Chronic kidney disease (CKD) is defined as the presence of alterations in kidney structure or function that negatively impact health for more than 3 months. The combination of glomerular filtration rate (GFR) and albuminuria allows for risk stratification of various adverse outcomes, including progression to kidney failure requiring kidney replacement therapy and premature death from cardiovascular (CV) and non-CV causes.1–4 In fact, the increased risk of premature death is the main consequence of CKD and is not corrected by dialysis or transplantation. These factors are associated with a loss of life expectancy of up to 44 years as compared to the general population.5 Consequently, CKD is expected to become the third leading cause of death in Spain before 2050, this is largely due to the aging of the population.6 Type 2 diabetes mellitus (T2DM) is a significant risk factor for the development of CKD which affects one-third of patients with T2DM.7 Multiple factors contribute to the pathogenesis of CKD, primarily metabolic, hemodynamic, and inflammatory/fibrotic alterations.1,8–10

In Spain, the prevalence of T2DM has been estimated at 7.8% in the adult population, increasing to 13.8% when undiagnosed patients are included.11 Among adults with T2DM, a 33.8% have CKD, and 21.2% have albuminuria (category A2–A3).7

Despite the current treatments, many patients with T2DM develop severe forms of CKD and maintain a high residual risk of CV death and disease progression, even despite receiving renin-angiotensin system (RAS) inhibitors and sodium-glucose cotransporter 2 (SGLT2i) inhibitors.8,12,13 This may be influenced by poor glycemic control, blood pressure, and patient lifestyle.14 Furthermore, the absolute residual risk is increased with higher albuminuria or lower baseline GFR.15 The dynamic nature of the residual risk depends on disease duration and the effectiveness of therapeutic interventions. It is crucial to consider in clinical trials factors such as disease duration, glycemic control, blood pressure, proteinuria, and renal function to adequately identify and manage residual risk in patients with CKD and T2DM.16 The pharmacological approach to residual risk is based on a comprehensive approach based on pharmacological control of glucose, lipids, and hypertension, as well as inflammation and fibrosis. Clinical guidelines suggest the use of SGLT2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), aldosterone-reducing enzyme inhibitors (RAAS) with angiotensin-converting enzyme inhibitors (ACE inhibitors), or angiotensin II receptor blockers (ARBs1,17,18). Furthermore, nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) have demonstrated benefits in renal and cardiovascular protection,19 and are recommended by clinical practice guidelines such as the Kidney Disease Improving Global Outcomes (KDIGO), the American Diabetes Association (ADA), and the European Society of Cardiology guidelines.4,17,20–22

However, currently no consensus definition of residual risk has been established in patients with CKD and T2DM. In this sense, there are still areas of residual risk associated with CKD that remain unknown, such as the interaction of genetic factors with the environment, the complete molecular mechanisms, and the long-term effectiveness of new treatments.

Given the uncertainty surrounding residual risk in patients with CKD and T2DM, the objective of this study was to evaluate the degree of multidisciplinary consensus on the persistent residual risk, from the perspectives of nephrology, endocrinology, and family medicine, despite standard treatment in Spain of these patients and its possible therapeutic approach.

A 100% response rate was obtained from the 60 specialists in the two rounds of the Delphi study. A 72% of the panelists had more than 15 years of work experience, 70.0% saw more than 25 patients with CKD associated with T2DM monthly, and all belonged to a scientific society (Appendix B, Table S1 of the supplementary material).

In the first round of Delphi, the defined level of agreement was reached for 43 statements out of the 76 statements initially included (56.6%). The consensus-based statements were excluded from the next round, but two new statements were added and another one was reformulated. In the second round, the defined level of agreement was reached for 10 statements out of a total of 35 statements (28.6%). Overall, after the two rounds, the defined level of agreement was reached for 53 of the 78 statements included in the questionnaire (67.9%).

The section with the highest number of consensus statements was the residual risk section (86.4%), followed by the section of therapeutic strategy (73.9%), and the therapeutic management section (51.5%) (Fig. 2, Appendix B, Table S1 of the supplementary material). The statements and results (median, 25th percentile, and 75th percentile) from the first and second rounds are presented in Appendix B, Table S2 of the supplementary material.

Figure 2.

Results of Delphi study grouped and per sections.

This study gathers the experience-based opinions of various specialists, including nephrologists, endocrinologists, and family physicians, providing diverse perspectives on residual risk and its management in patients with CKD and T2DM.

The results of the Delphi study indicated that patients with CKD associated with T2DM have a high residual risk of disease progression, renal and cardiovascular complications, and premature death. Furthermore, the panelists considered that this residual risk persists despite current therapeutic interventions and underscored the urgent need for more effective approaches.

It was found that there are numerous studies published showing that, despite receiving standard treatment, many patients with CKD associated with T2DM continue to be at high risk of complications, highlighting the importance of more comprehensive and personalized approaches. However, identifying and managing residual risk is complex and requires ongoing assessment and a personalized approach to the treatment. This involves not only controlling traditional risk factors but also considering other factors that may contribute to disease progression.25

Given this challenge, the panel considered that residual risk management must be comprehensive and dynamic to adequately address the needs of these patients. Strategies to address residual risk in patients with T2DM and CKD, supported by the Delphi study consensus, include the simultaneous, early, and intensive implementation of the three pillars of treatment: RAAS inhibitors, SGLT2 inhibitors, and nsMRAs. These drugs, with complementary mechanisms of action, offer significant benefits in managing residual risk for these patients.

It should be taken into consideration that first, the use of RAASi have been shown to reduce renal progression in both diabetics26,27 and non-diabetics,28 but only modestly, leaving much residual risk to be resolved. Second, SGLT2i improves glycemic control, reduce intraglomerular pressure and proteinuria, and offer benefits of cardiovascular disease and heart failure. However, 10% or more of patients with CKD treated with SGLT2i and RAASi experienced disease progression during a relatively short follow-up of 2–3 years.29,30 Blood pressure levels are higher in patients with more advanced CKD, up to 15% in those patients with higher albuminuria. These treatments do not directly target inflammation, oxidative stress, and fibrosis pathways, so additional therapeutic options are needed to block these pathogenic mechanisms.31 Third, nsMRAs significantly reduce proteinuria and slow the progression of CKD, thus improving kidney function and reducing CV risk in a complementary manner to the two axes mentioned above.8,32 Furthermore, the triple combination was safer than dual combinations.33 Therefore, the combination of these treatments addresses multiple pathogenetic pathways of CKD and T2DM, providing a robust and multidimensional therapeutic strategy.

The international clinical practice guidelines that were considered reference guidelines by the panelists' consensus, namely the KDIGO and ADA guidelines,17,20 also reinforce this approach by covering all three treatment pillars. The therapeutic algorithms of Spanish scientific societies, including the consensus document by García-Maset et al.1 in 2022, recommend a holistic approach to the disease, although at the time of publication, finerenone was not yet marketed. In other diabetes and CKD guidelines, such as the one from the redGDPS foundation, prepared in 2023, the approach of the 3 pathways is recommended in a manner aligned with the KDIGO and ADA guidelines,34 as well as the guidelines for the management of patients with CKD and DM published by the Spanish Society of Nephrology and the Spanish Diabetic Nephropathy Study Group (GEENDIAB).22

Sin embargo, es importante resaltar que los panelistas no lograron alcanzar un consenso o, en su defecto, lo hicieron con puntuaciones intermedias (de 4 a 6 en la escala) en relación con las afirmaciones sobre el manejo y seguimiento de los pacientes, así como en lo que respecta a la administración de tratamientos en la práctica clínica. Esto refleja que persiste la necesidad de avanzar en este ámbito y optimizar la gestión de estos pacientes, ya que actualmente hay una gran variabilidad en el manejo de los mismos en la práctica clínica.

Por lo tanto, es fundamental adoptar un enfoque integral y multidisciplinar que permita minimizar el riesgo residual y optimizar los resultados a largo plazo en pacientes con ERC asociada a DMT2.

La metodología Delphi permite a los participantes expresarse libremente sin la influencia de líderes de grupo. Sin embargo, el estudio presenta las limitaciones propias del método Delphi, como el sesgo de selección de los expertos, porque los criterios para la selección de los panelistas puede que no hayan identificado adecuadamente a los que cuenten con mayor experiencia en este campo. No obstante, los miembros del comité científico sí que contaban con una amplia experiencia con el trato de pacientes en este ámbito. Por otro lado, el uso de un cuestionario estructurado podría restringir los resultados del estudio.

The panel also agreed on a series of non-pharmacological strategies that could be beneficial for effectively addressing residual risk, such as lifestyle modification and closer monitoring of the urine albumin-to-creatinine ratio and GFR. Furthermore, mitigating therapeutic inertia was considered essential, making advisable to establish continuous monitoring and proactive treatment adjustments to respond to disease progression and individual patient needs.

Another agreed strategy was the effective coordination of different levels of care for the comprehensive management of residual risk. Indeed, fluid communication and collaboration between primary care, specialized care, and other health services would ensure a cohesive and continuous approach to patient care, optimizing clinical outcomes.

Finally, promoting telemedicine could facilitate patient follow-up, allowing easier access to care and continuous monitoring of their health. Telemedicine in the management of CKD allows patients to access remote consultations and monitoring, facilitating health follow-up without the need for travel.35 Furthermore, it would promote patient education and multidisciplinary collaboration, thereby improving the quality of care and treatment adherence.35 Implementing these strategies can help mitigate residual risk and improve the quality of life of patients with CKD.

However, it is important to highlight that the panelists either failed to reach consensus or, alternatively, reached intermediate scores (4–6 on the scale) regarding statements about patient management and follow-up, as well as the administration of treatment in clinical practice. This reflects the persistent need to advance in this area and optimize the management of these patients, since currently there is great variability in their management in clinical practice.

Therefore, it is essential to adopt a comprehensive and multidisciplinary approach that minimizes residual risk and optimizes long-term outcomes in patients with CKD associated with T2DM.

The Delphi methodology allows participants to express themselves freely without the influence of group leaders. However, the study suffers from the limitations inherent to the Delphi method, such as expert selection bias, as the criteria for selecting panelists may not have adequately identified those with the most experience in this field. However, the members of the scientific committee did have extensive experience treating patients in this field. Furthermore, the use of a structured questionnaire could restrict the study's results.

Multidisciplinary consensus was reached that in patients with CKD and T2DM have a high residual risk of disease progression, premature death, and renal and cardiovascular complications. Measures considered relevant to reduce residual risk in these patients, in which there is multidisciplinary consensus, include simultaneous, early, and intensive initiation of the three treatment pillars (ACE inhibitors/ARBs + SGLT2 inhibitors + nsMRAs), avoiding therapeutic inertia, and promoting coordination between the different levels of care.

This work was funded by Bayer. Bayer participated in the design, data analysis, and writing of the manuscript. The authors received no honoraria for authorship.