Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis

Table 1 Subgroup analysis of polymyxin-induced nephrotoxicity

Category	Subgroups	No. of studies	No. of nephrotoxicity patients	No. of patients	Events rate (95%CI)	Model	Heterogeneity (I2)		P value
Overall		83	4027	12234	0.348 (0.308-0.389)	Random		95.90	NA
Severity	Severe nephrotoxicitya	47	648	5163	0.127 (0.103-0.150)	Random		89.60	NA
	Mild nephrotoxicity	49	1378	5163	0.258 (0.216-0.299)	Random		96.80
Continent	Africa	4	53	209	0.215 (0.087-0.343)	Random		82.10	0.394
	Asia	31	1230	3099	0.340 (0.264-0.416)	Random		96.30
	Europe	35	1192	2904	0.364 (0.283-0.446)	Random		97.00
	South America	6	249	628	0.399 (0.295-0.503)	Random		84.60
	North America	6	1283	5213	0.329 (0.200-0.459)	Random		92.40
Polymyxins	Colistin	72	3623	11211	0.355 (0.311-0.398)	Random		96.10	0.151
	Polymyxin B	11	262	903	0.268 (0.171-0.364)	Random		92.20
Loading dose	Loading dose	32	1305	3233	0.391 (0.321-0.461)	Random		95.00	0.051
	No loading dose	48	2333	8340	0.309 (0.260-0.357)	Random		95.20
Maintenance doseb	Higher dose	5	109	281	0.395 (0.302-0.487)	Random		52.00	0.363
	Normal dose	62	2867	9588	0.324 (0.278-0.371)	Random		96.00
Dosing interval	Q12H or BID	32	1494	3200	0.421 (0.356-0.485)	Random		93.40	0.0011
	Q8-6H or TID	21	380	1322	0.251 (0.172-0.330)	Random		93.90
Nephrotoxicity Criteria	RIFLE	38	1667	3985	0.396 (0.339-0.454)	Random		93.80	0.0001
	KDIGO	10	627	1369	0.465 (0.359-0.571)	Random		93.80
	AKIN	8	284	761	0.373 (0.274-0.473)	Random		87.40
	Others	26	1473	6298	0.214 (0.159-0.269)	Random		94.20
Age (yr)c	< 65 yr	59	2450	8980	0.307 (0.263-0.351)	Random		95.10	0.0031
	≥ 65 yr	19	1123	2328	0.451 (0.382-0.520)	Random		91.40
Sex proportion	Males > 50%	60	3064	99908	0.344 (0.297-0.391)	Random		96.10	0.417
	Males ≤ 50%	8	332	757	0.406 (0.243-0.569)	Random		94.50
APACH II score	< 20	23	653	1690	0.305 (0.209-0.401)	Random		95.80	0.115
	≥ 20	29	1053	2601	0.384 (0.307-0.461)	Random		95.00
Publication yr	< 2010	10	42	333	0.138 (0.085-0.192)	Random		44.10	0.0001
	2010-2015	25	612	2099	0.270 (0.205-0.334)	Random		93.10
	2015-2022	48	3386	9875	0.421 (0.365-0.476)	Random		96.70
Study design	Cohort study	72	3685	11491	0.340 (0.296-0.384)	Random		96.50	0.785
	Case-control study	5	185	457	0.410 (0.164-0.656)	Random		96.70
	RCT	8	158	407	0.341 (0.224 - 0.459)	Random		82.70
Study qualityd	Low	11	1402	5715	0.215 (0.130-0.299)	Random		97.30	0.0031
	Fair	50	1912	4925	0.363 (0.314-0.411)	Random		93.70
	High	17	599	1324	0.412 (0.329-0.494)	Random		90.10
Sample size	≤ 50	30	284	1026	0.261 (0.199-0.323)	Random		87.00	0.0001
	50-100	27	657	1965	0.341 (0.260-0.423)	Random		95.40
	> 100	28	3130	9480	0.436 (0.370-0.501)	Random		97.30

¹Significant at P value < 0.05.

^aSevere nephrotoxicity defined as RIFLE grade of ‘failure’ or above, AKIN grade of 3 or KDIGO grade of 3 or required renal replacement therapy.

^bMaintenance dose varied among studies, higher dose as identified as > 9 MIU/d or > 2.5-5.0 mg CBA/kg/d for colistin, or > 2.5-3 mg/kg/d for polymyxin B in this study.

^cAge cut-off value based on the mean or median age of patients included.

^dQuality assessment was applied using Newcastle Ottawa Scale assessment for cohort studies and case control studies. Articles that scored less than 4 were classified as low methodological quality, articles with score between 5 and 7 were classified as fair quality, and those with score more than 8 were classified as high quality.

AKIN: Acute Kidney Injury Network; APACHE II: Acute Physiology and Chronic Health Evaluation II; BID: twice daily; CI: Confidence Interval; KIDGO: Kidney Disease Improving Global Outcomes; RCT: Randomized Controlled Trials; RIFLE: Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease; TID: Three times daily; NA: Not available.

Table 2 Meta-regression analysis for polymyxin-induced nephrotoxicity incidence

Variable	Coefficient	Standard error	Lower 95%CI	Upper 95%CI	P value	R2, %
Univariable analysis
Continent	0.0148	0.0222	-0.0294	0.0590	0.508	-0.64
Polymyxins	-0.0865	0.0597	-0.2052	0.0322	0.151	1.41
Loading dose	-0.0814	0.0412	-0.1634	0.0005	0.051	3.62
Maintenance dosea	-0.0845	0.0928	-0.2703	0.1004	0.363	-0.41
Dosing interval	-0.1704	0.0476	-0.2659	-0.0749	0.0011	20.58
Nephrotoxicity criteria	-0.0577	0.0141	-0.0858	-0.0295	0.0001	18.55
Ageb	-0.1427	0.0470	-0.2362	-0.0492	0.0031	11.08
Gender	0.0627	0.0768	-0.0907	0.2162	0.417	-0.20
APACH II score	0.0812	0.0505	-0.0204	0.1827	0.115	3.52
Publication yr	0.1377	0.0261	0.0857	0.1896	0.0001	26.95
Study design	0.0096	0.0351	-0.0601	0.0794	0.785	-1.15
Study qualityc	0.0966	0.0313	0.0343	0.1590	0.0031	10.66
Sample size	0.0873	0.0220	0.0435	0.1311	0.0001	17.08
Multivariable analysis
Nephrotoxicity criteria	-0.0344	0.0141	-0.0625	-0.0064	0.017	40.00
Publication yr	0.0940	0.0278	0.0386	0.1495	0.001
Sample size	0.0357	0.0203	-0.047	0.0760	0.082
Study qualityc	0.0387	0.0267	-0.0144	0.0919	0.151

¹Significant at P value < 0.05.

^aMaintenance dose varied among studies, higher dose as identified as > 9 MIU/d or > 2.5-5.0 mg CBA/kg/d for colistin, or > 2.5-3 mg/kg/d for polymyxin B in this study.

^bAge was mean or median age of patients included.

^cQuality assessment was applied using Newcastle-Ottawa Scale assessment for cohort studies and case-control studies. Articles that scored less than 4 were classified as low methodological quality, articles with score between 5 and 7 were classified as fair quality, and those with score more than 8 were classified as high quality.

Table 3 Pooled odds ratio estimates for potential predictors of polymyxin-induced nephrotoxicity

Variables	Effect size				Heterogeneity
	OR (95%CI)	Model	Z	P value	I2 (%)	P value
Pooled OR, RR, HR based on univariate analysis
Male gender	1.570 (0.930-2.660)	Fixed	1.67	0.095	0	0.964
Female gender	0.773 (0.418-1.427)	Random	0.82	0.410	65.6	0.033
Age (yr)	1.025 (1.012-1.039)	Random	3.65	0.0001	51.9	0.052
Age (> 61 yr)	2.072 (1.092-3.933)	Fixed	2.23	0.0261	0	0.576
APACHE II score	1.036 (1.002-1.071)	Fixed	2.06	0.0391	14.7	0.319
Sepsisa	2.114 (1.412-3.164)	Fixed	3.64	< 0.0011	45.3	0.139
Baseline eGFR (mL/min/1.73 m2)	0.883 (0.820-0.952)	Fixed	3.26	0.0011	0	0.696
Albumin (hypoalbuminemia)b	2.795 (1.620-4.825)	Fixed	3.69	< 0.0011	0	0.565
Diabetes mellitus	1.229 (0.624-2.421)	Fixed	0.60	0.550	0	0.542
Concomitant diuretics	0.853 (0.252-2.890)	Random	0.26	0.799	77.2	0.004
Concomitant vancomycin	2.110 (1.190-3.730)	Fixed	2.55	0.0111	0	0.667
Concomitant vasopressor	1.496 (1.007-2.222)	Random	2.00	0.0461	72.0	0.013
Daily dose (mg/kg/d)	0.996 (0.991-1.000)	Fixed	1.77	0.077	0	0.523
Duration of therapy (d)	1.019 (0.979-1.061)	Fixed	0.92	0.359	34.5	0.191
Pooled OR, RR, HR based on multivariate analysis
Age (yr)	1.035 (1.021-1.050)	Fixed	4.95	< 0.0011	0	0.863
APACHE II score	1.031 (1.017-1.045)	Fixed	4.36	0.000	26.1	0.255
Concomitant vasopressor	3.099 (1.169-8.219)	Random	2.27	0.0231	80.4	0.002
Concomitant diuretics	2.979 (1.290-6.882)	Fixed	2.56	0.0111	2.6	0.358

¹Significant at P value < 0.05.

^aSepsis or septic shock were pooled.

^bHypoalbuminemia and serum albumin levels < 2 g/dL were pooled.

APACHE II: Acute Physiology and Chronic Health Evaluation II; CI: Confidence interval; eGFR: Estimated glomerular filtration rate; HR: Hazard ratio; OR: Odds ratio; RR: Relative risk.