Renal Immune-Related Adverse Event Difficult to Diagnose during Nivolumab Treatment for Hypopharyngeal Carcinoma: Case Report

Nivolumab is an anti-programmed cell death 1 (PD-1) antibody approved for the treatment of recurrent and metastatic squamous cell carcinomas of the head and neck that prove refractory to platinum agents, and are considered Category 1 under the 2024 National Comprehensive Cancer Network guidelines [1]. The Checkmate 141 trial reported a significantly longer median overall survival of 7.5 months in the nivolumab group compared to the standard treatment group, along with a significantly lower incidence of grade 3 or higher adverse events [2]. Immune checkpoint inhibitors (ICIs), including nivolumab, can cause immune-related adverse events (irAEs) in various organs, most commonly as skin symptoms, interstitial pneumonia, and endocrine disorders. Although the extent varies from report to report, an association between the occurrence of irAEs and patient prognosis has been described [3]. IrAEs can also appear as renal dysfunction, with a reported frequency of 2.2–3.0% [4, 5]. We encountered a case in which renal failure was difficult to diagnose due to the mildness of the renal dysfunction. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540373).

A 64-year-old man was treated for right hypopharyngeal squamous cell carcinoma (cT4aN3bM0, stage IVB) with pharyngolaryngectomy, bilateral neck dissection, and pharyngeal reconstruction with free jejunum. Histopathological examination of resected specimens showed extranodal invasion and the patient was considered at high risk of recurrence. Radiation therapy (60 Gy in 30 fractions) with cisplatin (80 mg/m² every 3 weeks) was administered as postoperative adjuvant therapy. Multiple lung metastases were identified 3 months after the last dose of cisplatin (Fig. 1), so we considered the cancer as refractory to platinum agents and started nivolumab (240 mg every 2 weeks). At the time nivolumab was initiated, the patient was taking lansoprazole, which was switched to esomeprazole during treatment. Following the administration of nivolumab, the lung metastases were seen to be shrinking and no adverse events were identified until day 203 of treatment. At this point, laboratory abnormalities such as an increase in C-reactive protein (CRP) to 16.3 mg/dL and urinary leukocytes 3+ were identified, and nivolumab was therefore discontinued. Considering the possibility of urinary tract infection, clarithromycin was started, but CRP level continued to increase and urinary nitrite tests from 203 to 271 and urine cultures performed on days 215 and 262 yielded negative results. At the time of nivolumab discontinuation, tubular markers were mildly elevated, with urinary β2-microglobulin (β2MG) at 845 μg/L and urinary N-acetylglucosaminidase (NAG) at 16.4 IU/L. However, serum creatinine was only slightly elevated, at 1.3 mg/dL, and we considered the possibility of renal irAEs unlikely.

The general condition of the patient continued to deteriorate and he was urgently admitted to the hospital on day 260. On admission, symptoms included anorexia and arthralgia in both elbows and knees. Blood and urine cultures were negative and the computed tomography revealed no heat source. After discontinuing nivolumab, urinary leukocytes were negative, but tubular markers elevated further (urinary β2MG: 8,742 μg/L; urinary NAG: 30.1 IU/L). However, because of the lack of creatinine elevation, irAE was not diagnosed and steroids were not considered to be indicated. Gallium scintigraphy was performed to search for the cause of inflammation, revealing multiple accumulations in joints, particularly in the large joints (Fig. 2). Ultrasonography of the knee joints showed thickening of the synovial membrane and increased blood flow, and negative results for various collagen markers led to the diagnosis of irAE arthritis. Treatment was initiated with 20 mg of prednisolone (PSL) and arthralgia improved, unexpectedly, tubular markers also improved markedly after PSL administration (Table 1). An outline of the case is shown in Figure 3.

The dose of PSL could not subsequently be tapered due to arthritic symptoms, and nivolumab could not be resumed. However, lung metastases have shown no further growth since the discontinuation of nivolumab (Fig. 4).

In this case, the lack of any clear elevation in creatinine levels made renal irAEs difficult to diagnose. However, the presence of renal irAEs was suggested based on the prolonged elevations of urinary leukocytes and tubular markers and the improvement of these abnormalities once nivolumab was discontinued and a steroid was administered. This case shows the possibility of renal irAEs manifesting as aseptic pyuria or elevated tubular markers in the absence of elevated serum creatinine levels.

When programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2) bind to PD-1 expressed on T cells, T-cell activity is suppressed [6]. Accordingly, the binding of PD-L1 expressed in tumor cells to PD-1 is involved in allowing the tumor to evade immune responses. Nivolumab, as an anti-PD-1 antibody, inhibits tumor growth by inhibiting this signaling pathway [2, 7]. PD-L1 expression is seen in 50–60% of head and neck squamous cell carcinomas and the Checkmate 141 trial demonstrated the efficacy of nivolumab against recurrent metastatic squamous cell carcinoma of the head and neck [2, 8].

ICIs, including nivolumab, are known to cause irAEs in various organs, with kidney damage reported at a frequency of around 3% [4, 5]. Risk factors for renal irAEs include concomitant use of proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs, pre-existing renal insufficiency, and the development of extrarenal irAEs [5, 9‒11]. The patient in this case was taking the PPIs lansoprazole and esomeprazole and showed complications of arthritis as an irAE. The clinical features of renal irAE are a high frequency of leukocyturia [9]. In addition, CRP has been reported to be more elevated in ICI-associated renal injury compared to non-ICI-associated renal injury [12]. The present case also showed marked leukocyturia and elevated CRP. Although pyuria is a finding most typically seen with urinary tract infections, cultures and urinalysis during the disease course failed confirm the presence of any bacteria in the urine.

The most common renal irAE is acute tubulointerstitial nephritis [4, 9], but cases with complications of glomerular disease have been reported [13]. In addition to tubular damage, irAEs may be associated with glomerular disease, which may lead to diverse clinical presentations. This case exhibited abnormally high levels of NAG and β2MG, which are elevated in proximal tubular disorders, and also had a marked increase in urinary leukocytes. However, as there was no obvious increase in creatinine, it was difficult to make a diagnosis. Therefore, it is possible that this was not a typical case of acute tubulointerstitial nephritis. Although elevated creatinine represents an important finding in the diagnosis of renal injury as an irAE, renal injury may be present as a latent irAE, as in this case.

As a limitation, no biopsy was performed in this case and a definitive diagnosis of nephritis was not made. According to the American Society of Clinical Oncology guidelines, renal biopsy is used for the diagnosis of renal irAE, but the invasiveness of this procedure means that biopsy is not recommended unless the condition is refractory to treatment, and PSL administration is indicated when serum creatinine is at least twice the baseline level [14]. Laboratory findings in this case improved with the administration of PSL for arthritis as an irAE. Referring the patient to a nephrologist and initiating treatment should be considered if abnormal urinary findings are identified. In our case, various culture tests were negative, and no medications that could potentially cause tubular damage, other than PPIs, were being administered. We also considered the possibility of an autoimmune disease, such as sarcoidosis. However, apart from joint and kidney symptoms, there were no other relevant findings. Based on these observations, we considered the possibility of renal injury as an irAE. However, a histological diagnosis would have allowed for a more accurate diagnosis and earlier treatment. In any case, communication between nephrologists and otorhinolaryngologists is important.

Renal irAE is a relatively infrequent adverse event of ICIs. In this study, a renal irAE was difficult to diagnose because of the mildness of the renal impairment. When leukocyturia is prominent despite an absence of clearly elevated creatinine, close examination should be performed with the possibility of renal irAE kept in mind.

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors declare that there are no conflicts of interest regarding the publication of this article.

This study was not supported by any sponsor or funder.

Sorane Maezumi contributed to the writing, review, and submission of the manuscript to the journal. Takuro Okada provided critique and feedback on the manuscript. Takuma Kishida was involved in the management of the patient. Yasuo Ogawa and Kiyoaki Tsukahara supervised all phases of writing.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.