Urinary non-albumin protein-creatinine ratio is an independent predictor of mortality in patients with type 2 diabetes: a retrospective cohort study.

Albuminuria is a well-known predictor of chronic kidney disease in patients with type 2 diabetes mellitus (DM). However, proteinuria is associated with chronic complications in patients without albuminuria. In this retrospective cohort study, we explored whether non-albumin proteinuria is associated with all-cause mortality and compared the effects of non-albumin proteinuria on all-cause mortality between patients with and without albuminuria. We retrospectively collected data from patients with type 2 DM for whom we had obtained measurements of both urinary albumin-to-creatinine ratio (UACR) and urinary protein-to-creatinine ratio (UPCR) from the same spot urine specimen. Urinary non-albumin protein-creatinine ratio (UNAPCR) was defined as UPCR-UACR. Of the 1809 enrolled subjects, 695 (38.4%) patients died over a median follow-up of 6.4 years. The cohort was separated into four subgroups according to UACR (30 mg/g) and UNAPCR (120 mg/g) to examine whether these indices are associated with all-cause mortality. Compared with the low UACR and low UNAPCR subgroup as the reference group, multivariable Cox regression analyses indicated no significant difference in mortality in the high UACR and low UNAPCR subgroup (hazard ratio [HR] 1.189, 95% confidence interval [CI] 0.889-1.589, P = 0.243), but mortality risks were significantly higher in the low UACR and high UNAPCR subgroup (HR 2.204, 95% CI 1.448-3.356, P < 0.001) and in the high UACR with high UNAPCR subgroup (HR 1.796, 95% CI 1.451-2.221, P < 0.001). In the multivariable Cox regression model with inclusion of both UACR and UNAPCR, UNAPCR ≥ 120 mg/g was significantly associated with an increased mortality risk (HR 1.655, 95% CI 1.324-2.070, P < 0.001), but UACR ≥ 30 mg/g was not significantly associated with mortality risk (HR 1.046, 95% CI 0.820-1.334, P = 0.717). In conclusion, UNAPCR is an independent predictor of all-cause mortality in patients with type 2 DM.

The impact of urinary albumin-creatinine ratio and glomerular filtration rate on long-term mortality in patients with heart failure: The National Health and Nutrition Examination Survey 1999-2018.

BACKGROUND AND AIMS: The urinary albumin‒creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are important markers of renal dysfunction, but few studies have simultaneously examined their impact on long-term mortality in patients with heart failure (HF). METHODS AND RESULTS: This study included patients with HF from the National Health and Nutrition Survey from 1999 to 2018. The fully adjusted Cox proportional risk model was adopted, and propensity score matching (PSM) was also used for risk adjustment. Among 988 patients, a median follow-up of 7.75 years was recorded. A higher UACR corresponded to a higher risk of cardiovascular death (P < 0.001 for trend). No statistically significant difference was found in the trend of eGFR risk stratification on the risk of cardiovascular death (P = 0.09 for trend). After PSM, the results showed that when grouped by UACR, the high-risk group had a higher risk of cardiovascular death regardless of a cutoff value of 30 or 300 mg/g (all P < 0.05). When grouped by eGFR, regardless of a cutoff value of 45 or 30 mL/min/1.73 m2, compared to the low-risk group, the high-risk group did not have a statistically significant increase in cardiovascular death (P = 0.086 and P = 0.093, respectively). The subgroup analysis of the main outcome showed an interaction between the UACR and eGFR (P = 0.044). CONCLUSIONS: Both the UACR and eGFR are markers for predicting the progression of HF, but the UACR may be a more important indicator than the eGFR, and they synergistically and complementarily reflect the long-term cardiovascular risk of HF patients.

Albuminuria as a predictor of mortality in type II diabetic patients after living-donor liver transplantation.

PURPOSE: Diabetes mellitus (DM) increases the risk of morbidity and mortality after liver resection. Albuminuria is associated with a higher risk for all-cause and cardiovascular mortality. This study evaluated albuminuria as a predictor of the outcome of living donor liver transplantation (LDLT) in patients with pre-existing DM. METHODS: This retrospective study involved 103 type II diabetic patients with end-stage liver disease who received LDLT. Preoperative spot urine albumin: creatinine ratio was used to determine the degree of albuminuria. The primary outcome measure was the impact of urinary albumin excretion on the 3-year mortality rate after LDLT in this diabetic cohort. RESULTS: Hepatitis C virus infection was the main cause of cirrhosis. Albuminuria was detected in 41 patients (39.8%); 15 had macroalbuminuria, while 26 had microalbuminuria. Patients with microalbuminuria were significantly older than those with macroalbuminuria and normal albumin in urine. After 3 years, twenty-four patients (23.3%) died within 3 years after LT. Myocardial infarction was the leading cause of death (25%). Albuminuria was an independent factor affecting 3-year mortality with an odds ratio of 5.17 (95% CI: 1.86-14.35). CONCLUSION: Preoperative albuminuria is an independent factor affecting mortality within 3 years after LDLT in type II diabetic patients. Myocardial infarction was the leading cause of death in 25% of cases, followed by hepatocellular carcinoma recurrence, sepsis, and graft failure.KEY MESSAGESDiabetes mellitus (DM) increases the risk of morbidity and mortality after liver resection.Albuminuria is associated with a higher risk for all-cause and cardiovascular mortality.Preoperative albuminuria is a significant predictor of mortality within 3 years after LDLT in diabetic patients.

Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease.

BACKGROUND: Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. METHODS: Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. RESULTS: At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4-13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30-0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29-0.93, P = 0.027). CONCLUSION: MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Accounting for the Competing Risk of Death to Predict Kidney Failure in Adults With Stage 4 Chronic Kidney Disease.

Importance: Kidney failure risk prediction has implications for disease management, including advance care planning in adults with severe (ie, estimated glomerular filtration rate [eGFR] category 4, [G4]) chronic kidney disease (G4-CKD). Existing prediction tools do not account for the competing risk of death. Objective: To compare predictions of kidney failure (defined as estimated glomerular filtration rate [eGFR] <10 mL/min/1.73 m2 or initiation of kidney replacement therapy) from models that do and do not account for the competing risk of death in adults with G4-CKD. Design, Setting, and Participants: This prognostic study linked population-based laboratory and administrative data (2002-2017) from 2 Canadian provinces (Alberta and Manitoba) to compare 3 kidney risk models: the standard Cox regression, cause-specific Cox regression, and Fine-Gray subdistribution hazard model. Participants were adults with incident G4-CKD (eGFR 15-29 mL/min/1.73 m2). Data analysis occurred between July and December 2020. Main Outcomes and Measures: The performance of kidney risk models at prespecified times and across categories of baseline characteristics, using calibration, reclassification, and discrimination (for competing risks). Predictive characteristics were age, sex, albuminuria, eGFR, diabetes, and cardiovascular disease. Results: The development and validation cohorts included 14 619 (7070 [48.4%] men; mean [SD] age, 74.1 [12.8] years) and 2295 (1152 [50.2] men; mean [SD] age, 71.9 [14.0] years) adults, respectively. The 3 models had comparable calibration up to 2 years from entry. Beyond 2 years, the standard Cox regression overestimated the risk of kidney failure. At 4 years, for example, risks predicted from standard Cox were 40% for people whose observed risks were less than 30%. At 2 years (risk cutoffs 10%-20%) and 5 years (risk cutoffs 15%-30%), 788 (5.4%) and 2162 (14.8%) people in the development cohort were correctly reclassified into lower- or higher-risk categories by the Fine-Gray model and incorrectly reclassified by standard Cox regression (the opposite was observed in 272 patients [1.9%] and 0 patients, respectively). In the validation cohort, 115 (5.0%) individuals and 389 (16.9%) individuals at 2 and 5 years, respectively, were correctly reclassified into lower- or higher-risk categories by the Fine-Gray model and incorrectly reclassified by the standard Cox regression; the opposite was observed in 98 (4.3%) individuals and 0 individuals, respectively. Differences in discrimination emerged at 4 to 5 years in the development cohort and at 1 to 2 years in the validation cohort (0.85 vs 0.86 and 0.78 vs 0.8, respectively). Performance differences were minimal during the entire follow-up in people at lower risk of death (ie, aged ≤65 years or without cardiovascular disease or diabetes) and greater in those with a higher risk of death. At 5 years, for example, in people aged 65 years or older, predicted risks from standard Cox were 50% where observed risks were less than 30%. Similar miscalibration was observed at 5 years in people with albuminuria greater than 30 mg/mmol, diabetes, or cardiovascular disease. Conclusions and Relevance: In this study, predictions about the risk of kidney failure were minimally affected by consideration of competing risks during the first 2 years after developing G4-CKD. However, traditional methods increasingly overestimated the risk of kidney failure with longer follow-up time, especially among older patients and those with more comorbidity.

The ratio and difference of urine protein-to-creatinine ratio and albumin-to-creatinine ratio facilitate risk prediction of all-cause mortality.

The role of the difference and ratio of albuminuria (urine albumin-to-creatinine ratio, uACR) and proteinuria (urine protein-to-creatinine ratio, uPCR) has not been systematically evaluated with all-cause mortality. We retrospectively analyzed 2904 patients with concurrently measured uACR and uPCR from the same urine specimen in a tertiary hospital in Taiwan. The urinary albumin-to-protein ratio (uAPR) was derived by dividing uACR by uPCR, whereas urinary non-albumin protein (uNAP) was calculated by subtracting uACR from uPCR. Conventional severity categories of uACR and uPCR were also used to establish a concordance matrix and develop a corresponding risk matrix. The median age at enrollment was 58.6 years (interquartile range 45.4-70.8). During the 12,391 person-years of follow-up, 657 deaths occurred. For each doubling increase in uPCR, uACR, and uNAP, the adjusted hazard ratios (aHRs) of all-cause mortality were 1.29 (95% confidence interval [CI] 1.24-1.35), 1.12 (1.09-1.16), and 1.41 (1.34-1.49), respectively. For each 10% increase in uAPR, it was 1.02 (95% CI 0.98-1.06). The linear dose-response association with all-cause mortality was only observed with uPCR and uNAP. The 3 × 3 risk matrices revealed that patients with severe proteinuria and normal albuminuria had the highest risk of all-cause mortality (aHR 5.25, 95% CI 1.88, 14.63). uNAP significantly improved the discriminative performance compared to that of uPCR (c statistics: 0.834 vs. 0.828, p-value = 0.032). Our study findings advocate for simultaneous measurements of uPCR and uACR in daily practice to derive uAPR and uNAP, which can provide a better mortality prognostic assessment.

Cystatin C-based estimated GFR and albuminuria are independently associated with all-cause and CVD mortality in Korean population: The Dong-gu Study.

OBJECTIVE: To assess the associations among the estimated glomerular filtration rate (eGFR), albumin to creatinine ratio (ACR), and all-cause and CVD mortality rate and to compare the performances of eGFRMDRD, eGFRCKD-EPI, and eGFRcys using receiver operating characteristic (ROC) analysis in Korean adults aged ≥ 50 years. METHODS: Of the 9,260 subjects who participated in the baseline survey of a prospective longitudinal study conducted in Korea, 9,009 (men: 3,574 (39.7%); women: 5,435 (60.3%)) were included in this analysis after the exclusion of 217 subjects with missing eGFR and 34 subjects with missing ACR data. MAIN OUTCOME MEASURE: The associations of eGFR and ACR with all-cause and CVD mortality were investigated using Cox proportional hazards models that included sex, age, waist circumference, smoking, alcohol intake, degree of physical activity, hypertension, diabetes, systolic blood pressure, log-HbA1c, total cholesterol, log-triglyceride, log-HDL and log-ACR or eGFR. RESULTS: After adjustment for covariates, independent associations were found between all-cause mortality and the eGFRcys (mL/min per 1.73 m2) [HR 1.23, 95% confidence interval (CI) 1.05-1.43 for 60-89 vs. ≥ 90; HR 1.87, 95% CI 1.49-2.34 for 45-59 vs. ≥ 90; HR 2.38, 95% CI 1.77-3.20 for 30-44 vs. ≥ 90; HR 2.82, 95% CI 1.89-4.23 for <30 vs. ≥ 90] and ACR (µg/mg creatinine) [HR 1.09, 95% CI 0.88-1.34 for Q2 vs. Q1; HR 1.34, 95% CI 1.10-1.63 for Q3 vs. Q1; HR 1.49, 95% CI 1.22-1.81 for Q4 vs. Q1]. In addition, independent associations of CVD mortality with the eGFRcys and ACR were significant. In the comparison of eGFR performance, the ROC-plot AUC for all-cause mortality was significantly greater for the eGFRcys than for the eGFRMDRD and eGFRCKD-EPI. CONCLUSION: The eGFRcys and ACR were associated independently with all-cause and CVD mortality after adjustment for covariates, including the eGFRcys and ACR. In addition, the ROC-plot AUC for all-cause mortality was greater for the eGFRcys than for the eGFRMDRD and eGFRCKD-EPI in Korean adults aged ≥ 50 years.

Effects of Intensive Blood Pressure Control in Patients with and without Albuminuria: Post Hoc Analyses from SPRINT.

BACKGROUND AND OBJECTIVES: It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). RESULTS: Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. CONCLUSIONS: Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study.

BACKGROUND: Reactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients. METHODS: Asymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED). RESULTS: In total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17). CONCLUSIONS: PED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Lipoprotein(a)and renal function decline, cardiovascular disease and mortality in type 2 diabetes and microalbuminuria.

AIMS: Lipoprotein(a)(Lp(a)) has emerged as an independent risk marker for cardiovascular disease (CVD) in the general population and among persons with existing CVD. We investigated associations between serum Lp(a)concentrations and renal function decline, incident CVD and all-cause mortality in individuals with type 2 diabetes (T2D) and microalbuminuria. METHODS: Prospective study including 198 individuals with T2D, microalbuminuria and no CVD. Yearly p-creatinine was measured after baseline in 176 of the participants. The renal endpoint was defined as decline in eGFR of >30% from baseline. CVD events and mortality were tracked from national registries. Cox regression analyses were applied both unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin creatinine ratio (UAER)). RESULTS: Baseline mean (SD) age was 59 (9)years, eGFR 89 (17) mL/min/1.73 m2, 77% were male, and median [IQR] UAER was 103 [38-242] mg/24-h. Median Lp(a)was 8.04 [3.42-32.3] mg/dL. Median follow-up was 6.1 years; 38 CVD events, 26 deaths and 43 renal events were recorded. For each doubling of baseline Lp(a), the following hazard ratios (95% confidence intervals) were found before and after adjustment respectively: 0.98 (0.84-1.15) and 1.01 (0.87-1.18) for decline in eGFR > 30%, 0.96 (0.81-1.13) and 0.99 (0.82-1.18) for CVD events, 1.04 (0.85-1.27) and 1.06 (0.87-1.30) for all-cause mortality. CONCLUSIONS: In this cohort of individuals with T2D and microalbuminuria, the baseline concentration of Lp(a)was not a risk marker for renal function decline, CVD events or all-cause mortality.

Effect of low-protein intake on all-cause mortality in subjects with an estimated glomerular filtration rate higher than 60 mL/min/1.73 m2 with or without albuminuria.

BACKGROUND: We aimed to investigate the effect of a low-protein intake on all-cause mortality in subjects with an estimated glomerular filtration rate (eGFR) ≧60 mL/min/1.73 m2 with or without albuminuria using data from the National Health and Nutrition Examination Survey (NHANES). METHODS: We analysed participants in the NHANES from 2003 to 2010. We excluded participants with an eGFR less than 60 mL/min/1.73 m2 from the analyses. Low-protein intake was defined as a protein intake of less than 0.8 g/kg/day. The Healthy Eating Index 2010 was used to assess diet quality. The vital status of all participants in the NHANES was determined by linking to the National Death Index through the end of 2011. The hazard ratios (HRs) for the association of low-protein intake and mortality were determined using weighted Cox proportional hazards regression models. RESULTS: A total of 7730 participants were included in the analyses. After a median follow up of 4.7 years, 462 participants died. A low-protein intake was associated with a higher risk of mortality (HRs 1.394, 95% CI 1.121-1.734, P = .004) with adjustment for diet quality and relevant risk factors. The higher risk of mortality associated with a low-protein intake was consistent in subjects with or without albuminuria (P interaction .280). CONCLUSION: A protein intake of less than 0.8 g/kg/day was associated with a higher risk of mortality in subjects with an eGFR ≧60 mL/min/1.73 m2 , irrespective of whether they had albuminuria.

Impaired glucose tolerance and albuminuria in patients with chronic heart failure: a subanalysis of the SUPPORT trial.

AIMS: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with ß-blockers and/or angiotensin-converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all-cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with ß-blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14-4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35-1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17-3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1-year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39-38.98, P = 0.019). CONCLUSIONS: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF.

Novel "Predictor Patch" Method for Adding Predictors Using Estimates From Outside Datasets　- A Proof-of-Concept Study Adding Kidney Measures to Cardiovascular Mortality Prediction.

BACKGROUND: Cardiovascular guidelines include risk prediction models for decision making that lack the capacity to include novel predictors.Methods and Results:We explored a new "predictor patch" approach to calibrating the predicted risk from a base model according to 2 components from outside datasets: (1) the difference in observed vs. expected values of novel predictors and (2) the hazard ratios (HRs) for novel predictors, in a scenario of adding kidney measures for cardiovascular mortality. Using 4 US cohorts (n=54,425) we alternately chose 1 as the base dataset and constructed a base prediction model with traditional predictors for cross-validation. In the 3 other "outside" datasets, we developed a linear regression model with traditional predictors for estimating expected values of glomerular filtration rate and albuminuria and obtained their adjusted HRs of cardiovascular mortality, together constituting a "patch" for adding kidney measures to the base model. The base model predicted cardiovascular mortality well in each cohort (c-statistic 0.78-0.91). The addition of kidney measures using a patch significantly improved discrimination (cross-validated ∆c-statistic 0.006 [0.004-0.008]) to a similar degree as refitting these kidney measures in each base dataset. CONCLUSIONS: The addition of kidney measures using our new "predictor patch" approach based on estimates from outside datasets improved cardiovascular mortality prediction based on traditional predictors, providing an option to incorporate novel predictors to an existing prediction model.

Mediation analysis of the relationship between type 2 diabetes and cardiovascular events and all-cause mortality: Findings from the SMART cohort.

AIM: To quantify the magnitude and specific contributions of known cardiovascular risk factors leading to higher cardiovascular risk and all-cause mortality caused by type 2 diabetes (T2D). METHODS: Mediation analysis was performed to assess the relative contributions of known classical risk factors for vascular disease in T2D (insulin resistance, systolic blood pressure, renal function, LDL-cholesterol, triglycerides and micro-albuminuria), and what proportion of the effect of T2D on cardiovascular events and all-cause mortality these factors mediate in the Second Manifestations of ARTerial disease (SMART) cohort consisting of 1910 T2D patients. RESULTS: Only 35% (95% CI 15-71%) of the excess cardiovascular risk caused by T2D is mediated by the classical cardiovascular risk factors. The largest mediated effect was through insulin resistance [proportion of mediated effect (PME) 18%, 95% CI 3-37%], followed by elevated triglycerides (PME 8%, 95% CI 4-14%) and micro-albuminuria (PME 7%, 95% CI 3-17%). Only 42% (95% CI 18-73%) of the excess mortality risk was mediated by the classical risk factors considered. The largest mediated effect was by micro-albuminuria (PME 18%, 95% CI 10-29%) followed by insulin resistance (PME 15%, 95% CI 1-33%). CONCLUSION: A substantial amount of the increased cardiovascular risk and all-cause mortality caused by T2D cannot be explained by traditional vascular risk factors. Future research should focus on identifying non-classical pathways that might further explain the increased cardiovascular and mortality risk caused by T2D.

Mortality prediction in systemic lupus erythematosus patients with pulmonary infection.

OBJECTIVE: The impact of pulmonary infection (PI) on mortality of patients with systemic lupus erythematosus (SLE) has been established. Nevertheless, the effect of risk factors in mortality remains controversial. The objective of this study is to determine the risk factors of short-term mortality among SLE patients with PI. METHOD: The clinical data of 54 SLE patients with 59 episodes of PI who were hospitalized from January 2013 to May 2018 was retrospectively analyzed. Demographic data, clinical features, and outcomes were collected. Logistic regression analysis was carried out to determine the independent predictors of 60-day mortality during hospitalization. We used receiver operating characteristics (ROC) curves to verify the indices as mortality predictors in the study patients. RESULTS: There were a total of 54 patients with 59 episodes of PI. There were 12 deaths during hospitalization. In multivariate analysis, 24-hour urinary protein (24h-PRO) (odds ratio [OR]: 2.713, 95% CI: 1.234-5.965, P = 0.013), peripheral lymphocyte count (OR: 0.066, 95% CI: 0.005-0.887, P = 0.040), and serum complement 3 level (C3) (OR: 0.097, 95% CI: 0.010-0.954, P = 0.045) were associated with mortality among our cohort of SLE patients with PI. ROC curve values were 0.818 for lymphocyte count (95% CI: 0.696-0.907, P = 0.001), 0.894 for 24h-PRO (95% CI: 0.786-0.959, P < 0.001) and 0.825 for C3 (95% CI: 0.704-0.912, P = 0.001). The cut-off value of lymphocytes, 24h-PRO and C3 were 0.53 × 109 /L, 0.92 g and 0.52 g/L, respectively. CONCLUSION: The presence of albuminuria, lymphopenia and low complement C3 levels were independent prognostic predictors of short-term mortality in SLE patients with PI.

Uric Acid Is an Independent Risk Factor for Decline in Kidney Function, Cardiovascular Events, and Mortality in Patients With Type 1 Diabetes.

OBJECTIVE: Previous studies have provided inconclusive results on the role of uric acid (UA) in risk prediction. Here we aimed to improve the power and precision of the predictive value of UA for the risk of decline in kidney function, cardiovascular events (CVEs), and mortality in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Plasma UA was measured in 670 patients with T1D and various degrees of albuminuria, ranging from normoalbuminuria to macroalbuminuria. Associations of UA with an estimated glomerular filtration rate (eGFR) decline of ≥30%, CVEs, and mortality were analyzed. The median follow-up time was 5.3 years [interquartile range (IQR) 2.7-6.2 years] for a decline in eGFR of ≥30%, 5.8 years (2.5-6.4 years) for progression in albuminuria status, 5.1 years (4.7-5.6 years) for CVE, and 6.2 years (5.8-6.7 years) for mortality. Both univariable and multivariable associations of UA with relevant outcomes and variables were reported. Hazard ratios (HRs) were calculated per doubling of the UA level. RESULTS: A doubling in UA level was associated with a higher risk of decline in eGFR of ≥30% (n = 89) (HR 3.18 [IQR 1.71-5.93]; P < 0.001), CVE (n = 94) (HR 2.25 [IQR 1.20-4.21]; P = 0.011), and mortality (n = 58) (HR 2.58 [IQR 1.12-5.90]; P = 0.025) in adjusted analyses. Adding UA to the adjusted model including conventional risk factors improved the relative integrated discrimination index by 12.6% for a decline in eGFR of ≥30% (P < 0.001), 6.5% for CVE (P = 0.010), and 11.8% (P = 0.003) for mortality. A doubling in UA level was also associated with a steeper decline in eGFR (P < 0.0026) and a steeper increase in urine albumin-to-creatinine ratio (P < 0.0027) in adjusted analysis. CONCLUSIONS: In individuals with T1D, a higher UA level is associated with a higher risk of decline in kidney function, CVE, and mortality, independently of other risk factors. Our results suggest that UA has a promising role in risk stratification among individuals with T1D.

Albuminuria Regression and All-Cause Mortality among Insulin-Treated Patients with Type 2 Diabetes: Analysis of a Large UK Primary Care Cohort.

BACKGROUND: Overt albuminuria (urinary albumin-creatinine ratio [ACR] > 300 mg/g) is an established risk factor for progression of nephropathy and total mortality. However, whether a reduction in ACR translates into a reduction in mortality and/or cardiovascular (CV) events among insulin-treated patients with type 2 diabetes (T2D) in routine practice is currently not known. METHODS: We obtained data on a large cohort of insulin users with T2D and nephropathy (baseline ACR ≥300 mg/g) from UK general practices between 2007 and 2014. Their corresponding ACR values after 1year of follow-up were thereafter categorized into: (1) < 300 mg/g (i.e., albuminuria regression) or (2) > 300 mg/g (i.e., nonregression of albuminuria), and the cohort was followed-up for 5 years for all-cause mortality and CV events. Cox proportional hazard models were fitted to estimate the risk of all-cause death. RESULTS: A total of 11,074 patients with insulin-treated T2D met the inclusion criteria. Their mean age was 62.3 (13.6) years; mean HbA1c: 8.7 (1.8) and 53% were male. A total of 682 deaths occurred after a follow-up period of 43,393 person-years with a mortality rate of 16 per 1,000 person-years. Five-year survival was markedly reduced in the group whose proteinuria persisted or progressed (91 vs. 95%; log-rank p value < 0.001). Compared to patients whose ACR levels remained above 300 mg/g, all-cause mortality and CV events were 31 and 27% lower in those whose albuminuria regressed to < 300 mg/g (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52-0.91; p = 0.008 and aHR 0. 73; 95% CI 0.54-0.98; p = 0.041), respectively. CONCLUSION: In patients with insulin-treated T2D and nephropathy in routine practice, a regression in albuminuria (e.g., via better BP or glycemic control) is associated with a significant reduction in all-cause mortality. Thus, albuminuria is not only simply a risk marker of renal and CV disease but also an independent target for therapy. Albuminuria reduction should be viewed as a goal for renal and CV protection.

Relationship of mildly increased albuminuria and coronary artery revascularization outcomes in patients with diabetes.

BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type-II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.