Cardiorenal Impact of Anti-Cancer Agents: The Intersection of Onco-Nephrology and Cardio-Oncology

The field of cancer medicine has rapidly evolved in the past decade, marked by significant advancements in oncological treatments that have substantially improved the prognosis of cancer patients. While these innovative therapies bring renewed hope, they also bring forth a myriad of new adverse effects, most prominently cardiotoxicity and nephrotoxicity. Furthermore, as the malignancy-related relapse/progression-free survival improves, the risk of long-term cardiovascular (CV) and kidney related complications related to anti-cancer drug exposure becomes increasingly important.

To address these new challenges, the fields of cardio-oncology and onco-nephrology have emerged as novel disciplines. These areas focus on the prevention and management of cardiac and renal toxicities in cancer patients. While each specialty approaches the patient from its unique perspective, there is growing recognition that collaborative management by onco-nephrologists and cardio-oncologists is crucial for negotiating the complex interplay between the toxicities affecting these two organ systems. Indeed, the crosstalk between the heart and the kidney is even more complex in cancer patients. Not only can both organs be affected by cancer itself, but they are often prominently impacted by the treatments administered for it. In addition, most cancer patients have underlying shared risk factors for renal and cardiac disease, such as diabetes, obesity, and smoking, which require aggressive management.

This work aims to explore the intersection between cardio-oncology and onco-nephrology. A detailed review will be undertaken, focusing on onco-hypertension (HTN) and the cardiorenal toxicities of chemotherapeutic agents, with a specific emphasis on the adverse effects associated with immune checkpoint inhibitors (ICIs).

HTN is the most frequently observed comorbidity in cancer patients [1]. The simultaneous occurrence of HTN and cancer can be attributed to the sharing of similar risk factors such as advancing age, physical inactivity, obesity, smoking, and diabetes. These common risk factors lead to oxidative stress, endothelial injury, and inflammation which are hallmarks of both diseases. The relationship between HTN and cancer is also bidirectional. HTN has been associated with the development of certain cancers such as renal cell carcinoma (RCC), breast cancer, and prostate cancer [2]. Conversely, cancer therapy can cause new-onset HTN in over two-thirds of patients [3].

The diagnosis of HTN in cancer patients can be challenging, owing to a multitude of confounding factors. Pain, anxiety, and the white coat effect increase in-office blood pressure (BP) readings [4], but masked HTN is also common. In a study that followed 119 patients receiving bevacizumab, HTN was detected at a much higher frequency with home-based blood pressure measurements (HBPM) compared with office blood pressure measurements (54.6 vs. 24.4%, p < 0.01). Therefore, it is likely that HTN is significantly underdiagnosed in the cancer population. The American Heart Association (AHA) recommends that all patients undergo baseline screening for HTN at the beginning of cancer treatment [5] since baseline HTN has been identified as an independent risk factor for worsening BP control during cancer therapy [6] and for treatment related to cardiac dysfunction.

Meticulous BP monitoring is also essential during the course of chemotherapy to mitigate both cancer and CV mortality, which are often competing risks in the cancer patient. In fact, uncontrolled BP may result in treatment interruptions or dose reductions in chemotherapy, which undermine anti-tumor efficacy and compromise overall outcomes. In addition, severely uncontrolled HTN exacerbates short-term CV complications, leading to irreversible end-organ damage. A growing body of evidence suggests that untreated HTN increases the risk of anthracycline- and trastuzumab-induced cardiomyopathy [7, 8], and precipitates acute decompensation of congestive heart failure (CHF) in patients receiving vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSPIs) [9]. Furthermore, it contributes to an increased incidence of long-term complications, such as heart failure, myocardial infarction (MI), peripheral vascular disease, and CV death, similar to those observed in the non-cancer population.

HTN in cancer patients can have various causes. The most common are pre-existing HTN and cancer therapy-related hypertension (CTRH). Additionally, elevated BP can result as an adverse effect of non-antineoplastic drugs frequently used in the cancer population, including non-steroidal anti-inflammatory drugs, antidepressants (monoamine oxidase inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors), glucocorticoids, or oral contraceptive pills.

Paraneoplastic syndromes may also contribute. For instance, HTN has been reported in up to 40% of patients with RCC [10], attributed to the secretion of vasoactive paracrine peptides such as endothelin-1, urotensin-II, and adrenomedullin. Upregulation of the renin-angiotensin-aldosterone (RAAS) system can even occur due to direct compression of kidney parenchyma or blood vessels by the malignant tumor itself. Paraneoplastic HTN is also associated with hepatocellular carcinoma, resulting from ectopic secretion of renin, angiotensinogen, and angiotensin 1 within the tumor [11]. Other instances include carcinoid tumors (increased corticotropin-releasing hormone) and pheochromocytoma/paraganglioma, where HTN is typically paroxysmal and occurs in 50% of patients, mediated by vasoactive catecholamines.

CTRH is the predominant cause of HTN in cancer patients. While initially associated primarily with VSPIs, including monoclonal VEGF inhibitors and tyrosine kinase inhibitors (TKIs), increasing evidence indicates an association with other classes of drugs as well. Table 1 provides a summary of the incidence and various mechanisms of CTRH associated with different chemotherapeutic drug classes. An increase in BP from baseline is seen in nearly all patients receiving VSPIs, with new or aggravated HTN occurring in up to 80% of cases. Age >70 years, history of genitourinary malignancy, and treatment with direct anti-VEGF angiogenic agents are the most important risk factors for grade ≥3 HTN [21]. HTN develops soon after exposure to VSPIs, primarily attributed to vasoconstriction and sodium retention. However, its mediation shifts subsequently to glomerular injury and renal dysfunction later on. Thrombotic microangiopathy may also manifest and is typically considered as a contraindication to drug rechallenge. Other mechanisms of CTRH include increased capillary rarefaction, mitochondrial dysfunction, decreased angiogenesis, nephrotoxicity, and increased sympathetic outflow [12]. Interestingly, ICIs have not been implicated with CTRH to date [22].

Adjunctive cancer therapies can also trigger HTN. For instance, corticosteroids may result in salt and water retention, along with an increase in peripheral vascular resistance. Additionally, erythropoiesis-stimulating agents, employed for cancer-related anemia, have been associated with HTN and thrombotic complications due to heightened blood viscosity, increased sensitivity to endogenous vasopressors, and elevated vascular resistance to nitric oxide. Therefore, discontinuation of their use is recommended if BP is poorly controlled. Calcineurin inhibitors used in the context of bone marrow transplant can cause HTN through tubular damage, increased activity of the thiazide-sensitive sodium chloride cotransporter, and renal vasoconstriction [23].

Because cancer patients are frequently excluded from HTN clinical trials, therapy thresholds are poorly defined and are extrapolated from HTN guidelines in the general population. However, managing HTN in cancer patients presents unique challenges. First, side effects are often poorly tolerated. Second, BP exhibits a labile nature, significantly influenced by the time since chemotherapy administration and its dosage. Due to poor accommodation of autoregulatory mechanisms, an abrupt rise in BP after chemotherapy can actually result in more pronounced end-organ damage at lower BP levels than with chronic HTN. Third, there are important interactions between BP medications and anti-cancer drugs as summarized in Table 2; [24, 25]. Therefore, precision medicine is needed for HTN treatment in cancer patients. Management must be tailored to patient comorbidities, side effect profiles, and pharmacologic interactions. BP goals should also be individualized, considering the patient’s CV risk factors such as coronary artery disease (CAD), peripheral vascular disease, CHF, stroke, diabetes, and proteinuric chronic kidney disease (CKD), and especially taking into account their cancer prognosis [5].

Figure 1 illustrates important considerations for BP management in cancer patients before, during, and after undergoing antineoplastic therapy. BP should be measured at baseline in all patients, particularly those planned to receive VSPIs. If office BP is high, confirmation should be sought through ambulatory BP monitoring if possible or HBPM using a validated device [5]. A comprehensive evaluation for secondary causes of HTN (if indicated) can be undertaken and dietary sodium restriction emphasized given its known beneficial effects on VSPI-induced HTN and proteinuria [26]. Pre-existing HTN needs to be adequately managed before beginning cancer therapy.

Once chemotherapy is begun, BP should be checked weekly after the first cycle and then every 2–3 weeks with subsequent cycles [27]. Patients should also monitor BP at least daily at home. Office readings may not be necessary every 2–3 weeks as long as the patients provide reliable home BP readings. Patients should be educated about the role of optimal BP control in minimizing chemotherapy interruption and toxicity, enabling optimal dosing and tumor control, and improving overall outcomes. BP should be closely observed throughout therapy, and medication adjusted as needed, to avoid over or under-treatment. For example, VSPIs and proteasome inhibitors can cause a dose dependent, reversible rise in BP a few days after administration, followed by normalization. The continued administration of antihypertensive drugs may therefore lead to hypotension if not carefully monitored. Interestingly, some observations suggest that the occurrence of VSPI-induced HTN may be a marker of improved anti-tumor response, associated with longer progression-free and overall survival compared to normotensive patients [28]. Importantly, the treatment of HTN does not negate this mortality benefit. HTN resulting from Bruton’s TKIs can, on the other hand, manifest several months or years after treatment initiation and persist after drug cessation [29]. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines, therefore, recommend ambulatory BP monitoring or HBPM, particularly when initiating or adjusting medications like VSPIs [5].

There is general consensus that BP exceeding 160/100 mm Hg should be treated in all cancer patients to prevent life-threatening complications. Although the 2022 European Society of Cardiology (ESC) guidelines allow lenient BP goals (<160/100 mm Hg) for asymptomatic patients with metastatic cancer and a prognosis of less than 1-year survival, the goal BP remains <130/80 mm Hg for patients at high CV risk (atherosclerotic CV disease >10%) and 140/90 mm Hg if the patient has no CV risk factors [30]. Combination therapy is often necessary to control BP. The International Cardio-Oncology Society (IC-OS) 2021 consensus also recommends initiating therapy in the presence of an exaggerated BP response, defined as an increase in systolic blood pressure (SBP) >20 mm Hg or mean arterial pressure >15 mm Hg. Anti-cancer agents should be withheld if BP exceeds 180/110 mm Hg and can only be safely restarted if office BP is <160/100 mm Hg and home BP is <150/95 mm Hg. Hypertensive emergencies associated with end-organ damage, such as pulmonary edema, cardiac ischemia, encephalopathy, papilledema, or posterior reversible encephalopathy syndrome, may warrant permanent discontinuation of cancer therapy.

RAAS blockers are considered first-line agents for the treatment of onco-HTN due to their cardioprotective effects. RAAS blockade has even been demonstrated to exert anti-proliferative effects which enhance the anti-cancer properties of chemotherapy [31] and to improve overall survival and progression-free survival in metastatic RCC [32]. In addition, RAAS blockers play a crucial role in reducing VSPI-induced proteinuria. In fact, patients on VSPI therapy are recommended to undergo periodic screening for proteinuria. VSPIs are usually held if proteinuria exceeds 2 g/day and a kidney biopsy is considered if proteinuria exceeds 3/day, persists for more than 3 months after discontinuation of therapy, or if there is microscopic hematuria [33]. Identification of VSPI-induced thrombotic microangiopathy on kidney biopsy is an indication for permanently discontinuing VSPI. Podocytopathies have also been reported with certain VSPIs. Switching within the class of the VSPIs can sometimes resolve the podocytopathies to allow for anti-tumor effect and avoidance of the proteinuria [34].

Apart from RAAS blockers, dihydropyridine calcium channel blockers are preferred for their vasodilatory properties. Thiazides can be used, but caution should be exercised when administering them in cancer patients who are at high risk of intravascular volume contraction, such as those experiencing diarrhea, vomiting, or salt wasting, as they may exacerbate volume contraction and electrolyte imbalances. Thiazide diuretics should also be avoided in patients with hypercalcemia. Non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, can increase plasma levels of TKIs by inhibiting the CYP3A4 enzyme [24]. Beta-blockers are used in the presence of coexisting CHF, CAD, or arrhythmias and are effective in high sympathetic tone related to stress and anxiety. Nebivolol is the preferred beta-blocker due to its effects on nitric oxide bioavailability. Carvedilol is avoided in patients on asciminib due to the potential of increased levels [25]. Spironolactone and other potassium-sparing diuretics are particularly suitable for HTN induced by glucocorticoids, as they counteract salt and water retention as well as hypokalemia associated with their mineralocorticoid effect. Finally, Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors are frequently used for their anti-proteinuric, cardioprotective, and nephroprotective effects; however, studies proving their benefits, specifically pertaining to the VSPI population, are lacking.

BP monitoring should not stop after cancer therapy is complete, as cancer survivorship has been associated with long-term CV sequelae including HTN and CHF. Indeed, Armstrong et al. [35] found that the incidence of CHF was 12 times higher in childhood cancer survivors who developed HTN compared to those who remained normotensive. HTN significantly increased risk for CAD (RR 6.1), CHF (RR 19.4), valvular disease (RR 13.6), and arrhythmia (RR 6.0). HTN was also independently associated with the risk of cardiac death (RR 5.6; 95% CI, 3.2–9.7). Therefore, it is highly advisable that cancer survivors be followed closely in survivorship clinics, where a special emphasis is placed on aggressive CV risk factor management.

Both older and newer generations of chemotherapeutic agents have been linked to concurrent cardiotoxicity and nephrotoxicity through various mechanisms. Cardiac toxicity can affect all cardiac compartments including the myocardium, pericardium, and coronary arteries, and manifest as myocarditis, pericarditis, CHF, reduction in left ventricular (LV) function, arrhythmias, or MI/acute coronary syndrome [36]. Conversely, nephrotoxicity can also occur in all kidney compartments including the glomeruli, vascular epithelium, and tubulo-interstitium. Acute or chronic kidney failure may ensue and may be irreversible after chemotherapy interruption. Table 3 summarizes the cardiac and renal toxicities of commonly used chemotherapeutic agents.

Another observed mechanism of cardiotoxicity and nephrotoxicity with anti-cancer drugs is the occurrence of cardiorenal syndrome, characterized by acute decline in kidney function due to acutely decompensated CHF. This phenomenon is often associated with chemotherapy-related cardiomyopathy, which is classically described with anthracyclines (such as doxorubicin and daunorubicin) and trastuzumab. Cardiomyopathy can lead to a range of manifestations, from subclinical ventricular dysfunction to severe cardiomyopathy and overt CHF. The reported incidence of CHF with anthracyclines is 1.8% at 1-year post-treatment [52]. However, this risk escalates over the lifetime of childhood cancer survivors, who face a heightened risk of cardiac events at a young age, and around 5% risk of CHF at 40 years after cancer diagnosis [53]. The exact mechanism of cardiotoxicity with anthracyclines remains incompletely understood, but it is believed to be linked to the formation of iron complexes and the stimulation of free-radical formation leading to lipid peroxidation and DNA damage mediated by topoisomerase 2β. The cumulative dose of anthracyclines is the most predictive measure for the development of cardiotoxicity, although a genetic predisposition is also likely [54‒56].

On the other hand, trastuzumab can lead to LV dysfunction in 15–20% of patients. Trastuzumab-related cardiac dysfunction is typically reversible with discontinuation of therapy, and patients who have recovery of LV ejection fraction (LVEF) to above 40% after treatment cessation are candidates for rechallenge under close monitoring, especially if they are asymptomatic and if the perceived benefits outweigh potential risks in the context of limited alternative treatment options [30].

Both European and US guidelines [36] recommend a baseline cardio-oncology evaluation for screening and optimal management of CV risk factors before initiating chemotherapy. Early and aggressive screening for cardiotoxicity during treatment is also recommended, including the use of biomarkers such as cardiac troponin and natriuretic peptides (BNP and NT-proBNP) at baseline followed by serial assessment after subsequent chemotherapy cycles. Transthoracic echocardiography (TTE) is the preferred imaging modality for monitoring cardiac function and determining LVEF. If New York Heart Association (NYHA) class III or IV CHF develops, treatment should be held pending management and initiation of goal-directed medical therapy in collaboration with cardio-oncology. ACC guidelines suggest repeating TTE at least every 5 years in survivors, along with ongoing aggressive management of CV risk factors to mitigate the risk of long-term cardiotoxicity [57].

ICIs, encompassing anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1), and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies constitute an important milestone in cancer therapy within the last decade. Their application extends across various malignancies and disease contexts, reshaping established standards of care [58]. While these agents have demonstrated effectiveness, their application may trigger immune-related adverse events (IrAEs) affecting any organ system, including the lungs, gastrointestinal tract, skin, liver, heart, kidney, nervous system, blood vessels, endocrine glands, and eyes. IrAEs may occur in up to 50% of patients, influenced by the specific ICI administered, exposure time, screening approach, administered dose, and patient factors [59]. Combined anti-CTLA-4 and anti-PD-1 drug therapy often leads to more severe toxicities [60, 61]. Myocarditis and acute tubulointerstitial nephritis (AIN) are the most important manifestations of cardiac and renal toxicities, respectively [62], though subclinical and less fulminant forms of myocarditis and nephritis may have long-term implications which remain as yet unappreciated.

ICI can cause acute kidney injury (AKI) due to glomerular or tubulointerstitial disease, proteinuria, and electrolyte imbalances [63]. Renal IrAEs are much less common compared with other side effects such as colitis and skin toxicity. The incidence of ICI-related AKI is estimated to be around 2.2–3.5% in individuals undergoing PD-1 inhibitor therapy [64, 65]. This incidence increases significantly when combination therapy is used, reaching around 5% [66]. The use of non-steroidal anti-inflammatory drugs and proton pump inhibitors (PPIs) is associated with an odds ratio (OR) of 2.57 (95% confidence interval [CI] 1.68–3.93) and 2.42 (95% CI 1.96–2.97) for ICI-related AKI respectively [67]. The median interval between ICI initiation and AKI is about 14–16 weeks [68, 69] but it can also be much longer.

AIN, either independently or in conjunction with other kidney lesions such as acute tubular injury or immune-complex glomerulonephritis is the most prevalent cause of AKI on kidney biopsies, observed in 82–93% of cases [68, 69]. Pathological findings in cases of AIN-pattern injury show similarities to other drug-induced AIN characteristics, characterized by T-cell dominant infiltration in the renal interstitium, occasionally accompanied by plasma cells and eosinophils. Granuloma formation can be seen [70].

The cornerstone of ICI-related AKI consists of discontinuing the implicated agents, as well as administering a course of systemic steroids. Most cases achieve a full recovery, especially if steroids are started early (<3 days following ICI-AKI) [68, 71]. More potent immunosuppressive medications such as infliximab may be used in severe, refractory, relapsing and steroid-intolerant cases, or if there are coexisting non-renal IrAEs, but steroids still remain the standard of care [72]. Rechallenge with ICI is feasible, with only 16.5–23% of cases developing recurrent AKI [68, 69]. The role of prophylactic low-dose steroids with rechallenge has been proposed but remains debatable and requires more data.

ICI-related myocarditis is a rare but often devastating CV adverse event occurring early in ICI treatment, at a median onset of 27 days following ICI exposure [70, 73]. Its incidence rate is around 0.5%, lower than that of other CV toxicities seen with ICI exposure such as pericardial tamponade, MI, stroke, and CHF [74]. The clinical presentation of ICI-induced myocarditis is diverse, ranging from asymptomatic elevation in cardiac biomarkers to mild chest pain, and extending to life-threatening disease with cardiac study abnormalities and acute circulatory collapse [75]. Active myocardial inflammation is often noted on a cardiac MRI, but endomyocardial biopsy is more sensitive for establishing the diagnosis and should be considered when the diagnosis is unclear [76]. Fatality rates are higher with combined ICI therapy (anti-PD-1 or PD-L1 plus anti-CTLA-4), reaching 67% of cases, compared to 36% of cases with anti-PD1 or PD-L1 monotherapy [73].

Treatment of ICI-myocarditis is extrapolated from other IrAEs, generally consisting of ICI cessation, supportive therapy, and early high-dose steroid administration. Steroids should be started within the first 24 h of hospital admission as early, high-dose steroids are associated with improved MACE-free survival [77, 78]. Abatacept and Janus kinase (JAK) inhibitors (tofacitinib and ruxolitinib) have also been used successfully [79, 80], but robust evidence supporting this practice is lacking. Randomized trials are in progress to address these gaps in evidence.

The exact mechanisms by which ICIs cause myocarditis and nephritis are yet to be fully elucidated, but several mechanistic hypotheses exist [70]. First, ICIs can bind directly to non-lymphocytic cells in normal tissues to induce tissue injury through complement activation. Second, ICI may reactivate previously dormant antigen-specific T cells, which can recognize not only antigens expressed by tumor cells but also those expressed in healthy tissues such as the heart or kidney. Third, some evidence indicates that the inhibition of immune checkpoint molecules may increase levels of circulating cytokines within affected tissues, facilitating the infiltration of inflammatory molecules into non-target tissues. Lastly, another possibility is that the administration of antibodies against ICIs might increase the levels of autoantibodies against target organs or encourage the development of new autoantibodies.

In summary, the fields of onco-nephrology and cardio-oncology have developed over the last decade to address the challenges that accompany advances in the treatment of cancer patients. There are multiple intersections between these two specialties, highlighting the importance of multidisciplinary communication between oncologists, cardiologists, nephrologists, and other healthcare team members. This collaborative approach is essential to tailor therapy to the individual patient and to achieve the best anti-cancer effects while effectively mitigating side effects.

Rose Mary Attieh is the Galdi fellow in Glomerular Diseases and Onconephrology at Northwell with grant support from Greg and Linda Galdi. Kenar D. Jhaveri reports consultancy agreements with PMV pharmaceuticals, Secretrome, George Clinicals, Calliditas, and Otsuka Pharmaceuticals and reports honoraria from the American Society of Nephrology and Lexicomp; is a paid contributor to UpToDate.com; is section editor for Onconephrology for Nephrology Dialysis Transplantation; serves on the editorial boards of American Journal of Kidney Diseases, CJASN, Clinical Kidney Journal, Frontiers in Nephrology, Journal of Onco-Nephrology, and Kidney International; and serves as the Editor-in-Chief of ASN Kidney News. Belen Nunez and Robert S. Copeland-Halperin have nothing to disclose.

No funding was required for this manuscript.

R.M.A. and K.D.J. wrote the first draft. B.N. and R.C.-H. edited the final draft.