Given the complexity of managing patients with renal cell carcinoma, here’s an essential review of nephrotoxic mechanisms, personalized risk assessments, and tailored therapeutic interventions.
The dynamic landscape of anticancer therapeutics continues to make significant strides with novel therapeutic strategies, including targeted therapies and immunomodulators, to improve patient outcomes.
However, a significant challenge persists: the collateral damage inflicted on healthy organs by some anticancer drugs. The dichotomy of treating renal cell carcinoma (RCC) is that these are the same agents that can cause nephrotoxicity.
Given the inherent complexity of managing RCC, a nuanced understanding of nephrotoxic mechanisms, personalized risk assessment, and tailored therapeutic interventions are essential.
A Delicate Balance: The Susceptibility of the Kidneys
The kidneys are particularly vulnerable to damage for several reasons, including the high rate of blood flow they receive and its role in regulating blood volume, ions, pH, and filtering of waste products, including biotransformation, which may inadvertently be more toxic. The significance is heightened by the fact that most drugs are excreted through the kidneys, and this holds especially true for 50 percent of anticancer medications. While there are many effective RCC treatment modalities, they come with unique nephrotoxic potential.
Cisplatin, a mainstay in RCC treatment regimens, causes nephrotoxicity through the formation of platinum-DNA that adducts oxidative stress and mitochondrial dysfunction, causing damage to DNA, inflammation culminating in proximal tubular injury, and renal dysfunction.
Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors can induce nephrotoxicity through vascular endothelial dysfunction like thrombotic microangiopathy, which is a condition due to blood clot formation in small blood vessels within the kidneys. This impairs renal autoregulation, manifesting as hypertension, proteinuria, and even acute kidney injury (AKI).
Also, the emergence of immunotherapy, including immune checkpoint inhibitors, introduces some renal toxicities that are mediated by immune-related mechanisms, like autoimmune glomerulonephritis, tubulointerstitial nephritis, and AKI.
Collectively, this further emphasizes the need for individualized treatment plans.
Risk Stratification in RCC Patients
The identification of RCC patients at heightened risk of nephrotoxicity from anticancer therapy is pivotal in guiding personalized treatment decisions and optimizing clinical outcomes. Pre-existing renal dysfunction, advanced age, hypertension, diabetes, and concomitant nephrotoxic medications constitute significant risk factors for nephrotoxicity in RCC patients.
Additionally, pharmacogenetic variations in drug-metabolizing enzymes and renal transporters contribute to interindividual variability in drug response and toxicity profiles, underscoring the importance of individualized risk stratification strategies in this patient population.
Advanced Assessment and Management Strategies
The clinical assessment and management of nephrotoxicity in RCC patients undergoing anticancer therapy necessitate a sophisticated and multidimensional approach, encompassing meticulous monitoring of renal function, fluid status, and urinary parameters. Serial serum creatinine, estimated glomerular filtration rate, electrolytes, and urinalysis facilitate early detection of renal dysfunction and guide therapeutic decision-making.
Furthermore, the incorporation of emerging biomarkers of renal injury, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and interleukin-18, enables proactive intervention and risk stratification in high-risk cohorts.
Proactive advanced management strategies are prudent for renal protection. Strategies like mitigation of drug-drug interactions, use of nephroprotective interventions, including renoprotective agents such as intravenous fluids, loop diuretics, and acetylcysteine, dose optimization, discontinuation, and hydration protocols, all offer nephroprotection in patients at high risk. In cases of established nephrotoxicity, supportive measures such as renal replacement therapy may be necessary to mitigate renal injury and optimize patient outcomes.
Nephrotoxicity in RCC therapy represents a complex and multifaceted clinical challenge, demanding a sophisticated and interdisciplinary approach. By unraveling the intricacies of nephrotoxic mechanisms and adopting proactive and multidisciplinary approaches, this can help mitigate the risks of nephrotoxicity, optimize patient outcomes, preserve renal function, and ensure the delivery of safe and effective anticancer therapy to patients with RCC.
References
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