Overcoming Renalism: A Roadmap Towards Equitable Kidney Care

Classical form of renalism: CVD-related care for CKD patients

Several studies have reported an almost 50% lower use of coronary intervention in patients with CKD versus those who do not have CKD.⁹ The paradox of underutilization of percutaneous coronary interventions (PCI) for the CKD population, who represent the patient group with the highest risk of death due to CVD, is driven primarily by intention to avoid harm, i.e., AKI due to contrast agents (i.e., contrast-associated AKI- CA-AKI). A meta-analysis reported a 12% burden of AKI post-angiography, with a pooled incidence of 20% CA-AKI-associated mortality. While higher AKI stages correlate with worse outcomes,¹⁰ adjusted hazard ratios for death of 2.0 in stage 1 AKI and 3.72 in stage 2 or 3, its long-term impact on renal function¹¹ remains debated. A study linked post-angiography AKI to sustained decline in kidney function. However, in the modern era of safer contrast agents and lower doses, the absolute risk of contrast-associated AKI is low. In advanced CKD, even a minor decline in kidney function might have significant consequences,¹² but CA-AKI, when it occurs, has a high likelihood of recovery. Avoiding contrast in patients with symptomatic, undertreated coronary artery disease (CAD) may lead to far greater harm than the risk of transient kidney injury.^13,14 In these studies, the comparator group generally consists of patients who did not have AKI post-coronary angiography. However, there are several factors to consider: what is the proportion of various stages of AKI post-angiography? What is the comparator group? What are the outcomes of patients with significant coronary disease who do not undergo intervention?

Amongst patients who develop AKI, most patients develop stage 1 AKI. Studies have shown that the urinary biomarkers of acute kidney injury were not raised in those who were diagnosed to have AKI compared to those who did not have AKI as per KDIGO staging criteria.^15,16 A recent study by Kim et al.¹⁷ showed that the AKI post PCIs is more of an outcome resulting from decreased systemic reserve rather than the contrast agent itself. A study by Kimura et al. showed that the deleterious long-term effects of AKI were mitigated in patients who were hemodynamically stable at the time of discharge from the hospital.¹⁸ It is possible that those with AKI had a worse CVD initially and were in definite need of PCIs. Hence, when analyzing the impact of the post-PCI-AKI, the comparator group must be adjusted for baseline coronary/cardiac disease severity, which is practically difficult because coronary angiography itself is the gold standard investigation to estimate the severity of CVD. Over the last few years, there have been several improvements in CA-AKI risk estimation¹⁹ as well as widespread availability of low-osmolar and iso-osmolar contrast media, which have helped in reducing renalism in this context. Instead of depriving the CKD patients of a possible life-saving PCI, it is prudent to risk-stratify these patients for the risk of AKI and institute preventive measures meticulously. This can lead to improved outcomes as demonstrated by a large study by Hirano et al.²⁰

Renalism in other cardiovascular outcome trials

A report from two decades ago by Charytan et al.²¹ revealed that >80% of large randomized cardiovascular trials excluded patients with ESKD, while 75% excluded those with moderate to severe CKD. In contrast, patients with other risk factors, such as diabetes, hypertension, or a history of smoking, were excluded in <4% of these trials. Adding to the issue of exclusion is the lack of reporting on renal function in many studies. Only 7% of cardiovascular trials reported the baseline renal function of participants, making it challenging to generalize their findings to the CKD population.²¹ This omission is particularly concerning given the high cardiovascular mortality rates among CKD patients and their altered response to standard therapies.²² Hypertension, more so when uncontrolled, is one of the most important risk factors for worse outcomes in CKD. The landmark trials in hypertension clearly show renalism in their recruitment.²³ This has steadily improved over the last few years, with many studies focusing on hypertension in CKD. A summary of some of the large hypertension trials^24-29 has been shown in Table 1.

Recent cardiovascular outcome trials such as FIDELIO-DKD and FIGARO-DKD have challenged the entrenched notion that patients with CKD are unlikely to benefit from intervention, a key driver of renalism. FIDELIO-DKD, which included patients with GFR as low as 25 mL/min/1.73m², demonstrated a significant reduction in kidney disease progression and cardiovascular events with finerenone therapy.³⁰ FIGARO-DKD, enrolling patients across a broader CKD spectrum (GFR 25–90 mL/min/1.73 m²), showed a clear cardiovascular benefit, particularly in reducing hospitalization for heart failure.³¹ The pooled FIDELITY analysis further reinforced these findings across over 13,000 participants.³² These trials send a powerful message: having CKD does not mean the therapeutic window has closed.

These exceptions notwithstanding, severe CKD and ESKD continue to be exclusion criteria for most of the hypertension trials. A similar exclusion of moderate to severe CKD is evident in most of the renal denervation trials³³ and heart failure trials,^34-36 [Table 2]. Renalism gets compounded with ageism because most elderly patients have reduced GFR and are likely to be excluded from CV trials.³⁷

Even for widely used medications like statins, data in advanced CKD, particularly in dialysis patients, remains less robust than for the general population. In the Cholesterol Treatment Trialists’ Collaboration meta-analysis,³⁸ participants with GFR ≤30 mL/min/1.73m² (12,421) were vastly outnumbered by those with GFR >60 mL/min/1.73m² (123,560). Consequently, major coronary events were also far fewer (893 vs. 7,378), leading to imprecise and uncertain estimates of benefit. Even today, the role of statins in dialysis remains debated. For dialysis and transplant patients, renalism results in delayed or uncertain guidance on widely used therapies, from cardiovascular drugs like statins to novel therapeutics. Dialysis patients are frequently excluded due to concerns about drug clearance, while transplant recipients face exclusion due to immunosuppressive therapy interactions.

Large observational studies have shown that the patient and graft survival after kidney transplantation have steadily improved in the last few decades owing to the availability of efficacious immunosuppressants. The common causes of mortality in kidney transplant recipients are cardiovascular events³⁹ and infections.⁴⁰ Despite this, there are inconsistencies in the reporting of cardiovascular outcomes, and trials aiming to improve cardiovascular morbidity and mortality in this population subset are scarce.⁴¹

Renalism in non- CVD diseases and COVID-19

Renalism is evident in other clinical domains such as infectious disease, eg, COVID-19, oncology, critical care, and some rheumatological diseases, as shown in Table 3.

Renalism in COVID-19 trials

The implications of renalism became even more evident during the COVID-19 pandemic. Patients with advanced CKD, including those on dialysis, are at a higher risk for severe outcomes from COVID-19 due to their immunocompromised state. Yet, a 2020 review by Major et al.⁴² found that nearly half of all registered COVID-19 trials excluded CKD patients. This exclusion extended to studies evaluating pivotal treatments such as nirmatrelvir/ritonavir (Paxlovid), despite its potential relevance to this vulnerable population. Subsequent advocacy efforts have proposed dose adjustments and pharmacy oversight to safely extend Paxlovid use to advanced CKD patients and kidney transplant recipients, underscoring the need for more inclusive clinical trial approaches.⁴³

Renalism in onconephrology

Despite ongoing efforts by regulatory agencies, such as the U.S. FDA, to encourage the inclusion of CKD patients in clinical trials, significant gaps persist. For instance, a study by Butrovich et al. analyzing anticancer agents approved between 2015 and 2019 found that 95% of trials included kidney-related exclusion criteria.⁴⁴ Despite the high prevalence of kidney disease among cancer patients, these individuals are often excluded from clinical trials of cancer therapies.

A systematic review of 310 randomized controlled trials across the five most common solid tumors found that 85% explicitly excluded patients with CKD. The majority applied serum creatinine or creatinine clearance thresholds, often excluding those with CrCl <60 mL/min, rather than more accurate eGFR-based estimates.⁴⁵ Notably, many of these trials involved agents such as immunotherapies or targeted biologics, for which renal clearance is negligible and exclusion may not be clinically justified. As a result, oncologists are frequently left without evidence-based guidance for treating this substantial and high-risk subgroup, perpetuating therapeutic uncertainty and reinforcing renalism.

The situation is even more concerning in hematologic malignancies like multiple myeloma, where renal impairment is both common and prognostically significant. Up to 30-50% of patients with myeloma present with renal dysfunction, yet most major trials, including the recent PERSEUS (“A Phase 3 Study Comparing Daratumumab, VELCADE® (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) with VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects with Untreated Multiple Myeloma for Whom Hematopoietic Stem Cell Transplant Is Not Planned as Initial Therapy”) study, have excluded those with eGFR <30 mL/min/1.73m² or dialysis dependence.⁴⁶ This continued exclusion leads to a gap in randomized data, leaving clinicians to rely on limited observational studies and clinical judgment. Importantly, clinical experience suggests that patients with advanced CKD or on dialysis can respond well to myeloma therapies when appropriately managed. Renal dysfunction should not be equated with therapeutic futility.

The adverse effects of renalism are particularly evident in the treatment of metastatic urothelial carcinoma (mUC), as demonstrated in a study by Côté et al., published recently.⁴⁷ The study found that patients with kidney disease who were excluded from standard cisplatin-based chemotherapy had significantly worse survival compared to those who received the standard treatment. This finding highlights the urgent need to reassess cisplatin eligibility criteria for patients with kidney disease and underscores the importance of exploring alternative treatment strategies, including immunotherapy, targeted therapies, and other novel approaches for treating mUC in CKD patients.

Renalism in critical care

Another notable example of renalism in clinical trials is the limited representation of patients with CKD in studies evaluating fluid selection and management in critically ill patients.⁴⁸ Fluid management is a key component of critical care, especially in conditions like sepsis, acute respiratory distress syndrome (ARDS), or shock. The approach to fluid resuscitation and de-escalation, along with the choice of fluids, can significantly impact patient outcomes. However, despite the high prevalence of kidney disease among critically ill patients, CKD individuals are often excluded from trials exploring fluid management strategies. This precautionary approach may be preventing the inclusion of a vulnerable and high-risk population in studies that could benefit from better-tailored fluid management strategies. As fluid selection is a critical component of critical care, it is essential that studies in this area begin to include CKD patients, as they represent a significant proportion of those treated in intensive care units. In the absence of data specific to CKD patients, clinicians may resort to general treatment guidelines, which do not account for the unique challenges faced by patients with kidney disease. What is perpetuating Renalism in non-CVD trials?

The exclusion of patients with renal impairment in most of the non-CVD trials is typically based on serum creatinine levels, a crude marker of kidney function, rather than more accurate measures such as the GFR.⁴⁹ Furthermore, it is often applied even for drugs that do not rely on kidney metabolism or clearance, raising concerns about the validity of such decisions. As a result, the lack of clinical trial data specific to CKD patients translates into limited information for clinicians, preventing many patients from receiving potentially life-saving or life-prolonging therapies.

Relevance and measures of reducing renalism

The Global Burden of Disease (GBD) Chronic Kidney Disease Collaboration reports a 29.3% increase in CKD prevalence globally from 1990 to 2017.^50,51 CKD has been identified as a leading contributor to premature mortality among NCDs, with deaths rising by 50% from 2000 to 2019.⁵² The future of care for patients with kidney disease seems hopeful with efforts such as the Global Kidney Health Atlas by the International Society of Nephrology⁵³ and WHO-backed initiatives aiming to increase awareness and prioritize kidney health on the global health agenda. Addressing renalism requires eliminating biases, enhancing early detection, and ensuring equitable access to quality kidney care for all individuals.

Renalism, therefore, effectively denies individuals their fundamental right to health by perpetuating inequities in access to both clinical care and clinical research. Vulnerable groups, such as elderly patients, women, and ethnic minorities with CKD, are doubly disadvantaged, receiving less evidence-based care while also being underrepresented in clinical trials. Addressing renalism requires a multi-pronged strategy: eliminating implicit bias, enhancing early detection, optimizing therapeutic decisions, and ensuring equitable access to both established and novel therapies.

At the level of caregivers, efforts to combat renalism require a paradigm shift in how CKD patients are perceived and treated. One of the most concerning manifestations of renalism is the systematic underuse of guideline-directed medical therapies in CKD patients. For example, data from large cardiovascular registries and observational studies consistently show that patients with moderate to advanced CKD are significantly less likely to receive standard-of-care therapies such as RAAS inhibitors, SGLT2 inhibitors, or statins, even when clearly indicated. In the PARADIGM-HF trial, only 15% of participants had an eGFR <60 mL/min/1.73m², despite CKD being common among patients with heart failure. Similarly, in routine practice, patients with eGFR <15 mL/min/1.73m² are often excluded from therapies like GLP-1 receptor agonists, mineralocorticoid receptor antagonists, despite emerging evidence of safety and benefit when dosed appropriately. Overcoming renalism requires proactive inclusion strategies, such as pharmacokinetic-guided dosing and dedicated subgroup analyses, ensuring these high-risk populations receive evidence-based care rather than being left in a clinical gray zone. Educating clinicians about the nuanced risks of interventions in CKD patients can help dispel myths that perpetuate therapeutic nihilism.

Designing research studies and generating evidence on the impact of renalism on clinical outcomes can go a long way in sensitizing treating physicians to treat patients with kidney disease with the best available care. Similar to the efforts being made to include women and children in clinical trials,^54,55 especially on drugs or interventions likely to benefit these population, regulatory mandates and funding agencies should ensure CKD inclusion in clinical trials, particularly those evaluating interventions with high cardiovascular, critical illnesses, and oncological relevance [Table 4]. There should be a mandate on testing new drugs or therapeutic modalities in CKD patients of all stages within a stipulated timeframe, if not initially.

Beyond regulated industry trials, renalism also extends to investigator-initiated trials, but it is possible to mitigate renalism. A notable example is the evolution of renal function-based eligibility criteria from ACCORD to SPRINT. In ACCORD BP, kidney function was only used as an exclusion criterion, whereas SPRINT deliberately enriched its study population with CKD patients, aiming to assess outcomes in those with and without CKD. This shift reflected growing awareness of renalism over the intervening years, as well as the involvement of nephrologists in trial design, development, and steering committees. SPRINT initially planned for 46% of participants to have CKD (GFR 20-59 mL/min/1.73m²), though the final proportion reached only 28%. Table 5 summarises renalism in critical care, and depicts renalism in clinical trials across domains, causes, and solutions. Figure 1 shows the actionable steps that can be taken to mitigate renalism.

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Figure 1:

Actionable steps to overcome renalism.

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In conclusion, reducing renalism is not a matter of scientific complexity but of ethical and systemic reform. The global burden of CKD necessitates urgent, coordinated action to eliminate the longstanding exclusion of CKD patients from clinical trials and evidence-based care. Regulatory authorities must mandate the inclusion of CKD populations in pivotal trials, with exclusions justified only by robust early-phase or pharmacokinetic data, and ensure that drug labels provide nuanced dosing guidance rather than categorical contraindications. Achieving equity in kidney care requires a paradigm shift across academic, clinical, and regulatory domains, one that prioritizes inclusion, scientific integrity, and informed therapeutic decision-making. Through such reform, CKD patients can be meaningfully integrated into the mainstream of healthcare innovation and delivery.