Arterial spin labeling can detect discreet changes of renal perfusion after oral application of the pain medication diclofenac in healthy subjects
Susanne Tewes1, Marcel Gutberlet1, Van Dai Vo Chieu1, Dagmar Hartung1, Sebastian Rauhut2, Matti Peperhove1, Frank Wacker1, Faikah Gueler2, and Katja Hueper1

1Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany, 2Clinic for Nephrology, Hannover Medical School, Hannover, Germany

Synopsis

Diclofenac is a nonsteroidal anti-inflammatory drug that is frequently prescribed to reduce inflammation and pain. It reduces the prostaglandin-synthesis and may consequently have an effect on renal perfusion. We investigated whether arterial spin labeling can detect reduction of renal perfusion after oral and topical application of diclofenac compared to baseline measurements. Ten healthy subjects underwent functional MRI of the kidney. After oral application of diclofenac renal perfusion was reduced compared to baseline measurements (321±13 vs. 345±16 ml/(min*100g), p<0.01). No significant changes were found after topical application. In conclusion, ASL can detect discreet changes of renal perfusion that occur after application of diclofenac.

Purpose

Diclofenac is a nonsteroidal anti-inflammatory drug that is frequently prescribed in order to reduce inflammation and pain. It is a non-selective inhibitor of the enzyme cyclooxygenase (COX), resulting in a reduction of prostaglandin-synthesis and may consequently reduce renal perfusion. Therefore, it is potentially harmful in patients at risk for renal function impairment. Diclofenac is available for oral and topical application and has been reported to reach measurable plasma concentration after repeated topical application(1). With contrast-enhanced ultrasound (CEUS) a discreet decrease of renal perfusion within one hour after oral diclofenac application could be detected in healthy subjects(2), while no changes in para-aminohippuric acid (PAH)-clearance, the clinical standard to measure renal blood flow over a period of 24 hours, was found(3). Arterial spin labeling (ASL) is a robust method for accurate quantification of renal perfusion and results are non-dependent on the investigator. The purpose of this study was to evaluate whether systemic or topical application of diclofenac is associated with renal perfusion impairment in healthy subjects measured by ASL.

Material and Methods

Ten healthy subjects were examined on three different days within a period of two weeks: 1) baseline examination without any medication, 2) 60-100 minutes after oral application of 50 mg diclofenac-sodium (Voltaren)(4), 3) after topical application of diclofenac (Voltaren Emulgel Gel, 1,16%) over 4 days (three applications per day) on an area of 21 x 27cm. Blood pressure, serum creatinine and diclofenac blood levels were measured at each time point. MRI was performed on a 1.5 Tesla scanner (Avanto, Siemens, Germany) and renal perfusion was measured by using a flow alternating inversion recovery (FAIR) trueFISP ASL sequence as described previously(5). Alternating, after slice-selective and global inversion, images were acquired in free breathing in the coronal plane with the following parameters: TR/TE 4.0/2.0 ms, inversion time = 1200 ms, FOV 420x420 mm, slice thickness 5 mm, repetitions 30. Following motion correction of ASL images with elastic registration, maps of renal perfusion were calculated. ROIs were placed in the upper, middle and lower third of the kidneys and mean perfusion values were calculated. Paired t-tests were used for statistical analysis. Values are given as mean±SEM.

Results

Out of 10 healthy subject, 3 were male, 7 were female. Mean age was 30±2 years (22-49 years), mean body weight 65±4 kg (53-80 kg), mean height 73±3 cm (160-188 cm). Mean blood pressure was 111±4/78±3 mmHg. Representative perfusion maps at baseline and after oral and topical application of diclofenac are shown in figure 1. After oral application of diclofenac, renal perfusion significantly decreased compared to baseline conditions (321±13 vs. 345±16 ml/(min*100g), p<0.01, figure 2). No significant changes were found after topical application compared to baseline (346±20 ml/(min*100g), p=0.4, ns, figure 2).

Conclusion

ASL can detect discreet changes in renal perfusion that occur after single oral application of 50 mg diclofenac in healthy subjects. No significant changes in renal perfusion were detected after topical application of diclofenac. The fact that diclofenac induced measurable changes in renal perfusion even in healthy subjects should be considered in therapy plans of patients with pre-existing renal function impairment. ASL being able to detect discreet changes in renal perfusion could be useful for further studies on nephrotoxic side effects of novel medication or nephroprotective effects of novel treatment strategies in clinical studies since it is a non-invasive, robust and quantitative technique.

Acknowledgements

No acknowledgement found.

References

1. Brunner M, Davies D, Martin W, Leuratti C, Lackner E, Mueller M. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. Br J Clin Pharmacol 2011; 71: 852–859

2. Imamura H, Hata J, Iida A, Manabe N, Haruma K. Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study. Eur J Clin Pharmacol 2012; 69: 161-165

3. Fredman B, Zohar E, Golan E, Tillinger M, Bernheim J, Jedeikin R. Diclofenac does not decrease renal blood flow or glomerular filtration in elderly patients undergoing orthopedic surgery. 1999; Anesth Analg 88:149–154

4. Manvelian G, Daniels S, Gibofsky A. The pharmacokinetic parameters of a single dose of a novel nano-formulated, lower-dose oral diclofenac. Postgrad Med 2012; 124:117–123

5. Martirosian P, Klose U, Mader I, Schick F. FAIR true-FISP perfusion imaging of the kidneys. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine 2004;51:353-361.

Figures

Example of perfusion maps. Kidneys of a 22-year old male healthy subject. Mean perfusion values of both kidneys were lower after oral application of diclofenac compared to baseline conditions (313 vs 352 ml/(min*100g)). No perfusion changes were found after topical application (385 vs 352 ml/(min*100g)).

Mean±SEM of renal perfusion at baseline and after oral and topical application of diclofenac are shown and significant differences are indicated. Mean values of renal perfusion were significantly lower after oral application of diclofenac compared to baseline (p<0.01). No differences were found after topical application compared to baseline measurements.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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