The relationship between low levels of albuminuria and mortality among adults without major cardiovascular risk factors.

AIMS: 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.

Serum and Urine Metabolites and Kidney Function.

BACKGROUND: Metabolites represent a read-out of cellular processes underlying states of health and disease. METHODS: We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with "X" in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities (ARIC) Study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and UACR in longitudinal analyses. RESULTS: At visit 5 of the ARIC study, the mean age of participants was 76 years (SD 6), 56% were women, mean eGFR was 62 ml/min/1.73m2 (SD 20), and median urine albumin-to-creatinine level (UACR) was 13 mg/g (IQR 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected p < 4.0E-5 for serum analyses and p < 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including 7 shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate, N2,N2-dimethylguanosine, hydroxy-N6,N6,N6-trimethyllysine, X-13844, and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (HR 2.3 [1.6,3.2], p = 2.7E-5) and urine X-12117 (HR 1.7 [1.3,2.2], p = 1.9E-5) were risk factors for UACR doubling, whereas urine sebacate (HR 0.86 [0.80,0.92], p = 1.9E-5) was inversely associated. Compared to clinical characteristics alone, including the top 5 endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (AUCs for eGFR decline: clinical model = 0.79, clinical + metabolites model = 0.87, p = 8.1E-6; for UACR doubling: clinical model = 0.66, clinical + metabolites model = 0.73, p = 2.9E-5). CONCLUSIONS: Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.

Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification.

BACKGROUND AND AIMS: Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed. METHODS: In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score. RESULTS: Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10-5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10-5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P = .001). C-statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787). CONCLUSIONS: Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population.

Nephrologists' perspectives and experiences with hospice among older adults with end-stage kidney disease.

BACKGROUND: Hospice care leads to improved patient and family outcomes. Hospice use among older adults with end-stage kidney disease (ESKD) is markedly lower than among older adults with other serious illnesses, and the majority of those with ESKD who use hospice enroll in the last days of life. Here, our aim was to explore barriers to timely receipt of high-quality hospice care for older adults with ESKD. METHODS: Utilizing a qualitative study design, we conducted a secondary analysis focused on hospice, a theme that we identified in our larger overarching study that involved semi-structured interviews with 20 nephrologists in the United States focused on treatment decision-making in older adults with advanced chronic kidney disease. We analyzed the interview transcripts using emergent thematic analysis to develop an understanding of barriers to high-quality hospice. RESULTS: With a couple notable exceptions, nephrologists voiced general support for the concept of hospice, but few recalled patients of theirs who had received hospice. Nephrologists' interviews revealed two interrelated contributors to the lack of timely access to high-quality hospice care for seriously ill older adults with ESKD: (1) nephrologists view dialysis and hospice as mutually exclusive models of care; (2) nephrologists feel unsure who should manage hospice care for patients with ESKD. The first contributor was rooted in nephrologists' narrow vision of when to consider hospice (informed, in part, by policy barriers) and, in a couple of cases, strong discomfort with hospice. The second stemmed from nephrologists' belief that neither they nor hospice are adequately prepared to provide hospice care for ESKD. CONCLUSIONS: Our findings suggest that, in addition to Medicare policy change, nephrologists need to receive more training in primary palliative care skills including in indications for hospice, initiating conversations about hospice with patients, and collaborating with hospice clinicians to care for these vulnerable patients.

Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria : A Cohort Study.

BACKGROUND: Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. OBJECTIVE: To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). DESIGN: Multicenter prospective cohort study. SETTING: 7 U.S. clinical centers. PARTICIPANTS: 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin-creatinine ratio (UACR) less than 30 mg/g. MEASUREMENTS: Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. RESULTS: Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. LIMITATION: UACR was measured once. CONCLUSION: Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. PRIMARY FUNDING SOURCE: None.

Combination therapy for kidney disease in people with diabetes mellitus.

Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20-40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin-angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.

Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy.

A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct kidney anatomical regions. We generated transcriptomes of 446,267 cells and chromatin accessibility profiles of 401,875 cells and developed a package to analyze 408,218 spatially resolved metabolomes. We find that the same cell type, including thin limb, thick ascending limb loop of Henle and principal cells, display distinct transcriptomic, chromatin accessibility, and metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene profiles revealed non-overlapping metabolic signatures between nephron segments and dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating multimodal omics with clinical data identified PLEKHA1 as a disease marker, and its in vitro knockdown increased gene expression in PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying the human kidney anatomy.

Clinical Decision Support for Hypertension Management in Chronic Kidney Disease: A Randomized Clinical Trial.

Importance: Chronic kidney disease (CKD) affects 37 million adults in the United States, and for patients with CKD, hypertension is a key risk factor for adverse outcomes, such as kidney failure, cardiovascular events, and death. Objective: To evaluate a computerized clinical decision support (CDS) system for the management of uncontrolled hypertension in patients with CKD. Design, Setting, and Participants: This multiclinic, randomized clinical trial randomized primary care practitioners (PCPs) at a primary care network, including 15 hospital-based, ambulatory, and community health center-based clinics, through a stratified, matched-pair randomization approach February 2021 to February 2022. All adult patients with a visit to a PCP in the last 2 years were eligible and those with evidence of CKD and hypertension were included. Intervention: The intervention consisted of a CDS system based on behavioral economic principles and human-centered design methods that delivered tailored, evidence-based recommendations, including initiation or titration of renin-angiotensin-aldosterone system inhibitors. The patients in the control group received usual care from PCPs with the CDS system operating in silent mode. Main Outcomes and Measures: The primary outcome was the change in mean systolic blood pressure (SBP) between baseline and 180 days compared between groups. The primary analysis was a repeated measures linear mixed model, using SBP at baseline, 90 days, and 180 days in an intention-to-treat repeated measures model to account for missing data. Secondary outcomes included blood pressure (BP) control and outcomes such as percentage of patients who received an action that aligned with the CDS recommendations. Results: The study included 174 PCPs and 2026 patients (mean [SD] age, 75.3 [0.3] years; 1223 [60.4%] female; mean [SD] SBP at baseline, 154.0 [14.3] mm Hg), with 87 PCPs and 1029 patients randomized to the intervention and 87 PCPs and 997 patients randomized to usual care. Overall, 1714 patients (84.6%) were treated for hypertension at baseline. There were 1623 patients (80.1%) with an SBP measurement at 180 days. From the linear mixed model, there was a statistically significant difference in mean SBP change in the intervention group compared with the usual care group (change, -14.6 [95% CI, -13.1 to -16.0] mm Hg vs -11.7 [-10.2 to -13.1] mm Hg; P = .005). There was no difference in the percentage of patients who achieved BP control in the intervention group compared with the control group (50.4% [95% CI, 46.5% to 54.3%] vs 47.1% [95% CI, 43.3% to 51.0%]). More patients received an action aligned with the CDS recommendations in the intervention group than in the usual care group (49.9% [95% CI, 45.1% to 54.8%] vs 34.6% [95% CI, 29.8% to 39.4%]; P < .001). Conclusions and Relevance: These findings suggest that implementing this computerized CDS system could lead to improved management of uncontrolled hypertension and potentially improved clinical outcomes at the population level for patients with CKD. Trial Registration: ClinicalTrials.gov Identifier: NCT03679247.

Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (ß = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (ß = 0.430, SE = 0.073; p = 4.2E-9), and V (ß = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.

Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing.

Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured proximal tubule cells fails to undergo normal repair and assumes a proinflammatory and profibrotic phenotype that may promote fibrosis and chronic kidney disease. The healthy to failed repair change is marked by cell state-specific transcriptomic and epigenomic changes. Single nucleus joint RNA- and ATAC-seq sequencing offers an opportunity to study the gene regulatory networks underpinning these changes in order to identify key regulatory drivers. We develop a regularized regression approach to construct genome-wide parametric gene regulatory networks using multiomic datasets. We generate a single nucleus multiomic dataset from seven adult human kidney samples and apply our method to study drivers of a failed injury response associated with kidney disease. We demonstrate that our approach is a highly effective tool for predicting key cis- and trans-regulatory elements underpinning the healthy to failed repair transition and use it to identify NFAT5 as a driver of the maladaptive proximal tubule state.

Higher NT-proBNP levels and the risk of intradialytic hypotension at hemodialysis initiation.

INTRODUCTION: Elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) is a potent predictor of adverse outcomes in hemodialysis initiation. These patients often experience intradialytic hypotension, which may partially reflect cardiac dysfunction, but the association of NT-proBNP with intradialytic hypotension is not clear. METHODS: We performed a post hoc analysis of a randomized trial that tested mannitol versus placebo in 52 patients initiating hemodialysis (NCT01520207). NT-proBNP was measured prior to the first and third sessions (n = 87). Mixed-effects models (adjusting for randomized treatment, sex, race, age, diabetes, heart failure, catheter use, pre-dialysis systolic blood pressure, pre-dialysis weight, ultrafiltration volume, serum sodium, bicarbonate, urea nitrogen, phosphate, albumin, hemoglobin, and session length) were fit to examine the association of NT-proBNP with systolic blood pressure decline (pre-dialysis minus nadir systolic blood pressure). Additionally, mixed-effects Poisson models were fit to examine the association with intradialytic hypotension (≥20 mmHg decline in systolic blood pressure). FINDINGS: Mean age was 55 ± 16 years; 33% had baseline heart failure. The median NT-proBNP was 5498 [25th-75th percentile 2011, 14,790] pg/mL; 26 sessions (30%) were complicated by intradialytic hypotension. In adjusted models, each unit higher log-NT-proBNP was associated with 6.0 mmHg less decline in systolic blood pressure (95%CI -9.2 to -2.8). Higher pre-dialysis NT-proBNP, per log-unit, was associated with a 52% lower risk of intradialytic hypotension (IRR 0.48, 95%CI 0.23-0.97), without evidence for effect modification by randomized treatment (P-interaction = 0.17). DISCUSSION: In patients initiating hemodialysis, higher NT-proBNP is associated with less decline in intradialytic systolic blood pressure and lower risk of intradialytic hypotension. Future studies should investigate if higher pre-dialysis NT-proBNP levels may identify patients who might tolerate more aggressive ultrafiltration.

Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis.

Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.

Joint Associations of Pregnancy Complications and Postpartum Maternal Renal Biomarkers With Severe Cardiovascular Morbidities: A US Racially and Ethnically Diverse Prospective Birth Cohort Study.

Background Pregnancy complications are risk factors for cardiovascular disease (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods and Results This study included 566 mothers of diverse races and ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and CysC (cystatin C) were measured 1 to 3 days after delivery. CVD during follow-up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time-to-CVD events were assessed using Cox proportional hazards models. During an average of 10.3±3.2 years of follow-up, 30 mothers developed 1 or more CVDs. Only a modest association was observed between creatinine and risk of CVD. In comparison, we found that per 0.1 mg/L increase of CysC was associated with a hazard ratio (HR) of 1.2 (95% CI, 1.1-1.4) for CVD after adjusting for covariates. Compared with those without preeclampsia and with normal CysC level (≤75th percentile), mothers with preeclampsia and elevated CysC (>75th percentile) had the highest risk of CVD (HR, 4.6 [95% CI, 1.7-17.7]), whereas mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions In this sample of US, traditionally underrepresented multiracial and multiethnic high-risk mothers, elevated maternal plasma CysC, independently and jointly with pregnancy complications, increased risk of CVD later in life. These findings warrant further investigation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03228875.