Immune checkpoint inhibitor-related acute kidney injury: A diagnostic and therapeutic challenge for nephrologists

Table 1 Reported risk factors for immune checkpoint inhibitor-related acute kidney injury

Risk factor	Details/evidence
Type of immunotherapy	Highest incidence with anti-CTLA-4 followed by anti-PD-1 and anti-PD-L1[12-14]
Combination therapy	Increased risk with anti-CTLA-4 and anti-PD-1/anti-PD-L1 combination, however not confirmed in meta-analysis[13-15]
Extrarenal irAEs	Prevalence 62-87% in ICI-related AKI, and most precede the development of AKI[3,11,13,16]; Common: Colitis, thyroiditis, hypophysitis; Others: Dermatitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies
Concomitant drugs	NSAIDs, PPIs, various antibiotics, fluindione, ACEIs and diuretics have been shown to increase risk[2,3,13,17]
Pre-existing conditions/factors	CKD and diabetes[2,17]. Older age, male sex, and gynaecological/genitourinary malignancies suggestive but not confirmed in meta-analysis[1,17-20]

CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; PD-1: Programmed cell death receptor 1; PD-L: Programmed cell death ligand 1; irAE: Immune-related adverse event; ICI: Immune checkpoint inhibitor; AKI: Acute kidney injury; NSAID: Non-steroidal anti-inflammatory drug; PPI: Proton pump inhibitor; ACEI: Angiotensin-converting enzyme inhibitor; CKD: Chronic kidney disease.

Table 2 Summary of key trials examining immune checkpoint inhibitor-related acute kidney injury in the last five years

Ref.	Study details and key findings
Seethapathy et al[3], 2019	Of 1016 patients who received ICIs treatment were included. AKI was defined using the KDIGO criterion of at least 1.5 times rise in SCr from the baseline within 12 months. Overall, 17% of patients developed AKI from all causes. Only 3% patients had ICI-related AKI
Cortazar et al[13], 2020	Of 138 patients with ICI-related AKI vs 276 patients on ICI treatment without AKI were included. AKI was defined as a 2-fold increase in SCr from the baseline or new dialysis requirement directly attributed to ICIs. Lower baseline eGFR, PPI use, and combination ICI treatment were independent risk factors for ICI-related AKI. An extrarenal irAE occurred in 43% of patients, and 69% received a concomitant potential ATIN-causing medication. ATIN was the pathology in 90% of the patients who underwent a kidney biopsy, 86% of patients were treated with steroids, 40% had complete and 45% had incomplete renal recovery. Non-recovery of renal function was associated with higher mortality, 22% were rechallenged with ICIs, out of which 23% developed recurrent AKI
Gupta et al[20], 2021	Of 429 patients with ICI-related AKI vs 429 patients without ICI-related AKI. AKI was defined as a 50% increase in SCr from baseline, with one other criterion, including ATIN on kidney biopsy, withholding of ICI treatment with corticosteroids due to suspected ICI-related AKI, or a 100% increase in SCr from baseline with RRT. Lower baseline eGFR, PPI use, and extrarenal irAEs were associated with a higher risk of ICI-related AKI. ATIN was the commonest pathology found in 82.7% of patients who underwent biopsy. Renal recovery occurred in 64.3% of patients at a median of 7 weeks. Initiation of corticosteroids within 3 days of ICI-related AKI was associated with a higher odd of renal recovery. Only 16.5% of patients rechallenged with ICIs developed recurrent ICI-related AKI
Koks et al[18], 2021	Of 676 patients receiving ICIs were included. AKI was defined using the KDIGO criterion of at least 1.5 times rise in SCr from the baseline. The overall incidence of AKI was 14.2%. ICI-related AKI occurred in only one-third of the patients who developed AKI
Isik et al[22], 2021	Of 37 patients with ICI-related AKI compared to 13 non-ICI-related AKI. At the time of AKI, SCr, CRP, and uRBP/Cr were significantly higher in the ICI-related AKI group. Among the ICI-related AKI patients, complete renal recovery occurred in 39% of patients by the third month, 43% were rechallenged with ICIs, out of which 19% developed recurrent AKI
Sise et al[23], 2023	In comparison to ICI-treated controls without immune-related irAEs, patients not receiving ICIs with hemodynamic AKI, and patients not on ICIs with biopsy-proven ATIN from other causes, individuals with ICI-related AKI exhibited significantly elevated peripheral blood sIL-2R levels. An sIL-2R threshold of 1.75-fold above the upper limit of normal was highly indicative of ICI-nephritis. Key immunological findings in ICI-related AKI included decreased absolute counts of CD8+ T cells, CD45RA+ CD8+ T cells, and memory CD27+ B cells, along with increased plasmablast expansion. Additionally, renal tissues from patients with ICI-related AKI demonstrated markedly higher gene expression of IL2RA, IL-2 signalling pathways, and T cell receptor signalling compared to control groups
Farooqui et al[25], 2023	Of 14 patients with ICI-related AKI were compared to 10 patients with AKI due to other causes. An increase in specific immune cell population, including CD4 memory cells, T helper cells, and dendritic cells, was observed in kidney tissue, along with elevated urinary cytokines IL-2, IL-10, and TNF-α, in patients who developed ICI-related AKI. The ability of TNF-α to discriminate between causes of AKI was notably robust
Awiwi et al[26], 2023	A total of 34 patients with ICI-related AKI were included in the study. Compared to baseline measurements, total kidney volume assessed via CT scans was significantly increased at the onset of nephritis. On PET-CT imaging, the renal parenchymal SUVmax-to-blood pool ratio was markedly elevated during nephritis relative to baseline, whereas the renal pelvis SUVmax-to-blood pool SUVmean ratio was notably decreased at nephritis compared to baseline
Zhou et al[21], 2024	Of 904 patients who received ICIs were analysed. AKI was defined as a rise of SCr by 1.5-fold or ≥ 26.5 μmol/L from the baseline. Incidence of ICI-related AKI was 5.1%. A lower baseline eGFR and use of antibiotics and diuretics were associated with higher risk of ICI-related AKI, 43% had complete recovery and 3% had partial recovery. Recurrent AKI occurred in only one out of 14 patients who were rechallenged with ICIs

ICI: Immune checkpoint inhibitor; AKI: Acute kidney injury; KDIGO: Kidney Disease Improving Global Outcomes; SCr: Serum creatinine; eGFR: Estimated glomerular filtration rate; PPI: Proton pump inhibitor; CRP: C-reactive protein; uRBP/Cr: Urine retinol binding protein to urine creatinine ratio; irAE: Immune-related adverse event; ATIN: Acute tubulointerstitial nephritis; RRT: Renal replacement therapy; sIL-2R: Soluble interleukin-2 receptor; IL2RA: Interleukin-2 receptor; IL: Interleukin; TNF-α: Tumour necrosis factor alpha; CT: Computed tomography; PET: Positron emission tomography; SUV: Standardised uptake value.

Table 3 Histopathological causes of biopsy proven immune check point inhibitor-related acute kidney injury

Histopathology	Frequency
Acute tubulointerstitial nephritis
Gupta et al[20] (n = 429)	82.7%
Cortazar et al[13] (n = 60)	93.3%
Glomerular diseases
Kitchlu et al[10] (n = 45)
Pauci-immune glomerulonephritis	26.7%
Minimal change disease (with acute tubular injury)	20.0%
C3 glomerulonephritis	11.1%
Immunoglobulin A nephropathy	8.9%
Amyloid A amyloidosis	8.9%
Anti-glomerular basement membrane disease	6.7%
Thrombotic microangiopathy	4.4%
Immune-complex glomerulonephritis	4.4%
Focal segmental glomerulosclerosis	4.4%
Lupus-like nephritis	2.2%
Membranous nephropathy	2.2%

Acute tubular nephritis is the commonest underlying cause of immune checkpoint inhibitor-related acute kidney injury. Glomerular diseases occur in less than 20% of cases. Among glomerular diseases, pauci-immune glomerulonephritis, minimal change disease, and C3 glomerulonephritis are the commonest aetiologies.

Table 4 Biomarkers for immune checkpoint inhibitor-related acute kidney injury

Biomarker	Sample type	Evidence/findings
C-reactive protein	Biochemistry	Elevated in ICI-AKI vs non-ICI-AKI[22]
Urine retinol binding protein to urine creatinine ratio	Urine	Elevated in ICI-AKI vs non-ICI-AKI[22]
Soluble interleukin-2 receptor	Biochemistry	1.75 × ULN cut-off: 81% sensitivity, 100% specificity for ICI-AITN (n = 24) vs ICI-treated (n = 10) and haemodynamic AKI (n = 6) controls[23]
CD8+ T lymphocytes	Flow cytometry	Lower counts in ICI-related ATIN[23]
CD45RA+CD8+ T lymphocytes	Flow cytometry	Lower counts in ICI-related ATIN[23]
Memory CD27+ B lymphocytes	Flow cytometry	Lower counts in ICI-related ATIN[23]
Plasmablasts	Flow cytometry	Expansion associated with ICI-related ATIN[23]
TNF-α	Urine	Strong predictor of ATIN[24] Elevated in ICI-AKI vs non-ICI-AKI[25]
IL-9	Urine	Elevated in ICI-AKI vs other AKI[24]
IL-2, IL-10	Urine	Elevated in ICI-AKI vs non-ICI-AKI[25]

All biomarkers are nonspecific and not diagnostic; validation in larger studies is required before routine clinical use. ICI: Immune checkpoint inhibitor; AKI: Acute kidney injury; ULN: Upper limit of normal; ATIN: Acute tubulointerstitial nephritis; TNF-α: Tumour necrosis factor alpha; IL: Interleukin.

Table 5 Recommendations for kidney biopsy and treatment of immune checkpoint inhibitor-related acute tubulointerstitial nephritis

Society/guideline	Biopsy recommendation	Treatment recommendation
American Society of Clinical Oncology, 2022[28]	Biopsy only if AKI is refractory to steroids or immunosuppression	Empiric treatment with steroids is reasonable if no alternate cause for AKI is identified
European Society of Medical Oncology, 2022[29]	Case-by-case decision after oncologist-nephrologist discussion	Empiric treatment with steroids is reasonable if no alternate cause for AKI is identified
National Comprehensive Cancer Network, 2019[30]	Consider biopsy for severe AKI (grade ≥ 3): Creatinine > 3 × baseline or > 4 mg/dL (353.68 μmol/L)	Nephrology consults for moderate AKI (grade 2): Creatinine > 2 × baseline
American Society of Onco-Nephrology, 2025[1]	Strongly recommends kidney biopsy for all KDIGO stage 2-3 AKI, unless absolute contraindication or clear alternate cause identified	Empiric steroids treatment is reasonable if biopsy is unavailable or contraindicated, and there is a high clinical suspicion of ICI-related ATIN to avoid > 3-day delay in starting treatment

AKI: Acute kidney injury; KDIGO: Kidney Disease Improving Global Outcomes; ICI: Immune checkpoint inhibitor; ATIN: Acute tubulointerstitial nephritis.