OBJECTIVE: The determine if elevated levels of albuminuria within the low range (urinary albumin-to-creatinine ratio, UACR <30 mg/g) are linked to cardiovascular death in adults lacking major cardiovascular risk factors.
METHODS: The association between UACR and cardiovascular mortality was investigated among 12,835 participants in the 1999-2014 National Health and Nutrition Examination Survey using Cox proportional hazard models and confounder-adjusted survival curves. We excluded participants with baseline cardiovascular disease, hypertension, diabetes, pre-diabetes, estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, currently pregnant, and those who had received dialysis in the last year.
RESULTS: Over a median follow-up of 12.3 years, 110 and 621 participants experienced cardiovascular and all-cause mortality. In multivariable-adjusted models, each doubling of UACR was associated with a 36% higher risk of cardiovascular death [HR 1.36 (95% confidence interval (CI) 1.02-1.82)] and a 24% higher risk of all-cause mortality [HR 1.24 (95% CI 1.10-1.39)]. The 15-year adjusted cumulative incidences of cardiovascular mortality were 0.91%, 0.99%, and 2.1% for UACR levels of <4.18 mg/g, 4.18 to <6.91 mg/g, and ≥6.91 mg/g, respectively. The 15-year adjusted cumulative incidences of all-cause mortality were 5.1%, 6.1%, and 7.4% for UACR levels of <4.18 mg/g, 4.18 to <6.91 mg/g, and ≥6.91 mg/g, respectively.
CONCLUSIONS: Adults with elevated levels of albuminuria within the low range (UACR <30 mg/g) and no major cardiovascular risk factors had elevated risks of cardiovascular and all-cause mortality. The risks increased linearly with higher albuminuria levels. This emphasizes a risk gradient across all albuminuria levels, even within the supposedly normal range, adding to the existing evidence.
In this study of 12,835 adults without major cardiovascular risk factors (such as hypertension, cardiovascular disease, diabetes, pre-diabetes, or chronic kidney disease), we investigated the association between higher albuminuria levels within the low range (urine albumin-to-creatinine ratio (UACR) <30 mg/g) and both cardiovascular and all-cause mortality. Our findings revealed a linear increase in excess risk for both outcomes with rising albuminuria among relatively healthy adults. Each doubling of albuminuria was associated with a 36% higher risk of cardiovascular death (HR 1.36, 95% CI 1.02-1.82) and a 24% higher risk of all-cause mortality (HR 1.24, 95% CI 1.10-1.39). Each 10 mg/g increase in albuminuria was associated with 66% higher risk of cardiovascular mortality (HR 1.66, 95% CI 1.20, 2.28) and 41% higher risk of all-cause mortality (HR 1.41, 95% CI 1.17-1.68). These results challenge the assumption that UACR values below 30 mg/g are non-prognostic in adults without major cardiovascular risk factors.

UNASSIGNED: Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.
UNASSIGNED: Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.
UNASSIGNED: Two genome-wide significant (P < 5 × 10-8) UACR-associated loci were identified, one in the BMP6 region on chromosome 6, in the meta-analysis of resident African individuals, and another in the HBB region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including THB53, GATM, and ARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.
UNASSIGNED: This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.

The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes increasingly evident that guideline-directed medical therapy cannot be one-size-fits-all across a wide range of ejection fractions (EFs) and various aetiologies. Therefore, classifications solely relying on EF and natriuretic peptide make optimization of treatment challenging, and there is a growing exploration of new indicators that enable efficient risk stratification of HF patients. Particularly when considering HF as a multi-organ interaction syndrome, the cardiorenal interaction plays a central role in its pathophysiology, and albuminuria has gained great prominence as its biomarker, independent from glomerular filtration rate. Albuminuria has been shown to exhibit a linear correlation with cardiovascular disease and HF prognosis in multiple epidemiological studies, ranging from normal (<30 mg/g) to high levels (>300 mg/g). However, on the other hand, it is only recently that the details of the pathological mechanisms that give rise to albuminuria have begun to be elucidated, including the efficient compaction/tightening of the glomerular basement membrane by podocytes and mesangial cells. Interestingly, renal disease, diabetes, and HF damage these components associated with albuminuria, and experimental models have demonstrated that recently developed HF drugs reduce albuminuria by ameliorating these pathological phenotypes. In this review, facing the rapid expansion of horizons in HF treatment, we aim to clarify the current understanding of the pathophysiology of albuminuria and explore the comprehensive understanding of albuminuria by examining the clinically established evidence to date, the pathophysiological mechanisms leading to its occurrence, and the outcomes of clinical studies utilizing various drug classes committed to specific pathological mechanisms to put albuminuria as a novel axis to depict the pathophysiology of HF.

OBJECTIVE: Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring.
METHODS: Descriptive cross-sectional analysis.
METHODS: People with type 2 diabetes (n=826, 67.1 [IQR, 60.3-72.4] years, 64.9% male) participating in the Progression of Diabetic Complications (PREDICT) cohort study.
METHODS: Four spot urine collections for measurement of urinary albumin-creatinine ratio (UACR) within 4 weeks.
RESULTS: Variability of UACR.
METHODS: We characterized within-individual variability (coefficient of variation [CV], 95% limits of random variation, intraclass correlation coefficient), developed a calculator displaying probabilities that any observed difference between a pair of UACR values truly exceeded a 30% difference, and estimated the ranges of diagnostic uncertainty to inform a need for additional UACR collections to exclude or confirm albuminuria. Multiple linear regression examined factors influencing UACR variability.
RESULTS: We observed high within-individual variability (CV 48.8%; 95% limits of random variation showed a repeated UACR to be as high/low as 3.78/0.26 times the first). If a single-collection UACR increased from 2 to 5mg/mmol, the probability that UACR actually increased by at least 30% was only 50%, rising to 97% when 2 collections were obtained at each time point. The ranges of diagnostic uncertainty were 2.0-4.0mg/mmol after an initial UACR test, narrowing to 2.4-3.2 and 2.7-2.9mg/mmol for the mean of 2 and 3 collections, respectively. Some factors correlated with higher (female sex; moderately increased albuminuria) or lower (reduced estimated glomerular filtration rate and sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment) within-individual UACR variability.
CONCLUSIONS: Reliance on the mean of 4 UACR collections as the reference standard for albuminuria.
CONCLUSIONS: UACR demonstrates a high degree of within-individual variability among individuals with type 2 diabetes. Multiple urine collections for UACR may improve capacity to monitor changes over time in clinical and research settings but may not be necessary for the diagnosis of albuminuria.
UNASSIGNED: Albuminuria (albumin in urine) is a diagnostic and prognostic marker of diabetic chronic kidney disease. However, albuminuria can vary within an individual from day to day. We compared 4 random spot urinary albumin-creatinine ratio (UACR) samples from 826 participants. We found that a second UACR collection may be as small as a fourth or as large as almost 4 times the first sample\'s UACR level. This high degree of variability presents a challenge to our ability to interpret changes in albuminuria. Multiple collections have been suggested as a solution. We have constructed tools that may aid clinicians in deciding how many urine collections are required to monitor and diagnose albuminuria. Multiple urine collections may be required for individual monitoring but not necessarily for diagnosis.

UNASSIGNED: The prevalence of chronic kidney disease (CKD) in Australia varies substantially across reports. Using a large, nationally representative general practice data source, we determined the contemporary prevalence and staging of CKD in the Australian primary care.
UNASSIGNED: We performed a retrospective, community-based observational study of 2,720,529 adults with ≥1 visit to a general practice participating in the MedicineInsight program and ≥1 serum creatinine measurement (with or without a urine albumin-to-creatinine ratio [UACR] measurement) between 2011 and 2020. CKD prevalence was estimated using 3 definitions based on estimated glomerular filtration rate (eGFR) and UACR measurements with varying degrees of rigidity in terms of the number of measurements assessed to define CKD (\"least\", \"moderate\" and \"most\" rigid).
UNASSIGNED: CKD prevalence in the cohort progressively increased over the 10-year study period, irrespective of the method used to define CKD. In 2020, CKD prevalence in the cohort was 8.4%, 4.7%, and 3.1% using the least, moderate, and most rigid definition, respectively. The number of patients with UACR measurements was low such that, among those with CKD in 2020, only 3.8%, 3.2%, and 1.5%, respectively, had both eGFR and UACR measurements available in the corresponding year. Patients in whom both eGFR and UACR measurements were available mostly had moderate or high risk of CKD progression (83.6%, 80.6%, and 76.2%, respectively).
UNASSIGNED: In this large, nationally representative study, we observed an increasing trend in CKD prevalence in primary care settings in Australia. Most patients with CKD were at moderate to high risk of CKD progression. These findings highlight the need for early detection and effective management to slow progression of CKD.

UNASSIGNED: Albuminuria is associated with cardiovascular events among adults with underlying cardiovascular disease and diabetes, even at low levels of urinary albumin excretion. We hypothesized that low levels of albuminuria in the \'normal\' range (urinary albumin-to-creatine ratio (UACR) <30 mg/g) are associated with cardiovascular death among apparently healthy adults.
UNASSIGNED: We studied adults who participated in the 1999-2014 National Health and Nutrition Examination Survey. We excluded participants with baseline cardiovascular disease, hypertension, diabetes, estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, those who were currently pregnant, and those who had received dialysis in the last year. After excluding these conditions, only 5.0% of the remaining population had UACR ≥30 mg/g (N=873) and were excluded. The final sample size was 16,247. We assessed the relationship between UACR and cardiovascular and all-cause mortality using multivariable-adjusted Cox proportional hazards models. Models were adjusted for age, sex, race or ethnicity, smoking status, systolic blood pressure, hemoglobin A1c, total cholesterol, health insurance, food insecurity, serum albumin, body mass index, use of statins, and eGFR.
UNASSIGNED: Mean age was 38.9 years (SD 13.6) and 53.7% were women. The median length of follow-up was 12.2 years. In multivariable-adjusted models, each doubling of UACR (within the <30 mg/g range) was associated with a 36% higher risk of cardiovascular death [HR 1.36 (95% confidence interval (CI) 1.11-1.65)] and a 28% higher risk of all-cause mortality [HR 1.28 (95%CI 1.17-1.41)]. The highest tertile of UACR (7.1-29.9 mg/g) was associated with an 87% higher risk of cardiovascular death [HR 1.87 (95%CI 1.20-2.92)] and 59% higher risk of all-cause mortality [HR 1.59 (95%CI 1.28-1.96)], compared with the lowest tertile (< 4.3 mg/g).
UNASSIGNED: In a nationally representative sample of relatively healthy community-dwelling adults, higher levels of albuminuria in the conventionally \"normal\" range <30 mg/g in healthy individuals are associated with greater mortality. Overall, our findings contribute to the growing body of evidence on the existence of a risk gradient across all levels of albuminuria, even in the so-called normal range.

The objective of this study was to investigate changes in serum tumor markers in type 2 diabetes mellitus (T2DM) with microalbuminuria and analyze the relationship between tumor markers and microalbuminuria.
A total of 956 T2DM patients aged 40-70 years hospitalized in the Department of Endocrinology, Xinhua Hospital, China, affiliated with Shanghai Jiaotong University School of Medicine, were enrolled from January 2018 to December 2020. The sample comprised 313 T2DM patients with microalbuminuria and 643 T2DM patients with normal urinary microalbumin levels. After assessing the changes in serum tumor markers in T2DM with microalbuminuria, we analyzed the risk of microalbuminuria by the serum tumor marker category using multiple logistic regression analysis.
Serum CEA, CA199, CA125, CA153, CA211, SCC, CA242, and CA50 levels were significantly higher in T2DM patients with microalbuminuria than in those without microalbuminuria, while serum AFP levels were lower in the microalbuminuria group (P < 0.05). Following adjustment of confounders, serum CEA, CA211, and SCC were independently associated with microalbuminuria in T2DM. An ROC curve was used to estimate the cutoff point of tumor markers for microalbuminuria. Taking the values under the cutoff points as a reference, values for CEA, CA211, and SCC above the cutoff points indicated a significantly high risk of microalbuminuria. The OR of increased CEA for microalbuminuria was 2.006 (95%CI 1.456-2.765), the OR of increased CA211 for microalbuminuria was 1.505 (95%CI 1.092-2.074), and the OR of increased SCC for microalbuminuria was 1.958 (95%CI 1.407-2.724).
Several serum tumor markers were related to microalbuminuria in T2DM. Serum tumor markers such as CEA, SCC, and CA211 may indicate early diabetic nephropathy, particularly when elevated in combination.

OBJECTIVE: To perform dose-exposure-response analyses to determine the effects of finerenone doses.
METHODS: Two randomized, double-blind, placebo-controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m2 , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finerenone 10 or 20 mg versus placebo on top of standard of care. The outcomes were trajectories of plasma finerenone and serum potassium concentrations, UACR, eGFR and kidney composite outcomes, assessed using nonlinear mixed-effects population pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time-to-event models.
RESULTS: For potassium, lower serum levels and lower rates of hyperkalaemia were associated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The PK/PD model analysis linked this observed inverse association to potassium-guided dose titration. Simulations of a hypothetical trial with constant finerenone doses revealed a shallow but increasing exposure-potassium response relationship. Similarly, increasing finerenone exposures led to less than dose-proportional increasing reductions in modelled UACR. Modelled UACR explained 95% of finerenone\'s treatment effect in slowing chronic eGFR decline. No UACR-independent finerenone effects were identified. Neither sodium-glucose cotransporter-2 (SGLT2) inhibitor nor glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment significantly modified the effects of finerenone in reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone\'s treatment effect on kidney outcomes. No eGFR-independent effects were identified.
CONCLUSIONS: The analyses provide strong evidence for the effectiveness of finerenone dose titration in controlling serum potassium elevations. UACR and eGFR are predictive of kidney outcomes during finerenone treatment. Finerenone\'s kidney efficacy is independent of concomitant use of SGLT2 inhibitors and GLP-1RAs.

UNASSIGNED: Soluble urokinase plasminogen activation receptor (suPAR) is an immune-derived pathogenic factor for kidney and atherosclerotic disease. Whether the association between suPAR and cardiovascular (CV) outcomes is dependent on the severity of underlying kidney disease is unclear.
UNASSIGNED: We measured serum suPAR levels in 4994 participants (mean age 60 years; 60% men; 36% with diabetes mellitus; mean estimated glomerular filtration rate (eGFR) 49 ml/min per 1.73 m2, SD 18) of the German Chronic Kidney Disease (GCKD) cohort and examined its association with all-cause death, CV death, and major CV events (MACE) across the range of eGFR and urine albumin-to-creatinine ratio (UACR).
UNASSIGNED: The median suPAR level was 1771 pg/ml (interquartile range [IQR] 1447-2254 pg/ml). SuPAR levels were positively and independently correlated with age, eGFR, UACR, and parathyroid hormone levels. There were 573 deaths, including 190 CV deaths and 683 MACE events at a follow-up time of 6.5 years. In multivariable analyses, suPAR levels (log2) were associated with all-cause death (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.21-1.53), CV death (HR 1.27, 95% CI 1.03-1.57), and MACE (HR 1.13, 95% CI 1.00-1.28), and were not found to differ according to diabetes mellitus status, baseline eGFR, UACR, or parathyroid hormone levels. In mediation analysis, suPAR\'s direct effect on all-cause death, CV death, and MACE accounted for 77%, 67%, and 60% of the total effect, respectively; whereas the effect mediated through eGFR accounted for 23%, 34%, and 40%, respectively.
UNASSIGNED: In a large cohort of individuals with chronic kidney disease (CKD), suPAR levels were associated with mortality and CV outcomes independently of indices of kidney function, consistent with its independent role in the pathogenesis of atherosclerosis.

Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking.
This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy.
Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2 ± 1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1 g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT.
After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p < 0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated.
Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.