Topic 10 –GFR in Practice: assessment of glomerular filtration rate in

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Introduction

Practising veterinarians use information from several sources to detect kidney disease, including elements from the history, physical examination and various diagnostic aids (for example, urine specific gravity and protein content, blood creatinine and urea concentrations, renal imaging...). In most cases, careful consideration of these findings will enable the clinician to determine whether overall kidney function is significantly compromised.

But the decision is not always clear-cut and some difficult cases remain – for example, those with polyuria/polydipsia where other diagnostic possibilities have been excluded, or where there is persistent, unexplained azotaemia.

In such instances, further assessment of renal function might be desired. One approach might be to institute "watchful waiting", that is, to continue monitoring and to reassess at intervals subsequently.

An alternative could be to determine the dog's glomerular filtration rate (GFR), as GFR is considered to be the single most useful and sensitive indicator of overall renal function. One recent study demonstrates that measurement of GFR is useful in non-azotemic dogs.1

In the past, GFR assessment has been considered impractical in most veterinary clinics, but two recently described plasma clearance methods have improved the situation.

Both these methods require repeated blood sampling over a period of several hours following intravenous administration of a suitable marker. A suitable marker is a substance that is filtered freely by glomeruli, undergoes no renal tubular resorption or secretion, and is neither metabolized nor eliminated by extrarenal means. Both iohexol and creatinine have been shown to be suitable markers in dogs and cats. While laboratory analysis of serum creatinine analysis is available to the practitioner, medical grade creatinine suitable for i.v. injection is not. Iohexol, however, is sold as a medical grade reagent for diagnostic imaging, and analysis of iohexol is commercially available (see below) through a limited number of centres.

Using these techniques, GFR can be estimated by measuring the plasma clearance (Cl) of the marker. Cl is calculated by dividing the intravenous dose administered (D) by the area under the curve (AUC) of plasma concentration plotted against time (i.e., GFR = Cl = D/AUC). The AUC is determined manually or by computer using a 1-compartment or 2-compartment model, or by the trapezoidal method (Heiene and Moe 1998). If using creatinine, first subtract the basal (preinjection) sample value from the measured concentrations in each of the other timed samples.

Whichever method is chosen, accuracy is important for the dose of marker administered and the exact times samples are collected – errors with either will give false results when calculating GFR. For example, if the 120 minute sample is collected 4 minutes late, record the collection time as 124 minutes, because it is this exact sampling time that is required when calculating AUC and therefore GFR.

Further studies are needed to clarify reference ranges for GFR in dogs, and these may depend on the method chosen and some laboratory factors. However, most published GFR values for dogs are from approximately 2 to 5 ml/min/kg, so values < 1.5 ml/min/kg can be considered abnormal (Heiene and Lefebvre 2007).

Presented here is a summary of the techniques used to measure GFR with iohexol and creatinine. More detailed information on GFR assessment can be found in the accompanying article "Glomerular filtration rate in dogs and cats" (www.iris-kidney.com).

Plasma iohexol clearance

Materials required

Iohexol solution (300 mg iodine/ml).
Sterile saline (0.9% NaCl)
Intravenous catheter with stopper, and syringes, needles and tubes for blood samples
Timer

Procedure

Fast patient overnight.
Hospitalize patient, continuing to provide water but not food.
Record current body weight (kg).
Taking care to be accurate, administer the iohexol solution as a bolus through the intravenous catheter with stopper, using 0.5 ml/kg for dogs with azotaemia or 1 ml/kg for those without.
Flush the dead space of the catheter with 2 ml of saline, immediately start the timer, then remove the catheter.
Collect blood samples (each at least 1 ml) at 2, 3 and 4 hours after administration of iohexol, using sites different from where iohexol was administered to avoid contamination by residual iohexol at this site. Note the exact time each sample is collected. Make sure the tubes are correctly labelled with the time of sample collection.
Centrifuge samples and harvest plasma to send to the laboratory. Two laboratories currently offering iohexol assays on a commercial basis are:
It is advisable to contact the laboratory beforehand for information on pricing and sample requirements, and to ascertain the laboratory's reference range and the method used to determine the clearance value.

Advantages

Iohexol is stable and samples can be mailed to the laboratory without special precautions.
Total time for the procedure is short.
The laboratory assaying iohexol will normally calculate the GFR based on the information you provide (dose and timing of sampling) and the concentrations they measure at each time point

Disadvantages

Samples have to be sent away for analysis.
The cost of iohexol may be a limiting factor for some owners of large dogs.
Adverse reactions have been reported (very rare in dogs).
A correction needs to be applied to the clearance value calculated with the 3 samples to improve accuracy (Heiene and Moe 1999). The correction formula is:
Clcorr = - 0.03 +1.06 (Clobs) - 0.07012(Clobs)2
where Clcorr = corrected value and Clobs is the value determined from the 3 samples. Some laboratories will apply this correction before giving the GFR result, and give their reference ranges (check with the laboratory you use to determine whether a correction factor has been applied).

Plasma creatinine clearance

Materials required

Anhydrous creatinine powder (Sigma Aldrich)
Sterile saline (0.9% NaCl)
Filter (0.2 μm) to be obtained via a pharmacy and used with their instructions.
Intravenous catheter with stopper, and syringes, needles and tubes for blood samples
Timer

Procedure

Fast patient overnight.
Hospitalize patient, continuing to provide water but not food.
Record current body weight (kg).
Collect blood sample to measure basal value (creatinine concentration at time zero).
Prepare creatinine solution (80 mg/ml): dissolve creatinine in saline and sterilize by filtration through a 0.2 μm filter.
Taking care to be accurate, administer the creatinine solution (1 ml/kg) as a bolus through the intravenous catheter with stopper, followed by 2 ml of saline, and immediately start the timer. Remove the catheter.
Collect 1 ml blood samples at 10 minutes and at 1, 2, 6 and 10 hours after administration, noting exact time each sample was collected. Collection sites should be different from the administration site to avoid contamination by residual injected creatinine.
Determine creatinine concentrations in all 6 samples in the same batch of assays.
Calculate the plasma clearance value from the dose administered and the area under the plasma creatinine vs. time curve (AUC), after first subtracting the basal value from each of the 5 post-administration values.

Advantages

Assays for creatinine in plasma or serum are readily available in practice laboratories or externally.
Required sample volume is small.
Time required to perform creatinine assays is short.

Disadvantages

A suitable creatinine solution must be prepared by an appropriate laboratory or pharmacy to ensure it is sterile and pyrogen-free, and that the concentration is precise (for an exact dose).
Substantially longer hospitalization is required than with iohexol.
The data has to be used to calculate the GFR by the practitioner rather than by the laboratory performing the test

1. McKenna M, Pelligand L, Elliott J, et al. Clinical utility of estimation of glomerular filtration rate in dogs. Journal of Veterinary Internal Medicine 2020;34:195-205.

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Topic 10 –GFR in Practice: assessment of glomerular filtration rate in dogs

Introduction

Plasma iohexol clearance

Plasma creatinine clearance

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