Faculty Bibliography

BACKGROUND:NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. AIMS:We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. METHODS:We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. RESULTS:. CONCLUSION:Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population.

RATIONALE & OBJECTIVE/UNASSIGNED:Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD. STUDY DESIGN/UNASSIGNED:Observational cohort study. SETTING & PARTICIPANTS/UNASSIGNED:Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5. EXPOSURE/UNASSIGNED:Circulating proteins. OUTCOME/UNASSIGNED:All-cause mortality. ANALYTICAL APPROACH/UNASSIGNED:Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD. RESULTS/UNASSIGNED:-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide) were available in the ARIC data, with all 3 significantly associated with death in ARIC. LIMITATIONS/UNASSIGNED:Possibility of unmeasured confounding. Cause of death was not known. CONCLUSIONS/UNASSIGNED:Using large-scale proteomic analysis, proteins were reproducibly associated with mortality in 2 cohorts of participants with CKD. PLAIN-LANGUAGE SUMMARY/UNASSIGNED:-microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide (BNP)) were also measured in ARIC and were significantly associated with death. Additional studies assessing biomarkers associated with mortality among patients with CKD are needed to evaluate their use in clinical practice.

BACKGROUND:Recent guidance suggests clinicians increase use of cystatin C for the estimation of GFR. Discrepant levels of creatinine-versus cystatin C-based eGFR (eGFRcr versus eGFRcys) can occur and might signify inaccurate estimation of GFR using creatinine alone. This study sought to enhance the knowledge of the risk factors and clinical implications of having a large eGFR discrepancy. METHODS:Participants in the Atherosclerosis Risk in Communities Study, a prospective cohort study of US adults, were followed over 25 years. eGFR discrepancy was measured at five clinical visits and defined as eGFRcys either 30% lower or higher than eGFRcr, the current clinical standard of care. The associations between eGFR discrepancies and kidney-related laboratory parameters were assessed using linear and logistic regression and long-term adverse outcomes, including kidney failure, AKI, heart failure, and death, using Cox proportional hazards models. RESULTS:Among 13,197 individuals (mean age 57 [SD 6] years, 56% women, 25% Black race), 7% had eGFRcys 30% lower than eGFRcr at visit 2 (1990-1992), and this proportion increased over time to 23% by visit 6 (2016-2017). By contrast, the percent with eGFRcys 30% higher than eGFRcr was relatively stable (3%-1%). Independent risk factors for having eGFRcys 30% lower than eGFRcr included older age, female sex, non-Black race, higher eGFRcr, higher body mass index, weight loss, and current smoking. Those with eGFRcys 30% lower than eGFRcr had more anemia and higher uric acid, fibroblast growth factor 23, and phosphate levels as well as higher risk of subsequent mortality, kidney failure, AKI, and heart failure compared with those with similar eGFRcr and eGFRcys values. CONCLUSIONS:Having eGFRcys lower than eGFRcr was associated with worse kidney-related laboratory derangements and a higher risk of adverse health outcomes.

RATIONALE & OBJECTIVE/OBJECTIVE:) and risk of adverse kidney outcomes in patients with diabetes. STUDY DESIGN/METHODS:Observational study. SETTING & PARTICIPANTS/METHODS:93,598 adults with diabetes undergoing routine care in Stockholm, Sweden. EXPOSURES AND PREDICTORS/UNASSIGNED:measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group. OUTCOME/RESULTS:Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria. ANALYTICAL APPROACH/METHODS:Multivariable Cox proportional hazards regression. RESULTS:or alternative metrics of variability. LIMITATIONS/CONCLUSIONS:Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration. CONCLUSIONS:variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria. PLAIN-LANGUAGE SUMMARY/UNASSIGNED:test.

Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease.

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

SIGNIFICANCE STATEMENT:Although gene expression changes have been characterized in human diabetic kidney disease (DKD), unbiased tissue proteomics information for this condition is lacking. The authors conducted an unbiased aptamer-based proteomic analysis of samples from patients with DKD and healthy controls, identifying proteins with levels that associate with kidney function (eGFR) or fibrosis, after adjusting for key covariates. Overall, tissue gene expression only modestly correlated with tissue protein levels. Kidney protein and RNA levels of matrix metalloproteinase 7 (MMP7) strongly correlated with fibrosis and with eGFR. Single-cell RNA sequencing indicated that kidney tubule cells are an important source of MMP7. Furthermore, plasma MMP7 levels predicted future kidney function decline. These findings identify kidney tissue MMP7 as a biomarker of fibrosis and blood MMP7 as a biomarker for future kidney function decline. BACKGROUND:Diabetic kidney disease (DKD) is responsible for close to half of all ESKD cases. Although unbiased gene expression changes have been extensively characterized in human kidney tissue samples, unbiased protein-level information is not available. METHODS:We collected human kidney samples from 23 individuals with DKD and ten healthy controls, gathered associated clinical and demographics information, and implemented histologic analysis. We performed unbiased proteomics using the SomaScan platform and quantified the level of 1305 proteins and analyzed gene expression levels by bulk RNA and single-cell RNA sequencing (scRNA-seq). We validated protein levels in a separate cohort of kidney tissue samples as well as in 11,030 blood samples. RESULTS:Globally, human kidney transcript and protein levels showed only modest correlation. Our analysis identified 14 proteins with kidney tissue levels that correlated with eGFR and found that the levels of 152 proteins correlated with interstitial fibrosis. Of the identified proteins, matrix metalloprotease 7 (MMP7) showed the strongest association with both fibrosis and eGFR. The correlation between tissue MMP7 protein expression and kidney function was validated in external datasets. The levels of MMP7 RNA correlated with fibrosis in the primary and validation datasets. Findings from scRNA-seq pointed to proximal tubules, connecting tubules, and principal cells as likely cellular sources of increased tissue MMP7 expression. Furthermore, plasma MMP7 levels correlated not only with kidney function but also associated with prospective kidney function decline. CONCLUSIONS:Our findings, which underscore the value of human kidney tissue proteomics analysis, identify kidney tissue MMP7 as a diagnostic marker of kidney fibrosis and blood MMP7 as a biomarker for future kidney function decline.

SIGNIFICANCE STATEMENT:Large discordances between eGFR on the basis of creatinine (eGFR cr ) or cystatin C (eGFR cys ) are common in clinical practice. However, which GFR estimating equation (eGFR cr , eGFR cys , or eGFR cr-cys ) is most accurate in these settings is not known. In this real-world study of 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance, all three equations performed similarly when eGFR cr and eGFR cys were similar (45% of cases). However, with large discordances (55% of cases), eGFR cr-cys was much more accurate than either alone. These findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer who have been underrepresented in research cohorts. Thus, when eGFR cr and eGFR cys are largely discordant in clinical practice, eGFR cr-cys is more accurate than eGFR cr or eGFR cys . BACKGROUND:Cystatin C is recommended as a confirmatory test to eGFR when more precise estimates are needed for clinical decision making. Although eGFR on the basis of both creatinine and cystatin (eGFR cr-cys ) is the most accurate estimate in research studies, it is uncertain whether this is true in real-world settings, particularly when there are large discordances between eGFR based on creatinine (eGFR cr ) and that based on cystatin C (eGFR cys ). METHODS:We included 6185 adults referred for measured GFR (mGFR) using plasma clearance of iohexol in Stockholm, Sweden, who had 9404 concurrent measurements of creatinine, cystatin C, and iohexol clearance. The performance of eGFR cr , eGFR cys , and eGFR cr-cys was assessed against mGFR with median bias, P30 , and correct classification of GFR categories. We stratified analyses within three categories: eGFR cys at least 20% lower than eGFR cr (eGFR cys <eGFR cr ), eGFR cys within 20% of eGFR cr (eGFR cys ≈eGFR cr ), and eGFR cys at least 20% higher than eGFR cr (eGFR cys >eGFR cr ). RESULTS:eGFR cr and eGFR cys were similar in 4226 (45%) samples, and among these samples all three estimating equations performed similarly. By contrast, eGFR cr-cys was much more accurate in cases of discordance. For example, when eGFR cys <eGFR cr (47% of samples), the median biases were 15.0 (overestimation), -8.5 (underestimation), and 0.8 ml/min per 1.73 m 2 for eGFR cr , eGFR cys , and eGFR cr-cys , respectively; P30 was 50%, 73%, and 84%, respectively; and correct classification was 38%, 45%, and 62%, respectively. When eGFR cys >eGFR cr (8% of samples), the median biases were -4.5, 8.4, and 1.4 ml/min per 1.73m 2 . The findings were consistent among individuals with cardiovascular disease, heart failure, diabetes mellitus, liver disease, and cancer. CONCLUSIONS:When eGFR cr and eGFR cys are highly discordant in clinical practice, eGFR cr-cys is more accurate than either eGFR cr or eGFR cys .