Incidence, predictors, and survival impact of acute kidney injury in patients with melanoma treated with immune checkpoint inhibitors: a 10-year single-institution analysis

Figures & data

Table 1. Distribution of the patients (N = 1664) by demographic and clinical characteristics and AKI definition

Covariate	Levels	Patient Characteristics		AKI by Definition 1a, n (%)		AKI by Definition 1b, n (%)
		Frequency(n)	Percent ofTotal	Yes	No	Yes	No
Sex	Female	566	34.01	17 (3%)	549 (97%)	25 (4.4%)	541 (95.6%)
	Male	1098	65.99	41 (3.7%)	1057 (96.3%)	47 (4.3%)	1051 (95.7%)
Race/ethnicity	Asian	12	0.72	2 (16.7%)	10 (83.3%)	3 (25%)	9 (75%)
	Black or African American	10	0.60	0 (0%)	10 (100%)	0 (0%)	10 (100%)
	White or Caucasian	1642	98.68	56 (3.4%)	1586 (96.6%)	69 (4.2%)	1573 (95.8%)
Drug	Atezolizumab	22	1.32	0 (0%)	22 (100%)	0 (0%)	22 (100%)
	Ipilimumab	474	28.49	18 (3.8%)	456 (96.2%)	21 (4.4%)	453 (95.6%)
	Ipilimumab/nivolumab	159	9.56	8 (5%)	151 (95%)	10 (6.3%)	149 (93.7%)
	Ipilimumab/pembrolizumab	242	14.54	23 (9.5%)	219 (90.5%)	28 (11.6%)	214 (88.4%)
	Nivolumab	331	19.89	4 (1.2%)	327 (98.8%)	9 (2.7%)	322 (97.3%)
	Pembrolizumab	436	26.20	5 (1.1%)	431 (98.9%)	4 (0.9%)	432 (99.1%)
Coronary artery disease (CAD)	No	1661	99.82	58 (3.5%)	1603 (96.5%)	72 (4.3%)	1589 (95.7%)
	Yes	3	0.18	0 (0%)	3 (100%)	0 (0%)	3 (100%)
Congestive heart failure (CHF)	No	1658	99.64	58 (3.5%)	1600 (96.5%)	72 (4.3%)	1586 (95.7%)
	Yes	6	0.36	0 (0%)	6 (100%)	0 (0%)	6 (100%)
Hypertension	No	1213	72.90	49 (4%)	1164 (96%)	58 (4.8%)	1155 (95.2%)
	Yes	451	27.10	9 (2%)	442 (98%)	14 (3.1%)	437 (96.9%)
Liver disease/cirrhosis	No	1653	99.34	57 (3.4%)	1596 (96.6%)	71 (4.3%)	1582 (95.7%)
	Yes	11	0.66	1 (9.1%)	10 (90.9%)	1 (9.1%)	10 (90.9%)
PVD	No	1658	99.64	58 (3.5%)	1600 (96.5%)	71 (4.3%)	1587 (95.7%)
	Yes	6	0.36	0 (0%)	6 (100%)	1 (16.7%)	5 (83.3%)
NSAIDs	No	1531	93.81	52 (3.3%)	1479 (96.6%)	61 (3.9%)	1470 (96%)
	Yes	101	6.19	6 (5.9%)	95 (94.1%)	11 (10.9%)	90 (89.1%)
No. of PPIs	0	1366	83.70	41 (2.9%)	1350 (97.1%)	50 (3.7%)	1316 (96.3%)
	1	266	16.30	17 (6.4%)	249 (93.6%)	22 (8.3%)	244 (91.7%)
Baseline eGFR	≥60 ml/min/1.73 m^2	1383	84.74	51 (3.7%)	1332 (96.3%)	65 (4.7%)	1318 (95.3%)
	<60 ml/min/1.73 m^2	249	15.26	7 (2.8%)	242 (97.2%)	7 (2.8%)	242 (97.2%)

AKI, acute kidney injury; CAD, coronary artery disease; CHF, congestive heart failure; GFR, glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor; PVD, peripheral vascular disease.

Table 2. Univariable analysis of association between time to first AKI by patient characteristics and ICI regimens

Parameter	Category	AKI Definition 1a				AKI Definition 1b
		Hazard Ratio	95% CI	P-Value for Comparison with Reference	P-Value for Overall Effect	Hazard Ratio	95% CI	P-Value for Comparison with Reference	P-Value for Overall Effect
Drug (ref = ’ pembrolizumab’)	Ipilimumab	3.402	1.260–9.186	0.0157	0.0002	4.932	1.695– 14.346	0.0034	<0.0001
	Ipilimumab/nivolumab	4.713	1.542–14.404	0.0065		7.384	2.328– 23.417	0.0007
	Ipilimumab/pembrolizumab	6.281	2.413–16.349	0.0002		9.559	3.370– 27.112	<.0001
	Nivolumab	1.136	0.306–4.222	0.8491		3.242	1.002– 10.490	0.0496
Age_Years	Per year increase	0.980	0.964–0.997	0.0191	0.0191	0.975	0.960– 0.990	0.0009	0.00009
Age (ref = ’Age≤60)	Age>60 years	0.610	0.364–1.021	0.0601	0.061	0.549	0.346– 0.873	0.0112	0.0112
Gender (ref = ’Male’)	Female	0.775	0.440–1.365	0.3775	0.7787	0.989	0.610– 1.604	0.9651	0.9651
Race(ref = ’White’)	Asian	4.995	1.282–19.463	0.0205	0.0205	5.970	2.164– 16.470	0.0006	0.0006
Hypertension	Yes vs No	0.536	0.264–1.089	0.0847	0.0847	0.711	0.397– 1.276	0.2533	0.2533
Liver Disease	Yes vs No	3.096	0.445–21.555	0.2538	0.2538	2.503	0.355– 17.620	0.3570	0.3570
NSAID use	Yes vs No	1.677	0.719–3.913	0.2313	0.2313	2.730	1.436– 5.194	0.0022	0.0022
PPI use	Yes vs No	2.211	1.249–3.915	0.0065	0.0065	2.359	1.424– 3.905	0.0009	0.0009
Baseline eGFR	<60 ml/min/1.73 m2 vs ≥60 ml/min/1.73 m2	0.727	0.332–1.595	0.4268	0.4268	0.567	0.261–1.230	0.1509	0.1509

Table 3. Multivariable analysis of association of AKI by patient characteristics and ICI regimens

Parameter	Category	AKI Definition 1a				AKI Definition 1b
		HazardRatio	95% ConfidenceInterval		P-value for Comparison with Reference	P-Value for Overall Effect		HazardRatio	95% ConfidenceInterval			P-value for Comparison with Reference	P-Value for Overall Effect
Drug (ref = ’ pembrolizumab’)	Ipilimumab	3.281	1.213	8.873	0.0192	<0.0001		4.096	1.415		11.856	0.0093	<0.0001
	Ipilimumab/nivolumab	3.725	1.144	12.134	0.0291			5.101	1.554		16.745	0.0072
	Ipilimumab/pembrolizumab	6.305	2.436	16.318	0.0001			9.041	3.246		25.177	<0.0001
	Nivolumab	1.022	0.270	3.872	0.9749			2.693	0.824		8.806	0.1012
Age	Per year increase							0.981	0.966		0.996	0.0152	0.0152
Race (ref = ’White’)	Asian	4.182	1.090	16.043	0.0370	0.0370		4.387	1.519		12.664	0.0063	0.0063
PPI	Yes vs No	2.387	1.328	4.291	0.0036	0.0036	2.355		1.393	3.983		0.0014	0.0014

Figure 1. Cumulative incidence plots of AKI (Definition 1a: (≥0.3 mg/dl increase in creatinine over 48 hours). (a) Whole cohort. (b) Subgroups by type of ICI

Figure 2. Cumulative incidence plots of AKI (Definition 1b: (≥50% increase in creatinine over 7 days). (a) Whole cohort. (b) Subgroups by type of ICI

Table 4. Association of AKI with OS adjusting for the other covariates in a joint model

Parameter	Category	AKI Definition 1a						AKI Definition 1b
		Post Mean	Std Dev	Std Err	2.50%	97.50%	P-Value	Post Mean	Std Dev	Std Err	2.50%	97.50%	P-Value
Age in Yrs	Per year increase	−0.0046	0.0032	0.0001	−0.0116	0.0010	0.126	−0.0044	0.0031	0.0001	−0.0108	0.0014	0.138
Gender	Male vs Female	0.0156	0.0853	0.0025	−0.1579	0.1858	0.874	0.014	0.0824	0.0023	−0.1488	0.1847	0.848
Race (ref = ’Other’)	Black or African American	−0.2667	0.647	0.0177	−1.6108	0.9449	0.692	−0.3274	0.6727	0.0194	−1.7553	0.9434	0.628
	White or Caucasian	−0.4191	0.3824	0.0139	−1.0866	0.4315	0.282	−0.4567	0.3816	0.0161	−1.1265	0.3686	0.244
Drug (ref = ’atezolizumab’)	Ipilimumab	−0.1381	0.4167	0.0133	−0.873	0.7266	0.734	−0.1451	0.4096	0.016	−0.8678	0.7216	0.674
	Ipilimumab/nivolumab	−0.3717	0.4245	0.0179	−1.134	0.4830	0.412	−0.3924	0.4129	0.0149	−1.1317	0.4698	0.344
	Ipilimumab/pembrolizumab	−0.8383	0.4202	0.018	−1.6116	0.0390	0.06	−0.863	0.4151	0.017	−1.6253	0.0442	0.058
	Nivolumab	−0.4012	0.4296	0.0198	−1.2162	0.4397	0.36	−0.4133	0.4118	0.0138	−1.1481	0.4340	0.322
	Pembrolizumab	−0.404	0.4199	0.0153	−1.1568	0.4515	0.352	−0.4226	0.4046	0.0148	−1.1122	0.4361	0.322
PPI (ref = ’No’)	Yes	0.8643	0.1083	0.0017	0.6704	1.0846	<0.0001	0.8716	0.1071	0.0036	0.6672	1.0842	<0.0001
AKI	Per unit increase	−0.0595	0.0435	0.0065	−0.1526	0.0184	0.14	−0.1067	0.0839	0.0196	−0.3079	0.0233	0.12

Figure 3. Kaplan-Meier curves for overall survival by AKI status within 6 months after initiation of ICI therapy. (a) Definition 1a of AKI. (b) Definition 1b of AKI