Use of non-steroidal anti-inflammatory drugs in renal transplant patients: A retrospective study

Abstract

BACKGROUND:

Renal transplants are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for analgesic purposes.

OBJECTIVE:

Considering the dearth of data, we carried out the present study to evaluate the use of various NSAIDs and the incidence of acute kidney injury (AKI) in transplant patients.

METHODS:

A retrospective study amongst renal transplant patients prescribed at least one dose of NSAID was carried between January and December 2020 at the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. The patients’ demographic details, serum creatinine values, and drug-related details were obtained. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used for defining AKI.

RESULTS:

Eighty-seven patients were included. Forty-three patients were prescribed diclofenac, 60 received ibuprofen, six received indomethacin, 10 were administered mefenamic acid, and 11 received naproxen. Due to multiple courses of NSAID prescription, a total of 70 prescriptions were identified for diclofenac, 80 for ibuprofen, six for indomethacin, 11 for mefenamic acid, and 16 for naproxen. No significant differences were observed in the absolute (p = 0.08) and percent changes in serum creatinine (p = 0.1) between the NSAIDs. Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. Age (OR: 1.1, 95% CI: 1.007, 1.2; p = 0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p = 0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p = 0.005) administration were observed with significant risk of NSAID-induced AKI.

CONCLUSION:

We observed possible NSAID-induced AKI to an extent of around 15.2% in our renal transplant patients. No significant differences were observed in the incidence of AKI between various NSAIDs and none of them had either graft failure or death.

Keywords

Diclofenac indomethacin ibuprofen naproxen mefenamic acid kidney transplant AKI NSAIDs

1. Background

Patients with renal transplantation suffer from a huge burden of pain episodes (mainly abdominal); a recent meta-analysis revealed a prevalence of 56% [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common analgesics used worldwide [2]. A European study revealed that 63% of their renal transplant patients were taking over-the-counter analgesics of which nearly one-fifth of them were taking it several times in a week, while 4% daily [3]. NSAIDs act mainly by inhibiting cyclooxygenase enzyme thereby reducing the production of vasodilating prostaglandins, resulting in reduced renal perfusion [4]. NSAIDs can also cause electrolyte imbalance and interstitial nephritis and produce renal damage [5]. There is a dearth of information on the evaluation of NSAIDs in renal transplant patients. A published longitudinal cohort study of adult kidney transplant recipients retrospectively followed in the VA system from 2001–10 that assessed for risk of AKI with NSAID prescriptions and which included 5100 patients revealed an incidence of AKI to an extent of 5.4% [6]. Similarly, a more recent retrospective cohort study of adult kidney transplant recipients from 2008 to 2017 in Alberta, Canada involving 1730 patients revealed incidence of AKI to be 13% [7]. Our unit has around 300 transplant patients and we observed prescriptions of NSAIDs by medical specialists (mostly family physicians). Previously, we carried out a drug utilization study in renal transplant patients and observed that a large quantity of prescribed drugs had significant interactions with a potentially increased risk of adverse events [8]. We carried out the present study to evaluate the use of NSAIDs concerning their dosing regimens and the impact on renal function (measured by serum creatinine values) in renal transplant patients.

2. Methods

2.1. Study design and ethics

The present study had a retrospective design and was carried out as a part of the drug utilization study at the Department of Nephrology, Salmaniya Medical Complex between January, and December 2020. Ethical approval was obtained from the Institutional Ethics Committee (E05-PI-5/21). The study was carried out in compliance with the latest Declaration of Helsinki guidelines.

2.2. Study procedure

Hospital records of the patients who have undergone renal transplantation and are being followed up in the outpatient clinic who were prescribed at least one dose of NSAID were obtained. The following details were extracted: demographics (age, sex, duration of renal transplantation, and concomitant diseases), drug-related details, and serum creatinine values. We adhered to the Kidney Disease Improving Global Outcomes (KDIGO) criteria for evaluating acute kidney injury (AKI) where a raise in absolute serum creatinine of ≥0.3 mg/dl within 48 hours or 1.5–1.9 times the baseline was considered stage 1, and >2 times elevation as stage 2 [9]. The following threshold was considered for classifying the daily doses of NSAIDs into low or high: diclofenac – 100 mg; ibuprofen – 1200 mg; indomethacin – 75 mg; mefenamic acid – 1500 mg; and naproxen – 1000 mg [6]. Amongst the concomitant medications, nephrotoxic antimicrobials were not administered and only the calcineurin inhibitors were considered as potentially nephrotoxic.

2.3. Statistical analysis

Descriptive statistics were used for representing the demographic variables. Kruskal-Wallis H test was used for analyzing the differences between continuous variables between the NSAID groups. Odds ratio (OR) with a 95% confidence interval (95% CI) was used for expressing the risk of AKI with each NSAID. One way ANOVA was used for analyzing the significance between the absolute and percent changes in serum creatinine between NSAIDs. Mann-Whitney U test was used for comparing the cumulative doses between of the NSAIDs between AKI and non-AKI cohorts. Logistic regression analysis was carried out with AKI as dependent variable and age, sex, duration of renal transplantation, high or low doses of NSAID, duration of NSAID therapy, and concomitant immunosuppressive drugs as independent variables. A p-value of ≤0.05 was considered significant. SPSS (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.) was used for statistical analysis.

3. Results

3.1. Demographics

Eighty-seven patients were recruited, and the summary of demographic characteristics is mentioned in Table 1. The majority of the study participants were receiving mycophenolate mofetil followed by cyclosporine as the concomitant immunosuppressant drug.

Table 1
Demographic characteristics of the study participants (N = 87)

Variables Values

Age (years) 47.5 (14–75)

Male: Female 60: 27

Duration of renal transplantation (years) 7 (1–25)

Concomitant diseases (n) Systemic hypertension 66

Dyslipidemia 48

Diabetes mellitus 35

Hyperuricemia 10

Immunosuppressant drugs (n) Azathioprine 1

Azathioprine & Everolimus 2

Azathioprine & Cyclosporine 2

Everolimus 2

Mycophenolate mofetil 40

Mycophenolate mofetil & Azathioprine 2

Mycophenolate mofetil & Cyclosporine 23

Mycophenolate mofetil, Azathioprine, & Everolimus 3

Mycophenolate mofetil, Cyclosporine, & Everolimus 2

Mycophenolate mofetil & Everolimus 5

Prednisolone 5

Variables	Values
Age (years)	47.5 (14–75)
Male: Female	60: 27
Duration of renal transplantation (years)	7 (1–25)
Concomitant diseases (n)	Systemic hypertension	66
	Dyslipidemia	48
	Diabetes mellitus	35
	Hyperuricemia	10
Immunosuppressant drugs (n)	Azathioprine	1
	Azathioprine & Everolimus	2
	Azathioprine & Cyclosporine	2
	Everolimus	2
	Mycophenolate mofetil	40
	Mycophenolate mofetil & Azathioprine	2
	Mycophenolate mofetil & Cyclosporine	23
	Mycophenolate mofetil, Azathioprine, & Everolimus	3
	Mycophenolate mofetil, Cyclosporine, & Everolimus	2
	Mycophenolate mofetil & Everolimus	5
	Prednisolone	5

The values are in median (range), unless specified otherwise.

3.2. NSAID details

Sixty patients were prescribed ibuprofen, diclofenac in 43, naproxen in 11, mefenamic acid in 10, and indomethacin in 6 patients. Due to the multiple courses of NSAID prescription, a total of 80 prescriptions were identified for ibuprofen, 70 for diclofenac, 16 for naproxen, 11 for mefenamic acid, and 6 for indomethacin. A summary of the dosing regimen for each NSAID administered in the study participants is listed in Table 2. High doses were prescribed in 20/80 (25%) courses with ibuprofen and two/six (33.3%) courses with indomethacin.

Table 2
Dosing regimen for the prescribed NSAIDs

Drugs Dose/day (mg) Duration (days) Cumulative doses (mg)

Diclofenac (n = 70) 100 (50–100) 10 (1–120) 1000 (75–12000)

Ibuprofen (n = 80) 800 (400–2400) 5 (1–30) 5500 (400–24000)

Indomethacin (n = 6) 25 (25–100) 15 (5–30) 750 (350–3000)

Mefenamic acid (n = 11) 1500 (500–1500) 5 (3–14) 7500 (3500–14000)

Naproxen (n = 16) 500 (250–1000) 6 (2–60) 3500 (750–30000)

Drugs	Dose/day (mg)	Duration (days)	Cumulative doses (mg)
Diclofenac (n = 70)	100 (50–100)	10 (1–120)	1000 (75–12000)
Ibuprofen (n = 80)	800 (400–2400)	5 (1–30)	5500 (400–24000)
Indomethacin (n = 6)	25 (25–100)	15 (5–30)	750 (350–3000)
Mefenamic acid (n = 11)	1500 (500–1500)	5 (3–14)	7500 (3500–14000)
Naproxen (n = 16)	500 (250–1000)	6 (2–60)	3500 (750–30000)

N = total number of courses of NSAID therapy; the values are in median (range), unless specified otherwise.

3.3. Serum creatinine levels during NSAID therapy

Baseline, post-NSAID therapy, absolute changes, and percent changes in serum creatinine for each NSAID are mentioned in Table 3. No significant differences were observed in the absolute changes (p = 0.08) and percent changes in serum creatinine (p = 0.1) between the NSAIDs.

Table 3
Serum creatinine with NSAID therapy

Drugs Baseline serum creatinine (mg/dl) Absolute change in the serum creatinine (mg/dl) Percent change in serum creatinine

Diclofenac (n = 70) 1.1 (0.5–17.5) −0.006 (−2 to 2.5) −0.6 (−25.3 to 134.8)

Ibuprofen (n = 80) 1.1 (0.5–14.2) 0 (−3 to 6.2) 0 (−25.5 to 61.8)

Indomethacin (n = 6) 1.1 (0.6–4.8) 0.2 (−0.01 to 0.7) 15.4 (−1.4 to 28.3)

Mefenamic acid (n = 11) 1.1 (0.5–12.5) 0 (−1.3 to 0.1) 0 (−28.1 to 19)

Naproxen (n = 16) 1.2 (0.5–18.8) 0.1 (−3.9 to 2.7) 3.8 (−26.1 to 44.1)

p-values^a 0.6 0.08 0.1

Drugs	Baseline serum creatinine (mg/dl)	Absolute change in the serum creatinine (mg/dl)	Percent change in serum creatinine
Diclofenac (n = 70)	1.1 (0.5–17.5)	−0.006 (−2 to 2.5)	−0.6 (−25.3 to 134.8)
Ibuprofen (n = 80)	1.1 (0.5–14.2)	0 (−3 to 6.2)	0 (−25.5 to 61.8)
Indomethacin (n = 6)	1.1 (0.6–4.8)	0.2 (−0.01 to 0.7)	15.4 (−1.4 to 28.3)
Mefenamic acid (n = 11)	1.1 (0.5–12.5)	0 (−1.3 to 0.1)	0 (−28.1 to 19)
Naproxen (n = 16)	1.2 (0.5–18.8)	0.1 (−3.9 to 2.7)	3.8 (−26.1 to 44.1)
p-values^a	0.6	0.08	0.1

N = total number of courses of NSAID therapy; the values are in median (range), unless specified otherwise; a – estimated using one-way ANOVA.

3.4. AKI with NSAID therapy

Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. The numbers of courses observed with each KDIGO criterion for the individual NSAID are mentioned in Table 4. None met the criteria with mefenamic acid and only one (16.7%) with indomethacin. With indomethacin as a reference standard, no significant differences were observed in the risk of AKI with diclofenac (OR: 1.86, 95% CI: 0.2, 17), ibuprofen (OR: 0.7, 95% CI: 0.1, 6.8), and naproxen (OR: 1.7, 95% CI: 0.2, 18.9). Logistic regression analysis revealed a significant association with age (OR: 1.1, 95% CI: 1.007, 1.2; p = 0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p = 0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p = 0.005) administration. No significant differences were observed in the cumulative doses of any of the NSAIDs between those with AKI and those without (Table 5). No significant (p = 0.7) differences were observed in the incidence of AKI between the courses of high doses of NSAIDs (1/12, 8.3%) compared to low doses (27/171, 15.8%). Similarly, we did not observe any statistically significant (p = 0.5) differences in the duration of NSAID therapy between those with AKI (median: 5 days; range: 1–30 days) and those without (median: 5 days; range: 1–120 days). Additionally, we did not observe any significant (p = 0.5) differences in the AKI incidence between those receiving a calcineurin inhibitor (9/55, 16.4%) and those not receiving (19/128, None of the AKI episodes resulted in either graft failure or death.

Table 4
Number of courses of NSAID therapy meeting the KDIGO criteria for AKI

Drugs Serum creatinine ≥ 0.3 mg/dl 1.5–1.9 times elevation from baseline serum creatinine Stage 1 AKI Stage 2 AKI

Diclofenac (n = 70) 13 2 13 6

Ibuprofen (n = 80) 10 1 10 0

Indomethacin (n = 6) 1 0 1 0

Mefenamic acid (n = 11) 0 0 0 0

Naproxen (n = 16) 4 0 4 0

Drugs	Serum creatinine ≥ 0.3 mg/dl	1.5–1.9 times elevation from baseline serum creatinine	Stage 1 AKI	Stage 2 AKI
Diclofenac (n = 70)	13	2	13	6
Ibuprofen (n = 80)	10	1	10	0
Indomethacin (n = 6)	1	0	1	0
Mefenamic acid (n = 11)	0	0	0	0
Naproxen (n = 16)	4	0	4	0

N = total number of courses of NSAID therapy; AKI – Acute kidney injury.

Table 5

Comparison of cumulative doses of NSAIDs between the AKI and non-AKI cohorts

NSAIDs	AKI cohort	Non-AKI cohort	p-values
Diclofenac (mg)	1000 (700–1000)	1000 (75–12000)	0.3
Ibuprofen (mg)	4800 (3600–24000)	5500 (400–12000)	0.9
Indomethacin (mg)	500 (350–3000)	2000	NA
Naproxen (mg)	2000 (750–3500)	6000 (1500–30000)	0.06

Values are mentioned in median (range); p-values are calculated using Mann-Whitney U test; Not applicable.

4. Discussion

We carried out the present study in renal transplant patients to evaluate the use of NSAIDs along with the incidence and determining factors for AKI. Ibuprofen followed by diclofenac sodium was the most prescribed NSAID. Twenty-eight (15.2%) met the criteria for AKI and no significant differences in the risk profile between the NSAID were observed. Age and concomitant everolimus or mycophenolate + cyclosporine + azathioprine were identified as the risk factors for possible NSAID-induced AKI.

A recent meta-analysis revealed that in the general population, OR of NSAID-induced AKI was 1.73 (95% CI: 1.44 to 2.07), with a slightly increased risk in older individuals (OR: 2.51, 95% CI: 1.52 to 2.68) [10]. The authors in the same meta-analysis also revealed that in people with chronic kidney disease, the OR was 1.63 (95% CI: 1.22 to 2.19). We have observed a slightly higher incidence of NSAID-induced AKI in our renal transplant patients. However, our results are in corroboration with Jeong et al. that was carried out in the Canadian population where 13% were observed with NSAID-induced AKI and 5% had hyperkalemia [7]. In the same study, 189/1730 (11%) renal transplant patients had at least one NSAID prescribed with a similar estimate like in the present study. On the other hand, a 10-year cohort study from the US revealed a small proportion (671/5100, 5.4%) of renal transplants being prescribed a NSAID, with a one NSAID course associated with 5% higher odds of AKI [6]. Although we did not observe any significant differences in the incidence of AKI with high/low doses and duration of NSAID therapy, Chiasson et al. [6] observed a higher OR of AKI with high doses (OR: 2.83), and chronic use of NSAIDs (OR: 3.25). Probably the limited sample size in the present study might have precluded us in identifying this association. Also, even though we observed AKI to an extent of 15%, none of those developed either graft failure or death, thus suggesting that NSAID-induced AKI episodes are self-limiting. Alternatively, the criteria for NSAID-induced AKI in renal transplant patients must be revisited. We observed a similar incidence of AKI episodes between different NSAIDs like in a previous study [4]. However, we did not observe any AKI episodes with mefenamic acid that were not evaluated in the previous study. Only preliminary evidence suggestive of relative renal safety with sulindac and ibuprofen exists, and no firm conclusions can be reached on the relative differences in the AKI incidence between various NSAIDs [11]. Concomitant immunosuppressant drugs were observed with an increased risk of NSAID-induced AKI in the present study. Almost all renal transplant patients require life-long immunosuppressive drugs and so the prescription of NSAID should be weighed carefully in these patients. However, recently, a bioengineered mobilized cellular product enriched for hematopoietic stem cells and tolerogenic graft facilitating cells combined with nonmyeloablative conditioning was shown to facilitate immune tolerance, thereby reducing the chances of lifelong immunosuppressant therapy [12]. Also, we observed that an increase in the patients’ age by 1 year increases the risk of NSAID-induced AKI by nearly 10% (95% CI ranges between 0.7 to 20%). Age-related reduction in the blood flow and consequently reduced glomerular function has been observed starting from the second decade of life [13]. Similarly, the incidence of glomerular sclerosis increases with age beyond 40 years [14]. It has been well established that the advanced age of the donor’s kidneys was associated with poorer graft survival than younger donors [15]. However, we could not evaluate the donor age and the specialty of the prescriber of NSAIDs could not be retrieved in the present study. Further, the study is limited in sample size, in not evaluating the glomerular filtration rate, and none of our patients received long-term (≥6 months) NSAID therapy and could not evaluate the impact of chronic use.

5. Conclusion

Footnotes

Author contributions

KS – conceived the idea; KS, SS – data collection, interpretation, and analysis; KS – drafted the manuscript. Both authors were involved in the revision and acceptance of the final version of the manuscript.

Conflict of interest

None to report.

Data availability statement

The data is available from the corresponding author upon reasonable request.

Ethics statement

The study was approved by the Institutional Ethics Committee of CMMS, AGU (approval number E05-PI-5/21).

Informed consent

Not applicable as the study was retrospective.

Funding

None to report.

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