In the ever-evolving field of onconephrology, 2024 should witness some notable emerging trends that may hold promise for kidney function assessment in patients with cancer and mitigating drug-induced injury.
The role of cystatin C in eGFR
Accurate evaluation of kidney function in patients with cancer is crucial, as it can significantly impact decisions regarding the initiation or discontinuation of advanced therapies, including chemotherapy and immunotherapy. Recent trends, as highlighted in the oral onconephrology presentations at Kidney Week 2023, indicate a notable shift toward incorporating cystatin C (cys) for estimated glomerular filtration rates (eGFRs) in patients with cancer. This approach, reflected in two significant abstracts (1, 2), underscores the importance of establishing baseline kidney function and defining acute kidney injury (AKI) in this vulnerable population.
The first abstract explores the performance of creatinine (cr)-based eGFR equations in patients with malignancy, revealing potential limitations compared with the general population (1). The study, conducted retrospectively at the Mayo Clinic from 2017 to 2023, involved patients with neoplasia, excluding in situ and benign lesions. The analysis incorporated a urinary iothalamate clearance measured GFR (mGFR) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for neoplasia up to 1 year prior to the mGFR date. Results demonstrated that median bias aligned with existing literature among 3719 patients with eGFR based on cr alone. However, among the subset of 522 patients with both cr and cys measurements, eGFRcrcys exhibited superior accuracy (15.5%) compared with eGFRcr (26.7%) and eGFRcys (25.5%). This improvement was consistent across different cancer types. The study concludes that, particularly in patients with solid or hematological malignancies, the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) eGFRcrcys better reflects mGFR, suggesting its potential superiority for clinical decision-making.
The second abstract focuses on cisplatin-induced AKI in children, aiming to detect and mitigate AKI early to prevent long-term consequences (2). Serum cys was investigated as a potential, early biomarker compared with serum cr, particularly as it is largely unaffected by muscle mass. The prospective study involving 159 children treated with cisplatin reveals that cys-AKI and serum cr-AKI had only an 83% agreement, indicating a low level of concordance between the two definitions. Furthermore, cys was not a strong predictor of serum cr-AKI in this pediatric population. The study suggests the need for future investigations with more measurement time points to ascertain whether the observed differences result from the earlier rise of cys compared with cr.
SGLT2 inhibitors in drug-induced AKI
Other significant presentations at Kidney Week 2023 have shone a spotlight on the potential for sodium-glucose cotransporter-2 (SGLT2) inhibitors to ameliorate the side-effects of cisplatin chemotherapy on the kidney, a notorious cause of AKI that afflicts approximately one-third of recipients and often progresses to CKD. Given the absence of US Food and Drug Administration-approved preventative treatments for drug-induced kidney damage, the findings could herald a new era in onconephrology.
In a mouse model designed to replicate clinical conditions—repeated low-dose cisplatin administration in the presence of lung adenocarcinoma—daily treatment with SGLT2 inhibitors, specifically empagliflozin or dapagliflozin, was initiated 1 week before the first cisplatin dose and continued for 28 days (3). The results were promising: SGLT2 inhibitors mitigated the alterations in kidney function and injury typically induced by cisplatin. Markers of kidney fibrosis, such as transforming growth factor-β, α-smooth muscle actin, fibronectin, and collagen, were notably reduced in the treatment group versus the control without any adverse impact on tumor growth or cisplatin response.
These preclinical findings, however, must be juxtaposed with real-world clinical data to appreciate the full scope of the impact of SGLT2 inhibitors. In a retrospective analysis of 5478 patients with diabetes and cancer, those prescribed SGLT2 inhibitors experienced higher rates of adverse events (4). The cohort accumulated 11,175 patient-years on these medications, within which 424 adverse events were documented, translating to a higher-than-expected incidence of diabetic ketoacidosis (DKA) at 5.1 per 1000 patient-years—surpassing the 0–2.2 range reported in recent meta-analyses and observational studies. Rates of urinary tract infections, genital mycotic infections, and non-vertebral fractures were also elevated.
The dichotomy of these findings underscores the complexity of translating promising animal model results into clinical practice, particularly for a patient population that has been historically excluded from large clinical trials due to their cancer diagnosis. While the renoprotective effects observed in the mouse model are undeniably significant, the higher incidence of adverse events in the human study prompts a reassessment of the risk-benefit ratio for SGLT2 inhibitor use in oncologic settings.
As we stand on the cusp of potentially integrating SGLT2 inhibitors into the therapeutic regimen for patients with cancer at risk of cisplatin-induced AKI, these studies collectively advocate for a tempered approach. They call for rigorous clinical trials to elucidate the safety and efficacy of SGLT2 inhibitors in this unique cohort, emphasizing vigilant monitoring for adverse events. Only with such due diligence can we protect our patients’ kidney health without compromising their oncological outcomes.
In conclusion, these emerging trends in onconephrology for 2024 could show potential in evaluating kidney function in individuals with cancer and reducing injury caused by drug administration. The integration of cys in eGFR holds promise but requires further refinement, whereas the potential use of SGLT2 inhibitors demands cautious exploration through rigorous clinical trials. As the field progresses, a balanced approach that considers both the advancements and challenges will be pivotal for improving outcomes in patients with cancer and related adverse effects on the kidney.
Footnotes
References
- 1.↑
Titan S, et al. Performance of creatinine and cystatin C-based equations among patients with hematological or solid cancers: Real-world data from a clinical cohort [Abstract]. J Am Soc Nephrol 2023; 34:28. https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=3944821
- 2.↑
Hessey E, et al. Cystatin C-defined AKI in children treated with cisplatin [Abstract]. J Am Soc Nephrol 2023; 34:29. https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=3938500
- 3.↑
Sanchez Vega D, et al. SGLT2 inhibitor protects from repeated low-dose cisplatin-induced chronic kidney damage [Abstract]. J Am Soc Nephrol 2023; 34:29. https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=3946126
- 4.↑
Shaikh A, et al. Safety outcomes of sodium-glucose cotransporter-2 inhibitors in patients with diabetes mellitus and cancer [Abstract]. J Am Soc Nephrol 2023; 34:31. https://www.asn-online.org/education/kidneyweek/2023/program-abstract.aspx?controlId=3940988