Abstract and Introduction
Abstract
Graphical Abstract
The chronic kidney disease (CKD) 'blind spot' concept establishes that most patients with CKD and mild albuminuria preceding an estimated glomerular filtration rate < 60 mL/min/1.73 m2 are not recognized nor treated. CKD will progress and 50% of functional kidney mass will be lost before diagnosis. Albuminuria is a major risk factor for the progression of cardiovascular disease (CVD), starting from values not yet considered as defining CKD. The key point is early diagnosis of CKD as a risk factor for CVD and the widespread implementation of albuminuria screening, the assessment of early biomarkers and new therapies application to control early stages of albuminuria will diminish the cardiovascular burden related to CKD. GLP1-RAs, glucagon-like peptide 1 receptor agonists; SGLT2is, sodium-glucose cotransporter-2 inhibitors; UACR, urinary albumin/creatinine ratio.
Chronic kidney disease (CKD) is projected to become a leading global cause of death by 2040, and its early detection is critical for effective and timely management. The current definition of CKD identifies only advanced stages, when kidney injury has already destroyed >50% of functioning kidney mass as reflected by an estimated glomerular filtration rate <60 mL/min/1.73 m2 or a urinary albumin/creatinine ratio >six-fold higher than physiological levels (i.e. > 30 mg/g). An elevated urinary albumin-excretion rate is a known early predictor of future cardiovascular events. There is thus a 'blind spot' in the detection of CKD, when kidney injury is present but is undetectable by current diagnostic criteria, and no intervention is made before renal and cardiovascular damage occurs. The present review discusses the CKD 'blind spot' concept and how it may facilitate a holistic approach to CKD and cardiovascular disease prevention and implement the call for albuminuria screening implicit in current guidelines. Cardiorenal risk associated with albuminuria in the high-normal range, novel genetic and biochemical markers of elevated cardiorenal risk, and the role of heart and kidney protective drugs evaluated in recent clinical trials are also discussed. As albuminuria is a major risk factor for cardiovascular and renal disease, starting from levels not yet considered in the definition of CKD, the implementation of opportunistic or systematic albuminuria screening and therapy, possibly complemented with novel early biomarkers, has the potential to improve cardiorenal outcomes and mitigate the dismal 2040 projections for CKD and related cardiovascular burden.
Introduction
According to the Global Burden of Disease Study, chronic kidney disease (CKD) was the 16th and 10th global cause of death in 2016 and 2019, respectively, and it is likely to climb higher by 2040.[1–3] CKD thus ranks among the fastest-growing disease burdens and preventive initiatives are urgently needed to minimize its impact on cardiovascular outcomes and healthcare costs.
CKD is diagnosed when abnormalities of kidney structure or function with negative consequences for health are present for more than 3 months. Currently, the most commonly used criteria to categorize CKD are albuminuria (>30 mg/24 h or >30 mg/g urinary creatinine) or a significant fall (<60 mL/min/1.73 m2) in the estimated glomerular filtration rate (eGFR).[1] The cut-off level for albuminuria is more than six-fold greater than physiological levels, and the association between the urinary albumin/creatinine ratio (UACR) and cardiovascular disease (CVD) risk is linear from levels of 1 mg/g.[4] Indeed, the Losartan Intervention For Endpoint reduction study identified UACR thresholds ranging from 6.45 to 9.37 mg/g (depending on sex and type of analysis) that were already associated with increased CVD risk.[5,6] Additionally, meeting the definition of CKD following the eGFR threshold implies that >50% of the functional kidney mass has already been lost,[7] indicating that these diagnostic criteria and thresholds distinguish only late-stage disease.
The global prevalence of CKD oscillates between 11 and 13%,[8,9] and the majority of patients are in the G3 stage (eGFR 30–59 mL/min/1.73 m2).[10] This distribution pattern further highlights a major shortcoming in the current conceptualization of CKD, namely that early-stage disease is often overlooked. In the majority of clinical conditions, milder early stages are generally more prevalent than the more severe later stages. In this sense, CKD stages G1 and G2––evidence of kidney injury (UACR >30 mg/g) in the presence of normal (≥90) or mildly decreased (60–90 mL/min/1.73 m2) eGFR––should theoretically be more common than G3, but we lack diagnostic tools to identify them. This has been described as the blind spot in CKD, namely that kidney injury is already present with a progressive loss of eGFR from normal values of ~120 to <60 mL/min/1.73 m2.[7,11] This unmet need is clearly illustrated in the case of autosomal dominant polycystic kidney disease (ADPKD), a condition where sonography strongly supports the diagnosis of CKD decades before the current eGFR and UACR thresholds are met.[7,11] Additional diagnostic tests are thus needed for early identification of the disease (Table 1). Notably, the currently available eGFR and albuminuria indicators are not typically assessed in most patients, contributing to the invisibility (and late diagnosis) of CKD. Moreover, physicians' unawareness of the concept of CKD adds to the high cardiovascular burden even when eGFR and albuminuria measures are available.[12] Thus, CKD may progress untreated until diagnosed at more advanced stages, at which time the impact of treatment is likely to be suboptimal.[13] This inevitably increases the risk of adverse cardiorenal outcomes, as no regenerative therapy is available for CKD, and it does not typically regress.[13]
Albuminuria and low eGFR are independent predictors for a higher risk of CVD-related death that, in patients with CKD, is greater than the risk of needing kidney replacement therapy,[14,15] and a high UACR clearly increases renal and CVD risk even against a background of preserved eGFR.[16,17] Furthermore, patients presenting with both albuminuria and diminished eGFR are at high cardiorenal risk, with major consequences for CVD-related morbidity and mortality. Based on these premises, the 2021 guidelines of the European Society of Cardiology (ESC) on cardiovascular prevention[18] recommend measuring albuminuria and eGFR as part of routine assessment. UACR or eGFR values indicative of moderate or severe CKD automatically place the individual at high or very-high CVD risk, respectively, regardless of the presence or not of traditional cardiovascular risk factors.[19] Correspondingly, adding albuminuria to the Systematic Coronary Risk Estimation[19] scale increases the prevalence of high or very-high CVD risk in patients with CKD.[18] Controlling albuminuria through therapeutic intervention is associated with a lower risk of renal and cardiovascular outcomes independent of eGFR values.[20,21] Former guidelines proposed that albuminuria should be routinely measured in patients at high risk of CVD owing to the presence of arterial hypertension, Type 2 diabetes mellitus (T2DM), obesity, heart failure (HF), coronary artery disease, or hyperlipidaemia.[22] However, given the high cost associated with CKD, which in Europe exceeds that of cancer and T2DM,[1] and the low cost of measuring albuminuria, in addition to the need for identifying previously undetected patients at high CVD risk, the 2021 ESC cardiovascular prevention guidelines propose that opportunistic or systematic assessment of albuminuria should be considered in all men above the age of 40 and in all women above the age of 50 (or post-menopausal).[19] Unfortunately, albuminuria is assessed in only 35% of patients with T2DM and in 4% of those with hypertension in the best of circumstances.[23] A similar situation exists for individuals with normoalbuminuria in the normal-high blood pressure (BP) range who are already at increased risk but for whom no intervention is recommended through guidelines for hypertension, T2DM, or HF.[24] The low implementation of albuminuria assessment has been partly attributed to the lack of effective and safe treatments; however, a recent wave of clinical trials and scientific guidelines now emphasize the actionability of high albuminuria or low eGFR to diagnose CKD. This might promote the prescription of new drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide 1 receptor agonists (GLP1-RAs), and novel mineralocorticoid receptor antagonists (MRAs) such as finerenone (see later). While the kidney and cardiovascular protective effects of these drugs were first demonstrated in T2DM, the indications are rapidly expanding to non-diabetic populations who are also at high CVD risk, including the SGLT2i dapagliflozin for CKD or HF or the GLP1-RAs semaglutide for overweight or obesity.[25,26]
Here, we review the current status of albuminuria as a cardiorenal risk factor, including novel factors and biomarkers that promote albuminuria and facilitate the early induction of cardiorenal injury, together with shortcomings in their implementation and awareness. We also discuss novel approaches regarding the CKD 'blind spot' (Figure 1 and Graphical Abstract). Finally, we review recently available therapeutic strategies for patients with CKD that can improve cardiorenal outcomes.
Figure 1.
Illustration of CKD 'blind spot' concept and the different clinical settings in which measurement of albuminuria is mandatory to manage cardiorenal disease and prevent CVD outcomes.
Eur Heart J. 2023;44(13):1112-1123. © 2023 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.
