Acute kidney injury in patients treated with immune checkpoint inhibitors

Abstract

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.

Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.

Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.

Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Keywords: CTLA-4 antigen; immunotherapy; programmed cell death 1 receptor.

Figure 1

Risk factors for ICPi-AKI. Total n=856, of whom 429 had ICPi-AKI and 427 did not have ICPi-AKI. All model covariates are shown in the figure. *Denotes PPI use in the 14 days preceding ICPi-AKI among those with ICPi-AKI, and PPI use at the time of ICPi initiation among patients without ICPi-AKI. **Extrarenal irAEs were assessed prior to (>14 days) or concomitant (within 14 days before or after) with ICPi-AKI diagnosis among patients with ICPi-AKI, and at any time after ICPi initiation among patients without ICPi-AKI. eGFR, estimated glomerular filtration rate; ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; PPI, proton pump inhibitor.

Figure 2

Clinical features of ICPi-AKI. (A) The number of weeks between ICPi initiation and ICPi-AKI diagnosis. (B) The number of weeks between the last ICPi cycle and ICPi-AKI diagnosis. (C) Distribution of AKI severity. (D) Serum creatinine trend (median, IQR). (E) Frequency of extrarenal irAEs occurring before (>14 days) or concomitant (within 14 days before or after) with ICPi-AKI diagnosis. Other irAEs include hypophysitis (0.7% prior, 1.4% concomitantly), adrenalitis (0.2% prior, 1.4% concomitantly), type 1 diabetes mellitus (0% prior, 0.5% concomitantly), and myocarditis (1.2% prior, 0.2% concomitantly). (F) Distribution of pathologies among the 151 patients who underwent biopsy. Other includes 2 patients with FSGS and one patient with each of the following: reactive amyloidosis, AA amyloidosis, focal proliferative glomerulonephritis with C3 deposits, immune complex deposition disease not otherwise specified, mesangial proliferative immune complex mediated glomerulonephritis, pauci-immune glomerulonephritis, minimal change disease and thrombotic microangiopathy. (G) Frequency of potential ATIN-causing medications taken within 14 days before ICPi-AKI diagnosis. (H) Frequency of blood on UA at the time of ICPi-AKI. (I) Frequency of leukocyte esterase on UA at the time of ICPi-AKI. (J) Frequency of pyuria on UA at the time of ICPi-AKI. (K) Frequency of proteinuria at the time of ICPi-AKI. (L) Frequency of eosinophilia at the time of ICPi-AKI. AKI, acute kidney injury; ATIN, acute tubulointerstitial nephritis; ATN, acute tubular necrosis; FSGS, focal segmental glomerulosclerosis; HPF, high-power field; ICPi, immune checkpoint inhibitor; MN, membranous nephropathy; UA, urinalysis; UPCR, urine protein-to-creatinine ratio; WBCs, white blood cells.

Figure 2

Clinical features of ICPi-AKI. (A) The number of weeks between ICPi initiation and ICPi-AKI diagnosis. (B) The number of weeks between the last ICPi cycle and ICPi-AKI diagnosis. (C) Distribution of AKI severity. (D) Serum creatinine trend (median, IQR). (E) Frequency of extrarenal irAEs occurring before (>14 days) or concomitant (within 14 days before or after) with ICPi-AKI diagnosis. Other irAEs include hypophysitis (0.7% prior, 1.4% concomitantly), adrenalitis (0.2% prior, 1.4% concomitantly), type 1 diabetes mellitus (0% prior, 0.5% concomitantly), and myocarditis (1.2% prior, 0.2% concomitantly). (F) Distribution of pathologies among the 151 patients who underwent biopsy. Other includes 2 patients with FSGS and one patient with each of the following: reactive amyloidosis, AA amyloidosis, focal proliferative glomerulonephritis with C3 deposits, immune complex deposition disease not otherwise specified, mesangial proliferative immune complex mediated glomerulonephritis, pauci-immune glomerulonephritis, minimal change disease and thrombotic microangiopathy. (G) Frequency of potential ATIN-causing medications taken within 14 days before ICPi-AKI diagnosis. (H) Frequency of blood on UA at the time of ICPi-AKI. (I) Frequency of leukocyte esterase on UA at the time of ICPi-AKI. (J) Frequency of pyuria on UA at the time of ICPi-AKI. (K) Frequency of proteinuria at the time of ICPi-AKI. (L) Frequency of eosinophilia at the time of ICPi-AKI. AKI, acute kidney injury; ATIN, acute tubulointerstitial nephritis; ATN, acute tubular necrosis; FSGS, focal segmental glomerulosclerosis; HPF, high-power field; ICPi, immune checkpoint inhibitor; MN, membranous nephropathy; UA, urinalysis; UPCR, urine protein-to-creatinine ratio; WBCs, white blood cells.

Figure 3

Treatment of ICPi-AKI. (A) Frequency of treatment with oral or intravenous corticosteroids by stage of initial ICPi-AKI. (B) Frequency of treatment with intravenous pulse dose corticosteroids by stage of initial ICPi-AKI. (C) Distribution of days between ICPi-AKI diagnosis and initiation of corticosteroids. (D) Distribution of initial corticosteroid dose (in prednisone equivalent units [mg]). AKI, acute kidney injury; ICPi, immune checkpoint inhibitor.

Figure 4

Characteristics of renal recovery among patients with ICPi-AKI. (A) Renal recovery overall and according to initial ICPi-AKI stage. (B) Time (in weeks) from ICPi-AKI diagnosis to renal recovery. (C) Predictors of renal recovery (total n=405, of whom 270 (66.7%) had renal recovery and 135 (33.3%) did not). Renal recovery was defined as a return of serum creatinine to ≤50% of the baseline value within 90 days of ICPi-AKI. Patients who died within 14 days of ICPi-AKI (n=24) were excluded. All model covariates are shown in the figure. *Denotes receipt of NSAIDs, PPIs, or antibiotics in the 14 days preceding ICPi-AKI. **Extrarenal irAEs were assessed concomitantly (within 14 days before or after) with ICPi-AKI diagnosis. ***Refers to oral or intravenous corticosteroids initiated within 14 days following ICPi-AKI. AKI, acute kidney injury; ATIN, acute tubulointerstitial nephritis; eGFR, estimated glomerular filtration rate; ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitor; UPCR, urine protein-to-creatinine ratio.

Figure 5

Risk factors for death in patients with ICPi-AKI. (A) Survival among patients with stages 1 and 2 ICPi-AKI versus stage 3. (B) Multivariable Cox regression model showing predictors of death among patients with ICPi-AKI (total n=405, of whom 144 (35.6% (died)). Patients who died within 14 days of ICPi-AKI (n=24) were excluded. All model covariates are shown in the figure. *Denotes receipt of NSAIDs, PPIs, or antibiotics in the 14 days preceding ICPi-AKI. **Extrarenal irAEs were assessed prior to (>14 days) or concomitant (within 14 days before or after) with ICPi-AKI. ***Refers to oral or intravenous corticosteroids initiated within 14 days following ICPi-AKI. AKI, acute kidney injury; ATIN, acute tubulointerstitial nephritis; eGFR, estimated glomerular filtration rate; ICPi, immune checkpoint inhibitor; irAEs, immune-related adverse events; NSAIDs, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitor.