Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report

Abstract

BackgroundAcute tubulointerstitial nephritis (ATIN) has been increasingly recognized as an important manifestation of kidney injury associated with the use of immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). While the exact pathophysiology remains unknown, corticosteroids are the mainstay of management.Case presentationWe describe a 67-year-old man with stage IV non-small-cell lung cancer who developed kidney injury during treatment with the anti-PD-1 antibody nivolumab. A kidney biopsy showed ATIN without granuloma formation. Considering their mechanism of action, immune checkpoint inhibitors can alter immunological tolerance to concomitant drugs that have been safely used for a long time. For more than 4 years before the initiation of nivolumab therapy, the patient had been receiving the proton pump inhibitor lansoprazole, known to cause drug-induced ATIN, without significant adverse events including kidney injury. He showed rapid improvement in kidney function in 3 days (creatinine decreased from 2.74 to 1.82 mg/dl) on discontinuation of lansoprazole. He then received 500 mg intravenous methylprednisolone for 3 days followed by 1 mg/kg/day oral prednisolone and his creatinine levels eventually stabilized around 1.7 mg/dl. Drug-induced lymphocyte stimulation test (DLST) for lansoprazole was positive.ConclusionsThe rapid improvement of kidney function after discontinuation and DLST positivity indicate that lansoprazole contributed to the development of ATIN during nivolumab therapy. Considering the time course, it is plausible that nivolumab altered the long-lasting immunological tolerance against lansoprazole in this patient. To the best of our knowledge, this is the first case report of DLST positivity for a drug that had been used safely before the initiation of an immune checkpoint inhibitor. Although corticosteroid therapy is recommended, the recognition and discontinuation of concomitant drugs, especially those known to induce ATIN, is necessary for the management of kidney injury associated with anti-PD-1 therapy.

Nivolumab‐induced severe acute kidney injury with a long latent phase in a patient with non‐small‐cell lung cancer: A case report

“…One case was managed with PPI discontinuation only, without administration of corticosteroid, and nivolumab was continued for 8 months after discontinuation of PPI, indicating that PPI was the key drug causing AIN in this case. In a case report, lansoprazole‐induced AIN after administration of nivolumab and drug‐induced lymphocyte stimulation test for lansoprazole was proven to be positive 6. In our case, however, no culprit medication associated with AIN was administered, indicating that an endogenous antigen attacked the kidney.…”

Rapidly Progressive Acute Kidney Injury Associated with Nivolumab Treatment

“…The authors of that case also described the importance of recognizing concomitant medications causing AKI associated with PD-1 blockade by ICIs. In that case, the blockade of the intrinsic PD-1 signaling pathway by anti-PD-1 therapy possibly disrupted the patients' long-standing immunological tolerance against lansoprazole by modulating T-cell immunoreactivity [15]. Therefore, we should also consider the possibility of PPI-induced AKI triggered by nivolumab in our patient.…”

Nephrotoxicity in patients receiving immune checkpoint inhibitors

“…Renal biopsies show tubulointerstitial infiltrates and edema, with a predominance of CD3+ mononuclear T cells. Granulomas and eosinophils may be present, although they are neither sensitive nor specific for ICPI--associated ATIN 29,30,[32][33][34] . Cassol et al have identified a particular immunohistochemistry staining pattern for PD -L1 in inflammatory and tubular epithelial cells that seems to be only found in ICPI -induced ATIN 27 .…”

“…nonsteroidal anti -inflammatory drugs or proton pump inhibitors), could cause ATIN. The case presented by Koda et al is a good illustration, with a positive drug -induced lymphocyte stimulation test for lansoprazole alerting for the importance of recognizing medications known to cause ATIN 29 .…”