Albuminuria as a diagnostic criterion and a therapeutic target in heart failure and other cardiovascular disease

Abstract

The high disease burden and bidirectional relationship of chronic kidney disease (CKD), heart failure (HF) and other cardiovascular disease (CVD) necessitate the need for early diagnosis of these diseases. While current screening and detection methods are recommended by CKD and CVD guidelines, their adoption in practice is low. Urine albumin‐to‐creatinine ratio (uACR) is recognized as a diagnostic marker for CKD and a prognostic marker for CKD progression, HF and CVD outcomes, therefore albuminuria changes have been accepted as a surrogate outcome for kidney and cardiovascular endpoints. Furthermore, clinical trials investigating guideline‐directed medical therapies have shown that uACR reductions are accompanied by risk reductions for cardiovascular, HF and other CKD outcomes. However, uACR is not routinely measured in patients at risk of kidney and heart disease, and its utility for detection, risk stratification and prediction models may not be fully appreciated in routine clinical practice. This review will discuss the effectiveness and implications of uACR screening as a method for heart and kidney disease diagnosis and risk assessment.

Introduction

Individually, chronic kidney disease (CKD) and cardiovascular disease (CVD) are associated with substantial global disease burden. ¹ , ² Pre‐existing CKD increases the risk of developing CVD and heart failure (HF) (Figure  1 ). ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ CKD is also highly prevalent in people with CVD, and is the cause of approximately 1.9 million cardiovascular (CV)‐related deaths annually. ¹⁵ Approximately 50% of people with stage G4–5 CKD (estimated glomerular filtration rate [eGFR] 15–29 ml/min/1.73 m² and <15 ml/min/1.73 m², respectively) (Figure  1 ) have CVD, and 40–50% of deaths in this population are linked to CVD. ¹⁶ Also, CKD has been reported to be present in 60.4% of people hospitalized with HF and is associated with increased risk of death within the first year after discharge (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.15–2.30). ¹⁷

Figure 1.

KKDIGO: prognosis of CKD by GFR and albuminuria categories. CVD, cardiovascular disease; CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; uACR, urine albumin‐to‐creatinine ratio. Adapted from 2024 KDIGO guidelines ³ under the terms of the CC BY‐NC‐ND license.

Estimated GFR using serum creatinine is the most commonly used kidney function biomarker for the detection of kidney disease and for risk stratification of both kidney disease progression and CV risk for broad implementation. ³ , ¹⁸ , ¹⁹ , ²⁰ However, in specific clinical contexts, eGFR equations using serum creatinine concentration alone may be confounded by non‐GFR determinants of creatinine. These can include extremes of muscle mass, other conditions that may impact production or clearance of creatinine, and certain medications. ¹⁸ , ²¹ , ²²

A widely accepted measure of kidney damage is albuminuria (abnormal loss of albumin in urine), which is a recognized biomarker of endothelial and renal tubular dysfunction. ³ , ²³ , ²⁴ , ²⁵ Early change in albuminuria is an appropriate surrogate outcome for kidney endpoints. ²⁴ , ²⁵ Albuminuria is also a risk factor for the development of incident HF, ²⁴ , ²⁵ and is associated with worse outcomes (CV death, HF hospitalization, and all‐cause mortality) in patients with vascular disease and high‐risk diabetes or in patients with HF or CVD. ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ In adults with albuminuria and preserved eGFR, the risk of CV outcomes is worse than the risk of requiring dialysis. ³⁵ , ³⁶ Measuring urine albumin‐to‐creatinine ratio (uACR) is a simple measurement recommended in clinical practice guidelines to test for albuminuria in routine clinical practice, rather than a 24‐h urine collection. ³ The uACR overcomes potential biases associated with less or more diluted or concentrated urines by dividing by the urine creatinine level. ³ , ²⁴ Although uACR is an estimate of daily urinary albumin excretion, it can be less accurate in people with very low or very high urine creatinine levels. ³ In addition to eGFR, uACR is used in the definition, classification, and risk stratification of CKD. ²³ , ²⁴ , ²⁵ Furthermore, a meta‐analysis of studies investigating CV‐related mortality (defined as composite myocardial infarction, stroke, HF, or sudden cardiac death) in people with CKD underscored that increased uACR is associated with significantly increased risk of CV‐ and HF‐related mortality. ³⁷

Reduction in uACR and regression of severe albuminuria to moderately increased or normal to slightly increased albuminuria is a key outcome, which has been improved with guideline‐directed medical therapies for type 2 diabetes (T2D), CKD and HF (Table  1 ). ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ These comprise the following: renin–angiotensin system inhibitors (RASi), sodium–glucose cotransporter 2 (SGLT2) inhibitors, a non‐steroidal mineralocorticoid receptor antagonist (MRA; finerenone), and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs). ³ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ RASis, SGLT2 inhibitors, finerenone and, recently, GLP‐1 RAs have been associated with reductions in uACR and proteinuria. ³⁵ , ³⁸ , ⁶⁸ , ⁷⁴ , ⁷⁵ , ⁷⁶ However, studies with angiotensin receptor–neprilysin inhibitors have reported increases or non‐significant reductions in uACR levels. ⁶⁶ , ⁷⁷ In the PARADIGM‐HF study, which enrolled people with HF and eGFR ≥30 ml/min/1.73 m², modest increases from baseline in uACR were observed in those randomized to sacubitril/valsartan compared with enalapril. The change in uACR did not modify the observed effects on HF hospitalization and CV mortality. ⁶⁶ In the UK HARP‐III study, which enrolled people with CKD, sacubitril/valsartan versus irbesartan was associated with a similar reduction from baseline in uACR. ⁷⁷

Table 1.

Studies assessing CKD treatment for uACR reductions as well as protection against CKD progression and CV outcomes.

Drug class	Trial (drug)	Population	Treatment (n)	Placebo/ comparator (n)	Outcome		uACR
					CKD progression (95% CI)	CV–related hospitalization (95% CI)	Baseline in active arm	Change from baseline
RASis	RENAAL (losartan) 38 , 39 , 40	CKD	751	762	RR 16% (2–28)	RR 18% (9–25)	Median (mg/g) 1168 (IQR 538–2540)	6 months: –28.8%
	IDNT (irbesartan) 40 , 41	CKD	579	569	RR 20%	–	Median (mg/g): 1456 (IQR 799–2791)	6 months: –39.3%
SGLT2 inhibitors	EMPA‐KIDNEY (empagliflozin) 42 , 43	CKD	3304	3305	HR 0.71 (0.62–0.81)	HR 0.84 (0.67–1.07)	Median (mg/g): 331 (IQR 46–1061)	–28 to –14% across primary kidney disease subgroups at 30 months (placebo‐adjusted)
	DAPA‐CKD (dapagliflozin) 44	CKD	2152	2152	HR 0.61 (0.51–0.72)	HR 0.71 (0.55–0.92)	Median (mg/g): 965 (IQR 472–1903)	–
	CREDENCE (canagliflozin) 45	CKD	2202	2199	HR 0.70 (0.59–0.82)	HR 0.61 (0.47–0.80)	Median (mg/g): 913.5 (IQR 459–1794)	–31% (95% CI 26–35)
	EMPEROR‐Preserved (empagliflozin) 46 , 47	HFpEF	2997	2991	HR 0.95 (0.73–1.24)	HR 0.71 (0.60–0.83)	Diabetes (mg/g): 30.0 (IQR: 9.72–136.0) No diabetes (mg/g): 15.91 (IQR: 6.19–43.32)	–
	EMPEROR‐Reduced (empagliflozin) 48 , 49	HFrEF	1863	1867	–	HR 0.69 (0.59–0.81)	No CKD (mg/g): 15.0 (IQR: 6.0–44.0) CKD (mg/g): 36.0 (IQR: 11.0–194)	–
	DELIVER (dapagliflozin) 50 , 51	HFmrEF/ HFpEF	3131	3131	HR 1.08 (0.79–1.49)	HR 0.77 (0.67–0.89)	–	–
	DAPA‐HF (dapagliflozin) 52	HFrEF	2373	2371	HR 0.71 (0.44–1.16)	HR 0.70 (0.59–0.83)	–	–
	EMPA‐REG OUTCOME (empagliflozin) 53 , 54	T2D	4687	2333	–	HR 0.65 (0.50–0.85)	Median (mg/g): 17.7 (25th percentile: 6.2; 75th percentile: 71.6)	–7.3%, IQR: –44.5, 50 (at week 12)
	DECLARE‐TIMI (dapagliflozin) 55	T2D	8582	8578	HR 0.76 (0.67–0.87)	HR 0.83 (0.73–0.95)	–	–
	CANVAS (canagliflozin) 56	T2D	5795	4347	HR 0.60 (0.47–0.77)	HR 0.67 (0.52–0.87)	Median (mg/g): 12.4 (IQR 6.71–40.9)	−17% (placebo‐adjusted, at 12 or 26 weeks)
	VERTIS CV (ertugliflozin) 58 , 59	T2D	5499	2747	HR 0.81 (0.63–1.04)	HR 0.97 (0.85–1.11)	Median (mg/g): 18.0 (IQR 6.0–66.5)	−14.9% (placebo‐adjusted, at 18 weeks)
Steroidal MRAs	RALES (spironolactone) 60	Severe HF and LVEF	822	841	–	RR 0.70% (0.60–0.82)	–	–
	TOPCAT (spironolactone) 61 , 62	HFpEF	1722	1723	–	HR 0.89 (0.77–1.04)	Median (mg/g [IQR]) Normalbuminuria: 9 (5–18) Microalbuminuria: 79 (45–142) Macroalbuminuria: 704 (451–1393)	Placebo‐adjusted GMR of 1 year to baseline uACR All patients: 0.61 (0.49–0.77) Normalbuminuria: 0.65 (0.48–0.89) Microalbuminuria: 0.78 (0.55–1.11) Macroalbuminuria: 0.24 (0.10–0.56)
	EMPASIS‐HF (eplerenone) 63	Chronic systolic HF	1364	1373	HR 0.97 (0.37–2.58)	HR 0.63 (0.54–0.74)	–	–
	AMBER (spironolactone) 64 , 65	Hypertension and CKD	148	147	–	LS mean group difference of change in SBP from baseline between intervention and comparator (mmHg) 12 weeks: –1.0 (–4.4 to 2.4); p = 0.58	Median (mg/g): 73.0 (IQR 18.8–400.0)	Mean change from baseline to week 12: –49 mg/g
Nonsteroidal MRAs	FIDELITY (finerenone) 35	CKD	6519	6507	HR 0.77 (0.67–0.88)	HR 0.78 (0.66–0.92)	Median (mg/g): 514 (IQR 198–1129)	–32% (placebo‐adjusted, at 4 months)
ARNi	PARADIGM‐HF (sacubitril/valsartan) 66 , 67	HFrEF	4187	4212	HR 0.86 (0.65–1.13)	HR 0.79 (0.71–0.89)	Median (mg/dl): 1.13 ± 0.3	~0% from randomization to 8 months
GLP‐1 RA	FLOW (semaglutide) 68	CKD	1767	1766	HR 0.76 (0.66–0.88)	–	Median (mg/g): 582.3	At week 104: 0.6

Abbreviations: ARNi, angiotensin receptor/neprilysin inhibitor; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; GLP1–RA, glucagon–like peptide–1 receptor agonist; GMR, geometric mean ratio; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; IQR, interquartile range; LS, least squares; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitors; RR, risk ratio; SGLT2, sodium–glucose cotransporter 2; T2D, type 2 diabetes; uACR, urinary albumin–to–creatinine ratio.

Despite clinical evidence and guidelines supporting the utilization of uACR as a diagnostic, prognostic, and therapeutic target, uACR is not routinely measured in all patients at risk of kidney and heart diseases. ⁷⁰ , ⁷⁸ , ⁷⁹ Early‐stage kidney disease is usually asymptomatic, requiring laboratory tests for detection. ⁸⁰ Furthermore, the utility of uACR for detection, risk stratification, and prediction models may not be fully appreciated in routine clinical practice. ⁸¹ Here we discuss the effectiveness and implications of uACR screening as a method for heart and kidney disease diagnosis and risk assessment.

Role of urine albumin‐to‐creatinine ratio as a screening, diagnostic, and prognostic tool

Baseline uACR level and changes from baseline are prognostic of CKD and CVD progression/regression. ⁸² A meta‐analysis of 128 505 patients with diabetes showed that the presence of albuminuria was associated with an increased risk of all‐cause and CVD‐related mortality compared with undetectable uACR. ⁴ Another meta‐analysis of 637 315 individuals with diabetes and no CVD determined that uACR was a sensitive predictor of coronary heart disease, stroke, or HF. ³⁷ The authors identified that simultaneous assessment of eGFR and uACR improves CVD risk classification. ³⁷ A cross‐sectional analysis determined that albuminuria was recorded in 22.1% of adults with HF and was more likely to occur in patients with HF than without. ⁸³ Also, uACR levels of >30 mg/g were associated with development of incident HF across the 10 975 participants of the Atherosclerosis Risk in Communities study. ⁸⁴ uACR is an independent predictor of CV death, hospital admission for HF, and all‐cause mortality in patients with HF. ⁸⁵ Incorporating uACR in HF risk prediction models significantly improves the predicted 10‐year risk of developing CV events, CV death, and HF. ⁸⁶ Although elevated uACR is associated with the development and progression of HF, its role as a screening tool or therapeutic target has not been widely adopted. ⁸⁷

Mechanisms behind abnormal urine albumin‐to‐creatinine ratio in progression of heart and kidney disease

Albuminuria is linked with microvascular endothelial dysfunction arising from a persistent inflammatory state; increased activity of the renin–angiotensin system (RAS) results in further vascular injury and oxidative stress. ⁸⁷ , ⁸⁸ , ⁸⁹ Albuminuria with normal eGFR can be attributed to elevated central venous pressure in HF, leading to increased renal venous congestion, reduced perfusion pressure, and decreased eGFR. These can trigger the activation of RAS, development and progression of HF, and CVD. ⁸⁷ , ⁹⁰ , ⁹¹

Current urine albumin‐to‐creatinine ratio screening recommendations and guidelines

Urine albumin‐to‐creatinine ratio assessments in chronic kidney disease guidelines

There is no consensus on the prioritization of screening, early detection, and intervention to prevent development and progression of CKD. ⁷⁹ Early identification and intervention in CKD, as recommended by Kidney Disease: Improving Global Outcomes (KDIGO), involves CKD‐targeted screening or case finding for people with hypertension, diabetes, or CVD. ⁷⁹ Further, CKD screening was identified as imperative in high‐risk populations based on comorbidities, environmental exposures, or genetic risk factors. ⁷⁹ Lastly, it was recommended that the initiation, frequency, and termination of screening should be individualized based on kidney and CV risk profiles. ⁷⁹

The 2024 KDIGO guidelines recommend at least annual albuminuria assessment in adults and children with CKD. In addition, these guidelines emphasize that more frequent albuminuria and eGFR screening is important in individuals with higher risk of CKD progression. ⁹²

The National Kidney Foundation states that a high risk of kidney failure is present when albuminuria and eGFR are <30 mg/g and <45 ml/min/1.73 m², 30–300 mg/g and <60 ml/min/1.73 m², or >300 mg/g and <15–≥90 ml/min/1.73 m², respectively. ⁹³

The 2025 American Diabetes Association (ADA) clinical practice guidelines for kidney disease and diabetes recommend that uACR and eGFR should be assessed in patients with type 1 diabetes (T1D) for ≥5 years, and in all patients with T2D regardless of treatment. ⁷⁰ In patients with established CKD, the ADA recommend monitoring uACR and eGFR 1–4 times per year depending on disease stage. ⁷⁰ The 2023 European Society of Cardiology (ESC) guidelines also recommend regular eGFR and uACR screening to help manage CVD in patients with CKD. ²⁵

A simplified flowchart summarizing the guidelines and our expert recommendations for uACR screening is shown in Figure  2 .

Figure 2.

Flowchart of uACR‐targeted screening and pharmacological intervention recommendations. ADA, American Diabetes Association; CKD, chronic kidney disease; CVD, cardiovascular disease; ESC, European Society of Cardiology; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; HF, heart failure; KDIGO, Kidney Disease: Improving Global Outcomes; nsMRA, non‐steroidal mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T1D, type 1 diabetes; T2D, type 2 diabetes. Flowchart adapted from 2024 KDIGO guidelines ³ , 2025 ADA guidelines, ⁷⁰ and 2023 ESC guidelines ²⁵ for uACR screening and represents our expert opinion.

Urine albumin‐to‐creatinine ratio assessments in diabetes, hypertension, heart failure, and other cardiovascular disease guidelines

The ADA recommends that a ≥30% reduction of urinary albumin in patients with CKD and a uACR of >300 mg/g should be considered as a therapeutic target for the slowing of CKD progression. ⁷⁰ In addition, the use of angiotensin‐converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) is recommended in patients with diabetes and hypertension who have moderately or severely increased albuminuria (uACR 30–300 mg/g or >300 mg/g, respectively) or eGFR <60 ml/min/1.73 m². ⁷⁰ ACEis and ARBs are recommended in all individuals with CKD and increased albuminuria with and without diabetes. ⁹² The 2024 KIDGO guidelines also recommend the prioritization of SGLT2 inhibitors for the treatment CKD and CVD in patients with or without T2D and an eGFR ≥20 ml/min/1.73 m² or uACR ≥200 mg/g. ³

The ESC and the KDIGO guidelines recommend finerenone in addition to ACEis or ARBs in patients with T2D and eGFR >60 ml/min/1.73 m² with a uACR >300 mg/g, or an eGFR 25–60 ml/min/1.73 m² and uACR ≥30 mg/g to reduce CV events and kidney failure. ²⁵

The 2018 ESC/European Society of Hypertension guidelines for the management of hypertension recommended uACR screening in all hypertensive patients, as increased albuminuria is a predictor for the increased risk of CVD. ⁷²

Urine albumin‐to‐creatinine ratio assessments in other specialties

Urine albumin‐to‐creatinine ratio screening is recommended in other specialties, underscoring its practicality and feasibility. The United Kingdom's National Institute for Health and Care Excellence hypertension in pregnancy update in 2019 recommended uACR testing to screen for pre‐eclampsia in pregnant women with hypertension. ⁹⁴ The British Society for Rheumatology recommends uACR screening for proteinuria identification in adults with active or stable systemic lupus erythematosus. ⁹⁵

Differences between urine albumin‐to‐creatinine ratio and urine protein‐to‐creatinine ratio

Proteinuria is a therapeutic target associated with an increased risk of end‐stage kidney disease and all‐cause mortality in patients with CKD. ⁹⁶ While albuminuria is attributed to injuries of the glomerular filtration apparatus, protein loss is linked to a broader spectrum of kidney injuries including tubulointerstitial injury or systemic diseases such as multiple myeloma. ⁹⁷ The presence of proteinuria without albuminuria is indicative of non‐albumin proteinuria. ⁹⁷

Different uACR and urine protein‐to‐creatinine ratio (uPCR) levels correspond to KDIGO albuminuria categories (normal to mildly increased [mg/g]: <30 vs. <150; moderately increased: 30–300 vs. 150–650; severely increased: >300 vs. >650; nephrotic range: >2000 vs. >3500, respectively). ⁹⁸ CKD guidelines recommend uACR over uPCR for increased sensitivity for superior detection accuracy for low levels of albuminuria. ⁹⁹ , ¹⁰⁰

Both urine albumin and urine protein are biomarkers for CKD, CVD, and mortality in people with and without diabetes; however, albuminuria is a surrogate endpoint for early diabetic nephropathy, whereas proteinuria is a surrogate endpoint for eGFR decline in nephrotic syndrome. ¹⁰⁰

Spot urine testing for proteinuria

Dipstick‐positive proteinuria is associated with CVD outcomes including mortality, coronary heart disease, and progression to kidney failure, ¹⁰¹ but is not sensitive for detecting early CKD. ¹⁰² A large cohort study using dipstick proteinuria screening to assess CKD prevalence in adults found that among approximately 22 400 individuals, 3.4%, 31.8%, 40%, and 24.5% had G stage 1/2, 3, 4, and 5 CKD, respectively. ¹⁰² Another population‐based study determined that proteinuria screening using urine dipsticks was associated with increased risk of atrial fibrillation (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.10–1.16, 1.34 [1.31–1.38], 1.53 [1.48–1.58], 1.82 [1.71–1.94], and 1.86 [1.61–2.16] in individuals with trace, 1+, 2+, 3+, and 4+ proteinuria, respectively, compared with those without proteinuria). ¹⁰¹ Lastly, a population cohort study determined a positive dose–response relationship between the degree of dipstick proteinuria and T2D risk in adults. The presence of proteinuria was associated with an increased risk of T2D (HR 1.19, 95% CI 1.10–1.29). ¹⁰³

Prevalence and cost‐effectiveness of large‐scale urine albumin‐to‐creatinine ratio screening

Urine albumin‐to‐creatinine ratio is a recognized large‐scale screening tool; several large cohort studies have used it to detect risk for CKD and CVD in patients with diabetes. ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶

Given the high economic burden of kidney failure, CKD screening (uACR in combination with eGFR) in high‐risk groups is likely to be cost‐effective. ⁷⁹ In addition, identifying individuals with albuminuria but normal eGFR could detect high‐risk individuals who could benefit from ACEi/ARB treatment. ⁷⁹ uACR screening is cost‐effective in populations at increased risk of CKD, including individuals with diabetes, specific ethnic groups, and individuals from middle‐income countries. ¹⁰⁷ A systematic literature review investigating the cost‐effectiveness of CKD screening in adults worldwide determined that incremental cost‐effectiveness ratios (ICERs) ranged between $113–430 595, with a median of $26 662 per quality‐adjusted life year (QALY). ¹⁰⁷ Since the median ICER was below the predefined ICER of $50 000 per QALY, many of the studies demonstrated cost‐effectiveness. ¹⁰⁷ Screening for proteinuria/albuminuria was associated with lower ICERs per QALY than eGFR ($113–430 595 vs. $8576–113 226); similarly, the combination of uACR and eGFR screening was cost‐effective. ¹⁰⁷

Population‐based urine albumin‐to‐creatinine ratio screening

Population‐based screening involves identifying a large population who is at risk of developing a condition and detecting the incidence of this disease; the main purpose is to primarily establish risk of overdiagnosis. ¹⁰⁸

While there are many other biomarkers, uACR is recommended for routine practice as a widely available, non‐invasive marker for CKD and HF, with a high population‐attributable risk percentage. ¹⁰⁶ , ¹⁰⁹ Although guidelines highlight the requirement of annual uACR screenings following the diagnosis of albuminuria in patients with diabetes, there is also a need to improve targeted albuminuria testing. Early changes in kidney function may be detected by increases in uACR before changes in eGFR, which may affect risk of CVD. ¹¹⁰ A retrospective cohort study using the electronic medical data of over 7 million US adults identified that uACR screening was performed in approximately half as many patients with diabetes compared with eGFR screening (<40% and >90%, respectively). ¹¹¹ Moreover, albuminuria testing was associated with CKD detection, improved control of diabetes and increased use of kidney and CVD protective medications. ¹¹¹

Urine albumin‐to‐creatinine ratio screening rates differ across countries and there are various factors that contribute towards this. A retrospective cohort study assessing population‐based CKD screening rates determined substantial disparities across several regions. Among 126 242 adults screened for CKD worldwide, Mexico (n = 51 137) had the largest cohort followed by China (n = 47 204), the US (n = 15 643), India (n = 9817), and Senegal (n = 2441). Across all five settings, less than 15% of adults with CKD were aware they had this condition. The study investigators determined that factors such as access to healthcare, availability of low‐cost treatment for non‐communicable diseases, as well as the overall prevalence of CKD, contribute towards screening rates. ¹¹²

Population versus targeted testing for chronic kidney disease diagnosis

Targeted screening among populations at high risk of CKD using uACR and/or eGFR identifies a significant proportion of the population (7.1–49%) with CKD who were previously undiagnosed and untreated (Table  2 ). ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ , ¹²⁰ , ¹²¹ , ¹²² , ¹²³ , ¹²⁴ In one study, screened individuals at risk of kidney failure were more likely to receive comprehensive laboratory tests (5.0% [95% CI 0.1–9.8]), uACR or uPCR testing (5.8% [95% CI 0.7–10.9]), glycated haemoglobin tests (7.0% [95% CI 0.6–13.3]), antihyperglycaemic medications (7.7% [95% CI 2.7–12.6]), and nephrology visits (1.9% [95% CI 0.3–3.4]) compared with matched controls. ¹¹³ Modelling studies have indicated that screening for CKD followed by intervention in high‐risk patients may improve clinical outcomes and are likely to be cost‐effective (Table  2 ). ¹²¹ , ¹²²

Table 2.

Clinical and modelling studies assessing population‐based screening for CKD

Country/Region	Number/Population	Methods/Results
Clinical studies
Manitoba, Canada 113	1353 people screened vs. matched controls Rural and remote indigenous communities	44% of participants were at risk of kidney failure at screening. Compared with matched controls, the intervention (screened) group overall had a significantly greater change in comprehensive laboratory tests completed (5.0% [95% CI 0.1–9.8]), uACR or uPCR testing (5.8% [95% CI 0.7–10.9]), HbA1c (7.0% [95% CI 0.6–13.3]), antihyperglycaemic medications (7.7% [95% CI 2.7–12.6]), and nephrology visits (1.9% [95% CI 0.3–3.4]).
Hawaii, US 114	1190 people (3% with known kidney disease)	National Kidney Foundation of Hawaii Kidney Early Detection screening programme. uACR and spot urine albumin data measured. Abnormal uACR and urine albumin levels were detected in 13% and 49% of individuals, respectively.
Japan 115	332 174 people (40–74 years of age)	Nationwide screening programme of the Specific Health Checkup and Guidance System (Tokutei‐Kensin). Serum creatinine and dipstick urine test data were analysed. 5.4% had proteinuria. The prevalence of CKD stages 3, 4, and 5 was 14.2%, 0.2%, and 0.07%, respectively.
Ferrara, Italy 116	1341 people from the general population (50–70 years of age)	World Kidney Day screening programme. Dipstick urinalysis for the evaluation of proteinuria, haematuria, and leukocyturia. 24% had proteinuria.
Urmia, Iran 117	905 people with at least one risk factor for CKD	Urine dipstick tests to detect proteinuria and blood sample for serum creatinine. 23.4% had proteinuria. 37.9% had high creatinine.
Sheffield, UK 118	Random sample of population	The Kidney Evaluation and Awareness Programme in Sheffield. A single uACR measurement was collected. 7.1% had microalbuminuria (6.2% in non‐diabetic, non‐hypertensive subjects; 1.3% in participants with no CKD risk factors).
US 119	72 395 people with diabetes or hypertension, or with a first‐degree relative with diabetes, hypertension, or CKD	KEEP – free, community‐based, kidney disease screening programme designed to detect CKD early and promote follow‐up evaluation. Those with evidence of CKD were 24% more likely to report seeing a physician than those without CKD.
Low‐to‐middle‐income countries 120	15 079 people with T1D, 66 088 people with T2D	Improvement in screening and treatment for kidney disease in people with T1D and T2D attending non‐nephrology clinics. This was accompanied by decreasing proportions of people: With microalbuminuria (27.1–13.8%) With proteinuria (14.2–8.2%), Who reported receiving dialysis over a 12‐year period (1.4–0.3%).
Modelling studies
South Korea 121	Markov model of disease progression with CKD screening (dipstick proteinuria and eGFR) vs. no screening	Biannual screening starting at 40 years of age had an ICUR of $66 874/QALY relative to no screening. A targeted screening strategy had ICURs of $37 812/QALY and $40 787/QALY for people with diabetes and hypertension, respectively.
US 122	Markov model simulating the lifetime impact of screening with semiquantitative urine dipsticks in a primary care setting of patients with hypertension and T2D in the US	The modelling analysis indicated that screening for nephropathy followed by optimized antihypertensive therapy with renoprotective agents in people with hypertension and T2D may improve clinical outcomes with only marginally increased overall costs.

CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; ICUR, incremental cost–utility ratio; KEEP, Kidney Early Evaluation Programme; QALY, quality‐adjusted life year; T1D, type 1 diabetes; T2D, type 2 diabetes; uACR, urine albumin‐to‐creatinine ratio; uPCR, urine protein‐to‐creatinine ratio.

Population‐level urine albumin‐to‐creatinine ratio testing for heart failure and cardiovascular disease diagnosis

While early uACR screening can recognize risk factors for HF and identify patients who may benefit from treatment, it is not commonly incorporated into clinical practice and screening coverage has not been established. ¹²⁵

Currently, there are few large‐scale randomized controlled trials evaluating the effects of CKD screening, risk stratification, and treatment programmes compared with standard of care in the general population. ⁷⁹ In the Towards Home‐Based Albuminuria Screening (THOMAS) study of general population albuminuria screening, approximately 60% of 7552 participants assigned to home‐based uACR screening completed testing. ¹²⁶ , ¹²⁷ Albuminuria, hypertension, hypercholesterolaemia, and decreased kidney function were newly diagnosed in 62.1%, 35.5%, 24.2%, and 21.8% of participants, respectively. Furthermore, 89.5% of participants were referred to a physician because of newly diagnosed CVD or CKD risk factors. ¹²⁷

Suboptimal urine albumin‐to‐creatinine ratio screening rates despite current recommendations

Screening rates in people with chronic kidney disease and diabetes

In the US, uACR screening rates are suboptimal among patients with T2D and do not meet current guideline recommendation that all patients should have annual screenings. ¹²⁸ Specifically, uACR and albumin testing among Medicare and Medicaid beneficiaries with CKD and diabetes was approximately 60% in 2021. ¹²⁸ In the UK, 49.8% and 60.7% of patients with T1D and T2D, respectively, were screened for uACR in 2021–2022. ¹²⁹

With low rates of annual screening, CKD is underdiagnosed in people with T2D. ¹³⁰ For example, in a large US‐based cohort study, 54.1% of patients had stage G1–5 CKD based on eGFR and albuminuria; however, only 12.1% of those patients had been diagnosed by a clinician. ¹³⁰ eGFR was assessed in 85% of participants during the 15 months prior to the study, but only 47% had a uACR assessment. ¹³⁰ Another US‐based cohort study found that in 2007–2018 only 17.5% of adults with hypertension or diabetes were screened for albuminuria, which was therefore frequently underdetected. ¹⁰⁴ The investigators suggested that undertesting of uACR can lead to lower blood pressure treatment rates, as uACR screening was associated with 2.4‐ and 8.2‐fold higher chances of receiving ACEi/ARB and SGLT2 inhibitor treatment, respectively. ¹⁰⁴

Screening rates in heart failure and other cardiovascular disease

Urine albumin‐to‐creatinine ratio screening rates remain low. According to the 2023 United States Renal Data System report, 45.5–51.0% of insured adults with CKD received uACR testing, and only 30.4–40.8% of those with hypertension were tested. ¹²⁸

The importance of early albuminuria detection for improving clinical outcomes

Early uACR screening is important because of the initial asymptomatic stages of CKD linked with normal/high eGFR; early albuminuria reduction is associated with improved clinical outcomes. ⁸² In patients with T2D and high albuminuria, those with ≥50% reduction in albuminuria in ≤2 years exhibited smaller declines in kidney function than those who did not (−1.8 ml/min/1.73 m²/year and −3.1 ml/min/1.73 m²/year, respectively). ¹³¹ Similarly, a ≥50% reduction in albuminuria levels within the first 6 months of treatment in patients with T2D resulted in risk reductions of 18% and 27% for CVD outcomes (including myocardial infarction, stroke, first hospitalization for HF or unstable angina, coronary or peripheral revascularization, or CV death) and HF, respectively. ³⁹

Urine albumin‐to‐creatinine ratio as a chronic kidney disease endpoint in clinical trials and a surrogate for response to therapy

An early decrease in albuminuria levels may indicate favourable response to treatment. ¹³² A meta‐analysis found that a 30% decrease in geometric mean albuminuria by active treatment relative to control was associated with a 27% lower risk for the CKD‐associated clinical endpoint. ¹³² This risk was further decreased when restricting analyses to patients with a baseline albuminuria level of >30 mg/g. ¹³² Furthermore, estimated albuminuria reductions of 25–31% across small, large, and indefinite trial sample sizes are needed to provide a ≥97.5% confidence of a clinical benefit; when restricting to participants with an albuminuria baseline of >30 mg/g, reductions of 20–27% are required. ¹³² On average, a 30% reduction in albuminuria provides a HR for the clinical endpoint of 0.68 (95% prediction interval: 0.47–0.95). ¹³²

Reductions in baseline urine albumin‐to‐creatinine ratio levels correspond to risk reductions of chronic kidney disease‐ and cardiovascular‐related outcomes

The US Food and Drug Administration and European Medicines Agency consider uACR an important endpoint in CKD trials, because rising levels are associated with increased risk of adverse CV outcomes (including CV death, hospitalization, myocardial infarction, and hospitalization for HF) in people with CKD and T2D. ¹³³ In the Heart Outcomes Prevention Evaluation study, every increase of 0.4 mg/mmol (4 mg/g) in uACR was associated with an 11% increase in hospitalizations for HF and a 6% increase in the primary composite endpoint (myocardial infarction, stroke, and CV death). ²⁹

Table  1 outlines clinical trials that recorded reductions in uACR levels from interventional therapies (including ARBs, SGLT2 inhibitors, steroidal MRAs, finerenone, and GLP‐1 RAs) and accompanied reductions in CKD‐ and CV‐related outcomes. In people with T2D, ARBs reduce uACR levels as well as the risk of CKD progression and CV outcomes. ³⁹ , ⁴⁰ , ⁴¹ In people with T2D and CKD, SGLT2 inhibitors reduce uACR, corresponding with reduced risk of CKD progression and CV outcomes. ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁵⁸ , ⁵⁹ , ¹³⁴ The steroidal MRA spironolactone reduces uACR levels and risk of CV outcomes in people with HF and CKD. ⁶¹ , ⁶² , ⁶⁴ , ⁶⁵ The non‐steroidal MRA, finerenone, significantly reduces uACR, CV outcomes, and kidney outcomes in people with CKD. ³⁵ , ¹³⁵ GLP‐1 RAs are associated with reductions in uACR and CV events in people with CKD. ⁶⁸

How to do urine albumin‐to‐creatinine ratio screening in patients

Detection method

Table  3 outlines the barriers to, and limitations of, uACR testing. One of the barriers associated with routine assessment/identification of elevated quantitative uACR is the choice of detection method, as timed uACR collection and dipstick tests have some shortcomings. ¹³⁶ , ¹³⁷ Currently, albuminuria can be diagnosed using quantitative uACR testing, semiquantitative reagent strip urinalysis for albumin, or semiquantitative uACR with automated reading. For measurement of urine protein, uPCR, reagent strip urinalysis for total protein with automated reading or reagent strip urinalysis for total protein with manual reading can be used. ³ An analysis of the Korean National Health and Nutritional Examination Survey (2011–2014) among adults ≥20 years of age with available urinalysis data (n = 20 759) found that urine dipsticks underestimated CKD risk compared with uACR assessment. ¹³⁶ , ¹³⁷ Over half of participants at moderate or high risk of uACR increase were classified into lower‐risk categories when based on the dipstick results. ¹³⁶ , ¹³⁷ The 2024 KDIGO guidelines recommend quantitative versus semiquantitative albuminuria testing (Table  3 ). ³ The quantity of urine albumin, even at low levels, is strongly related to kidney risk, CKD risk, and observed CVD. ³ Albumin assays are more sensitive and precise than those measuring urine protein. ³

Table 3.

Barriers and limitations of uACR testing for CKD diagnosis

Limitation	Impact on CKD diagnosis
Detection method
Choice of detection method and type of screening 3 , 136 , 137	Timed uACR collection and dipstick tests can be associated with underestimation of CKD risk There is a relationship between quantity of urine albumin with CKD and CVD risk
False positives 138	Long‐term uACR testing is associated with false positives Less frequent testing may also lead to false negatives and missed diagnoses
Low diagnostic accuracy 139	Low specificity and sensitivity can lead to inaccurate CKD diagnosis
n‐Stability of samples and storage conditions 140	Sample stability changes across different storage conditions, therefore uACR detection can be hampered by cost of storage and/or processing speeds
Screening timing
Time of urine collection 141	Sampling in the morning is the gold standard for uACR detection
Patient factors
Physical activity, fever, stress and metabolic perturbations 142	Can increase uACR levels

CKD, chronic kidney disease; CVD, cardiovascular disease; uACR, urine albumin‐to‐creatinine ratio.

Although A3 albuminuria (>300 mg/g) is generally reproducible, A2 albuminuria (30–300 mg/g) may be transient, emphasizing the importance of repeat testing and monitoring. uACR testing has been associated with the presence of false positives in patients with T1D and A2 albuminuria (Table  3 ). ¹³⁸ A study modelling uACR testing using data from the Oxford Regional Prospective Study estimated that by 6 years of annual testing, 56% (95% CI 49–63) of positive diagnoses of A2 albuminuria would lead to false‐positive diagnoses. ¹³⁸ The study investigators also suggested that less frequent monitoring would result in fewer false‐positive diagnoses, but increase false negatives or missed diagnoses. ¹³⁸

Semiquantitative uACR testing can be associated with low diagnostic accuracy (Table  3 ). McTaggart et al. ¹³⁹ assessed uACR in patients with an increased risk of CKD and determined a sensitivity and specificity of point‐of‐care testing for albuminuria of 83.2% and 80.0%, respectively; positive and negative predictive vales were 51.2% and 95.0%, respectively. Furthermore, 3.6% of samples were omitted from the analysis due to reasons such as occurrence of data‐entry errors. ¹³⁹ The KDIGO guidelines recommend assessing semiquantitative devices to produce a positive result in ≥85% of people with significant albuminuria or >30 mg/g as part of the evaluation and consideration of using the device. Advantages of semiquantitative albuminuria testing include flexibility in testing site with immediate results available for the clinician and patient.

Urine albumin‐to‐creatinine ratio testing may also be limited by the stability of samples at different storage conditions (Table  3 ). Therefore, accurate uACR detection may be hampered by the cost of storage and sample‐processing speeds. ¹⁴⁰ A study assessing the stability of urine samples of patients with kidney disease showed that longer processing delays and higher storage temperatures led to uACR instability. ¹⁴⁰ uACR in samples held at 30°C before processing were stable at 2 days but not 4 days; a preservative allowed samples to be stored at 18°C for 7 days. ¹⁴⁰ uACR stability in urine samples was recorded at −80°C or −40°C for ≤6 months with a preservative. ¹⁴⁰

Screening times and patient conditions

Pre‐analytic factors, such as time of urine collection, may impact the identification of people with CKD based on urine albumin levels (Table  3 ). ¹⁴⁰ Urine sampling in the morning is a reliable indicator of albumin excretion as it corresponds closely with 24‐h urine collection, the gold standard for uACR detection. ¹⁴⁰ A study investigating the distribution of random and first morning urine measures recorded a greater percentage of uACR in random samples compared with morning samples (7.7% vs. 4.7%), respectively. ¹⁴⁰ However, due to the lower sensitivity and specificity of random sampling, the prevalence of albuminuria may be overestimated. ¹⁴⁰ The KDIGO guidelines suggest that a morning midstream sample is preferred in adults and children. ³ In addition, changes in urinary creatinine concentration make uACR more variable in the context of acute kidney injury. ¹⁴³ uACR levels can also be increased by physical activity, fever, stress, and metabolic perturbations (Table  3 ). ¹⁴²

Conclusion

Urine albumin‐to‐creatinine ratio is an established biomarker for the incidence and progression of CKD and CVD outcomes such as HF, especially when combined with eGFR. There are many detection methods for uACR‐targeted screening, which are all non‐invasive, cost‐effective, and scalable. Furthermore, annual albuminuria screening is especially important in individuals with an increased risk of CKD and CVD.

Glycaemia and blood pressure control as well as pharmacologic therapies can reduce albuminuria and confer significant improvements in kidney and CV outcomes. However, early albuminuria detection is essential to initiate therapies in a timely manner to prevent CKD progression and CV outcomes. Early detection can also help match the treatment intensity with the level of risk. Although uACR and eGFR screening is recommended in high‐risk populations, screening rates remain suboptimal, which can lead to underdiagnosis of CKD and being at risk for HF and other CVD. This may prevent patients from receiving suitable treatment, leading to adverse kidney, HF, and CV outcomes. In addition, targeted uACR screening, especially among populations at risk, particularly people with diabetes, hypertension, HF, ischaemic heart disease, stroke, and/or obesity, is needed to better detect CKD and classify risk, as this can help reduce adverse CVD outcomes.

Funding

This work was supported by Bayer AG. The authors wrote the paper independently with the assistance of a medical writer, who was funded by the sponsor. The sponsor is also the manufacturer of finerenone.

Medical writing support was provided by Hussain Merchant, MSc, and editorial support was provided by Melissa Ward, BA, both of Scion (a division of Prime, London, UK), supported by Bayer AG according to Good Publication Practice guidelines (https://www.acpjournals.org/doi/10.7326/M22‐1460).

Conflict of interest: B.B. reports consultancy: Abbott, Abiomed, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, Daiichi Sankyo, Johnson & Johnson, Lantheus, Liva Nova, Merck, Regeneron, Renovacor, Respicardia/Zoll, Roche, Sanofi‐Aventis, and Vifor. P.R. reports consultancy: Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, CinCor, Idorsia, KBP, Novartis, Novo Nordisk, Pharvaris, Sanofi, Servier, Sequana Medical, Vera Therapeutics and Vifor; ownership interests: G3P (stock options); research funding: Relypsa Inc. and Vifor Fresenius Medical Care Renal Pharma, a Vifor Pharma Group Company; honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, CinCor, Idorsia, KBP, Novo Nordisk, Sanofi, Servier, Sequana Medical, and Vifor; personal fees: AstraZeneca, Bayer, Boehringer Ingelheim, CinCor, Idorsia, KBP, Novo Nordisk, Sanofi, Sequana Medical, Servier, and Vifor; patents or royalties: advisory or leadership role: European Society of Hypertension ‘Hypertension and the Kidney’ working group board member (2016–current), Heart Failure Association ‘Cardiorenal’ (2016–2022), ‘Translational’ (2016–2022), and ‘Biomarkers’ (2022–2024) working groups board member; EuReCa‐M ERA‐EDTA working group board member (2021–2023); KDIGO executive committee member (2023–2025); and speakers bureau: AstraZeneca, Bayer, Boehringer Ingelheim, CSL Vifor, and Novo Nordisk. J.A.V. reports consultancy: Renalytix, Novo Nordisk, and Sanofi; and leadership role: National Kidney Foundation, Inc. (Chief Medical Officer).

Supporting information

Appendix S1. Supporting Information.