Commentary
Article
Immune Checkpoint Inhibitor-Associated Nephritis: A Case of Nivolumab-Induced Acute Kidney Injury in a Patient with Urothelial Carcinoma
This case highlights the importance of recognizing ICPI-AKI, implementing effective therapeutic interventions, and understanding the clinical context to prevent irreversible renal damage.
Introduction
Immune checkpoint inhibitors (ICPIs) have transformed the landscape of cancer therapy by harnessing the power of the immune system to target and eradicate tumors.1 These monoclonal antibodies enhance T-cell immune responses by blocking key inhibitory checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand PD-L1, thereby reversing T-cell suppression and promoting tumor regression, ultimately improving cancer outcomes.1 Since their introduction, ICPIs have revolutionized the oncology treatment paradigm, with numerous FDA-approved indications across major oncologic diseases, including non-small cell lung cancer, melanoma, breast cancer, and urothelial carcinoma.2-4 Most ICPIs can be used as monotherapy or in combination with other treatment modalities. The global cancer immunotherapy market has experienced remarkable growth, reaching $120 billion in 2022, with projections suggesting a value of approximately $220 billion by 2030, driven by advancements in treatment delivery and the demand for less toxic therapeutic options.5
3d image of kidneys | Image credit: peterschreiber.media | stock.adobe.com
Despite these transformative benefits, ICPIs are associated with numerous immune-related adverse reactions (irAEs) when used alone or in combination with other treatment modalities.6,7 Although most irAEs are mild and manageable, some are severe or even fatal, requiring early recognition and timely intervention to mitigate complications. Renal toxicities, specifically immune checkpoint inhibitor-associated acute kidney injury (ICPI-AKI), though relatively uncommon, represent a critical subset of irAEs.8-10 Clinical trial data for nivolumab monotherapy reported immune-mediated nephritis in 1.2% of patients (23/1994), with grade 2 (0.6%), grade 3 (0.5%), and grade 4 (<0.1%) toxicities observed.3 Although some studies report higher rates of 9% to 30% depending on diagnostic criteria, this variation likely reflects differences in definition and detection methods.11-14 The most frequently observed renal complications include acute tubulo-interstitial nephritis, glomerular lesions (immune complex glomerulonephritis), and electrolyte disturbances. ICPI-AKI typically develops between 1 and 12 months after treatment initiation, though immune complications may occur even months after treatment discontinuation due to these agents' extended half-life and lasting immunologic effects.11,15-17
The pathogenesis of ICPI-AKI involves multiple mechanisms, with kidney biopsies predominantly showing CD4-positive lymphocyte infiltration, suggesting an autoimmune process. Combination immunotherapy regimens, lower baseline renal function, advanced age, and genitourinary malignancies are known risk factors for developing ICPI-AKI.10,11,18-20 Although guidelines from organizations such as the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Society for Immunotherapy of Cancer offer recommendations for managing ICPI-related nephritis, gaps in evidence remain regarding early detection and optimal treatment strategies for this rare but significant complication.21-23 Here, we report a rare case of nivolumab-induced nephritis in a patient with urothelial carcinoma.
This case highlights the importance of recognizing ICPI-AKI, implementing effective therapeutic interventions, and understanding the clinical context to prevent irreversible renal damage. By sharing this experience, we aim to contribute to the growing knowledge base on ICPI-associated nephritis and provide insights to aid clinicians in managing this challenging adverse event.
Case
A 66-year-old male developed likely nivolumab-induced nephritis while receiving adjuvant immunotherapy for high-grade upper tract urothelial carcinoma (HGUC). His relevant medical history included depression, anxiety, essential hypertension, and benign prostatic hypertrophy.
The patient’s oncologic treatment course began with 4 cycles of neoadjuvant chemotherapy (cisplatin and gemcitabine), completed on June 23, 2022, during which his renal function remained stable. He then underwent a radical resection of his right kidney, ureter, and bladder collar (nephroureterectomy) on August 19, 2022. Following successful surgical recovery, he was started on adjuvant nivolumab (480 mg every 4 weeks) on September 22, 2022. This treatment choice aligned with a recent FDA-approved indication for HGUC recurrence prevention.
Over the course of 7 cycles of nivolumab, the patient experienced progressive decline in renal function, with serum creatinine rising to 2.2 mg/dL (Figure 1), glomerular filtration rate dropping to 30 mL/min/1.73m2 (Figure 2), and creatinine clearance decreasing (CrCl) to 61 mL/min (Figure 3). Given these concerning changes in renal function in a patient with a solitary kidney, nivolumab was discontinued on May 17, 2023.
Figure 1. Serum Creatinine
Figure 2. Glomerular Filtration Rate
Figure 3. Creatinine Clearance (CrCl)
Initial management consisted of immediate cessation of nivolumab therapy and initiation of oral prednisone 10 mg daily. Although asymptomatic, the patient completed a 3-month steroid course, consisting of 2 months at 10 mg daily followed by a 1-month taper. The patient’s renal function was monitored weekly during the initial treatment period, then biweekly during the steroid taper.
The patient demonstrated significant improvement with this conservative management approach. Renal function improved steadily throughout the course of steroid therapy, returning to post-nephrectomy baseline levels (serum creatinine 1.3 mg/dL) by October 2023. This improvement has been sustained, with stable renal function maintained in subsequent follow-up. Given the patient's high-risk features (solitary kidney) and adequate duration of adjuvant therapy (7 cycles), the decision was made not to rechallenge with nivolumab.
Discussion
This case illustrates several important clinical considerations in the diagnosis and management of nivolumab-induced nephritis. The patient’s renal dysfunction developed gradually over 7 treatment cycles, ultimately elevating the serum creatinine to 2.2 mg/dL. This timeline aligns with data from a large multicenter study, which reported a median onset of ICPI-AKI at around 14 weeks (range 6–37 weeks).24 Characteristically, ICPI-related nephrotoxicity commonly manifests 1 to 12 months after therapy initiation, a pattern attributable to the prolonged half-life of nivolumab (25–30 days) and its sustained immunologic effects, which may persist well after cessation of treatment.3,15,16
The patient's underlying diagnosis of urothelial carcinoma and post-nephroureterectomy status created a particularly challenging clinical scenario. Having a solitary kidney not only increased the stakes for proper management but also complicated the risk-benefit assessment of continuing immunotherapy. This case adds to the growing literature suggesting that patients with genitourinary malignancies may be at higher risk for ICPI-related nephrotoxicity. A multicenter study of 138 ICPI-AKI cases identified additional risk factors including lower baseline eGFR, proton pump inhibitor use, and combination immunotherapy.24
Our management approach for grade 2 nephrotoxicity (defined as an increase in SCr to 2-3 times baseline) included nephrology consultation and empiric glucocorticoid treatment after excluding other causes of AKI.21 This strategy aligned with established guidelines, as the NCCN recommends nephrology consultation for grade ≥2 toxicity, and ASCO supports empiric glucocorticoid treatment without routine kidney biopsy when serum creatinine is 2 to 3 times baseline. However, while guidelines suggest initial prednisone doses of 0.5 to 1 mg/kg/day, we opted for a more conservative approach of 10 mg daily, given the patient’s relatively mild presentation and a desire to minimize steroid-related toxicities.
The mild nature of the presentation, combined with our ability to closely monitor renal function, supported our decision to initially use a lower steroid dose of 10 mg daily. Ultimately, this approach proved successful and aligned with clinical trial data showing that systemic corticosteroids resolve nivolumab-induced nephritis in approximately 78% of cases.3 A large multicenter study of 138 ICPI-AKI cases further supports the efficacy of steroid therapy, demonstrating complete recovery in 40% of patients and partial recovery in 45%, with failure to achieve kidney recovery associated with increased mortality.24Our patient's positive response to a lower-dose steroid regimen suggests that selected patients, particularly those with mild presentations, may improve with less-intensive steroid therapy, though larger studies are needed to identify predictors of response to different dosing strategies.3,24-27
The decision to permanently discontinue nivolumab in this case was influenced by several factors: the patient's solitary kidney status, the steady decline in renal function despite previously normal markers, and the completion of 7 cycles of therapy. Although ASCO guidelines suggest considering ICPI rechallenge in patients who improve to grade 1 toxicity, studies report a 17% to 25% risk of recurrent nephritis with rechallenge.22,28-30 Given our patient’s solitary kidney and adequate duration of therapy, we opted for a more conservative approach. This highlights the importance of individualizing treatment decisions based on specific patient factors rather than adhering strictly to general guidelines. The successful resolution of nephritis with return to baseline renal function supports this conservative approach in high-risk patients.
This case also raises important questions about optimal monitoring strategies for ICPI-AKI. Despite regular monitoring of renal function, the decline was gradual and initially subtle. This underscores the need for careful trending of renal markers over time, as small changes may signal early toxicity. When such changes are detected, a thorough evaluation for other potential causes of AKI is crucial, including assessment of volume status, medication review, and evaluation of other comorbidities. The case supports recommendations for frequent monitoring of renal function in patients receiving ICPIs, particularly those with risk factors such as genitourinary malignancy or reduced renal reserve.
Conclusion
This case demonstrates successful management of ICPI-associated nephritis in a high-risk patient with a solitary kidney, highlighting several important clinical considerations. Although ICPI-AKI occurs in approximately 1.2% of patients receiving nivolumab monotherapy, our patient exemplified known risk factors including genitourinary malignancy and reduced renal reserve. The gradual decline in renal function over 7 cycles of therapy, despite regular monitoring, underscores both the challenges in early detection and the critical need for identifying early biomarkers of nephrotoxicity. Our experience suggests that selected patients may respond to more conservative steroid doses, though larger studies are needed to identify predictors of response to different dosing strategies. The decision to avoid rechallenge, despite its consideration in guidelines, illustrates the importance of individualizing treatment decisions based on patient-specific risk factors and treatment goals, particularly in high-risk populations such as those with solitary kidneys. As the use of ICPIs continues to expand, sharing such experiences contributes to our understanding of optimal monitoring strategies, steroid dosing approaches, and risk-stratified management decisions for this challenging adverse event.
