Editor’s Note: With targeted therapy plus immunotherapy (“targeted-immunotherapy” or T+I) now established as the standard of care for advanced renal cell carcinoma (RCC), treatment-related nephrotoxicity has become an increasingly prominent clinical challenge—one that significantly impacts treatment safety and long-term survival. At the 28th Annual Conference of the Chinese Society of Clinical Oncology (CSCO 2025), Professor Juan Li from Peking University Cancer Hospital / Beijing Gaobo Hospital presented key findings from her team’s research on this important topic. Following her presentation, Oncology Frontier invited Professor Li for an in-depth discussion, exploring the clinical features, underlying mechanisms, and systematic management strategies for kidney injury during T+I therapy, with the aim of providing valuable insights for clinical practice.Clinical Manifestations and Incidence of Kidney Injury
Oncology Frontier: T+I therapy has become the standard for advanced RCC, but kidney injury remains a critical issue. Based on your clinical experience and research, what are the main clinical manifestations and pathological types of kidney injury in this setting? How frequently does it occur, and how does it impact treatment?
Professor Li:This is indeed a very important question. As a genitourinary medical oncologist, I encounter numerous advanced RCC patients in daily practice. Both Chinese and international guidelines now recommend T+I therapy as the mainstream treatment approach, signifying that we have entered the era of combination therapy.
Assessment and management of kidney injury is a common yet complex issue in this setting. Many RCC patients have already undergone nephrectomy, and the causes of kidney injury generally fall into three categories: prerenal, renal, and postrenal. Among renal causes, drug-induced nephrotoxicity accounts for a considerable proportion, meaning RCC patients face a higher risk of kidney injury than most other solid tumor patients.
Pathologically, kidney injury from VEGF-targeted monotherapy usually manifests as glomerular damage, presenting clinically with hypertension and proteinuria. Immune checkpoint inhibitor monotherapy is more commonly associated with interstitial nephritis, which can lead to acute kidney injury (AKI). Kidney injury under T+I therapy is not a simple sum of these two toxicities—it is mechanistically more complex and more challenging to manage.Clinically, presentations vary widely. Some patients are asymptomatic and are only found to have elevated creatinine during routine testing; others develop hypertension and proteinuria suggestive of glomerular injury. A small proportion may develop severe AKI with oliguria or anuria. These patterns highlight the need for vigilant monitoring, timely diagnosis, and appropriate adjustment of therapy.
Mechanisms and Differential Diagnosis
Oncology Frontier: What are the potential mechanisms underlying these kidney injuries? How do you differentiate treatment-related injury from other causes, such as the tumor itself, dehydration, or contrast-induced nephropathy?
Professor Li: This is a highly practical clinical question. As mentioned, kidney injury can be classified as prerenal, renal, or postrenal.- Prerenal factors include hypovolemia, which can elevate serum creatinine.- Renal factors involve nephron loss due to surgery, tumor infiltration, or drug toxicity.- Postrenal factors are usually obstructive, such as tumor compression of the ureters causing impaired drainage.
Differential diagnosis begins with a detailed patient history—recent health status, urine output changes, and exposure to nephrotoxic agents must all be considered. Laboratory tests, including CBC, biochemistry, and urinalysis, are critical for determining the type and likely cause of kidney injury.Other causes, such as tumor-related AKI, dehydration, or contrast exposure, must also be ruled out. In some cases, a diagnostic treatment approach is applied—for example, if immune-related nephritis is suspected, a course of corticosteroids may be given; a rapid decline in creatinine supports the diagnosis. Renal biopsy remains the gold standard but is often underutilized due to low patient acceptance, so most diagnoses rely on comprehensive clinical evaluation and therapeutic response.
Management Strategies and Insights from Research
Oncology Frontier: Once kidney injury occurs, what systematic management strategies do you recommend? What key insights did your study provide for clinical practice?
Professor Li: At CSCO 2025, I presented a retrospective analysis of kidney injury during T+I therapy in advanced RCC. The study was based on over 200 patients enrolled in China’s first large-scale, randomized phase III trial in this field—the RENOTORCH study. Among these patients, 57 developed creatinine elevations of CTCAE Grade ≥1.
Our findings showed that the vast majority of patients recovered normal kidney function after appropriate management, and around 60% were able to continue on their original treatment regimen. Only three patients developed severe kidney injury (Grade ≥3); two of them returned to baseline or Grade 1 creatinine after steroid therapy and were able to safely continue treatment, achieving long-term survival.Importantly, our analysis revealed that the etiology of kidney injury varies by patient—some are primarily TKI-related, others immune-related, and some represent difficult-to-manage synergistic toxicities. Interestingly, patients who experienced kidney injury appeared to have longer progression-free survival (PFS), though the difference in overall survival (OS) was not statistically significant, likely due to limited sample size—this will require confirmation in larger cohorts.Overall, because advanced RCC patients face a higher risk of kidney injury during T+I therapy, comprehensive, proactive management is essential. We advocate for:- Pre-treatment assessment of baseline renal function- Thorough patient education and communication- Regular monitoring of laboratory and imaging parameters during treatment- Early intervention when abnormalities ariseMost patients, when treated promptly, recover well and can continue anti-cancer therapy.
For the small subset who develop Grade ≥3 kidney injury, therapy should be interrupted, and aggressive supportive treatment provided. If creatinine returns to baseline, re-challenge with the original regimen may be considered; if recovery is incomplete, permanent discontinuation and regimen switch may be necessary. This approach maximizes both treatment safety and patient survival—an essential part of our therapeutic strategy.
