Efficacy and Safety of Gout Flare Prophylaxis and Therapy Use in People With Chronic Kidney Disease

A Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-Initiated Literature Review

Huai Leng Pisaniello; Mark C. Fisher; Hamish Farquhar; Ana Beatriz Vargas-Santos; Catherine L. Hill; Lisa K. Stamp; Angelo L. Gaffo

Disclosures

Arthritis Res Ther. 2021;23(130)

Abstract and Introduction

Abstract

Gout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3–5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) < 60 ml/min/1.73 m²), and with exposure to colchicine, interleukin-1 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. All study designs were included. A total of 33 studies with efficacy and/or safety analysis stratified by renal function were reviewed—colchicine (n = 20), anakinra (n = 7), canakinumab (n = 1), NSAIDs (n = 3), and glucocorticoids (n = 2). A total of 58 studies reported these primary outcomes without renal function stratification—colchicine (n = 29), anakinra (n = 10), canakinumab (n = 6), rilonacept (n = 2), NSAIDs (n = 1), and glucocorticoids (n = 10). Most clinical trials excluded study participants with severe CKD (i.e. eGFR or CrCl of < 30 mL/min/1.73 m²). Information on the efficacy and safety outcomes of gout flare prophylaxis and therapy use stratified by renal function is lacking. Clinical trial results cannot be extrapolated for those with advanced CKD. Where possible, current and future gout flare studies should include patients with CKD and with study outcomes reported based on renal function and using standardised gout flare definition.

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Arthritis Res Ther. 2021;23(130) © 2021 BioMed Central, Ltd.
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Abstract and Introduction
Background
Methods
Results
Discussion
Conclusion
References

Table 1. An overview of efficacy and safety outcome reporting of gout flare prophylaxis and therapy use (with and without renal function stratification)
First Author (Year) (Trial Name)	Study Design	Number of participants by eGFR/CrCl at baseline (mL/min/1.73m²)				Total, n	Primary outcome data reporting with stratified renal function = Yes without stratified renal function = No
First Author (Year) (Trial Name)	Study Design	≥90	60–90	30–60	< 30	Total, n	Efficacy	Safety
COLCHICINE
AHERN 1987 [9]	RCT (single- centre)	22				22	No	No
BORSTAD 2004 [10]	RCT (single-centre)	14				14	No	No
WORTMANN 2010 (FACT, APEX, CONFIRMS) [11]	Three RCTs (post-hoc analyses)	371(F); 541(A); 786(C)	295(F); 154(A); 402(C)	94(F); 154(A); 402(C)		760(F); 1072(A); 2269(C)	No	No
PASCART 2016 (GOSPEL 2) [12]	Cross-sectional study (post-hoc analysis)	158	59	45	2	264	No	No
SOLAK 2014 [13]	Case-control				1	1	No	No
HUNG 2005 [14]	Retrospective observational (single-centre)	29 (concomitant arm) vs 8 (sequential arm)				37	No	No
KWON 2017 [15]	Retrospective observational (single-centre)	36/188 (colchicine with statin arm) vs 41/486 (colchicine without statin arm)				77	No	No
AKAR 2001 [16]	Case report				1	1	No	No
AKDAG 2006 [17]	Case report				1	1	No	Yes
ALAYLI 2005 [18]	Case report			1		1	Yes	Yes
ALTIPARMAK 2002 [19]	Case series				1	1	No	No
ALTMAN 2007 [20]	Case report			1		1	No	Yes
BAKER 2004 [21]	Case report			1		1	No	No
BONNEL 2002 [22]	Case series				1	1	No	Yes
BOOMERSHINE 2002 [23]	Case report				1	1	No	No
BOUQUIÉ 2011 [24]	Case report			1		1	No	Yes
CHENG 2005 [25]	Case series				1	1	No	No
CHOI 1999 [26]	Case report				1	1	No	No
DIXON 2001 [27]	Case report			1		1	No	No
ELEFTHERIOU 2008 [28]	Case report				1	1	No	Yes
GARROUSTE 2012 [29]	Case report				1	1	No	Yes
HSU 2002 [30]	Case report				1	1	No	No
HUH 2013 [31]	Case report			1		1	No	Yes
JUSTINIANO 2007 [32]	Case report			1		1	No	Yes
KUBLER 2000 [33]	Case report				1	1	Yes	Yes
KUNCL 1987 [34]	Case series	12				12	No	No
LAI 2006 [35]	Case report				1	1	No	Yes
LEE 1997 [36]	Case report			1		1	No	Yes
LY 2007 [37]	Audit (single centre)		22			22	No	Yes
MARCINIAK 2016 [38]	Case report			1		1	No	No
MEDANI 2016 [39]	Case series			1	1	2	No	Yes
MONTSENY 1996 [40]	Case series				4	4	No	No
MORRIS 2003 [41]	Case series				1	1	No	No
MULLINS 2011 [42]	Audit (single centre)	4	7	16	10	37	No	No
NASHEL 1982 [43]	Case series				2	2	No	No
NEUSS 1986 [44]	Case report				1	1	Yes	Yes
ORTEL 1974 [45]	Case report			1		1	No	No
PATEL 2016 [46]	Case report			1		1	No	Yes
PETERSEL 2007 [47]	Audit (single centre)	38				38	No	No
RANA 1997 [48]	Case series			3		3	No	No
RIEGER 1990 [49]	Case report				1	1	No	Yes
RUTKOVE 1996 [50]	Case series				4	4	No	No
SU 2015 [51]	Case report				1	1	No	No
VAN DER VALDEN 2008 [52]	Case report				1	1	No	No
WILBUR 2004 [53]	Case series			1	1	2	Yes	Yes
WRIGHT 2017 [54]	Audit	128				128	No	No
YOON 2001 [55]	Case report			1		1	Yes	Yes
YU 2018 [56]	Audit	9				9	No	No
ZAGLER 2009 [57]	Case report			1		1	No	Yes
IL-1 INHIBITORS
SCHLESINGER 2011 [58]	Phase 2 RCT – an extension of a phase 2 RCT by So et al., 2010 (multi-centre)	95				95	No	No
SCHLESINGER 2012 (β-RELIEVED & β-RELIEVED-II) [59]	Two phase 3 RCTs, followed by extension studies for both trials (multi-centre)		123	59		182	No	No
SO 2007 [60]	Pilot, open-labelled study (single-centre)	2	5	2	1	10	No	No
SO 2010 [61]	Phase 2 RCT (multi-centre)	95				95	No	No
SUNKUREDDI 2011 [62]	Post-hoc analyses of the RCTs (β-RELIEVED & β-RELIEVED-II) ACR abstract		188			188	No	No
SUNKUREDDI 2013 [63]	Post-hoc analyses of the RCTs (β-RELIEVED & β-RELIEVED-II) EULAR abstract		65			65	No	No
SUNKUREDDI 2014 [64]	Post-hoc analysis of an RCT (multi-centre) ACR abstract			24		24	No	No
TERKELTAUB 2009 [65]	Crossover trial (multi-centre)	2				2	No	No
TERKELTAUB 2012 [66]	Post-hoc analyses of RCTs (PRE-SURGE 1, PRE-SURGE 2 and RE-SURGE) ACR abstract		624	103		727	No	No
ADLER 2017 [67]	Case report				1	1	Yes	No
AOUBA 2015 [68]	Case series (single-centre)	1	1	1		3	Yes	Yes
BARTOV 2013 [69]	Case report				1	1	Yes	Yes
CHEN 2010 [70]	Case series (single-centre)		2	5	3	10	No	No
DIREZ 2012 [71]	Case report				1	1	Yes	Yes
DONMEZ 2014 [72]	Case report			1		1	No	No
FUNCK-BRENTANO 2011 [73]	Case report				1	1	No	No
GHOSH 2013 [74]	Case series (single-centre)			5		5	No	No
GRATTON 2009 [75]	Case report				1	1	No	No
LOUSTAU 2018 [76]	Case series (multi-centre)			6	25	31	Yes	Yes
MAROTTO 2018 [77]	Case report			1		1	Yes	Yes
MCGONAGLE 2007 [78]	Case report			1		1	No	No
OTTAVIANI 2013 [79]	Case series (multi-centre)			40		40	No	No
PALMA 2016 [80]	Case series (single-centre) ACR abstract			18		18	No	No
PEREZ-RUIZ 2013 [81]	Case series (single-centre) EULAR abstract	2		6		8	Yes	Yes
SINGH 2009 [82]	Case report			1		1	No	No
TRAN 2011 [83]	Case series			1		1	Yes	No
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
KAHL 1989 [84]	Case series			1	1	2	Yes	Yes
MIKHNEVICH 2013 [85]	Case series	82		15		97	No	No
SCHLONDORFF 1993 [86]	Case report		1			1	Yes	Yes
ZAGLER 2009 [57]	Case report			1		1	Yes	Yes
GLUCOCORTICOIDS
SUNKUREDDI 2014 [64]	Post-hoc analysis of an RCT (multi-centre) ACR abstract			24		24	No	No
BAJAJ 2004 [87]	Case series (single-centre)	4		2	4	10	No	No
FARGETTI 2012 [88]	Case report			1		1	No	No
HAUSCH 1991 [89]	Case report			1		1	No	No
HILL 2008 [90]	Case report				1	1	No	No
KARIMZADEH 2009 [91]	Case report			1		1	No	No
MAEKAWA 2014 [92]	Case report				1	1	No	No
RICHETTE 2006 [93]	Case report				1	1	No	No
SARMENTO 2009 [94]	Case report			1		1	No	No
TAUSCHE 2011 [95]	Case report			1		1	Yes	Yes
UDAYAKUMAR 2010 [96]	Case report			1		1	No	No
ZAGLER 2009 [57]	Case report			1		1	Yes	Yes

ACR: American College of Rheumatology; APEX: Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat; CONFIRMS: A Phase 3, Randomised, Multicenter, Double-Blind, Allopurinol-Controlled Study Assessing the Efficacy and Safety of Oral Febuxostat in Subjects With Gout; CrCl: creatinine clearance; eGFR: estimated glomerular filtration rate; EULAR: European League Against Rheumatism; FACT: Febuxostat Versus Allopurinol Control Trial in Subjects With Gout; GOSPEL 2: subgroup analysis of GOSPEL (goutte et observation des stratégies de prise en charge en médecine ambulatoire) survey; IL-1: interleukin-1; PRE-SURGE 1: Preventative Study Against Urate-Lowering Drug-Induced Gout Exacerbations 1; PRE-SURGE 2: Preventative Study Against Urate-Lowering Drug-Induced Gout Exacerbations; RCT: randomised controlled trial; RE-SURGE: Review of Safety Using Rilonacept in Preventing Gout Exacerbations; β-RELIEVED & β-RELIEVED-II: two phase three randomised studies (response in acute flare and in prevention of episodes of re-flare in gout)
Rows set in italics include studies described in the supplementary materials

Table 2. Efficacy outcome reporting of gout flare prophylaxis and therapy use with renal function stratification
First Author (Year) (Trial Name)	Study Design	Renal Function Exclusion Criteria or Baseline Renal Function – eGFR/CrCl (mL/min/1.73m²) or Serum Creatinine Level	Clinical Indication for Gout Flare	Actual/Mean Gout Flare Prophylaxis and Therapy Dose	Number of Participants by eGFR/CrCl at Baseline (mL/min/1.73m²)				Total, n	Efficacy Data with Renal Function Stratification
First Author (Year) (Trial Name)	Study Design		Clinical Indication for Gout Flare	Actual/Mean Gout Flare Prophylaxis and Therapy Dose	≥90	60–90	30–60	< 30	Total, n	Efficacy Data with Renal Function Stratification
COLCHICINE
AKDAG 2006 [17]	Case report	eGFR of 22 (serum creatinine of 3.1 mg/dL)	Gout flare prophylaxis	0.5 mg PO twice daily (for at least 15 years)				1	1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 7.6 mg/dL) during an episode of pneumonia requiring antibiotics (clarithromycin and cefepime).
ALAYLI 2005 [18]	Case report	eGFR of 44 (serum creatinine of 1.3 mg/dL)	Gout flare treatment	1.5 mg PO daily (for few days)			1		1	Gout flare resolution was achieved without worsening renal function (serum creatinine of 1.1 mg/dL – baseline of 1.3 mg/dL)
ALTMAN 2007 [20]	Case report	eGFR of 34 (serum creatinine of 2 mg/dL)	Gout flare treatment	1.5 mg PO daily (for at least 1 week)			1		1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 2.56 mg/dL).
BONNEL 2002 [22]	Case series	eGFR of 29 (serum creatinine of 2.3 mg/dL)	Gout flare treatment	2 mg IV loading dose, followed by 0.5 mg IV every 2 h until diarrhoea developed (total dose of 5.5 mg in 5 h)				1	1	Efficacy data not available. Renal function deteriorated rapidly (serum creatinine peaked at 4.9 mg/dL).
BOUQUIÉ 2011 [24]	Case report	eGFR of 32 (serum creatinine of 216 μmol/l)	Gout flare treatment	1 mg PO three times daily on day 1, 1 mg twice daily on day 2 and 3, and 1 mg once daily for 3 days			1		1	Efficacy data not available (colchicine was self-ceased after day 6). Renal function deteriorated on day 8 (serum creatinine peaked at 370 μmol/l).
ELEFTHERIOU 2008 [28]	Case report	ESRD with eGFR of 6–8	Gout flare treatment	1 mg PO daily (for at least 6 days)				1	1	Efficacy data not available. Renal function was stable.
GARROUSTE 2012 [29]	Case report	Renal transplant with eGFR of 41 (serum creatinine of 160 μmol/l)	Gout flare treatment	3 mg PO daily for 7 days				1	1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 512 μmol/l), but gradually recovered on day 34 (serum creatinine of 188 μmol/l).
HUH 2013 [31]	Case report	Renal transplant with eGFR of 34 (serum creatinine of 1.65 mg/dL)	Gout flare treatment	0.3 mg PO twice daily (for at least 3 weeks)			1		1	Efficacy data not available. Renal function deteriorated but returned to baseline 2 weeks after colchicine cessation.
JUSTINIANO 2007 [32]	Case report	eGFR of 57 (serum creatinine of 1.6 mg/dL)	Gout flare treatment	0.6 mg PO twice daily (for at least 2 weeks)			1		1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 1.7 mg/dL).
KUBLER 2000 [33]	Case report	eGFR of 26 (serum creatinine of 160 μmol/l)	Gout flare treatment	0.5 mg PO three times daily (for at least 12 days)				1	1	Gout flare resolution was achieved within 48 h, but ARF developed (serum creatinine peaked at 450 μmol/l) in the context of ongoing colchicine use (same dose and frequency).
LAI 2006 [35]	Case report	eGFR of 9 (serum creatinine of 565.8 μmol/l)	Gout flare treatment	0.5 mg PO three times daily for 3 days on a monthly basis (for at least 1 year); recent gout flare treatment with 0.5 mg PO twice daily (for at least 2 weeks)				1	1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 680.7 μmol/l).
LEE 1997 [36]	Case report	Renal transplant with eGFR of 49 (serum creatinine of 1.6 mg/dL)	Gout flare treatment	0.5 mg PO twice daily for 3 days			1		1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 2.7 mg/dL) but returned to baseline upon colchicine cessation.
LY 2007 [37]	Audit (single centre)	Patients with CKD (defined as serum creatinine of ≥0.17 mmol/L or CrCl of < 0.83)	Gout flare treatment	2.5 mg PO over 24 h or less		22			22	Efficacy data not available.
MEDANI 2016 [39]	Case series	CKD Stage 3b-4 (serum creatinine of 300 μmol/l in patient 1 and 200 μmol/l in patient 2)	Gout flare treatment	Patient 1: 0.5 mg PO three times daily for 6 weeksPatient 2: 0.5 mg PO once daily for at least 6 months			1	1	2	Efficacy data not available. Renal function deteriorated for both patients (serum creatinine peaked at 526 μmol/l in patient 1 and 255 μmol/l in patient 2).
NEUSS 1986 [44]	Case report	eGFR of 23 (serum creatinine of 2.3 mg/dL)	Gout flare prophylaxis	0.6 mg PO twice daily (long term)				1	1	No gout flare during therapy, but with multi-organ failure, including AKI (serum creatinine peaked at 3 mg/dL).
PATEL 2016 [46]	Case report	eGFR of 32 (serum creatinine of 1.87 mg/dL)	Gout flare prophylaxis	0.6 mg PO once daily (for > 5 years)			1		1	Efficacy data not available. Renal function deteriorated (serum creatinine peaked at 2.5 mg/dL) but returned to baseline upon colchicine cessation.
RIEGER 1990 [49]	Case report	ESRD with eGFR of < 30 on haemodialysis and underlying renal transplant	Gout flare prophylaxis	0.6 mg PO twice daily				1	1	Efficacy data not available.
WILBUR 2004 [53]	Case series	Patient 1: ESRD on peritoneal dialysisPatient 2: CKD Stage 3	Gout flare treatment	0.6 mg PO (variable frequency)			1	1	2	Patient 1: ongoing treatment due to recurrent flare (despite 0.6 mg PO three times daily for the first 3 days). Renal function worsened. Patient 2: ongoing treatment due to recurrent gout flare for at least 2 weeks (dosing was increased from 0.6 mg PO once daily to three times daily). Renal function was stable.
YOON 2001 [55]	Case report	eGFR of 39 (serum creatinine of 134 μmol/l)	Gout flare treatment	0.5 mg PO three times daily (total dose of 4.5 mg)			1		1	Gout flare persisted. Renal function deteriorated (CrCl peaked at 30 mL/min/1.73m²).
ZAGLER 2009 [57]	Case report	eGFR of 34	Gout flare treatment	1 mg PO once off dosing			1		1	Efficacy data not available. However, renal function deteriorated (serum creatinine increased from 2.4 to 5.2 mg/dL).
IL-1 INHIBITORS
ADLER 2007 [67]	Case report	eGFR of 27–30	Gout flare treatment	Anakinra 100 mg/d for 3 days				1	1	Complete clinical remission with stable renal function.
AOUBA 2015 [68]	Case series (single-centre)	eGFR of 20–40	Gout flare treatment	Anakinra 100 mg/d (up to 6 days)	1	1	1		3	2 patients achieved complete clinical remission after 5 days of treatment. 1 patient who received initial 3-day treatment required a second course (5-day period) due to recurrent gout flare. Renal function remained stable.
BARTOV 2013 [69]	Case report	eGFR of < 20	Gout flare treatment	Anakinra 100 mg every other day for 1 week				1	1	Complete clinical remission with no worsening renal function.
DIREZ 2012 [71]	Case report	CrCl of 14 mL/min/1.73m²	Gout flare treatment	Anakinra 100 mg/d for 5 days, followed by re-dosing of alternate-daily 100 mg dosing for 2 months (commenced 1 week after the first therapy)				1	1	Partial responder for the first course of treatment. During the second treatment, renal function deteriorated after 2 months (CrCl declined to 6 mL/min/1.73m²).
LOUSTAU 2018 [76]	Case series (multi-centre)	CKD stage 4–5 (mean eGFR 22 ± 6.6) and history of renal transplant (mean eGFR 41 ± 22.8)	Gout flare treatment	Anakinra 100 mg/d (except in 5 patients who had 100 mg every 48–72 h) for less than a week; in 10 patients, dose was maintained for > 15 days (up to 14 months) with progressive dose spacing due to frequent gout flare			6	25	31	Pooled efficacy outcome: complete clinical remission with a mean of 46 days (range 4–90 days). Decrease in pain VAS from 69.6 ± 13.4 mm to 10.4 ± 15.3 mm and CRP level from 160 ± 133 mg/mL to 11 ± 11 mg/mL. No significant change in eGFR (26.3 pre-treatment vs 26.9 post-treatment).
MAROTTO 2018 [77]	Case report	CKD stage 3 (CrCl of 56.47 mL/min/1.73m²)	Gout flare treatment	Canakinumab 100 mg single dose			1		1	Rapid clinical response 12 h after canakinumab administration. No worsening renal function.
PEREZ-RUIZ 2013 [81]	Case series (single centre)EULAR abstract	CKD stage 3–4	Gout flare treatment	Anakinra 100 mg/d (varying duration)	2		6		8	Pooled efficacy outcome: reduction in hsCRP level from 5.7 ± 7.3 to 0.56 ± 1.07 at 6 months post-treatment. Renal function remained stable (baseline CrCl 68 ± 28 vs 74 ± 43 at 6th month).
TRAN 2011 [83]	Case series	eGFR of 57 (serum creatinine of 118 μmol/l)	Gout flare treatment	Anakinra 100 mg/d			1		1	Clinical remission was achieved with CRP reduction. Renal function remained stable.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
KAHL 1989 [84]	Case series	Patient 1: eGFR of 32 (serum creatinine of 2.4 mg/dL)Patient 2: eGFR of 21 (serum creatinine of 3.3)	Gout flare treatment	Sulindac 200 mg twice daily and indomethacin 50 mg three times daily			1	1	2	No improvement in gout flare. Acute kidney injury developed in both patients.
SCHLONDORFF 1993 [86]	Case report	Creatinine clearance of 70 (serum creatinine of 1.8 mg/dL)	Gout flare treatment	Indomethacin 50 mg three times daily		1			1	Gout flare improved rapidly. Acute kidney injury ensued.
ZAGLER 2009 [57]	Case report	eGFR of 34	Gout flare treatment	Diclofenac 100 mg/d			1		1	No improvement in gout flare. However, renal function deteriorated (serum creatinine increased from 2.4 to 5.2 mg/dL).
GLUCOCORTICOIDS
TAUSCHE 2011 [95]	Case report	eGFR of 30	Gout flare prophylaxis	Prednisone 10 mg/d			1		1	Improvement in frequency of gout flare (in combination with regular low-dose colchicine use and low-dose NSAID as required; the duration for the gout flare prophylaxis use was not known). Renal function remained stable.
ZAGLER 2009 [57]	Case report	eGFR of 34	Gout flare treatment	Prednisone 40 mg/d			1		1	Gout flare treatment was effective. However, renal function deteriorated (serum creatinine increased from 2.4 to 5.2 mg/dL).

AKI acute kidney injury, CKD chronic kidney disease, CRP C-reactive protein, CrCl creatinine clearance, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, hsCRP highly sensitive C-reactive protein, IV intravenous, PO per os (by mouth), VAS visual analogue score

Table 3. Safety outcome reporting of gout flare prophylaxis and therapy use with renal function stratification
First Author (Year) (Trial Name)	Adverse/Serious Adverse Events Reported by Renal Function	Notable Findings
COLCHICINE
AKDAG 2006 [17]	Yes	Colchicine toxicity in the context of antibiotic use (clarithromycin and cefepime) for pneumonia. Besides worsening renal function, there was associated mild pancytopaenia and liver impairment.
ALAYLI 2005 [18]	Yes	Colchicine neuromyopathy in the context of concomitant statin use.
ALTMAN 2007 [20]	Yes	Colchicine-induced rhabdomyolysis.
BONNEL 2002 [22]	Yes	Fatal colchicine toxicity with rapidly deteriorating renal function and death.
BOUQUIÉ 2011 [24]	Yes	Colchicine-induced rhabdomyolysis with acute decompensation of pre-existing double heart/lung transplant and multi-organ failure.
ELEFTHERIOU 2008 [28]	Yes	Colchicine toxicity with multi-organ failure in the context of concomitant long-term cyclosporin therapy for heart transplant.
GARROUSTE 2012 [29]	Yes	Colchicine toxicity with neuromyopathy and multi-organ failure in the context of concomitant long-term cyclosporin use for renal transplant.
HUH 2013 [31]	Yes	Colchicine toxicity with gastrointestinal symptoms and neuromyopathy in the context of concomitant long-term cyclosporin use for renal transplant and statin use.
JUSTINIANO 2007 [32]	Yes	Colchicine-induced rhabdomyolysis in the context of concomitant statin use.
KUBLER 2000 [33]	Yes	Fatal colchicine toxicity with multi-organ failure and death.
LAI 2006 [35]	Yes	Colchicine neuromyopathy.
LEE 1997 [36]	Yes	Acute myopathy in the context of concomitant cyclosporin use for renal transplant.
LY 2007 [37]	Yes	One patient with CKD (serum creatinine of 0.21 mmol/L) developed colchicine myopathy.
MEDANI 2016 [39]	Yes	Colchicine neuromyopathy.
NEUSS 1986 [44]	Yes	Fatal colchicine toxicity with myopathy, multi-organ failure, severe neutropaenia with associated disseminated candidiasis and death.
PATEL 2016 [46]	Yes	Colchicine-induced rhabdomyolysis in the context of statin use and initiation of sofosbuvir/ledipasvir therapy for Hepatitis C.
RIEGER 1990 [49]	Yes	Colchicine neuromyopathy in the context of acute stage of post-renal transplant and cyclosporin use.
WILBUR 2004 [53]	Yes	Colchicine neuromyopathy.
YOON 2001 [55]	Yes	Colchicine toxicity with associated pancytopaenia, neuromyopathy and total alopecia.
ZAGLER 2009 [57]	Yes	Colonic perforation and acute on chronic CKD.
IL-1 INHIBITORS
ADLER 2007 [67]	No	Anakinra treatment: adverse event was not reported.
AOUBA 2015 [68]	Yes	Anakinra treatment: 1 patient with mild injection site reaction, transient diffuse pruritus and episodic diarrhoea.
BARTOV 2013 [69]	Yes	Anakinra treatment: adverse event was not observed.
DIREZ 2012 [71]	Yes	Anakinra treatment: non-complicated neutropaenia.
LOUSTAU 2018 [76]	Yes	Anakinra treatment: 1 patient with an infection (nosocomial pyelonephritis). No other adverse event was observed.
MAROTTO 2018 [77]	Yes	Canakinumab treatment: adverse event was not observed.
PEREZ-RUIZ 2013 [81]	Yes	Anakinra treatment: 1 patient with recurrent heart failure. No other adverse event was observed.
TRAN 2011 [83]	Yes	Anakinra treatment: adverse event was not reported.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
KAHL 1989 [84]	Yes	Acute kidney injury with sulindac and indomethacin use.
SCHLONDORFF 1993 [86]	Yes	Acute kidney injury with indomethacin use.
ZAGLER 2009 [57]	Yes	Colonic perforation and acute on chronic CKD.
GLUCOCORTICOIDS
TAUSCHE 2011 [95]	No	Adverse event was not reported.
ZAGLER 2009 [57]	Yes	Colonic perforation and acute on chronic CKD.