GFR in Practice: Assessment of Glomerular Filtration Rate in Dogs

Adapted from the IRIS education article by R Heiene (Oslo, Norway), HP Lefebvre (Toulouse, France) and ADJ Watson (Sydney, Australia). The previous version was written by the same authors in 2015.

Introduction

Practicing veterinarians use information from several sources to detect kidney disease, including the history, the physical examination, and diagnostic tests such as urine specific gravity and protein content, blood creatinine and urea concentrations, and kidney imaging. In most cases, careful consideration of these findings allows the clinician to decide whether overall kidney function is significantly compromised.

But the decision is not always clear-cut, and some difficult cases remain, for example dogs with increased thirst and urination (polyuria and polydipsia) in which other causes have been excluded, or dogs with persistent, unexplained azotemia.

In such cases, further assessment of kidney function may be wanted. One approach is "watchful waiting," continuing to monitor the dog and reassessing at intervals. An alternative is to measure the dog's glomerular filtration rate (GFR), which is considered the single most useful and sensitive indicator of overall kidney function. A recent study has shown that measuring GFR is useful in dogs that are not azotemic (reference 1).

In the past, GFR measurement was considered impractical in most veterinary clinics, but two plasma clearance methods have improved the situation.

Both methods require repeated blood sampling over several hours after intravenous injection of a suitable marker. A suitable marker is a substance that is filtered freely by the glomeruli, is neither reabsorbed nor secreted by the renal tubules, and is neither metabolized nor eliminated by any route other than the kidneys. Both iohexol and creatinine have been shown to be suitable markers in dogs and cats. Laboratory analysis of serum creatinine is readily available to practitioners, but medical-grade creatinine suitable for intravenous injection is not. Iohexol, however, is sold as a medical-grade contrast agent for diagnostic imaging, and iohexol assays are offered commercially by a limited number of laboratories.

With these techniques, GFR is estimated by measuring the plasma clearance (Cl) of the marker. Clearance is calculated by dividing the intravenous dose administered (D) by the area under the curve (AUC) of plasma concentration plotted against time, that is, GFR = Cl = D / AUC. The AUC is determined manually or by computer, using a one-compartment or two-compartment model or the trapezoidal method (Heiene and Moe, 1998). If creatinine is used, first subtract the baseline (pre-injection) value from the concentration measured in each of the other timed samples.

Whichever method is chosen, the dose of marker given and the exact times the samples are collected must be accurate, because errors in either will give false GFR results. For example, if the 120-minute sample is collected 4 minutes late, record the collection time as 124 minutes, because the exact sampling time is needed to calculate the AUC and therefore the GFR.

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

A summary of the techniques used to measure GFR with iohexol and with creatinine follows. More detailed information on GFR assessment is available in our article on glomerular filtration rate in dogs and cats.

Plasma Iohexol Clearance

Materials Required

  • Iohexol solution (300 mg iodine/mL)
  • Sterile saline (0.9% NaCl)
  • An intravenous catheter with stopper, and syringes, needles, and tubes for blood samples
  • A timer

Procedure

  1. Fast the patient overnight.
  2. Hospitalize the patient, continuing to provide water but not food.
  3. Record the current body weight in kilograms.
  4. Taking care to be accurate, give the iohexol solution as a bolus through the intravenous catheter: 0.5 mL/kg for dogs with azotemia, or 1 mL/kg for dogs without azotemia.
  5. Flush the dead space of the catheter with 2 mL of saline, start the timer immediately, and then remove the catheter.
  6. Collect blood samples of at least 1 mL each at 2, 3, and 4 hours after the iohexol injection, from sites other than the injection site to avoid contamination with residual iohexol. Record the exact time each sample is collected, and make sure each tube is labeled with its collection time.
  7. Centrifuge the samples and harvest the plasma to send to the laboratory.

Before starting, contact the laboratory for information on pricing and sample requirements, and ask for the laboratory's reference range and the method it uses to calculate the clearance value.

Advantages

  • Iohexol is stable, and samples can be mailed to the laboratory without special precautions.
  • The total procedure time is short.
  • The laboratory measuring iohexol will normally calculate the GFR from the information you provide (dose and sampling times) and the concentrations it measures at each time point.

Disadvantages

  • Samples must 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, although they are very rare in dogs.
  • A correction must be applied to the clearance value calculated from the three samples to improve its accuracy (Heiene and Moe, 1999). The correction formula is Cl(corr) = −0.03 + 1.06 × Cl(obs) − 0.07012 × Cl(obs)², where Cl(corr) is the corrected value and Cl(obs) is the value calculated from the three samples. Some laboratories apply this correction before reporting the GFR result and give their own reference ranges, so check with the laboratory you use whether a correction has been applied.

Plasma Creatinine Clearance

Materials Required

  • Anhydrous creatinine powder
  • Sterile saline (0.9% NaCl)
  • A 0.2 µm filter, obtained through a pharmacy and used according to its instructions
  • An intravenous catheter with stopper, and syringes, needles, and tubes for blood samples
  • A timer

Procedure

  1. Fast the patient overnight.
  2. Hospitalize the patient, continuing to provide water but not food.
  3. Record the current body weight in kilograms.
  4. Collect a blood sample to measure the baseline creatinine concentration at time zero.
  5. Prepare the creatinine solution (80 mg/mL): dissolve the creatinine in saline and sterilize it by filtration through a 0.2 µm filter.
  6. Taking care to be accurate, give the creatinine solution (1 mL/kg) as a bolus through the intravenous catheter, followed by 2 mL of saline, and start the timer immediately. Remove the catheter.
  7. Collect 1 mL blood samples at 10 minutes and at 1, 2, 6, and 10 hours after the injection, recording the exact time each sample is collected. Collect from sites other than the injection site to avoid contamination with residual injected creatinine.
  8. Measure the creatinine concentration in all six samples in the same batch of assays.
  9. Calculate the plasma clearance from the dose given and the area under the plasma creatinine versus time curve (AUC), after first subtracting the baseline value from each of the five post-injection values.

Advantages

  • Creatinine assays for plasma or serum are readily available, in practice laboratories or externally.
  • Only a small sample volume is required.
  • Creatinine assays are quick to perform.

Disadvantages

  • A suitable creatinine solution must be prepared by an appropriate laboratory or pharmacy, to make sure it is sterile and pyrogen-free and that its concentration is precise, for an exact dose.
  • A substantially longer hospital stay is required than with iohexol.
  • The practitioner, rather than the laboratory performing the assays, must calculate the GFR from the data.

References

  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.

Further Reading

  • Heiene R, Lefebvre HP (2007). Assessment of renal function. In: Elliott J, Grauer GF, eds. BSAVA Manual of Canine and Feline Nephrology and Urology, 2nd edition, pp. 117–125.
  • Heiene R, Lefebvre HP (2013). Glomerular filtration rate in dogs and cats. International Renal Interest Society, available on the IRIS website.
  • Heiene R, Moe L (1999). The relationship between some plasma clearance methods for estimation of glomerular filtration rate in dogs with pyometra. Journal of Veterinary Internal Medicine 13:587–596.