The improvement in survival rates worldwide presents new challenges in the fields of cardiology, nephrology, and clinical medicine in general. Elderly patients have unique characteristics that require a comprehensive geriatric assessment due to atypical disease presentations, susceptibility to polypharmacy, heterogeneity in aging, and multiple comorbidities (13).

Comprehensive geriatric assessment (CGA) is a diagnostic process that evaluates the cognitive, functional, and social conditions of elderly patients in a systematic, multidimensional, and dynamic manner. CGA is the most widely validated assessment in clinical practice that allows individualized diagnostic and therapeutic plans to be carried out to obtain the best results (1, 14). CGA requires time and specialized personnel. Scales like the Multidimensional Prognostic Index (MPI) and Edmonton Frail Scale (EFS) allow for an abbreviated assessment by non-geriatric physicians (15). The application of CGA is associated with lower mortality and improved survival rates (16). Furthermore, it is also associated with improved diagnostic accuracy, patient quality of life, quality of care, use of hospital resources, institutionalization, and costs.

HF is a clinical syndrome that mainly affects the elderly population and is the leading cause of hospitalization among those over 65 years of age (17). Hospitalization for HF is associated with increased comorbidity, requiring specific strategies aimed at this population. HF is characterized by the presence of cardinal symptoms and signs and results from a structural and/or functional cardiac abnormality, leading to decreased cardiac output and/or elevated filling pressures at rest or during exercise (18) (Figure 2).

Clinical guidelines use three categories to assess left ventricular ejection function: HF with reduced LVEF, HF with mildly reduced LVEF, and HF with preserved LVEF. Structural heart disease or diastolic dysfunction must be demonstrated in the last two cases, in addition to elevated natriuretic peptides. In HFrEF, treatment with neurohormonal blockers should be started with caution in elderly patients. Identifying the cause of cardiac dysfunction is crucial for determining appropriate treatment and deciding when non-intervention and palliative care are necessary. Frailty is a state of vulnerability due to a stressful situation associated with an increased likelihood of adverse outcomes. There are two approaches to characterizing frailty: •

On the one hand, the physical frailty phenotype considers frailty as a state before the disability. It relies primarily on finger grip strength tests and the gait speed test.

In acute situations, scales based on self-referenced questions or clinical judgment of healthcare personnel are helpful. A self-referenced question scale based on Fried's criteria can identify high-risk acute HF patients (23). The FRAIL scale and other scales based on impairment accumulation are also worthwhile. After symptom stabilization, measuring frailty with Fried's phenotype is feasible. Global scales such as the Clinical Frailty Scale or MPI may be useful in the advanced stages of the disease. Low physical activity and slow gait speed are independent predictors of death and rehospitalization for HF, and gait speed is not included in usual scores (24–26).

Frailty is not the same as disability. It is a stage prior to disability, which is associated with increased mortality, falls, hospitalization, functional deterioration, and institutionalization. For this reason, it should be assessed before disability occurs.

Although these patients are at greater risk of complications, the existence of frailty without an associated advanced disability does not in itself contraindicate any intervention. Decisions should be made in a multidisciplinary manner, requiring close monitoring and early intervention of those aspects that are modifiable.

Persistent symptoms characterize advanced HF despite maximal therapy, and its prevalence is increasing due to various factors (7). The prognosis is poor, with a one-year mortality rate ranging from 25% to 75%, and many patients die of cardiac causes unaware of their disease's prognosis (27). PC in HF patients improves the quality of life, depression, anxiety, and spirituality (28). Specific clinical, cardiac, and analytical markers were shown to be associated with poor HF prognosis (1).

When to consider palliative care? An interdisciplinary intervention in advanced HF patients consistently showed more significant benefits in quality of life, anxiety, depression, and spiritual well-being compared to usual care (28). Ideally, palliative care should be introduced early in the disease trajectory and increased as the disease progresses. Discussions about poor prognosis, the need for palliative care, and care goals can begin at annual HF review visits in less advanced stages or after each significant health-related event in more advanced stages (Figure 3).

Symptom control constitutes one of the essential pillars of PC. It enables relief of suffering, avoids futile life-prolonging measures, and promotes patient and family adaptation (Figure 3).

Bases of palliative care management in patients with HF: •

The treatment unit comprises the patient-family binomial (or inner circle). The family, as well as the patient, needs specific accompaniment and education for care and decision-making. Remember that the patient's fundamental nucleus of support resides both at home and in the hospital.

Patients with advanced HF and CKD (cardiorenal patients) may face similar considerations as other patients with advanced HF but with some specific factors. Due to their high comorbidity, symptom burden, and higher morbidity and mortality rates than the general population, cardiorenal patients are often suitable for PC. The palliative needs of cardiorenal patients and their families are like those of patients with progressive and incurable non-malignant diseases, such as cancer. Including PC in the care of cardiorenal patients can improve their quality of life, facilitate communication between patients and healthcare providers, optimize assessment and symptom management, promote functionality, provide psychosocial support, and help achieve adequate care coordination to reduce hospital admissions (31–33). Introducing PC programs would enable a smooth transition from active treatment to PC and facilitate the setting of care objectives that align with the patient's prognosis. These goals should prioritize the management of symptoms and respect the patient's preferences. They should be accessible from diagnosis to the end of life, and a multidisciplinary approach with effective coordination between specialists, primary care, and PC physicians is crucial (34) [Figure 5 (35)].

Although there is limited evidence, cardiorenal patients may benefit from traditional and modern guideline-recommended medication. However, when prescribing medications that may impact kidney hemodynamics or have increased accumulation and potential toxicity in the setting of kidney dysfunction, caution should be exercised. Renin-angiotensin-aldosterone system (RAAS) blockers and β-blockers are the most widely studied and used agents across the spectrum of CKD. Both can be used in patients on dialysis and those who are not, providing cardiovascular protection without an increased risk of adverse events (Figure 10). With regards to RAAS inhibitors, hyperkalemia is a well-known limitation in their prescription. New potassium-binding agents such as patiromer and zirconium cyclosilicate can reduce the risk of hyperkalemia and allow for more liberal use, preventing the need for dose reduction, suspending medications, and maintaining their benefits (49–51).

On the other hand, β-blockers should be included in the armamentarium of cardiorenal patients, especially in cases of heart failure with reduced ejection fraction (HFrEF) and chronic coronary syndromes. In patients requiring renal replacement therapies, the use of β-blockers should be based on dialysis treatment for adequate chronotherapy (i.e., pre- or post-dialysis session), [Figure 10 (52)].

Mineralocorticoid receptor antagonists (MRA) have demonstrated their protective effect in cardiorenal patients with solid evidence until glomerular filtration rate (GFR) 30 ml/min/1.73 m² (Figure 10). However, below GFR 30 ml/min/1.73 m², MRA should only be used in selected cases with strict control of renal function, potassium levels, and blood pressure. Similar precautions to those taken with RAAS blockers should be observed, mainly when combined. While non-steroidal MRAs such as finerenone have demonstrated a safer profile in diabetic kidney disease, there is still a lack of solid evidence endorsing their safety and efficacy in cardiorenal patients, as noted in Figure 10. New potassium binders can also reduce MRA-associated hyperkalemia, making their use safer (50).

Two novel therapeutic groups have recently emerged offering new tools for reducing residual renal and cardiac risk in non-dialysis CKD patients: angiotensin receptor–neprilysin inhibitors (ARNI) and sodium–glucose cotransporter two inhibitors (SGLT2i). Sacubitril/valsartan has strongly demonstrated a consistent reduction in cardiovascular events in patients with CKD (up to GFR 30 ml/min/1.73 m²) and HFrEF (Figure 10) (50). The indication of ARNI could be extended to HF with midrange ejection fraction (HFmrEF) and, with caution, to patients with advanced CKD (GFR 15–30 ml/min/1.73 m²) (51).

SGLT2i (empagliflozin, canagliflozin, and dapagliflozin) has established a new era in cardiorenal patient management. These agents have demonstrated a reduction in major adverse cardiovascular events (MACE) and major adverse kidney events (MAKE) in cohorts with and without diabetes, the whole spectrum of patients with HF (irrespective of left ventricular ejection fraction), and CKD (up to GFR 20 ml/min/1.73 m²) (Figure 10). In addition, iSGLT2 shows an excellent safety profile with very low adverse events (primarily genital and mild urinary tract infections) (50). Although the GFR limits their prescription, once started, they can be continued until renal replacement therapy is initiated. It should be noted that SGLT2i could present an initial and mild reduction in GFR that is not associated with adverse clinical events (53). Thus, this initial GFR decline should be comprehensively evaluated, avoiding withdrawal in most cases.

Deciding whether to prescribe medications for palliative care patients with cardiorenal disease is a clinical challenge due to the variable clinical course of the disease and the modest accuracy of mortality prediction models (54).

The advanced cardiorenal disease is characterized by a progressive decline in functional class and a gradual increase in the burden of symptoms that include pain, anxiety, depression, sleep disturbance, fatigue, and dyspnea (55).

While there are no defined guidelines for stopping medical treatments, it is essential to prioritize and discuss transitioning to symptom relief and improving the patient's comfort with the patient. In patients with severe functional or cognitive impairment and end-stage irreversible disease, medication withdrawal should be considered when the risks or futility outweigh the benefits, monitoring or administering the medication is challenging, or the patient's drug adherence is complicated (56). Guideline-recommended medical therapies such as ARNI and SGLT2i have improved dyspnea and quality of life (57). Thus, these therapies and others addressing symptom burden should be continued if well-tolerated (58). Potassium-binding agents like patiromer and zirconium cyclosilicate can counteract the risk of hyperkalemia and allow the use of RAAS blockade drugs (59). Beta-blockers can control tachycardia and angina, and digoxin may be considered for patients with atrial fibrillation and high heart rates if beta-blockers are stopped or reduced (60, 61). However, digoxin should be used cautiously or avoided in patients with decreased renal function (62). Regular review of medical therapy and monitoring for potential side effects such as hypotension or worsening kidney function is crucial. Dose reduction or discontinuation of therapies should be assessed individually (63).

On the other hand, congestion is a significant contributor to the development and worsening of dyspnea (64). Therefore, diuretic treatment and adjustment should be a therapeutic goal in all the phases of the disease. In advanced cardiorenal patients, sometimes higher doses of diuretics are required, and often in combination, for example, with a thiazide-like diuretic, metolazone, and carbonic anhydrase inhibitor, acetazolamide can be added to potentiate the natriuretic effects of loop diuretics (65).

Finally, re-adjustment or prescribing back therapies should be considered if the patient's clinical status improves.

Advanced cardiorenal patients often experience a cluster of symptoms, including asthenia, anorexia, and cachexia, which significantly impact their quality of life (66). Asthenia (Figure 14), a persistent feeling of fatigue and weakness, can be treated with non-pharmacological strategies such as exercise, sleep hygiene, and nutritional advice. In some cases, psychostimulants and nutritional supplements may be beneficial (73).

Around 60% of CKD patients suffer from pain, with increasing prevalence and intensity as the disease progresses (66–68). Pain has a significant impact on physical and mental quality of life, interfering with function, and is often undertreated due to incorrect assessment. The WHO analgesic ladder is a practical management approach, using paracetamol in the first step, tramadol in the second, and fentanyl, methadone, and buprenorphine in the third (74–76). In general, opioids with active metabolites that are excreted via the kidneys are not recommended, with a GFR of less than 30 ml/mn. Mainly including morphine, oxycodone, and hydromorphone, although there is much less data on the latter two (76–81).

Morphine clearance is similar in patients with altered and normal kidney function. However, some glucuronide metabolites significantly accumulate in patients with reduced kidney function. They may contribute to CNS depression, sedation, and severe and prolonged respiratory depression, which may be delayed in presentation (82).

There are no specific dose adjustments provided in the manufacturer's labeling. However, it is possible to find some recommendations on morphine dosing according to renal creatinine clearance (CrCl). For example, CrCl ≥60 ml/min: No dosage adjustment necessary; CrCl 30–<60 ml/min: Consider using an alternative opioid analgesic. If necessary, administer 50%–75% of the usual initial dose; also consider extending the dose interval. Titrate cautiously to response; CrCl 15–<30 ml/min: Avoid use. If necessary, administer 25%–50% of the usual initial dose; may also consider extending the dose interval. Titrate cautiously to response; CrCl <15 ml/min: Avoid use (83).

Pruritus, an unpleasant sensation that causes the desire to scratch, is common in advanced cardiorenal disease, affecting up to 40%–50% of patients (66, 67). Its multifactorial etiopathogenesis needs to be more adequately evaluated, leading to undertreatment. Treatment for uremic pruritus involves skin hydration as the primary measure. Additional therapies that have demonstrated efficacy include low-dose gabapentin and pregabalin, selective serotonin reuptake inhibitors, low-dose heterocyclic antidepressants, and opioid antagonists (84, 85).

Anxiety and depression are common in cardiorenal patients (66, 67). Depression is particularly prevalent and can lead to poor self-care and therapeutic adherence. Treatment for depression requires a multidisciplinary approach, including antidepressants, cognitive-behavioral therapy, or exercise training. SSRIs like fluoxetine and paroxetine are considered the safest and first-line choice if medication is necessary, while other options like trazodone and mirtazapine may also be used (86).

Insomnia is persistent difficulty initiating or maintaining sleep, accompanied by significant distress or impairment in functioning. Adequate sleep is essential for metabolic, endocrine, and immune system functioning. Cardiorenal patients often have sleep disorders and accompanying symptoms. Treatment involves addressing underlying factors, sleep hygiene, and medication (66–68). Restless leg syndrome (RLS) is a sensory-motor disorder characterized by uncomfortable sensations in the lower limbs during the night that are relieved by movement. Its prevalence in chronic kidney disease patients is up to 30%. Non-pharmacological approaches like cold dialysis, exercise, and physiotherapy have been effective in managing RLS, along with gabapentin as the preferred pharmacological treatment (87).

Shortness of breath is common in advanced stages of cardiorenal disease, and its intensity increases as the disease progresses. Dyspnea may be related to various factors, such as myopathy, sarcopenia, or frailty. However, it is often secondary to pulmonary congestion or low output caused by ventricular and/or valvular dysfunction. Maintaining drugs with cardiorenal benefits is vital to maintaining hemodynamic stability, achieving euvolemia, and decreasing venous congestion. In refractory dyspnea, opioids and home oxygen may be necessary during the final phase of the disease. Opioids improve dyspnea by acting on its central perception, achieving a decrease in metabolic rate and ventilation requirements. Its role in the control of dyspnea has been widely evaluated in the literature, with morphine being the most studied opioid and with the greatest experience of use, especially orally and subcutaneously. However, morphine (as explained above) (88) is not ideal due to the accumulation of active metabolites in renal failure with a higher risk of neurotoxicity (89). Alternative options should be proposed, considering first intranasal or subcutaneous fentanyl 100–200 mcg/4–6 h based on recent studies that include heart failure population, still limited for GFR under 15 ml/min. Evidence of absence or minimal neurotoxicity with these doses in scenarios like withdrawing dialysis suggests the potential benefit and absence of harm for these populations. However, there is still limited data (90–92). For opioids such as oxycodone, hydromorphone is still higher.

Whole-person care is essential for approaching ethically and clinically proper care during the last days of life for cardiorenal patients. Quality of care in this phase is highly determinant for the disease course. Poor quality of the dying process could take down the efforts experienced through the disease and therapeutic trajectory. No one can die again; it means we do not have a second chance for better care. The health care team and relatives have one opportunity to bring the best care in this profoundly human scenario, which should be understood more as a biographical than a clinical event (106).

The last days of life precede death and require specialized care emphasizing comfort and essential care. Recognizing this phase is challenging, particularly in hospitals focused on curative processes (107). When dyspnea or other symptoms are managed by dialysis, discontinuation may be appropriate. This change in therapeutic approach should be understood as one step in the overall therapeutic effort. Focusing on the human being and less on the dialysis technique can improve the quality of care (108).

It is described as a series of clinical signs of agony whose presence can predict death in the next few days. Mind and Hufkens evaluated eight criteria (107): (1)

White cold nose

The protocol Intro-PAC-WDC (90, 108) describes how to bring support for clinicians when withdrawal dialysis (WD) is needed. It focuses step by step on dealing with information for patients and relatives, teamwork regarding WD, bioethical considerations in every step, and adjustments of the therapeutic approach in the limiting therapeutic effort journey, among many other topics. It may be relevant for cardiorenal patients under dialysis.

The three most common symptoms in the last days of life are dyspnea, delirium, and pain (66, 109). Pain in the cardiorenal population is expected to be related to low cardiac output. Intranasal fentanyl has been shown to effectively control pain during the withdrawal of dialysis in a cohort of seven patients without signs of opioid-induced neurotoxicity (110). Midazolam may be prescribed in low doses for delirium, adjusted according to the Richmond Agitation Scale for Sedation (111, 112) [Figure 15 (111, 112)]. Palliative sedation therapy may be prescribed for refractory symptoms, but ethical authorization and selecting the right drug and doses are crucial. Keeping the family informed about drug prescriptions can help them understand and adjust to the end-of-life process (90).

It is essential to understand human and clinical suffering from an anthropological perspective. Clinicians who are not prepared to take care of suffering in clinical settings may act under one of these 3F: “flying,” avoiding the clinical scenario and providing poor quality of care; “frozen,” getting paralyzed and not running a decision-making process to provide the best care or “fighting” therapeutically and ordering diagnostic procedures or interventions not focused in the needed care (113). Being present and compassion are two essential elements clinicians should learn about to help the best care practice when the cardiorenal disease journey is approaching its end (114).

Patients with ACKD are not included in HF clinical trials. Furthermore, it is difficult to find funding to carry out clinical trials on symptomatic treatment adapted to cardiorenal patients, and sometimes ethical limitations may be found. For this reason, most of the recommendations are expert opinions. There is an evident need for further research to assess the efficacy of such care in areas such as symptom improvement, hospitalization reduction, impact on caregivers, and cost-effectiveness. This review is a promising foundation for future investigations in this crucial domain.

The writing group endorses the need for a dedicated palliative cardiorenal interdisciplinary team that leads the early identification of cardiorenal patients who need PC and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. This collaboration would also supervise cross-training among nephrology, cardiology, palliative care fellows, and nursing to foster a deeper understanding of the needs. This group also considers it mandatory to include patients with ACKD in clinical trials of drugs or devices indicated for HF. The results of clinical trials on SGLT2i or ARNI in patients on dialysis are awaited, which may provide us with more evidence-based recommendations.