Albuminuria in Cardiovascular, Kidney, and Metabolic Disorders: A State-of-the-Art Review

Unstructured Abstract

Albuminuria, or increased urine albumin excretion, is associated with cardiovascular mortality among patients with diabetes, hypertension, chronic kidney disease, and heart failure, as well as among adults with few cardiovascular risk factors. Many authors have hypothesized that albuminuria reflects widespread endothelial dysfunction, but additional work is needed to uncover if albuminuria is directly pathologic or causative of cardiovascular disease. Urinary albumin-to-creatinine ratio is an attractive, unifying biomarker of cardiovascular, kidney, and metabolic conditions that may be useful for identifying and monitoring disease trajectory. However, albuminuria may develop via unique mechanisms across these distinct clinical phenotypes. This state-of-the-art review discusses the role of albuminuria in cardiovascular, kidney, and metabolic conditions and identifies potential pathways linking albuminuria to adverse outcomes and provides practical approaches to screening and managing albuminuria for clinical Cardiologists. Future research is needed to determine how broadly and how frequently to screen patients for albuminuria, whether it is cost-effective to treat low-grade albuminuria (10-30 mg/g), and how to equitably offer newer anti-proteinuric therapies across the spectrum of cardiovascular-kidney-metabolic diseases.

Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide, and scalable, non-invasive biomarkers for CVD are a growing area of research interest.¹ Ideally, a CVD biomarker would accurately identify high-risk individuals, convey prognostic value, and allow early intervention in the disease course. Increased urinary albumin excretion is a known CVD risk factor among patients with diabetes, hypertension, chronic kidney disease (CKD), coronary artery disease, and heart failure,² and may even convey risk among those with few CVD risk factors.^3–5 Albuminuria is also a strong determinant of CKD progression in patients with and without metabolic diseases.⁶ Therefore, urinary albumin-to-creatinine ratio (UACR) is an attractive, unifying biomarker of cardiovascular, kidney, and metabolic conditions that may be useful for identifying and monitoring disease trajectory. The dose-response relationship between UACR and cardiovascular outcomes make this biomarker particularly relevant to Cardiology clinical practice.^7–9

This narrative, state-of-the-art review discusses the role of albuminuria in cardiovascular, kidney, and metabolic conditions and identifies potential pathways linking albuminuria to adverse cardiovascular outcomes. This review highlights the importance of testing for albuminuria in cardiovascular practice and provides suggestions for evidence-based treatment initiation in patients with cardiovascular, kidney, and metabolic disorders.

Measurement, classification, and etiology of albuminuria

In clinical practice, spot urine albumin is quantified using a fluorescent immunoassay or liquid chromatography and spot urine creatinine is measured using a standardized enzymatic method or the Jaffe reaction.¹⁰ While 24-hour urine collection is preferred, spot urinary albumin-to-creatinine ratio (UACR) is suitable for most clinical scenarios, so long as the assumption that an individual excretes ~1000 mg/day of creatinine holds.¹¹ These quantitative methods are strongly preferred to urine dipstick analysis, which has low sensitivity and detects only advanced albuminuria (typically ≥300 mg/g).¹² The value of dipstick proteinuria analysis is in the widespread availability and affordability that may increase screening in resource-constrained settings. However, where possible, quantitative methods are preferred (Table 1).

Table 1.

Methods to measure albuminuria

Method	Advantages	Disadvantages
Dipstick	Low cost Point-of-care testing	Low sensitivity Semi-quantitative Does not evaluate low levels of albuminuria well and thus only detects advanced disease
Spot ASG (mg/L)	Lower cost due to reliance on urine specific gravity and not creatinine concentration	Specific gravity may be impacted by external factors Lower accuracy with very dilute or very concentrated urine
Spot ACR (mg/g) †	Convenient for patients High sensitivity High specificity	More costly than dipstick May be impacted by diurnal variation in albumin excretion
First morning void ACR (mg/g) †	High sensitivity High specificity May be more closely correlated to 24h AER than spot ACR	Less convenient for patients than random spot ACR
24h AER (mg/hr)	High specificity High sensitivity Not impacted by diurnal variation in albumin excretion	Time consuming Cumbersome for patients Incomplete collections have low utility

^†Depending on the laboratory, the methods for quantifying urine creatinine may vary (e.g., Jaffe vs. enzymatic) and impact the reliability of results.

Abbreviations: ACR, albumin-creatinine ratio; AER, albumin excretion rate; ASG, albumin adjusted for specific gravity.

Under normal physiologic conditions, up to several grams of albumin may be filtered and reabsorbed by the early proximal tubule (either intact or following catabolism), though the precise glomerular sieving coefficient is debated (Figure 1).^13–15 Protein that is excreted into the urine can be benign or pathologic.¹¹ Transient causes of proteinuria include fever, orthostatic proteinuria, urinary tract infection, pregnancy, or vigorous exercise. Transient proteinuria can also be seen in patients with severe hypertension, poor glycemic control, and severe hyperlipidemia.¹¹ Persistent proteinuria is pathologic and may be tubular (albumin and non-albumin protein) or glomerular (albumin-predominant) in etiology.^{11 16,17,18}Glomerular proteinuria results from foot process effacement, glomerular basement membrane injury, or increased glomerular hydrostatic pressure that disrupts selective glomerular ultrafiltration.¹⁶ Albuminuria may be detectable in kidney disease before a decline in glomerular filtration rate (GFR).¹⁷

Figure 1: Pathophysiology of albuminuria.

Mechanisms of albuminuria include both loss of the glomerular basement membrane integrity and impaired proximal tubular albumin reabsorption. Created in https://BioRender.com/

Current clinical practice guidelines classify a UACR measurement of <30 mg/g (<3.4 mg/mmol) as ‘normal to minimally increased’, 30-300 mg/g (3.4-34 mg/mmol) as ‘moderately increased,’ and ≥300 mg/g (34 mg/mmol) as ‘severely increased.’¹⁸ Albuminuria above 3.0-3.5 g/day is considered ‘nephrotic range’. However, it is well recognized that a continuous relationship exists between increasing albuminuria and adverse clinical outcomes that begins far below the traditional ‘microalbuminuria’ threshold (<30 mg/g).^4–6,19,20 Prior authors have articulated issues with the current albuminuria classification system, principally the over-emphasis on thresholds.^21,22 The false dichotomization between ‘normal’ and ‘abnormal’ UACR at 30 mg/g obscures risk and may predispose clinicians to overlook opportunities for cardiorenal risk reduction. A new framework which incorporates the continuous relationship may improve clinical management of albuminuria, though multiple additional knowledge gaps remain (Table 2).

Table 2.

Knowledge Gaps

Diagnosis	- Should the general population be screened for albuminuria? - Is 30 mg/g still an appropriate threshold for diagnosing CKD given the associations between ACR <30 mg/g and adverse clinical outcomes?
Variability	- What are the cause(s) of intra-individual variability in repeated measurements of albuminuria? - What degree of variability is seen between repeat albuminuria measurements among patients without diabetes?
Monitoring	- How frequently should albuminuria be reassessed? Should the frequency of reassessment be different according to different clinical characteristics? - In patients with albuminuria, what degree of albuminuria reduction in response to treatment is sufficient? - Is there a % reduction or absolute threshold that should be the treatment target? - What degree of fluctuation between repeat collections should prompt additional diagnostic evaluation?
Treatment	- At what threshold of albuminuria should anti-proteinuric therapies be initiated?
Prognosis	- What is the relative contribution of albuminuria reduction to improved cardiovascular outcomes with anti-proteinuric therapies (versus other cardio-protective effects of these medications)? - Is initiation of anti-proteinuric therapy at ACR <30 mg/g associated with improved cardiovascular or kidney outcomes? - Is albuminuria reduction associated with decreased incidence of ASCVD in patients without additional pre-existing risk factors? - Is it cost-effective to treat ACR <30 mg/g?

One of the pitfalls of measuring albuminuria is the day-to-day variability in an individual’s urinary albumin excretion.^23,24 Therefore, repeat quantitative measurements are required for confirmation.²³ This is especially true in diabetes-associated CKD, where a repeated measurement of UACR can vary from 25% to 375% of the initial value,²⁴ though this variation may also be seen in other forms of CKD.²³

Clinical Phenotypes and Mechanisms Associated with Albuminuria

There are multiple mechanisms by which albuminuria can develop. These phenotypes of albuminuria and proposed mechanisms are summarized in Figure 2. In many patients, however, there may be overlapping or concomitant mechanisms by which albuminuria develops.

Figure 2: Clinical phenotypes and mechanisms of albuminuria.

Albuminuria may arise as a consequence of chronic kidney disease, heart failure, atherosclerotic cardiovascular disease, hypertension, or metabolic syndrome. These mechanisms converge on a final common pathway of kidney dysfunction and increase risk for adverse cardio-renal events. Created in https://BioRender.com/

In patients with CKD, podocyte foot process effacement leads to insufficient counterpressure and relaxation of the glomerular basement membrane (GBM) fiber matrix.^25,26 This causes increased glomerular capillary wall permeability and results in albuminuria. As glomerular disease progresses, the subpodocyte space may widen to cover a greater proportion of the filtration membrane and modulate filtration barrier permeability.²⁷ Expansion of the subpodocyte space and an increase in hydraulic resistance can lead to further podocyte detachment and worsening albuminuria.²⁷ Alternatively, or concurrently, albuminuria can arise from impaired albumin reabsorption in the proximal tubule.^13,28

In patients with hypertension, increased intraglomerular pressure causes glomerular hyperfiltration and hyperpermeability, while ongoing intraglomerular capillary endothelial damage can result in capillary albumin leak.^29,30 In one study, patients with albuminuria demonstrated normal tubular albumin reabsorption, indicating that hypertension increases glomerular albuminuria.³¹

In patients with heart failure, elevated central venous pressure can cause low renal perfusion pressure,^32,33 chronic tubulointerstitial damage,^34–36 or renal congestion,³⁵ any of which may precipitate albuminuria. Volume overload also increases release of natriuretic peptides, which may cause damage to the endothelial glycocalyx,³⁷ though this is debated,³⁸ and result in albuminuria.³⁶ Aldosterone escape in heart failure leads to sodium and water retention, as well as kidney fibrosis.³⁹ More broadly, increased aldosterone levels are associated with increased albuminuria.^40–43 Finally, high intraglomerular pressure increases transcapillary flux of the ultrafiltrate and results in albuminuria.⁴⁴

In patients with atherosclerotic cardiovascular disease, albuminuria can develop secondary to endothelial inflammation and endothelial dysfunction.^45,46 Endothelial disturbances are common in sustained atherogenic states and dyslipidemia. Albuminuria is associated with loss of the endothelial glycocalyx,⁴⁷ dynamic vascular elasticity,^48–50 perfusion,^51,52 and serologic markers of vascular health (such as nitric oxide and von Willebrand factor).^53,54 In one study, the authors argue that increased lipid infiltration of vascular structures increases glomerular transcapillary albumin leak.⁴⁵ Other common disturbances in atherosclerotic disease include reduced nitric oxide bioavailability, which promotes arterial stiffness and impaired vasodilation.⁵⁵

In patients with diabetes, many of whom also have metabolic syndrome, albuminuria may develop secondary to either alterations to glomerular charge selectivity or impaired proximal tubular albumin reabsorption.⁵⁶ Change in GBM size selectivity does not appear to be a contributing factor.⁵⁶ The Steno hypothesis argues that albuminuria is a consequence of global intima damage due to alterations in the extracellular matrix.^57,58 Serum albumin glycosylation is likely one mechanism by which albumin is able bypass GBM charge selectivity in diabetes.⁵⁹ Alterations to GBM proteoglycans also disrupt charge selectivity.^59,60 Insulin resistance can lead to endothelial dysfunction, while impaired vasodilation in the setting of reduced nitric oxide further impairs renal autoregulation.^55,61 Global alterations to the endothelium, as measured by von Willebrand factor, may precede albuminuria in diabetes.⁶²

Albuminuria is a Risk Factor for Cardiovascular Disease

Albuminuria is strongly associated with CVD mortality^7,20,63,64 and all-cause mortality in diverse populations.^7–9 Similarly, albuminuria is longitudinally associated with major cardiovascular complications such as nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, peripheral artery revascularization.^7,64–66 Albuminuria has also been identified as an independent risk factor for stroke and other cerebrovascular diseases.^67–69

Multiple authors have described associations between albuminuria and CVD risk factors. For example, albuminuria has been associated with left-ventricular hypertrophy,^49,70,71 vascular stiffness and remodeling,^{49,50,52,72,73} progression of coronary artery calcification.⁷⁴ Each of these conditions confers a high risk of CVD events and demonstrates the likely systemic vascular pathology associated with albuminuria.

Perhaps the most well-described relationships between albuminuria and CVD are in the context of heart failure.⁴⁴ Approximately 32% of U.S. adults with heart failure have albuminuria ≥30 mg/g.⁷⁵ Albuminuria is not only associated with greater risk of incident heart failure⁷⁶ and diastolic dysfunction,⁷⁰ but also confers risk of worsening CVD in patients with pre-existing heart failure regardless of ejection fraction.⁷⁷ Development of albuminuria is strongly associated with adverse outcomes such as increased hospitalizations for heart failure,^64,78 systemic vascular congestion,³⁴ and progressive systolic dysfunction.⁷⁷ While albuminuria is known to improve risk stratification in heart failure, current heart failure society guidelines do not comment on the need for albuminuria screening in this population.⁷⁹

In general, studies of albuminuria and CVD are performed in populations already at high cardiovascular risk and therefore offer limited insight into the mechanism behind the association of albuminuria and CVD mortality. Associations between albuminuria and incident hypertension⁸⁰ and incident atrial fibrillation^81,82 provide only slightly more evidence that interim development of additional CVD risk factors may contribute to the association with mortality, however, further work is needed.⁴⁶ One hypothesis is that the presence of albuminuria represents a systemic micro-inflammatory state characterized by diffuse endothelial dysfunction. This is supported by an association between albuminuria and elevated cardiac troponin T in adults without known CVD.⁸³

Low Levels of Albuminuria and CVD

Notably, albuminuria does not need to be high-grade to convey cardiovascular risk. One study found a linear association between low levels of albuminuria (UACR < 30 mg/g) and CVD mortality among adults without major cardiovascular risk factors.²⁰ In this and several other recent papers, cardiovascular risk appears to increase at UACR approximately 7-10 mg/g.^20,84,85 Low-grade albuminuria has been associated with adverse cardiovascular risk factors, including incident hypertension,⁶³ heart failure,⁷⁶ and coronary artery disease,¹⁹ as well as major adverse cardiovascular events^4,5,7,65 and mortality.^4,19,20 Data from the CKD Prognosis Consortium shows that low levels of albuminuria are associated with major adverse cardiovascular events in diverse populations with CKD.⁷

Albuminuria is a Risk Factor for Progressive Kidney Disease

While not all patients with CKD have albuminuria, increased urinary albumin excretion above 30 mg/g is one diagnostic criterion for CKD and albuminuria screening is standard component of the clinical CKD workup.¹⁸ However, lower levels of albuminuria are also a risk factor for incident CKD.^86,87 In patients with CKD, albuminuria below 30 mg/g is linearly associated with increased risk of CKD progression and incident ESKD.⁶ Risk for CKD progression appears to increase at UACR approximately 7-10 mg/g. Greater albuminuria and changes in albuminuria are independently associated with CKD progression and end-stage kidney disease (ESKD) in patients with and without diabetes.^7,88–90

Diabetes is the most common cause of CKD worldwide. Albuminuria is a common consequence of diabetes due to the sustained hyperglycemia, inflammation, and glomerular hyperfiltration that accompanies longstanding diabetes.⁹¹ Early studies of diabetes, kidney function, and UACR were limited by small sample sizes and lack of biopsy confirmation to determine whether changes consistent with DKD were present histologically.⁹² The classic trajectory of diabetic kidney disease (DKD) includes progressive albuminuria and eGFR decline. Greater albuminuria in DKD has been previously associated with increased risk of progressing to ESKD⁹¹ and a higher risk of adverse cardiovascular outcomes.^93,94 Rising UACR may precede a decline in eGFR for patients with progressive DKD, making it a useful prognostic marker for patients with the ‘classical’ DKD phenotype.⁹¹ A subset of patients with diabetes exhibit non- or minimally albuminuric disease phenotypes and nonetheless experience progressive eGFR decline.^91,95 An even smaller proportion of patients experience albuminuria regression and stabilization of kidney function. However, in one study, the risk for adverse CVD outcomes remained elevated in these patients.⁹⁶ Patterns of albuminuria prevalence and trajectories vary between type 1 and type 2 diabetes.⁹¹ A greater proportion of patients with type 2 diabetes progress to diabetic nephropathy compared to those with type 1 diabetes.⁹⁷ While patients with type 2 diabetes can frequently experience regression of albuminuria, patients with type 1 diabetes who develop CKD often exhibit progressive albuminuria over time.^91.

Albuminuria and Metabolic-Associated Disorders

A major limitation of the existing literature on the relationship between metabolic syndrome, MASLD, dysglycemia, and albuminuria is the reliance on cross-sectional studies.^98,99 Here we briefly outline the work examining albuminuria in the context of these metabolic-associated conditions, acknowledging the limitations.

Albuminuria and Obesity

Multiple measures of adiposity have been associated with albuminuria.¹⁰⁰ Central obesity, specifically, may be a crucial risk factor for incident albuminuria independent of diabetes status.^100–103 Obesity is an increasingly common etiology of secondary FSGS, which is characterized by significant proteinuria.¹⁰⁴ Obesity-associated FSGS typically involves an indolent course followed by progression to ESKD. It is hypothesized that increased oxidative stress, generalized inflammation, chronic glomerular hypoxia, and insulin resistance in obesity lead to the histologic changes in obesity-associated FSGS.¹⁰⁴ In patients with obesity, elevated intra-renal resistance on doppler ultrasound is associated with albuminuria, suggesting a possible mechanistic link between adiposity and the development of CKD and CVD events.^105–107 However, this cross-sectional evidence precludes any conclusions about causal pathways.

Albuminuria and Metabolic Dysfunction Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with albuminuria in epidemiologic studies and is a prominent CVD risk factor. Several studies have found an association between MASLD and albuminuria,^108,109 with one study noting that the association was independent of insulin resistance or obesity.¹¹⁰ Albuminuria below 30 mg/g may also be a risk factor for developing MASLD, as shown in one prospective, population-based study of Chinese adults.¹¹¹ In this study, risk appeared to increase at UACR around 2.5 mg/g. While the pathophysiology of how albuminuria may lead to steatotic liver disease – and the reverse -- are not clear, the epidemiologic association may be driven by a generalized state of endothelial inflammation or the incident development of obesity.

Albuminuria and Insulin Resistance

Insulin resistance – a key risk factor for metabolic syndrome, diabetes, MASLD, and CVD – is closely associated with albuminuria in patients without diabetes,^98,112 as well as those with prediabetes.⁹⁹ In patients without diabetes, insulin resistance and elevated glomerular hydrostatic pressure were cross-sectionally associated with albuminuria.⁹⁸ Longitudinally, elevated baseline HOMA-IR in adults without diabetes was associated with subsequent development of albuminuria.¹¹² Inflammatory or oxidative pathways may mediate the relationship between dysglycemia and albuminuria, though this hypothesis has yet to be explored.

Albuminuria Reduction and Cardiovascular-Kidney Outcomes

It is well described that CKD increases the risk of incident CVD events and CVD events increase the risk of CKD progression.^113,114 Cardio-kidney protective medications with antiproteinuric effects reduce incident CVD events and CVD mortality in high-risk populations, likely due to multifactorial pathways and mechanisms not directly related to albuminuria reduction.^115,116 These therapies include angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor-blockers (ARB), sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1-RA), and mineralocorticoid receptor antagonists (MRA). Importantly, the more recent cardiovascular and kidney trials on SGLT2i, GLP1-RA, and non-steroidal MRA demonstrate benefit among patients already treated with maximal ACEi/ARB. The additive benefit of these therapies has the potential to improve global cardiovascular outcomes, with the greatest evidence to date among patients with type 2 diabetes.¹¹⁷ Table 3 highlights recent cardiovascular trials which enrolled based on albuminuria, similar to other risk factor-based enrollment criteria (e.g., diabetes, prior CVD).

Table 3.

Cardiovascular outcomes trials enrolling based on albuminuria.

	Eligibility	Intervention	Outcomes
Specific ACR enrollment criteria
CREDENCE	- eGFR 30-90 ml/min per 1.73m2 and ACR 300-500 mg/g	Canagliflozin	- Doubling of SCr - ESKD - Death from kidney disease or CVD
DAPA-CKD	- eGFR 25-75 ml/min per 1.73m2 and ACR 200-5000 mg/g	Dapagliflozin	- eGFR decline >50% - ESKD - Death from kidney disease or CVD
EMPA-KIDNEY	- eGFR 20-45 ml/min per 1.73m2 - eGFR 45-90 ml/min per 1.73m2 and ACR ≥200 mg/g	Empagliflozin	- eGFR decline ≥40% - ESKD - eGFR decline to <10 - Death from CVD
FIDELIO-DKD	- eGFR 25-60 ml/min per 1.73m2 and retinopathy - eGFR 25-75 ml/min per 1.73m2 and ACR 300-5000 mg/g - ACR 30-300 mg/g	Finerenone	- eGFR decline ≥40% - ESKD - Death from kidney disease
FIGARO-DKD	- eGFR 25-90 ml/min per 1.73m2 and ACR 30-300 mg/g - eGFR >60 ml/min per 1.73m2 and ACR 300-5000 mg/g	Finerenone	- Death from CVD, nonfatal MI, nonfatal stroke, or hospitalization for heart failure
FLOW	- eGFR 50-75 ml/min per 1.73m2 and ACR 300-5000 mg/g - eGFR 25-50 ml/min per 1.73m2 and ACR 100-5000 mg/g	Semaglutide	- eGFR decline >50% - ESKD - Death from kidney disease or CVD
Non-specific proteinuria enrollment criteria
CANVAS and CANVAS-R	- Age >40 years and prior CVD - Age >50 and CVD risk factors (incl. microalbuminuria or proteinuria)	Canagliflozin	- Death from CVD, nonfatal MI, or nonfatal stroke
SCORED	- eGFR 25-60 ml/min per 1.73m2 - Age >18 and at least 1 major CVD risk factor - Age >55 and at least 2 minor CVD risk factors (incl. ACR 30-300 mg/g)	Sotagliflozin	- Death from CVD, hospitalization for heart failure, urgent visits for heart failure.
LEADER	- Patients >50 years with CVD comorbidities - Patients >60 years with CVD risk factors (incl. microalbuminuria or proteinuria)	Liraglutide	- Death from CVD, non-fatal MI, or nonfatal stroke
PIONEER-6	- Patients >50 years with major CVD risk factors - Patients >60 years with minor CVD risk factors (incl. microalbuminuria or proteinuria)	Semaglutide	- Death from CVD, nonfatal MI, or nonfatal stroke

Abbreviations: ACR, albumin:creatinine ratio; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; MI, myocardial infarction; SCr, serum creatinine.

The mechanisms by which cardio-kidney protective and antiproteinuric therapies provide CVD benefit are only partially understood. ACEi/ARB and angiotensin-receptor/neprilysin inhibitors (ARNI) improve cardiac remodeling following myocardial infarction.^118,119 Similarly, steroidal MRA, which have antiproteinuric effects, have been used for decades to improve CVD outcomes in patients with heart failure with reduced ejection fraction and new data show benefit of non-steroidal MRA in these patients with preserved ejection fraction.¹²⁰ The CVD protective effects of SGLT2i may be driven primarily by a reduction in hospitalization for heart failure,¹²¹ while the benefits of GLP1-RA appear to be more broadly cardioprotective in the setting of obesity.¹²² Both SGLT2i and GLP1-RA may act on metabolic pathways and can be used for cardiovascular benefit across a range of metabolic and cardiovascular conditions. It is important to note that none of these medications were initially developed for their cardioprotective effects, and the precise mechanism by which they improve CVD outcomes remains an active area of investigation.

Albuminuria reduction is also associated with a slower rate of CKD progression and a lower likelihood of progression to ESKD. Residual albuminuria following anti-proteinuric treatment is a very strong risk factor for disease progression.¹²³ The initial clinical trials of ACEi and ARBs made these therapies the cornerstone of CKD care for the next 20 years.^124,125 Recent evidence demonstrates improved kidney outcomes following treatment with SGLT2i,¹²⁶ GLP1-RA, ¹²⁷ and non-steroidal MRAs on a background of ACEi/ARB.¹²⁸ The data on steroidal MRAs and clinical kidney outcomes are less well established due to lack of randomized clinical trial data, though epidemiologic literature suggests some benefit.^128,129

The benefits of newer antiproteinuric medications in slowing CKD progression are multifactorial and likely extend beyond albuminuria reduction alone, particularly as non-albuminuric patients also derive benefit.¹³⁰ While other authors have pointed to post-hoc analyses of recent cardiovascular and kidney trials as exhibiting effect modification by baseline UACR, the p-values for interaction are non-significant in all but one trial (Table 4). Furthermore, these trials enrolled few patients with low levels of albuminuria and therefore subgroup analyses were underpowered.

Table 4.

Post-hoc analyses of cardiovascular and kidney trials, stratified by UACR

Trial	Intervention	Outcome	p-interaction	Event Rates in Control			Event Rates in Treatment			Effect Estimates for Study Drug HR (95% CI)
				<30 mg/g	30-300 mg/g	≥300 mg/g	<30 mg/g	30-300 mg/g	≥300 mg/g	<30 mg/g	30-300 mg/g	≥300 mg/g
FIGARO-DKD	Finerenone vs. Placebo	CV death, nonfatal MI, nonfatal stroke, or HHF	0.60	NA	4.42 per 100 py	4.49 per 100 py	NA	3.88 per 100 py	3.94 per 100 py	NA	0.87 (0.73-1.04)	0.90 (0.75-1.08)
		Composite kidney outcome†	0.02	NA	2.30 per 100 py	5.02 per 100 py	NA	2.63 per 100 py	3.83 per 100 py	NA	1.16 (0.91-1.47)	0.74 (0.62-0.90)
FIDELIO-DKD	Finerenone vs. Placebo	Composite kidney outcome*	NR	0/11	19/350	485/2470	2/12	20/335	578/2493	--	0.92 (0.49-1.72)	0.83 (0.73-0.93)
FIDELITY ¥	Finerenone vs. Placebo	Composite kidney outcomeπ	0.67	40/2023		424/4371	38/2076		321/4321	0.94 (0.60-1.47)		0.75 0.65-0.87)
CANVAS and CANVAS-R	Canagliflozin vs. Placebo	Composite kidney outcome†	0.37	NR	NR	NR	NR	NR	NR	0.50 (0.33-0.77)	0.64 (0.47-0.88)
EMPA-REG	Empagliflozin vs. Placebo	CV death, nonfatal MI, nonfatal stroke	0.40	134/1382	90/675	58/260	241/2789	158/ 1338	86/509	0.89 (0.72-1.10)	0.89 (0.69-1.16)	0.69 (0.49-0.96)
EMPA-KIDNEY	Empagliflozin vs. Placebo	CV death or progression of kidney disease	NR	42/663	78/937	438/1705	42/665	67/927	323/1712	1.01 (0.66-1.55)	0.91 (0.65-1.26)	0.67 (0.58-0.78)
EMPEROR-Pooled ‡	Empagliflozin vs. Placebo	CV death or HHF	0.71	8.2 per 100 py	16.2 per 100 py	22.2 per 100 py	6.6 per 100 py	11.8 per 100 py	18.3 per 100 py	0.80 (0.69-0.92)	0.74 (0.63-0.86)	0.78 (0.63-0.98)
DECLARE-TIMI 58	Dapagliflozin vs. Placebo	CV death or HHF	0.47	10.2 per 1000 py	21.8 per 1000 py	37.2 per 1000 py	9.2 per 1000 py	16.8 per 1000 py	28.5 per 1000 py	0.90 (0.75-1.08)	0.76 (0.61-0.95)	0.77 (0.55-1.06)
SCORED	Sotagliflozin vs. Placebo	CV death, HHF, urgent visits for HF	NR	4.2 per 100 py	9.4 per 100 py		4.4 per 100 py	6.3 per 100 py		1.05 (0.76-1.46)	0.67 (0.55-0.80)
LEADER	Liraglutide vs. Placebo	CV death, nonfatal MI, or nonfatal stroke	0.36	335/2821	338/1738		318/ 2894	277/1684		0.92 (0.79-1.07)	0.83 (0.71-0.97)
SUSTAIN 6	Semaglutide vs. Placebo	CV death, nonfatal MI, or nonfatal stroke	0.48	73/986	36/412	35/224	43/948	39/472	26/196	0.61 (0.42-0.89)	0.87 (0.55-1.37)	0.76 (0.46-1.28)
FLOW	Semaglutide vs. Placebo	Composite kidney outcome£	NR	62/552		348/1214	55/561		276/1205	0.86 (0.60-1.23)		0.74 (0.63-0.87)
SELECT	Semaglutide vs. Placebo	Composite kidney outcome€	0.70	31/7471	67/941	95/166	24/7377	47/1027	80/159	0.78 (0.46,1.33)	0.63 (0.44,0.92)	0.77 (0.57, 1.03)
PARADIGM-HF	Sacubitril-Valsartan vs. Enalapril	CV death or HHF	0.35	158/697	70/215		133/734	68/226		0.77 (0.61-0.97)	0.94 (0.67-1.31)

^*Includes kidney failure, sustained decreased of at least 40% in eGFR over at least 4 weeks, or death from renal causes.

^†Includes ≥40% reduction in eGFR, end-stage kidney disease, or death from renal causes.

^¥FIDELITY is a combined analysis of FIGARO-DKD and FIDELIO-DKD

^πIncludes ≥57% reduction in eGFR, end-stage kidney disease, or death from renal causes.

^‡EMPEROR Pooled is a combined analysis of EMPEROR-Preserved and EMPEROR-Reduced

^£Includes kidney failure, sustained decrease of at least 50% in eGFR over at least 28 days, or death from renal or cardiovascular causes.

^€Includes death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR<15 ml/min/1.73m², persistent ≥50% reduction in eGFR, or onset of persistent macroalbuminuria.

Abbreviations: CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; MI, myocardial infarction; NA, not applicable; NR, not reported; py, person years.

Cardio-kidney protective medications have effects beyond their albuminuria reduction which may be important components of their effect on CKD outcomes. Both SGLT2i and GLP1-RA improve blood pressure control and induce weight loss, while MRAs provide aldosterone antagonism. With SGLT2i specifically, there is ongoing investigation into mechanisms related to tubuloglomerular feedback in reducing intraglomerular pressure, as well as anti-inflammatory¹³¹ and metabolic¹³² effects. GLP1-RA may offer renoprotection via reduced kidney inflammation and fibrosis,¹³³ and results are awaited from the mechanistic REMODEL trial.¹³⁴ Finally, new data has brought additional attention to the role of aldosterone antagonism in treating albuminuric CKD^43,135 and preventing CVD events in these patients.¹³⁶ Investigators are also pursuing a related approach, aldosterone synthase inhibition, to reduce CKD progression.¹³⁷

Given the diversity of mechanism of action across cardio-kidney protective therapies with antiproteinuric effects, combination therapy using ACEi/ARB, SGLT2i, GLP1-RA, and MRA is an emerging area of research interest. While prior work of combination ACEi and ARB demonstrated reduced albuminuria without improving renal outcomes compared to monotherapy,¹³⁸ this does not appear to be the case for combination treatment across the newer medication classes for diabetic kidney disease.¹¹⁷ In the FLOW trial, there was no evidence of effect modification for the composite kidney outcome based on background SGLT2i use,¹²⁷ and in a meta-analysis of SGLT2i trials, there is no evidence of effect modification based on background GLP1-RA use.¹³⁹ These findings provide preliminary evidence of independent effects of these two classes. Additional work has demonstrated additive benefit of ACEi/ARB and SGLT2i in non-diabetic kidney disease.¹⁴⁰ Further work will be needed to assess any potential additive or synergistic benefits of ACEi/ARB, SGLT2i, GLP1-RA, and MRA and which patients should be considered for combination therapy.

As previously discussed, none of the more recent cardio-kidney protective drug classes were specifically designed for albuminuria reduction. Furthermore, current clinical trials do not assess whether improved outcomes are mediated by albuminuria reduction or whether albuminuria is instead a convenient biomarker of the yet undiscovered underlying mechanism. It is also important to recognize the heterogeneity in recent trials with respect to changes in albuminuria and clinical outcomes. This is especially true in the case of heart failure trials, where patients continue to exhibit kidney disease progression, or exhibit no renal benefit, despite improved CVD outcomes.^141,142 This apparent therapeutic disconnect has been described for ARB, ARNI, SGLT2i, and non-steroidal MRA and is largely attributed to recruitment of patients with low background risk of CKD progression (e.g. those with lower albuminuria and less advanced CKD)^141,143 or insufficient follow up time.¹⁴¹ Albuminuria data are also not routinely available in many previously cardiovascular trials.¹⁴³ For example, the PARADIGM-HF trial (ARNI vs. ACEi) demonstrated worsening albuminuria in the ARNI group despite improvement in heart failure outcomes.¹⁴⁴ This would seem to question the association between albuminuria reduction and improved CVD outcomes and suggest that the effects of ARNI are mediated by improved blood pressure and other cardiovascular intermediaries. However, the subsequent UK HARP III trial demonstrated no difference in kidney outcomes (and no worsening in albuminuria) among patients with CKD treated with ARNI versus ARB.¹⁴⁵ Whether these differences are related to the study population – heart failure patients in PARADIGM-HF versus patients without heart failure in UK HARP III – is an important unanswered question. Other authors have hypothesized that physiologic differences in heart failure specifically underly the divergence in renal outcomes in trials of patients with heart failure versus CKD.¹⁴¹ A pooled analysis of Finerenone trials demonstrates cardiovascular and kidney benefit with non-steroidal MRA in a mixed heart failure and CKD population, suggesting that the limitations of present heart failure trial design may be responsible for reported lack of CKD benefit in these participants.¹⁴⁶

Combination therapy is central to effective implementation of cardio-kidney protective therapies. Early, rapid sequence initiation and uptitration of these medications may prevent delays in care and limit therapeutic inertia.¹⁴⁷ Patients on multi-drug therapy are most likely to achieve the greatest benefit, including longer event-free survival.¹¹⁷ Though not well studied with the SGLT2i or oral GLP1-RA, the hypertension literature demonstrates that multidrug combination pills decrease pill burden for patients and can improve medication adherence.¹⁴⁸ Combination therapy may also reduce the need for ACEi/ARB and MRA discontinuation due to hyperkalemia. Given new data demonstrating that ACEi/ARB should not be pre-emptively stopped in advanced CKD due to worse cardiovascular outcomes,^149,150 managing hyperkalemia with SGLT2i, loop diuretics, dietary modification, and potassium binders is essential to delivering high quality cardio-kidney care.^151,152

Albuminuria as a biomarker of Cardiovascular-Kidney-Metabolic health

The American Heart Association (AHA) report on Cardiovascular-Kidney-Metabolic (CKM) syndrome highlights the importance of albuminuria in CKD and heart failure. However, the authors defer recommending albuminuria screening until the later stages of CKM syndrome when impaired eGFR is already present.¹¹⁶ Given the evidence described in this review, it may be prudent for clinicians to consider screening for albuminuria using a broader definition of risk than the CKM framework.¹⁵³ This could range from screening the general population (a strategy currently under evaluation by the United States Preventative Task Force Service for CKD surveillance)¹⁵⁴ to a risk-based approach incorporating obesity, liver disease, insulin resistance, and behavioral features (low physical activity, smoking, etc.).

Albuminuria screening is guideline-recommended for high-risk populations such as those with diabetes, those with chronic kidney disease, those with hypertension, and those at high risk of clinical CVD or CKD (Table 5). Unfortunately, rates of albuminuria screening among currently indicated patient groups remain severely low.^155–157 In the face of burgeoning treatments for CKD and preliminary cost-effectiveness analyses showing the benefits of screening,¹⁵⁸ strategies to promote screening across a greater range of high-risk populations (e.g., hypertension, diabetes, CKD, atherosclerotic cardiovascular disease, heart failure, metabolic syndrome) are urgently needed.

Table 5.

Recent guidelines for albuminuria screening

Society	Year	Patient Population(s)	Screening Recommendation
Kidney Disease Improving Global Outcomes	2024	Adults at risk for CKD, including hypertension, diabetes, cardiovascular disease, or those with genetic or environmental risk factors specific to region of residence.	First morning UACR is preferred. Confirm positive dipstick albuminuria with more accurate methods (such as UACR)
		Patients with CKD	UACR at least annually; assess albuminuria more frequently in patients at higher risk for CKD progression. A doubling of albuminuria warrants evaluation.
American Heart Association Statement on Cardiovascular-Kidney-Metabolic Health	2023	Stage 2 CKM syndrome: patients with metabolic risk factors or CKD	UACR annually
		Stage 3 CKM syndrome: patients with subclinical CVD in CKM syndrome	UACR at least annually, more frequently in those with CKD
		Stage 4 CKM syndrome: patients with clinical CVD and excess or dysfunctional adiposity, other CKM risk factors, or CKD	UACR at least annually, more frequently in those with higher KDIGO risk
American Diabetes Association	2023	Patients without established diabetic kidney disease:    - Type 1 diabetes duration of ≥5 years    - All patients with type 2 diabetes	Spot UACR annually
		Patients with established diabetic kidney disease	Spot UACR 1-4 times per year
National Institute for Health and Care Excellence	2021	Patients at risk for CKD, including those with diabetes, hypertension, previous acute kidney injury, cardiovascular disease, structural renal tract disease, recurrent renal calculi, multisystem diseases with potential kidney involvement, gout, family history of kidney disease, incidental detection of hematuria or proteinuria	Spot UACR with frequency depending on underlying risk factors. Monitor for progression of CKD for at least 3 years after acute kidney injury even if eGFR returned to baseline.
		Patients with diabetes	Annual UACR
European Society of Cardiology in collaboration with the European Association of Preventive Cardiology	2021	Patients with hypertension, diabetes, or CKD	Routine assessment of UACR (or dipstick urinary protein if ACR not available)
International Society of Hypertension	2020	Patients with hypertension	Routine assessment of spot UACR
		Pregnant patients with hypertension	Dipstick followed by ACR if positive, twice in pregnancy (early and late)
European Society of Cardiology in collaboration with the European Association for the Study of Diabetes	2019	Patients with diabetes or at risk of developing diabetes or cardiovascular disease	“Routine assessment of microalbuminuria should be carried out to identify patients at risk of developing renal dysfunction and/or CVD.”
European Society of Cardiology and the European Society of Hypertension	2018	Patients with hypertension	Annual UACR
		Pregnant patients with hypertension	Dipstick followed by ACR if positive, twice in pregnancy (early and late)

Most patients eligible for albuminuria screening currently are managed in primary care offices, where competing demands, limited time, clinical complexity, and clinician lack of awareness to evolving guidelines may be barriers to screening.¹⁵⁹ A 2014 study identified a major barrier to albuminuria screening for patients with non-diabetic CKD: the perception that it would not change management.¹⁶⁰ Whether clinician attitudes have changed since introducing newer anti-proteinuric medications is unknown. Implementation and improvement scientists will be critical to increasing real-world screening rates by designing systematic, scalable, and adaptable interventions. Increased support for primary care clinicians and developing novel workflows may increase guideline-directed albuminuria screening and treatment implementation. Alternatively, some researchers have proposed that home-based, population-wide screening approaches may be more scalable, though potentially more costly to implement.¹⁶¹

Cardiovascular practices can improve the care of patients with CVD and those at risk for worsening CKM syndrome by incorporating routine albuminuria testing. Once identified, patients with albuminuria can be monitored more closely (Figure 3). The 2023 AHA Predicting Risk of Cardiovascular Events (PREVENT) cardiovascular risk calculator includes UACR for improved prediction of CVD events.¹⁶² Patients with elevated PREVENT scores are recommended for statin therapy, similar to the ASCVD risk calculator. In addition to providing valuable risk-stratification, UACR can also guide treatment intensification (Figure 3). There are ongoing efforts within Nephrology to implement rapid sequence uptitration of guideline-directed medical therapy for diabetic kidney disease, including ACEi/ARB, SGLT2i, GLP1-RA, and nsMRA, similar to the Cardiology approach to heart failure therapies.¹⁴⁷ These same principles are directly applicable to cardiovascular clinical spaces for patients with CKM syndrome and CVD risk. Through appropriate UACR testing, cardiovascular practices will be at the forefront of detecting otherwise undiagnosed CKD through this approach. Patients can then be started on appropriate therapies based on their risk factor profile and/or referred to Nephrology, as appropriate.

Figure 3: Proposed algorithm for managing albuminuria in patients with known cardiovascular risk factors.

Simplified algorithm for evaluating and managing albuminuria in patients with known cardiovascular risk factors. Re-testing for albuminuria is critical to modifying cardiovascular risk. Created in https://BioRender.com/

Conclusion

In conclusion, albuminuria is a marker of widespread vascular dysfunction and subclinical cardiovascular risk that heralds evolving CKM dysfunction. As an inexpensive and non-invasive test, UACR provides a glimpse into the early development of CKM syndrome. Even low-grade albuminuria, below the traditional threshold of 30 mg/g, likely represents smoldering endothelial or vascular disease and carries substantial CVD and CKD risk. The literature on albuminuria as a CKM biomarker suggests that waiting for an eGFR decline to develop overlooks a key opportunity for disease prevention. Future research is needed to determine how broadly and how frequently to screen patients for albuminuria, whether it is cost-effective to treat low-grade albuminuria (for example, 10-30 mg/g), and how to equitably offer newer cardio-kidney protective therapies across the spectrum of CKM syndrome. Answering these questions may shift the clinical practice of cardiovascular risk reduction and improve population health.

Abbreviations:

ACEi

Angiotensin Converting Enzyme Inhibitor

AHA

American Heart Association

ARB

Angiotensin Receptor Blocker

ARNI

Angiotensin Receptor-Neprilysin Inhibitor

CKD

Chronic Kidney Disease

CVD

Cardiovascular Disease

DKD

Diabetic Kidney Disease

eGFR

Estimated Glomerular Filtration Rate

ESKD

End Stage Kidney Disease

FSGS

Focal Segmental Glomerulosclerosis

GBM

Glomerular Basement Membrane

GLP1-RA

Glucagon-like Peptide-1 Receptor Agonist

HOMA-IR

Homeostatic Model Assessment of Insulin Resistance

MASLD

Metabolic Associated Steatotic Liver Disease

MRA

Mineralocorticoid Receptor Antagonist

PREVENT

Predicting Risk of Cardiovascular Events

SGLT2i

Sodium-Glucose Cotransporter-2 Inhibitor

UACR

Urinary Albumin-to-Creatinine Ratio

U.S.

United States