. Moreover, the Jacobsson's formula for humans has not been validated for cats. Therefore, we focused on the formula described by Jacobsson, including the inulin dose, Vd, and serum concentration of inulin concentration and sample collection time as variable factors.
Using the single-blood-sample method, the basal reference GFR values obtained in clinically healthy cats almost resembled the previously reported GFR data,[17, 18] although the experimental conditions and procedures were very different.
It has been reported that the formula derived for the GFR calculation with 1 blood sample requires that the Vd value be known, and its accuracy determines the accuracy in the method. Likewise, when the Vd value of the tracer is known, the plasma disappearance curve can be closely approximated from a single, timed plasma measurement. In our investigations, a relationship between the estimated Vd values and serum inulin concentrations was critical as a prerequisite for an equation to calculate the estimated Vd value. In the Deming's method, however, one of the assumptions was that both x and y (the result of the 2 methods) were subjected to random error, but in such a way that the ratio Var(x)/Var(y) was constant and not infinite or zero throughout the data range. When the variance of x was constant throughout the data range, the variance of y must be constant too. Based on Bland and Altman bias presentation, all points obtained were within the agreement plots.
Jacobsson's formula can therefore be applied to cats, and the single-blood-sample method can be used for GFR estimation as an alternative to the multisample method. In contrast, because the GFR calculated from the estimated Vd value is based on many assumptions to predict the true GFR, and species differences have not been systematically evaluated in the formula from Jacobsson, further studies are necessary to collect cumulative background data including various typed nephropathies.
In conclusion, the single-blood-sample method using inulin, instead of the 3-sample method, provides a practicable and ethical alternative for estimating glomerular filtration rate in cats.