Abstract
Background
Evidence regarding the prognostic value of new-onset proteinuria during hospitalization among patients with atherosclerotic cardiovascular disease (ASCVD) is lacking.
Objectives
We aimed to examine the associations of new-onset proteinuria during hospitalization with cardiovascular (CV) mortality and composite kidney outcomes after discharge.
Methods
This observational cohort study included hospitalized adults with ASCVD and without proteinuria at admission from twenty-four academic hospitals participated in China Renal Data System. New-onset proteinuria during hospitalization was defined as a change in urinary protein test from negative to 1+ or more. The primary outcome was CV mortality after discharge. The secondary outcome was the composite of adverse kidney outcomes including sustained new-onset estimated glomerular filtration rate <60 mL/min/1.73 m2, >40% decline in estimated glomerular filtration rate, or end stage renal disease. The associations between new-onset proteinuria and outcomes were assessed by Cox proportional hazard models.
Results
In this nationwide cohort of 34,429 inpatients with the mean age of 64 years, new-onset proteinuria occurred in 7.5% of the population. With a mean follow-up of 4.6 years, new-onset proteinuria during hospitalization was significantly associated with an increased risk of CV mortality (HR: 1.30; 95% CI: 1.07-1.57) and adverse kidney outcomes (HR: 1.50; 95% CI: 1.04-2.17). The association between new-onset proteinuria and CV mortality was independent of the occurrence of acute kidney injury and showed similar trend across subgroups and multiple sensitivity analyses.
Conclusions
The presence of new-onset proteinuria during hospitalization among ASCVD patients demonstrated significant prognostic value and should be carefully monitored to improve patient care.
Key words: atherosclerotic cardiovascular disease, cardiovascular mortality, kidney outcome, new-onset proteinuria
Central Illustration
Atherosclerotic cardiovascular disease (ASCVD), including ischemic heart disease and cerebrovascular disease (mainly ischemic stroke), stands for the leading cause of global mortality, causing approximately 16 million deaths worldwide in 2020.1,2 Improving the prognosis of ASCVD hinges on the identification and early intervention of prognostic risk factors. Proteinuria is prevalent among patients with diabetes, hypertension, or ASCVD and is an independent predictor of adverse outcomes in these patients, beyond traditional risk factors.3, 4, 5, 6, 7 However, although urinary protein has been routinely screened at admission among patients with ASCVD, the vast majority of previous studies have focused only on patients with proteinuria at baseline, which mainly reflected the underlying pre-existing chronic kidney disease (CKD). Those without proteinuria at baseline and with new-onset proteinuria during hospitalization garnered less attention in clinical practice. The risk factors and clinical significance of new-onset proteinuria during hospitalization among patients with ASCVD remain unclear.
Previous studies had found that new-onset proteinuria was common and may offer prognostic insights in specific populations, such as pregnant women, COVID-19 patients, or those with acute kidney injury (AKI).5,8, 9, 10, 11, 12, 13, 14, 15 However, these results are difficult to generalize to the patients with ASCVD due to heterogeneous study populations, small sample sizes, and the varying time window for defining new-onset proteinuria.5,9, 10, 11, 12, 13, 14, 15 Consequently, there is an urgent need for high-quality studies using real-world data to elucidate the association between new-onset proteinuria during hospitalization and cardiovascular (CV) mortality, thereby identifying novel prognostic factors for ASCVD inpatients.
Using deidentified medical record from a nationwide cohort of hospitalized patients with ASCVD, this study aims to describe the incidence and risk factors of new-onset proteinuria during hospitalization, and assess the associations of new-onset proteinuria with the risks of CV death and kidney outcomes. By addressing these research objectives, we aim to enhance our understanding of the prognostic value of new-onset proteinuria during hospitalization and its clinical implications for kidney health among patients with ASCVD.
Methods
Study population
We conducted a multicenter, retrospective cohort study using data from the China Renal Data System (CRDS), which collaborates with the China Center for Disease Control and Prevention (CDC). At present, this collaborative network comprises 24 academic hospitals across multiple provinces in China. Electronic health records were collected and standardized in the database, which include demographic information, laboratory measurements, vital signs, physical examination, comedications, and comorbidity history. Inpatients with documented ASCVD from CRDS between 2012 and 2022 who had a urinary protein test within the first 3 days of hospitalization were included in the study (Figure 1). The definition of ASCVD included a history of acute coronary syndrome (ACS) (myocardial infarction or unstable angina), stable angina, arterial revascularization (coronary artery bypass graft surgery or vascular stent implantation), stroke, transient ischemic attack, or peripheral arterial disease. Patients were excluded if they had a positive initial urinary protein test, lacked serum creatinine (SCr) measurement or did not undergo a repeat urinary protein test during hospitalization. In addition, we excluded patients with urinary tract infections or leukocyturia ≥1+, as well as those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, a history of end-stage renal disease (ESRD), or those who were pregnant.
Figure 1.
Flowchart of the Study
34,429 participants were included. ASCVD = atherosclerotic cardiovascular disease; CRDS = China Renal Data System; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease.
The primary exposure of interest was new-onset proteinuria, defined as a change in the urine dipstick protein test from negative to 1+ or more during the hospitalization. According to standard semiquantitative urine dipstick thresholds, the level of proteinuria was categorized as 0: negative; trace: 10 to 29 mg/dL; 1+: 30 to 99 mg/dL; 2+: 100 to 299 mg/dL; 3+: 300 to 999 mg/dL; and >3+: ≥1,000 mg/dL.16 The index date of this study was the date of discharge.
The study protocol was approved by the Medical Ethics Committee of Nanfang Hospital, Southern Medical University (NFEC-2019-213) and the China Office of Human Genetic Resources for Data Preservation Application (2021-BC0037). Patient informed consent was waived because of the retrospective nature of study. This study was conducted in accordance with both the Declarations of Helsinki and Istanbul, as well as the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Outcomes
The primary outcome was CV mortality after discharge and the secondary outcome was the composite kidney outcome including sustained new-onset eGFR<60 mL/min/1.73 m2, >40% decline in eGFR, or ESRD.17 ESRD was defined as meeting any one of the following criteria: maintenance dialysis, kidney transplantation, or an eGFR <15 mL/min/1.73 m2. The death records and causes of death were traced by the national electronic cause-of-death reporting system of CDC.18 CV mortality was defined using International Classification of Diseases-10 code (I00-I99). Chronic Kidney Disease Epidemiology Collaboration 2021 equation was employed to calculate eGFR.19 For the primary outcome, patients were followed up from the index date until the date of death, or the end of the study period (December 31, 2022), whichever came first. For secondary outcomes, patients were followed up from the index date until the date of secondary outcome, the date after which there were no information of kidney function, or the end of the study period, whichever came first.
Covariates
The covariates included in this analysis were age at the admission, sex, geographic regions, body mass index (kg/m2), systolic blood pressure (SBP), diastolic blood pressure, intensive care units (ICUs) admission, surgery, laboratory measurement (eGFR, hemoglobin, low-density lipoprotein cholesterol, serum albumin, and urine specific gravity), Charlson Comorbidity Index (CCI),20 comorbidities (diabetes, hypertension, heart failure, ACS, stroke, AKI, sepsis, and cancer), comedication use (renin angiotensin system inhibitor [RASi], statins, loop diuretics, vasopressors, metformin, and aspirin). We calculated the age-adjusted CCI to quantify the overall comorbidity status (Supplemental Table 1). Baseline laboratory indicators were defined as the most recent measurements at the index date. Comorbidities were identified based on International Classification of Diseases-10 codes using the all diagnoses data before the index date. Prescription records within 1 year before the index date were used to determine comedications use according to the Anatomical Therapeutic Chemical code.
Statistical analysis
Baseline characteristics were compared between patients with and without new-onset proteinuria during hospitalization. Continuous covariates were summarized as median and IQR. To examine the potential risk factors of new-onset proteinuria, candidate predictors were inputted in the univariate logistic regression. Predictor with P value <0.05 were further included in the multivariable logistic regression. ORs and their 95% CI were reported. The candidate predictors included age, sex, SBP, eGFR, serum albumin, CCI, AKI, hypertension, heart failure, diabetes, sepsis, ICU admission, surgery, statins, loop diuretics, and vasopressors. To evaluate the relationship between new-onset proteinuria and long-term mortality, only patients who survived until discharge were included in the analysis. Ten-year mortality with their 95% CIs were estimated by the Kaplan-Meiermethod. The association was assessed using Cox proportional hazards regression analysis. HRs and their 95% CI were reported. The analysis was adjusted for potential confounding factors including age, sex, body mass index, ICU, surgery, SBP, diastolic blood pressure, eGFR, hemoglobin, low-density lipoprotein cholesterol, serum albumin, CCI, comorbidities, and comedications. We tested the proportional hazards assumption using Schoenfeld residuals.
Subgroup analyses were performed, stratified by baseline characteristics, including age (<50 years old, ≥50 years old) and sex, with or without hypertension, diabetes, stroke, heart failure, ACS, surgery, and use of RASi. Possible effect modification was examined by introducing multiplicative interaction terms between new-onset proteinuria and the potential effect modifiers into our Cox regression model. If the P value for the interaction term was <0.05, the effect modifications was considered as significant. In addition, the association between mild (1+) or severe (2+ or more) new-onset proteinuria and study outcomes was assessed.
A secondary analysis was conducted to examine potential differences in the associations between transient or persistent proteinuria and study outcomes. In this analysis, patients with at least 1 urinary protein test repeated within 90 day after discharge were included. Patients were considered as the transient new-onset proteinuria group if they had negative result of repeated urinary protein test after discharge. In contrast, patients with positive result of urinary protein test (remained 1+ or more) after discharge were considered as the persistent new-onset proteinuria group.
Several sensitivity analyses were performed to strengthen the robustness of the results. First, the analyses were conducted in a population without AKI considering the potential confounding impact of AKI. In this sensitivity analyses, the study population was restricted to patients with at least 2 SCr measurements in 7 days during the hospitalization to allow the accurate capture of AKI. Patients who were diagnosed with AKI21 were further excluded. The same analyses were performed in this population. Second, the sensitivity analyses were conducted after excluding patients who died within 90 days after discharge to preclude the reverse causality. Third, the association between proteinuria and study outcomes was reassessed by redefining new-onset proteinuria based on quantitative 24-hour urinary protein tests in addition to the urine dipstick protein test. The definition of new-onset proteinuria was revised as a quantitative urine protein test >0.15 g/24 h or urine dipstick protein test ≥1+. Fourth, we employed the propensity score matching of “greedy nearest neighbour” algorithm in a 1:1 ratio (caliper = 0.2 times the SD of logit of propensity score) using logistic regression models with confounders at baseline. Standardized mean differences were assessed for all covariates, with a value of <0.10 indicating good balance.
Multiple imputations by chained equations were performed to account for missing values. The missing data were imputed using 5 data sets and the results were pooled based on the Rubin criteria. All statistical analyses were performed using R software (version 4.1.2, R Foundation for Statistical Computing). P values were 2-sided and a P value less than 0.05 was considered statistically significant.
Results
Incidence and risk factors of new-onset proteinuria in hospitalized patients with ASCVD
A total of 34,429 inpatients were included in the analysis to estimate the incidence and the risk factors of new-onset proteinuria (Figure 1). Baseline characteristics of this population, stratified by the presence or absence of new-onset proteinuria and by all-cause mortality status, are presented in Supplemental Tables 2 and 3, respectively. The incidence of new-onset proteinuria was 7.5% (2,582/34,429) during the hospitalization. In various clinical settings (Supplemental Figure 1), patients with AKI had the highest incidence of new-onset proteinuria (23.8%), followed by intensive care (18.7%) and noncardiac surgery (13.0%). Supplemental Figure 2 showed the distribution of the time of urinary protein test during the hospitalization. The independent predictors of new-onset proteinuria are shown in Supplemental Table 3, including elevated SBP (OR: 1.07; 95% CI: 1.02-1.11 per 10 mm Hg increase), AKI (OR: 2.83; 95% CI: 2.26-3.56), ICU admission (OR: 1.76; 95% CI: 1.30-2.37) and surgery (OR: 1.72; 95% CI: 1.45-2.05), whereas higher serum albumin (OR: 0.83; 95% CI: 0.71-0.96, per 10 g/L increase) was associated with a lower risk of new-onset proteinuria.
Risk of mortality and composite kidney outcome according to new-onset proteinuria
After excluding 462 patients died during hospitalization, a total of 33,967 inpatients were identified to assess the association between new-onset proteinuria and study outcomes after discharge (Figure 1). Baseline characteristics among these patients with and without new-onset proteinuria were shown in Table 1. The median age at baseline was 64 (IQR: 54-72) years, with 57.0% of participants being male. In addition, 17.8% of individuals were admitted to the ICU during the hospitalization, and 22.6% underwent surgery. At baseline, the median eGFR was 93.0 mL/min/1.73 m2 (IQR: 81.7-103.5), and the proportions of diabetes and hypertension were 25.9% and 45.9%, respectively. The mean number of urine protein test among patients with and without new-onset proteinuria was 3.0 and 2.3, respectively.
Table 1.
Baseline Characteristics Among Patients With and Without New-Onset Proteinuria During Hospitalization
| Overall (N = 33,967) | No Proteinuria (n = 31,506) | New-Onset Proteinuria (n = 2,461) | |
|---|---|---|---|
| Age, y | 64 (54-72) | 64 (54-72) | 66 (55-75) |
| Male (%) | 19,350 (57.0) | 17,734 (56.3) | 1,616 (65.7) |
| BMI, kg/m2 | 21.8 (20.9-24.5) | 21.8 (21-24.5) | 21.9 (20.8-24.7) |
| SBP, mm Hg | 126 (116-139) | 126 (116-139) | 127 (117-140) |
| DBP, mm Hg | 76 (70-83) | 76 (70-83) | 76 (68-83) |
| ICU (%) | 6,030 (17.8) | 4,939 (15.7) | 1,091 (44.3) |
| Surgery (%) | 7,674 (22.6) | 6,596 (20.9) | 1,078 (43.8) |
| Geographic regions (%) | |||
| South | 16,243 (47.8) | 15,061 (47.8) | 1,182 (48.0) |
| North | 1,029 (3.0) | 997 (3.2) | 32 (1.3) |
| East | 11,125 (32.8) | 10,066 (31.9) | 1,059 (43.0) |
| Southwest | 3,570 (10.5) | 3,560 (11.3) | 10 (0.4) |
| Northwest | 2000 (5.9) | 1822 (5.8) | 178 (7.2) |
| Laboratory measurement | |||
| eGFR, mL/min/1.73 m2 | 93 (81.7-103.5) | 92.9 (81.6-103.2) | 94.3 (82.7-107.2) |
| Hemoglobin, g/L | 125 (110-139) | 126 (111-139) | 114 (97-129) |
| LDL-C, mmol/L | 2.4 (1.8-3.1) | 2.5 (1.9-3.1) | 2.2 (1.7-2.9) |
| Albumin, g/L | 38.3 (34.7-41.5) | 38.5 (35-41.6) | 35.5 (31.9-39.4) |
| Urine specific gravity | 1.01 (1.01-1.02) | 1.01 (1.01-1.02) | 1.01 (1.01-1.02) |
| Comorbidities (%) | |||
| Charlson Comorbidity Index | 5 (4-6) | 5 (4-6) | 5 (4-7) |
| Diabetes | 8,811 (25.9) | 8,228 (26.1) | 583 (23.7) |
| Hypertension | 15,591 (45.9) | 14,285 (45.3) | 1,306 (53.1) |
| Heart failure | 3,198 (9.4) | 2,894 (9.2) | 304 (12.4) |
| AKI | 2,171 (6.4) | 1,665 (5.3) | 506 (20.6) |
| Sepsis | 598 (1.8) | 454 (1.4) | 144 (5.9) |
| Cancer | 4,456 (13.1) | 4,029 (12.8) | 427 (17.4) |
| ACS | 2,605 (7.7) | 2,450 (7.8) | 155 (6.3) |
| Stroke | 14,590 (43.0) | 13,179 (41.8) | 1,411 (57.3) |
| Comedications (%) | |||
| RASi | 11,101 (32.7) | 10,269 (32.6) | 832 (33.8) |
| Statins | 18,176 (53.5) | 17,110 (54.3) | 1,066 (43.3) |
| Loop diuretics | 8,781 (25.9) | 7,680 (24.4) | 1,101 (44.7) |
| Vasopressor | 4,008 (11.8) | 3,395 (10.8) | 613 (24.9) |
| Metformin | 4,236 (12.5) | 4,012 (12.7) | 224 (9.1) |
| Aspirin | 14,489 (42.7) | 13,606 (43.2) | 883 (35.9) |
ACS = acute coronary syndrome; AKI = acute kidney injury; BMI = body mass index; DBP = diastolic blood pressure; eGFR = estimated glomerular filtration rate; ICU = intensive care unit; LDL-C = low density lipoprotein cholesterol; RASi = renin angiotensin system inhibitor; SBP = systolic blood pressure.
33,967 participants were included.
During a mean follow-up of 4.6 years, the event rates for CV mortality were 13.77% and 7.49% among inpatients with and without new-onset proteinuria, respectively (Table 2, Figure 2). After adjusting for confounders, patients with new-onset proteinuria were significantly associated with increased risks of CV mortality (HR: 1.30; 95% CI: 1.07-1.57) and adverse kidney outcomes (HR: 1.50; 95% CI: 1.04-2.17), compared to patients without new-onset proteinuria during hospitalization. Violation of the proportional hazards assumption was detected via Schoenfeld residuals testing (global test P < 0.001), indicating nonconstant HRs over time. To address this temporal dependence, we extended the Cox model by incorporating a time-varying coefficient through an interaction term between proteinuria status and log-transformed time. The time-dependent analysis revealed a dynamic hazard profile: newly-developed proteinuria was associated with an initial HR of 2.60 at early follow-up. This risk attenuated progressively over time, eventually stabilizing at approximately HR = 1.5 beyond 2 years of observation (Supplemental Figure 3).
Table 2.
The Association of New-Onset proteinuria With the Study Outcomes
| Outcomes | Event/N (%) |
Crude HR (95%CI) | P Value | Adjusted HR (95%CI)a | P Value | |
|---|---|---|---|---|---|---|
| New-Onset Proteinuria | No Proteinuria | |||||
| Cardiovascular mortality | 339/2,461 (13.77) | 2,360/31,506 (7.49) | 2.12 (1.89-2.37) | <0.001 | 1.30 (1.07-1.57) | 0.008 |
| Composite adverse kidney outcomes | 47/1,236 (3.8) | 523/14,210 (3.68) | 1.56 (1.13-2.14) | 0.007 | 1.50 (1.04-2.17) | 0.032 |
The association was assessed using Cox proportional hazards regression analysis, adjusted for age, sex, geographic regions, BMI, SBP, DBP, eGFR, hemoglobin, LDL-C, albumin, urine specific gravity, Charlson Comorbidity Index, comorbidities, and co-medications. Schoenfeld residuals violated the proportional hazards assumption (P < 0.001)
Figure 2.
Cumulative Incidence of Cardiovascular Mortality and Composite Kidney Outcomes
Kaplan-Meier (KM) method was employed. (A) P < 0.0001 for cardiovascular mortality aaand (B) P = 0.00036 for composite kidney outcomes.
We further classified patients with new-onset proteinuria into mild (1+) and severe proteinuria (≥2+) and observed higher HRs associated with study outcomes in the severe proteinuria group than mild proteinuria group (Supplemental Table 5). Among the 714 patients who developed new-onset proteinuria during hospitalization and underwent repeat urinary protein testing within 90 days after discharge, 565 (79.1%) tested negative and were classified into the transient new-onset proteinuria group, whereas the remaining 149 (20.9%) patients showed persistent proteinuria with positive results on repeat tests within 90 days postdischarge. Persistent new-onset proteinuria was associated with increased risks of CV mortality and composite kidney outcome compared to patients without proteinuria (Supplemental Table 6). Similar trend of associations was observed for the transient new-onset proteinuria, although these associations did not reach statistical significance (P > 0.05).
In the subgroup analyses (Figure 3), the associations between new-onset proteinuria and CV mortality were consistent across subgroups stratified by age, hypertension, ACS, surgery, and RASi use (P for interaction >0.05). Notably, the risk of CV mortality associated with new-onset proteinuria were more prominent in patients with diabetes (P for interaction = 0.006), chronic heart failure, and sex (P for interaction <0.001).
Figure 3.
Subgroup Analyses
∗HR were adjusted for age, sex, BMI, SBP, DBP, eGFR, hemoglobin, LDL-C, serum albumin, urine specific gravity, Charlson Comorbidity Index, comorbidities, and co-medications. Possible effect modification was examined by introducing multiplicative interaction terms between new-onset proteinuria and the potential effect modifiers into our Cox regression model. ACS = acute coronary syndrome; RASi = renin angiotensin system inhibitor.
Sensitivity analyses
After excluding patients without at least 2 creatinine measurements within 7 days (n = 14,1995) and those with AKI during hospitalization (n = 2,171), among the 17,601 patients without AKI during hospitalization, new-onset proteinuria was also significantly associated with increased risks of CV mortality (HR: 1.36; 95%CI: 1.09-1.71) and composite kidney outcomes (HR: 1.58; 95% CI: 1.02-2.45) (Supplemental Table 7). In addition, sensitivity analyses conducted after excluding patients who died within 90 days or using a new definition of new-onset proteinuria (defined by quantitative urinary protein tests) showed similar associations between new-onset proteinuria and study outcomes (Supplemental Tables 8 and 9). In the matching cohort, all covariates were well balanced (standardized mean difference <0.1) (Supplemental Table 10) and consistent association of new-onset proteinuria with clinical outcomes were obtained (Supplemental Table 11).
Discussion
In this nationwide cohort of hospitalized patients with ASCVD, new-onset proteinuria occurred in 7.5% of the population. Several risk factors for new-onset proteinuria were identified, including increased SBP, reduced serum albumin level, ICU admission, surgery, stroke, as well as the presence of AKI. More importantly, new-onset proteinuria during hospitalization was significantly associated with increased risks of CV mortality, and a composite endpoint of adverse kidney outcomes, independent of traditional risk factors such as AKI (as illustrated in the Central Illustration). Both severe and mild new-onset proteinuria exhibited adverse associations with prognosis.
Central Illustration.
The Association of New-Onset Proteinuria Cardiovascular Mortality
∗HR were adjusted for age, sex, BMI, SBP, DBP, eGFR, hemoglobin, LDL-C, serum albumin, urine specific gravity, Charlson Comorbidity Index, comorbidities, and co-medications. Possible effect modification was examined by introducing multiplicative interaction terms between new-onset proteinuria and the potential effect modifiers into our Cox regression model. ACS = acute coronary syndrome; RASi = Renin Angiotensin System inhibitor.
This study represents the largest investigation demonstrating the association between new-onset proteinuria during hospitalization and elevated risk of CV mortality among patients with ASCVD. These findings align consistently with previous analyses, which identified proteinuria as a predictor for mortality.5, 6, 7 However, a notable difference is that the urinary protein status was only assessed at baseline in these previous studies, which mainly reflected the underlying pre-existing CKD. In contrast, our study specifically focused on capturing the acute incidence of urinary protein within a more immediate timeframe by excluding patients with prior impaired kidney function and positive urinary protein at baseline. Thus, the findings from our study provide evidence supporting the concept that the sudden emergence of proteinuria during hospitalization conveys important prognostic information, underscoring the need for monitoring of urinary protein among hospitalized patients with ASCVD.
In stratified analyses, we observed that some specific comorbidities—including diabetes, stroke, or chronic heart failure—and sex modified the association between new-onset proteinuria and CV mortality. In patients with diabetes, stroke, or chronic heart failure, as well as in female patients, the association of new-onset proteinuria with the risk of CV mortality was significantly amplified. Notably, we also conducted a subgroup analysis to assess whether early interventions targeting proteinuria, such as RASi, could mitigate CV mortality risks associated with new-onset proteinuria. The results showed that a lower risk estimate was observed in the RASi group, although the interaction term was not statistically significant, suggesting that early RASi use in proteinuric patients may confer CV protective benefits. This finding should be confirmed in future well-designed interventional trials.
New-onset proteinuria during hospitalization is often accompanied by AKI in real-world clinical practice.16,22 Similarly, the present study also found that AKI was a risk factor of new-onset proteinuria in ASCVD patients during hospitalization. Prior perspectives have suggested that the concurrent AKI may predominantly drive the association between new-onset proteinuria and CV mortality, as AKI significantly increases the risk of adverse outcomes in patients with ASCVD.16,22, 23, 24, 25 In clinical practice, SCr increase gained much more attention in hospitalized patients with ASCVD than the acute changes in urinary protein. However, our observations show that the association is distinct from AKI, indicating an independent link of new-onset proteinuria to CV mortality. These findings underscore the importance of detecting new-onset proteinuria for improved management of patients with ASCVD.
The pathology processes between the independent association between proteinuria and CV mortality among patients with ASCVD are unclear. Several mechanisms may contribute to the association, including renal and nonrenal pathways. Urinary protein excretion reflects not only subclinical renal disease but also systemic endothelial dysfunction.26 Many previous studies had reported that proteinuria correlates with elevated high-sensitivity troponin T (a myocardial injury marker)27 and inflammation marker (eg, C-reactive protein),28 indicating its association with endothelial impairment. These biomarkers are well established and significantly associated with CV events.29,30 Thus, one theory is that endothelial dysfunction may disrupt vascular homeostasis, leading to exacerbating ASCVD progression.31,32 In addition, chronic low-grade inflammation may also account for the relationship between new-onset proteinuria and CV events.31,32 Besides, in renal pathways, proteinuria-induced degradation of the glomerular endothelial glycocalyx, a fragile layer of proteoglycans and glycoproteins coating the luminal surface, may critically bridge renal impairment to ASCVD progression.33 Moreover, proteinuria can lead to hypertension and an increased hemodynamic load due to the overactivation of the renin-angiotensin system, thereby increasing the risk of CV events.34 Consequently, the presence of new-onset proteinuria may serve as a prognostic clue for predicting short- and long-term outcomes in patients with ASCVD. Implementing proteinuria monitoring may enhance kidney disease assessment and inform clinical decision-making in patients with ASCVD. Furthermore, as a potential modifiable risk factor for CV mortality, new-onset proteinuria may offer a therapeutic target to improve the management in patients with ASCVD. Further investigations are warranted to validate the efficacy of monitoring and intervening in new-onset proteinuria among hospitalized patients with ASCVD.
In addition, our results also demonstrated that severe proteinuria (≥2+) independently predicts heightened CV mortality through multifaceted pathophysiological pathways. On the one hand, glomerular endothelial injury in heavy proteinuria provokes glycocalyx shedding and antithrombin-III deficiency, accelerating thrombogenesis.35,36 On the other hand, tubular overload of filtered proteins activates NF-κB-driven inflammation (interleukin-6, tumor necrosis factor-α) and oxidative stress, and promotes accumulation of uremic toxins, promoting atherosclerosis or myocardial fibrosis.37,38 Population studies robustly validate this risk gradient. Our prior study has established that heavy proteinuria (from 1+ to ≥2+) accelerates CKD progression.15 Furthermore, the renal function or proteinuria deterioration independently amplifies CV mortality risk through uremic cardiomyopathy and neurohormonal hyperactivation.39
Persistent proteinuria, which is a marker of kidney damage, is associated with an increased risk of CV mortality.40, 41, 42 In our study, we observed similar trend of associations between both transient and persistent new-onset proteinuria with CV mortality, which is in line with previous studies.43, 44, 45 However, the transient new-onset proteinuria did not achieve statistical significance. A possible explanation for this result is that the persistent proteinuria can lead to irreversible damage to the glomeruli, renal tubules, or vascular endothelium.46 The combined cardiorenal effects further contribute to CV mortality. With precise capture of new-onset proteinuria during hospitalization and rigorous identification of recovery within a 90-day time window, our observations emphasize the importance of monitoring the occurrence and recovery status of proteinuria during hospitalization, for precise risk stratification among patients with ASCVD. Further investigations are needed to elucidate the relationship between transient proteinuria and CV mortality.
Our study possesses several notable strengths. The large sample size and comprehensive medical information ensured the strict inclusion criteria. All patients with underlying CKD and urinary tract infections were excluded to enable the accurate identification of new-onset proteinuria. The real-world-based database facilitated analyses to adjust for multiple confounding, such as the blood pressure, and the occurrence of AKI. Second, our strict restriction in the time window of urine protein measurements allowed timely capture of changes in urine protein. In addition, subgroup analyses across various clinical settings and multiple sensitivity analyses were performed to enhance the robustness of the study findings. Finally, our access to the national electronic cause-of-death reporting system of the CDC provided reliable records of death for the survival analyses.
Study limitations
We acknowledge several limitations in our study. Firstly, despite our efforts to adjust for a wide range of variables, residual confounding may persist from unmeasured factors such as hydration status, pyrexia, dietary protein intake, and physical mobility. Secondly, we only included patients with at least 2 measurements of urinary protein and there is still a possibility of missing cases where proteinuria was not captured due to insufficient measurements. In that condition, population selection bias may introduce because patients with more tests may be more severe than the general inpatients. However, we employed comprehensive strategies to minimize the selection bias by adjusting for all potential indicators of disease severity, such as ICU admission, CCI, and vasopressor use and so on. Thirdly, the study used semiquantitative measurements of urinary protein to define new-onset proteinuria. The results of urine dipstick protein test may be affected by timing of collection, and intraobserver or interobserver variability, which were not adjusted for in our study. To reduce the possibility of false positive, trace positive result of the repeated dipstick protein test was not considered as new-onset proteinuria in our analysis. Furthermore, a sensitivity analysis was also performed adding quantitative measurements for proteinuria assessment and found the consistent associations. In fact, quantified measures such as urine albumin-to-creatinine ratio or 24-hour urinary protein are rarely obtained in routine clinical practice for this population. Considering that urine dipstick protein is a routine laboratory test at admission, the implementation of the urine dipstick screening method enhanced the generalizability of the results. Finally, the retrospective nature of this study inherently precludes causal inference. Future prospective studies are warranted to validate these relationships and elucidate potential causal mechanisms.
Conclusions
In conclusion, this study provides evidence of an association between new-onset proteinuria during hospitalization and increased risk of adverse outcomes, including CV mortality, and major adverse kidney events, among patients with ASCVD. The consistent relationship between new-onset proteinuria and CV mortality, independent of the occurrence of AKI, highlights the significance of routine measurements of urinary protein during the hospitalization of patients with ASCVD. By leveraging easily obtainable urinary protein data, clinicians can enhance risk stratification for long-term health in hospitalized patients with ASCVD, contributing to a holistic approach to the management of patients with ASCVD.
Perspectives.
COMPETENCY IN MEDICAL KNOWLEDGE: This observational cohort study included 34,429 hospitalized adults with ASCVD from the CRDS, without proteinuria at admission. Over a mean follow-up of 4.6 years, new-onset proteinuria was significantly associated with increased CV mortality and poor kidney outcome.
TRANSLATIONAL OUTLOOK: Our findings underscore the importance of monitoring new-onset proteinuria in hospitalized ASCVD patients to improve patient care.
Funding support and author disclosures
This study was supported by grants from the Funding by Science and Technology Projects in Guangzhou (Dr L. Su, grant No: 2024A04J5166), Guangdong Special Support Program (grant No. 0720240109), National Key R&D Program of China (grant No. 2021YFC2500200 and 2021YFC2500204), and the National Natural Science Foundation of China (grant No. 81770683, 81970586 and 81900626) The funders had no role in the design, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors acknowledge the support for the data provided by China Renal Data System study group.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For an expanded Methods section as well as supplemental tables and figures, please see the online version of this paper.
Contributor Information
Xin Xu, Email: xux007@163.com.
Sheng Nie, Email: niesheng0202@126.com.
Supplementary material
References
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