Abstract
The rise of immune-based combination therapies has revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC), offering significant improvements in response rates and survival. However, along with these advancements come challenges in managing treatment-related adverse events, particularly renal toxicities. Kidney biopsies represent the gold standard in diagnosing and managing these complications, providing insights into histopathological patterns and guiding therapeutic strategies. It is important to emphasize that in most of the cases expertise in onco-nephrology can enable accurate diagnosis and management of nephrotoxicities, and that in clinical practice, renal biopsy is often not easily feasible. Research efforts are underway to identify biomarkers and imaging techniques that can accurately detect renal damage characteristics without the need for invasive procedures. Promising candidates have been identified; however, validation studies are essential to enhance their effectiveness and integrate them into standard clinical practice. This paper underscores the importance of individualized approaches in managing renal adverse events and calls for further research to improve diagnostic capabilities for acute kidney injury in the context of immune-based combination therapies.
Introduction
The advent of immune-based combinations has greatly expanded the therapeutic options for metastatic renal cell carcinoma (mRCC). These combinations may consist of either a dual immune checkpoint inhibition (ICI-ICI), currently represented by ipilimumab + nivolumab, or of combinations of one ICI with one tyrosine kinase inhibitor (ICI-TKI), i.e., pembrolizumab + axitinib or lenvatinib, and nivolumab + cabozantinib. Notably, these combinations significantly improved both response rates and overall survival compared with conventional TKI monotherapy, establishing it as the standard first-line treatment for mRCC. 1 However, the introduction of combination therapy also led to an increase in adverse events (AEs). Given the overlap in AEs associated with ICIs and TKIs, differentiating which drug is causing the toxicity can be challenging for oncologists. 2
Management of renal toxicities from immune combination therapies
In our recently published position paper, 3 we provided literature evidence and expert-based recommendations for managing kidney toxicities secondary to immune-based combination therapies. Specifically, we extensively discussed the challenges represented by the management of treatment-related adverse events in patients treated with a ICI + TKI combination. To guide clinicians in managing these toxicities, we proposed practical recommendations and flow charts outlining the diagnosis and management of acute kidney injury (AKI) and proteinuria induced by ICI-TKI therapy.
On one hand we have proposed a systematic approach for patients who develop AKI Grade 2 or higher, that involves evaluating the characteristics of AKI to formulate an etiopathogenic hypothesis without performing a kidney biopsy. On the other hand, we have discussed a comprehensive flow chart for manage therapy-induced proteinuria.
While we strongly believe that a good understanding of the characteristics of specific nephrotoxicities caused by these drugs (etiology, histopathology, clinical manifestations, treatment response) can often lead to the identification of the responsible drug and subsequent treatment, there are selected cases where renal biopsy is still necessary to allow definitive diagnosis and subsequent proper therapy. 3
There may indeed be cases of typical renal damage refractory to standard treatments (e.g., steroid-refractory immune-related acute interstitial nephritis), there may be uncommon histopathological damage secondary to ongoing treatments (e.g., ICIs-related pauci-immune glomerulonephritis), or even kidney damage not secondary to oncological therapy (e.g., paraneoplastic membranous glomerulonephritis).
It is therefore undeniable that in case of renal AEs, only kidney biopsy provides a certain diagnosis of the renal toxicity profile.
Role of kidney biopsies
Acute interstitial nephritis (ATIN) is the most frequent histological pattern associated with ICIs treatment 4 ; large multicenter studies on ICIs-related AKI by Cortazar et al. and Gupta et al. reported kidney biopsy-proven ATIN in the 93% and 82.7% of cases, respectively.5,6
ATIN can present either alone or alongside various other glomerular or tubular pathologies5,7,8; indeed, a concomitant ATIN was reported in 41% of biopsy cases that exhibited another primary histological lesion. Pauci-immune glomerulonephritis and renal vasculitis (27%), podocytopathies (24%), e.g., minimal change disease, and C3 glomerulonephritis have been described among the most frequent glomerular lesions. 9 Although reports of ATN have emerged, ongoing investigation is required to ascertain whether ATN should be definitively classified as an irAE. 10
Kidney histological impairments secondary to TKIs define an extended spectrum, mainly taking into account how the VEGF-VEGFR signal pathway and many other key targets are critical for tumor cells’ survival. Izzedine et al., 11 among the first, described histological lesions of thrombotic microangiopathy (TMA) which may especially complicate the antiangiogenic cancer treatment; half of the cases showed exclusively renal-localized TMA lesions. Histological findings of podocytopathies, mainly minimal change disease and/or collapsing like focal segmental glomerulosclerosis, also consistently associate with TKIs as a cause of proteinuria, due to the swelling and detachment of the endothelial cell and interruption of the glomerular filtration barrier.11,12
As a consequence of advances and novel possibilities in cancer treatments, the paradigm of predictable kidney adverse events could change. Recently, a retrospective analysis focused on kidney injury patterns in cancer patients who underwent biopsy for AKI and/or proteinuria as the main indications; the dominant diseases were ATIN (39.9%), acute tubular necrosis (8.8%), IgA nephropathy (7.4%), membranous nephropathy (6.1%) and TMA (5.4%), describing 56% of reports caused by cancer therapies the patient received. ICIs emerge as the most recurring responsible agents (66% of ATIN cases). 13 In the same field of research, a single center experience reported on 30 cancer patients treated with novel cancer therapies (i.e., ICIs 30%, TKIs 26.7%, ICIs plus TKIs 13.3%, etc.), identifying ATIN in 30% of kidney biopsies. 14 Furthermore, Saiki et al. reported 17 cases of ICI-related nephrotic syndrome. 7 patients had minimal change disease, 3 membranous nephropathy, 1 IgA nephropathy, 1 AA-type amyloidosis and 1 pauci-immune glomerulonephritis with crescents in 1. 15
Evidence like these, suggest a new trend in histological kidney patterns, related to the evolving landscape of oncological therapies, thus overcoming the archetype of membranous nephropathy as the main paraneoplastic kidney disease.
In this complex scenario, kidney biopsy represents a unique tool able to establish the correct etiology of renal toxicities, triggered by different anticancer agents or their combination, and to guide the appropriate treatment according to the type of histological impairment (e.g., drug discontinuation, steroids, rituximab, eculizumab, plasmapheresis, etc.). 4 Furthermore, a systematic description of the tissue features, can help in predicting renal outcomes.
Despite these advantages, there is still a significant mismatch between kidney biopsy recommendations and real-life clinical practice. There are often concerns to perform biopsy, particularly in a single kidney condition, mainly for the risks of complications; indeed, a large meta-analysis 16 highlighted low rates of complications (i.e., 1.6% of bleeding requiring embolization, 0.3% of bleeding requiring intervention and 0.06% of death) and other recent publications confirmed these data.17,18
In clinical practice, kidney biopsy timing represents a potential limitation. Dedicated trails to perform it rapidly should be ensured: kidney toxicities may often be easily reversible with early diagnosis and management. This is particularly true for ICI-related nephrotoxicities, for which the timing of corticosteroid initiation represents a prognostic factor. Early administration within 3 days of diagnosis showed a greater likelihood of achieving renal recovery compared to initiation beyond 3 days. 19
In addition, the absence of precise indications in these setting limits the performance of kidney biopsy in cancer patients. Recently, in the context of the KDIGO global panel of multidisciplinary expertise for a controversies conference, 20 indications have been reinforced involving new onset proteinuria (defined as >1 g per day), worsening of renal function and absence of a unique diagnosis able to define care management. Several authors agreed that the current guidelines for oncologists do not value kidney biopsy sufficiently in ICIs related-AKI setting4,21; thus, the American Society of Clinical Oncology (ASCO) guidelines recommend directly administrating empiric steroid treatment for AKI ≥grade 2 if other causes can be ruled out 22 and the National Comprehensive Cancer Network (NCCN) guidelines suggest kidney biopsy only for high grade of renal toxicities (grade ≥3 or serum creatinine >3 times baseline or > 4.0 mg/dL). 23
Later, the European Society of Medical Oncology (ESMO) guidelines try to design the use of kidney biopsy on a case-by-case basis to confirm the clinical diagnosis of ATIN 24 and the Society for Immunotherapy of Cancer (SITC) guidelines strongly support the value of kidney biopsy recommending the procedure when feasible, particularly when an alternative etiology for AKI exists or urine exam is suggestive of glomerular disease. 22 According to this debate, Perazella M. et al. suggested an algorithm for the initial evaluation and management of ICI-related AKI: kidney biopsy should be performed in case of high-grade proteinuria, hematuria, granular casts, AKI stage 2 and 3, or stage 1 when AKI persists or worsen after monitoring.4,25
The diverse guidelines highlight the ongoing debate within the medical community concerning the significance and timing of renal biopsy in this complex scenario. This underscores the necessity for individualized assessments to determine the optimal approach for diagnosis and managing of renal AEs.
Furthermore, it should be noted that findings from case series reported by Palamaris K et al. and Saiki et al. indicate that in cases of ICI-related kidney damage, regardless of the detected histological damage, standard treatment with steroid therapy was initiated, as indicated in cases of ATIN.15,26
Another important consideration is that currently, a histological diagnosis of TKI-related TMA requires suspension of the oncologic treatment. This is because there are no specific guidelines for managing this adverse event related to this specific class of drugs, but only indications for managing general TMA. What has emerged from recent studies and clinical practice is that the clinical presentation and course of TMA secondary to anti-angiogenic drugs differ significantly from those of TMA in non-oncologic patients, or TMA secondary to cancer, or to chemotherapy. TMA associated with VEGF/VEGFR inhibitors, can presents with varying symptoms, including hypertension and proteinuria, typically without kidney failure or hematological manifestations. 27 This has led to a new classification of TMA in oncologic patients that distinguishes clearly the different entities and provides different treatment recommendation suggesting excellent patient and kidney prognosis after TKIS discontinuation and a relative safety rechallenge of the drug after symptoms resolutions. However, in most cases, these indications have not changed clinical practice.
Our opinion is that although kidney biopsy is a relatively safe procedure and each patient should be considered for it, at present, it should be reserved for selected cases with atypical clinical presentations or atypical clinical courses. What emerges is that currently, in most centers, it is not possible to perform a renal biopsy promptly, and often, the histological pattern does not significantly affect our therapeutic approach. 26 Lastly, in most cases, a specialist in Onco-Nephrology can identify the drug responsible for kidney adverse events without needing to perform a biopsy.
Therefore, a careful evaluation of the risks and benefits (Table 1) for every single patient is always necessary, considering the patient's prognosis, response to cancer treatment, availability of alternative oncological treatments, and setting (adjuvant or metastatic disease).
The role of kidney biopsy in immune-based combination therapy nephrotoxicity.
Advancements in non-invasive diagnostic approaches
In this complex scenario, the identification of biomarkers that allow for the reliable detection of renal damage characteristics without the need for invasive procedures, such as renal biopsy, would represent a turning point in clinical practice. Despite renal biopsy remains the present gold standard for definitive diagnosis, several studies are underway to identify these biomarkers, with the hope that they may aid both in diagnosis and in identifying at-risk patients.
Unfortunately, to date no validated serum or urine biomarker emerged which could be used in everyday clinical practice for diagnosing ICI-related nephritis. Nevertheless, several biomarkers are currently under investigation, showing potential as prospective indicators.
In particular, serum soluble interleukin-2 receptor (sIL-2R) elevation, 28 urinary tumor necrosis factor-alpha (TNF-α) and interleukin-9 levels have been proposed as biomarkers. The latter also allows for a differential diagnosis between ICI-related and non-ICI-related ATIN. 29 Another study has also identified elevated levels of serum C-reactive protein (CRP) and a higher ratio of urine retinol-binding protein (URBP) to creatinine as biomarkers to identify ICI-related AKI. Finally, a study conducted on non-oncologic patients identified an increase in urinary CXCL9 as a diagnostic biomarker for ATIN. 30
However, these are single-center studies, with a limited number of patients, requiring larger studies and, more importantly, external validation. Furthermore, Serum CRP and Serum sIL-2R often increase during an inflammatory response, thus determining false positives; furthermore, most of these biomarkers aren’t presently clinically available. 31
The domain of biomarkers for diagnosing nephrotoxicity from VEGF/VEGFR inhibitors is less explored.
Urinary NGAL, KIM-1, HIF-1α, and nephrin have been identified as early biomarkers of nephrotoxicity, but their efficacy in differentiating between renal damage from TKIs or ICIs has not been tested.32,33
Additional multicenter prospective studies are necessary to validate and enhance the effectiveness of these potential biomarkers and incorporate them into standard clinical practice for the timely and precise diagnosis of AKI.
Recently, some case reports and case series have been published proposing the use of 18fluorodeoxyglucose positron emission tomography (18FdG-PET) for the diagnosis of ICI-ATIN34–36; a method that, if proven effective, could potentially be used as a supportive tool in the non-invasive differential diagnosis with other causes of nephrotoxicity. Cases of ICI-ATIN have indeed been described, wherein PET-CT imaging revealed a notable increase in radiotracer uptake across the renal cortex, accompanied by a decrease in radiotracer activity within the renal pelvis. 34 Studies are certainly required to validate the effectiveness of this approach, considering that the accumulation of most tracers in the collecting system due to renal excretion can impact the sensitivity and specificity of various imaging studies for detecting kidney inflammation. 31
Conclusions
In conclusion, the management of renal adverse events induced by immune-based combinations necessitates an individualized approach. Renal biopsies play a crucial role in selected cases, probably more than presently expected, providing valuable diagnostic information and guiding treatment decisions. However, there remains a lack of reliable biomarkers for the non-invasive diagnosis of renal complications associated with antitumor therapies. Moving forward, further research and development are needed to enhance the effectiveness of potential biomarkers or imaging techniques and integrate them into standard clinical practice for the timely and precise diagnosis of acute kidney injury.
Footnotes
Author contributions
Marta Pirovano and Laura Cosmai contributed to the article conception and design.
Marta Pirovano, Giulia Vanessa Re Sartò and Carlo Ganini conducted the literature review and drafted the manuscript. Laura Cosmai and Camillo Porta critically revised the work. All authors read and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the course of this study.