The biomarkers serum C-reactive protein (CRP) and urine retinol-binding protein to urine creatinine ratio (uRBP/Cr) may help to differentiate acute kidney injury (AKI) due to immune checkpoint inhibitors (ICI) from AKI due to other nonsecondary causes, according to investigators.

“Immune checkpoint inhibitors have improved the prognosis for patients with a wide range of malignancies including melanoma, non-small cell lung cancer, and renal cancer,” Sandra Herrmann, MD, from the Mayo Clinic in Rochester, Minnesota, stated in a Mayo Clinic news release. “In some patients, this enhanced immune response may target kidney tissue, leading to acute kidney inflammation known as interstitial nephritis.”

Dr Herrmann’s team retrospectively compared test results from 37 patients with ICI-AKI and 13 patients with AKI due to causes other than ICIs. Patients were considered to have ICI-AKI if kidney biopsy confirmed acute interstitial nephritis or kidney function improved with steroids or worsened without steroids. Patients were considered to have AKI not related to ICIs if biopsy results indicated alternative causes or patients did not receive steroids and successfully resumed ICI therapy.

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At the time of the AKI event (defined as a 50% or greater increase in serum creatinine), median serum creatinine (2.0 vs 1.5 mg/dL), CRP (54.0 vs 3.5 mg/L), and uRBP/Cr (1927 vs 233 mcg/g Cr) were all significantly higher in the ICI-AKI group compared with the reference group, Dr Herrmann and colleagues reported in Kidney International Reports. Retinol-binding protein is a low-molecular-weight protein that is reabsorbed by renal proximal tubule cells where it is normally catabolized. When urinary retinol-binding protein levels are elevated, it possibly indicates proximal tubular dysfunction due to interstitial inflammation, the study authors explained.

“These biomarkers could assist with helping doctors discriminate treatment-associated kidney injury from other causes and may also help aid clinical decision-making related to whether immune checkpoint inhibitor therapy should be continued if the injury found is not related to immunotherapy,” Dr Herrmann stated. 

The biomarker findings may be of particular value when ICIs are used in association with other potentially nephrotoxic cancer agents or when a kidney biopsy cannot be obtained, she and her colleagues noted in their paper.

Patients with ICI-AKI experienced significantly more severe AKI than those with non-ICI-AKI (43.2% vs 7.7% for stage 2 and 32.4% vs 7.7% for stage 3, respectively). AKI also developed significantly faster among patients with ICI-AKI than without (median 4 vs 8.5 months, respectively). Among biopsied patients, acute interstitial nephritis was the predominant acute lesion found in ICI-AKI, whereas acute tubular injury was predominant in non-ICI-AKI. The ICI-AKI group had a significantly higher protein-to-creatinine ratio (median 0.8 vs 0.3), white blood cell count in blood tests (median WBC 8.3 vs 6.0), and red blood cell count in urine tests (1-3 RBCs in 37.5% vs 0% and 4-10 RBCs in 9.4% vs 8.3%), respectively.

Patients with ICI-AKI were significantly more likely to be taking proton pump inhibitors (67.6% vs 23.1%), so any patient taking these drugs should be monitored closely, according to the investigators.

In the ICI-AKI group, complete renal recovery occurred in 39% of patients by 3 months, and ICI rechallenge occurred in 16 (43%) patients, of whom 3 (19%) experienced AKI recurrence with no recovery.

ICIs include CTLA-4 inhibitors (ipilimumab), PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), and PD-L1 antibodies (atezolizumab, avelumab, and durvalumab).

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Isik B, Alexander MP, Manohar S, et al. Biomarkers, clinical features and rechallenge for immune checkpoint inhibitor renal immune-related adverse events. Published online February 1, 2021. Kidney Int Rep. doi:10.1016/j.ekir.2021.01.013

Dangor J. Study examines role of biomarkers to evaluate kidney injury in cancer patients undergoing immunotherapy [news release]. Mayo Clinic; February 3, 2021.