Renal failure isn't just a nephrologist problem

Abstract

In the collective perception, uraemic patients are often identified as those undergoing dialysis. In reality, however, dialysis patients represent only a small fraction of the total uraemic population. Conservative estimates indicate that one in ten individuals in the industrialized world has some degree of renal dysfunction, meaning that approximately 700 million people are affected [GBD-Chronic Kidney Disease Collaboration. Global, regional, and national burden of Chronic Kidney Disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020;395:709–33]. These figures have rapidly made chronic kidney disease (CKD)—the correct term for renal failure—a global public health issue, owing both to its unsustainable economic burden for healthcare systems and its high mortality rate, estimated at 2.6 million deaths in 2017 [Saran R, Robinson B, Abbott KC, Bragg-Gresham J, Chen X, Gipson D et al. US Renal Data System 2019 annual data report: epidemiology of kidney disease in the United States. Am J Kidney disease 2020;75:S1–S64]. To mitigate the impact of this true epidemic, new strategies must prioritize early detection and prevention. The first step, however, is conceptual: CKD should no longer be regarded as an exclusively nephrological disorder but as a multisystem condition requiring the attention of internists, cardiologists, diabetologists, and general practitioners alike.

Introduction

Traditionally, nephrologists have played a central yet temporally limited role in the management of chronic kidney disease (CKD), typically intervening only in the advanced stages, when the disease has become irreversible and therapeutic options are few. The phenomenon of ‘late referral’, frequently criticized by nephrologists, reflects this reality: patients are often referred only after substantial renal impairment has already occurred.

However, CKD develops silently over many years, often asymptomatic and underdiagnosed, evolving ‘before our eyes’. Early identification would allow clinicians to alter its trajectory and improve outcomes, particularly now that effective therapies are available.

Given that cardiovascular complications remain the leading cause of death among uraemic patients, CKD should be recognized not only as a renal disease but also as a major cardiovascular risk condition.

Definition and classification of chronic kidney disease

Beyond the need for harmonized definitions, the first clarification concerns the definition and staging of CKD (Figure 1). For decades, attention has focused on the glomerular filtration rate (GFR) threshold of 60 mL/min/1.73 m², below which an official diagnosis of CKD is made. While correct, this definition omits an equally crucial aspect:

Figure 1.

Definition and staging of chronic kidney disease. Modified by https:/kdigo.org.

Individuals with normal or even elevated GFR (≥100 mL/min) must also be considered uraemic if they present microalbuminuria, defined as urinary albumin excretion between 30 and 300 mg/day or a urinary albumin-to-creatinine ratio of 30–300 mg/g.

Once regarded merely as a renal damage marker, microalbuminuria is now known to be a powerful predictor of endothelial dysfunction and systemic organ injury, strongly associated with increased cardiovascular and all-cause mortality, even among the general population and independently of GFR.¹

This recognition has major clinical implications: in a hypertensive patient, for instance, blood pressure control alone is insufficient if proteinuria remains untreated, as CKD progression will persist.

Cardiovascular risk in CKD

It is well established that cardiovascular risk increases with CKD severity.² Yet, this assumption can be misleading. Hypothetically following a cohort of asymptomatic individuals with a GFR of 60 mL/min—without a formal diagnosis or therapy—would reveal that, after 5–10 years, most would have died from cardiovascular causes (myocardial infarction, stroke, or heart failure) rather than progressed to dialysis.

Thus, the vast majority of patients with any degree of renal impairment die from cardiovascular disease before reaching end-stage renal failure.³

From this perspective, early CKD detection and timely intervention would not only reduce the number of patients progressing to dialysis but also markedly lower cardiovascular morbidity and mortality.

Historically, therapeutic efforts have focused on optimizing blood pressure⁴ and glycaemic control⁵ to mitigate renal decline. Yet consensus on ideal targets remained elusive, as evidenced by the SPRINT Research Group’s findings on intensive vs. standard blood pressure control⁶ and persistent concerns regarding severe hypoglycaemia associated with conventional antidiabetic therapy.⁷

The therapeutic revolution: SGLT2 inhibitors and beyond

A radical transformation in CKD management has occurred with the advent of sodium–glucose co-transporter-2 inhibitors (SGLT2-i).⁸ Initially designed as antidiabetic agents, dapagliflozin and empagliflozin, in particular, demonstrated remarkable nephroprotective properties in cardiovascular safety trials, significantly slowing renal function decline and improving prognosis.^9,10

Their efficacy surpasses that of angiotensin-converting enzyme inhibitors (ACE-Is)¹¹ and angiotensin receptor blockers (ARBs),¹² which, even in combination, long represented the only available therapy.¹³ Given the complex pathophysiology of CKD, combination therapy remains essential.

Recent years have seen an expansion of our therapeutic armamentarium, with novel agents capable of influencing disease progression and countering the historical sense of therapeutic nihilism (Figure 2). Alongside ACE-Is and ARBs, incretin-based therapies have emerged, offering anti-inflammatory properties and potential restoration of the tubule-glomerular structure.¹⁴

Figure 2.

Combination therapy in chronic kidney disease. Modified by https:/kdigo.org.

Moreover, finerenone, the first non-steroidal mineralocorticoid receptor antagonist (MRA), has shown superior efficacy and tolerability compared with its predecessors, warranting broader clinical adoption.^15,16

Nevertheless, the agents that have most profoundly transformed CKD management are undoubtedly the gliflozins, owing to their direct action on the mechanisms driving renal decline and their ability to reduce cardiovascular mortality in a population with otherwise grim outcomes.

The landmark trials DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease)⁹ and EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease)¹⁰ are pivotal in this regard. Both employed similar designs, composite endpoints, and statistical approaches, and both were terminated early due to clear evidence of benefit.

Although they enrolled distinct patient populations, together they demonstrated the broad efficacy of SGLT2 inhibitors across the CKD spectrum, regardless of baseline GFR, proteinuria, age, or concomitant therapies, yielding a 31% reduction in all-cause mortality and a 39% reduction in the composite risk of renal function worsening, end-stage renal disease, or CKD-related death—independent of diabetic status.

Conclusions

Chronic kidney disease represents not merely a nephrological condition but a systemic disorder with profound cardiovascular implications. The emergence of novel therapeutic classes—particularly SGLT2 inhibitors, incretins, and non-steroidal MRAs—has fundamentally reshaped the prognosis of this once relentlessly progressive disease.

The challenge now lies in early identification and integrated management, engaging not only nephrologists but also cardiologists, internists, diabetologists, and primary care physicians, to intervene before irreversible damage occurs.

Chronic kidney disease must be recognized as both a renal and cardiovascular disease, and its prevention, detection, and management must be shared responsibilities across all medical disciplines.

Funding

None declared.

Data availability

The data underlying this article are available in the article.

Disclaimer

This paper was originally published in the Italian language as ‘Siamo certi che l'insufficienza renale sia un problema dei nefrologi?’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2026”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.