At the 29th Hong Kong Medical Forum, Professor Bobby Chacko of the University of Newcastle, Australia, discussed a topic of urgent global relevance: advancing renal protection strategies for a broader impact in chronic kidney disease (CKD). This editorial summarizes and expands upon the key points discussed — particularly the imperative to transition from knowledge to action in chronic kidney care.
The global burden: Beyond CVD and diabetes
Cardiovascular disease (CVD) remains the world’s leading cause of mortality. In parallel, diabetes continues its rapid ascent; the 11th edition of the IDF Diabetes Atlas, released at the recent World Diabetes Congress, reports 589 million people globally with diabetes — a figure expected to rise to 853 million by 2050. Yet, kidney disease is already at that threshold. The global burden of CKD reached an estimated 850 million as early as 2017. [Glob Heart 2024;19:11; IDF Diabetes Atlas, 11th edition; Kidney Int 2019;96:1048-1050]
“This convergence of conditions creates a high-risk triad: CVD, diabetes, and CKD — each influencing the other in a complex pathophysiological interplay,” highlighted Chacko.
Pumps, pipes, and filters: A simplified spectrum
“The cardio-kidney-metabolic continuum of diabetes can be envisioned as affecting the ‘pumps, pipes, and filters’. The pump represents the heart [with conditions such as heart failure and left ventricular hypertrophy], the pipes signify vasculature affected by atherosclerosis and major adverse cardiac events, and the filter is the kidney — compromised by albuminuria and declining function,” said Chacko.
These disease processes are not isolated. Hypertension, diabetes, and heart disease contribute in varying degrees to the development and progression of CKD, forming what can be called the cardio-kidney-metabolic (CKM) syndrome. [Circulation 2023;148:1606-1635; Circulation 2021;143:1157-1172]
Evidence-based pharmacotherapy: Time for broader implementation
“The past decade has seen transformative advances in pharmacologic management of CKD, particularly in patients with type 2 diabetes [T2D],” noted Chacko.
Agents such as sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) have demonstrated robust cardiorenal benefits. [N Engl J Med 2023;388:117-127; N Engl J Med 2020;383:1436-1446; N Engl J Med 2023;389:2221-2232; Eur Heart J 2022;43:474-484]
The 2022 and 2024 KDIGO Clinical Practice Guidelines now recommend SGLT2 inhibitors for nearly all CKD patients with an estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio (UACR) ≥200 mg/g, regardless of diabetes status. These recommendations carry a Class 1A designation — the highest level of evidence-based endorsement. SGLT2 inhibitors also received a 2B recommendation for treating CKD patients with an eGFR of 20–45 mL/min/1.73m2 and a UACR of <200 mg/g. [Kidney Int 2022;102:S1-S127; Kidney Int 2024;105:S117-S314]
“Management should begin with lifestyle modification, followed by metformin and SGLT2 inhibitors, renin-angiotensin system [RAS] blockers, and statins. GLP-1 receptor agonists and nsMRAs can be introduced as additional or adjunctive therapies based on glycaemic and blood pressure [BP] targets,” advised Chacko. “This algorithm reflects a necessary shift toward proactive, organ-protective prescribing.”
Safety profile of SGLT2 inhibitors in CKD management
“As the adoption of SGLT2 inhibitors expands across CKD and cardiometabolic care, it is vital to maintain a vigilant approach to their adverse event profile,” pointed out Chacko. “While these agents have demonstrated robust renal and cardiovascular protective effects, they are not without risks.”
Diabetic ketoacidosis, although rare, is a notable concern — particularly in patients reducing insulin doses or those experiencing prolonged fasting, such as during preoperative periods. To mitigate this risk, clinicians should avoid abrupt withdrawal of insulin and ensure appropriate pausing of therapy before surgery. [Diabetologia 2023;66:23-32]
Genitourinary infections, including urinary tract infections and genital mycotic infections, are relatively common and underscore the need for patient education on personal hygiene. [J Am Coll Cardiol 2024;83:1568-1578]
Volume depletion, while not universally problematic, warrants attention in elderly patients — especially those concurrently on diuretics with borderline low BP. In such cases, a prudent reduction in diuretic dosage at the time of SGLT2 inhibitor initiation may prevent hypotensive episodes. [Age Ageing 2022;51:afac201]
Finally, early signals of increased limb amputation risk associated with canagliflozin prompted concern, although this has not been observed with other agents such as dapagliflozin or empagliflozin. Nevertheless, routine foot examinations and regular podiatric follow-up remain essential, especially in patients with peripheral vascular disease or diabetes-related foot complications. [Cardiovasc Diabetol 2021;20:91]
“Proactive risk mitigation will be key to maximizing the therapeutic benefits of SGLT2 inhibitors while ensuring patient safety,” pointed out Chacko.
EMPA-KIDNEY: Protection in CKD patients with or without albuminuria
Empagliflozin continues to redefine the therapeutic landscape of CKD with its compelling evidence base. From the landmark EMPA-REG OUTCOME trial to the more recent EMPA-KIDNEY study, the breadth of protection offered by this SGLT2 inhibitor spans the full spectrum of kidney function: from low to high eGFR, and from no albuminuria to severely increased albuminuria. (Figure 1) [N Engl J Med 2015;373:2117-2128; N Engl J Med 2023;388:117-127]
Notably, the global prevalence of nonalbuminuric renal impairment in T2D is increasing. The increase may indicate changes in the underlying pathology of renal disease in T2D, with macroangiopathy becoming more prominent than microangiopathy. Additionally, changes in treatment strategies, particularly more rigorous control of blood glucose, lipids, and BP, may also contribute to this trend. (Figure 2) [J Hypertens 2011;29:1802-1809]
The multicentre RIACE study (n=15,733) revealed that among patients with T2D and renal impairment, 56.6 percent were nonalbuminuric. Nonalbuminuric stage ≥3 CKD was associated with a higher prevalence of CVD vs albuminuria with stage 1–2 CKD. These data showed that the phenotype of T2D and nonalbuminuric CKD was associated with a significant CVD burden. (Figure 2)
However, unlike EMPA-KIDNEY, normoalbuminuric CKD patients were not included in the CREDENCE and DAPA-CKD trials. (Figure 1) [N Engl J Med 2019;380:2295- 2306; N Engl J Med 2023;388:117-127; N Engl J Med 2020;383:1436-1446]
EMPA-KIDNEY: Shifting the paradigm toward early kidney protection
Importantly, the long-term findings of the EMPA-KIDNEY trial demonstrated a durable “legacy effect”. Benefits of empagliflozin persisted for up to 1 year after drug discontinuation, underscoring the depth of its disease-modifying potential. Notably, the most pronounced benefits were observed within the first 6 months of treatment — highlighting the importance of early initiation. [N Engl J Med 2025;392:777-787]
“However, this should not be misconstrued as a reason to stop therapy. On the contrary, sustained treatment is essential to maintain these protective effects over time,” emphasized Chacko.
“In essence, EMPA-KIDNEY has moved the needle decisively toward earlier intervention in CKD care, reinforcing the principle that renal protection should begin well before advanced disease sets in,” he remarked. “The message is clear: to preserve kidney function and improve outcomes, early and continuous empagliflozin use should be a cornerstone of CKD management.”
CKM syndrome: A new paradigm of holistic health
Emerging concepts like CKM syndrome, as described by the American Heart Association in 2023, emphasize the interconnectedness of obesity, inflammation, CVD, and CKD. The CKM framework stratifies disease progression from stage 0 to stage 4 and aligns with public health messages such as Life’s Essential 8 and the Eight Golden Rules of Kidney Health — a fusion of behavioural and physiological risk factor control. [Circulation 2023;148:1606-1635; www.heart.org/en/healthy-living/healthy-lifestyle/lifes-essential-8; www.worldkidneyday. org/about-kidney-health]
At the heart of this model is early detection. CKD is often silent — up to 90 percent of kidney function may be lost before symptoms emerge. Early screening, using serum creatinine (to estimate GFR), urine albumin tests, and BP measurements, must be prioritized. In resource-limited settings, urine dipstick testing remains a pragmatic alternative to formal UACR measurement. [www.betterhealth.vic.gov.au/health/conditionsandtreatments/kidney-disease; Kidney Int 2024;105:S117-S314; Hong Kong Med J 2024;30:478-487]
Clinical inertia: The hidden enemy of progress
Despite compelling evidence and clear guidelines, implementation remains dismal. Studies in the US showed that only 5.2 percent of eligible patients with T2D are treated with SGLT2 inhibitors. Even among those initiated on therapy, persistence beyond 90 days is low. [Eur J Prev Cardiol 2017;24:1637-1645; Diabetes Metab Res Rev 2021;37:e3350]
“This reflects the pervasive impact of clinical inertia — defined as delayed or inadequate action in disease management. Familiar phrases like ‘mild diabetes’ or ‘stable on current therapy’ belie an undercurrent of therapeutic complacency,” Chacko commented. “Often, changes are deemed inconvenient for both clinicians and patients, further widening the gap between evidence and execution.”
Bridging the gap: A call to action
“We must confront this inertia head-on. One in three people with diabetes, and one in five with hypertension, have CKD — yet most are unaware. Even among the aware, rates of proteinuria screening, RAS blockade, and glycaemic control are suboptimal. Uptake of SGLT2 inhibitors remains particularly poor,” said Chacko.
“The barriers are multifaceted: low screening rates, high out-of-pocket costs, and resistance to change. But these are not insurmountable. Clarifying the rationale for therapy, personalizing care, and embracing guideline-directed treatment can dramati-cally shift outcomes,” he continued.
Conclusion: Are your kidneys OK?
The World Kidney Day theme for 2025 asks a simple yet profound question: Are your kidneys OK? The answer lies in early detection, guideline-based intervention, and systemic dismantling of clinical inertia. [www. worldkidneyday.org/]
“As clinicians, researchers, and policymakers, we hold the responsibility to move from awareness to action — to detect early, protect kidney health, and save lives,” concluded Chacko.
