Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study.

Rationale & Objective: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD). Study Design: Prospective cohort study. Setting & Participants: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. Exposures: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. Outcomes: Incident CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2 with ≥25% estimated glomerular filtration rate decline relative to visit 1, hospitalization or death related to CKD, or end-stage kidney disease). Analytical Approach: Multivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C statistics assessed the ability of the metabolites to improve the discrimination of highest versus lower 3 quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and the intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident CKD. Results: Thirty significant associations were identified between protein-rich foods and serum metabolites (fish, n = 8; nuts, n = 5; legumes, n = 0; red and processed meat, n = 5; eggs, n = 3; and poultry, n = 9). Metabolites collectively and significantly improved the discrimination of high intake of protein-rich foods compared with covariates alone (difference in C statistics = 0.033, 0.051, 0.003, 0.024, and 0.025 for fish, nuts, red and processed meat, eggs, and poultry-related metabolites, respectively; P < 1.00 × 10-16 for all). Dietary intake of fish was positively associated with 1-docosahexaenoylglycerophosphocholine (22:6n3), which was inversely associated with incident CKD (HR, 0.82; 95% CI, 0.75-0.89; P = 7.81 × 10-6). Limitations: Residual confounding and sample-storage duration. Conclusions: We identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with a lower risk of CKD.

In this study, we aimed to identify associations between protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry) and serum metabolites, which are small biological molecules involved in metabolism. Metabolites significantly associated with a protein-rich food individually and collectively improved the discrimination of the respective protein-rich food, suggesting that these metabolites should be prioritized in future diet biomarker research. We also studied associations between significant diet-related metabolites and incident kidney disease. One fish-related metabolite was associated with a lower kidney disease risk. This finding supports the recent nutritional guidelines recommending a Mediterranean diet, which includes fish as the main dietary protein source.

Kidney Biopsy Utility: Patient and Clinician Perspectives from the Kidney Precision Medicine Project.

Rationale & Objective: Limited data exist on patient perspectives of the implications of kidney biopsies. We explored patients' perspectives alongside those of clinicians to better understand how kidney biopsies affect patients' viewpoints and the clinical utility of biopsies. Study Design: Prospective Cohort Study. Setting & Participants: Patient participants and clinicians in the Kidney Precision Medicine Project, a prospective cohort study of patients who undergo a research protocol biopsy, at 9 recruitment sites across the United States. Surveys were completed at enrollment before biopsy and additional timepoints after biopsy (participants: 28 days, 6 months; clinicians: 2 weeks). Analytical Approach: Kappa statistics assessed prebiopsy etiology concordance between clinicians and participants. Participant perspectives after biopsy were analyzed using a thematic approach. Clinician ratings of clinical management value were compared to prebiopsy ratings with Wilcoxon matched-pairs signed-rank tests and paired t tests. Results: A total of 167 participants undergoing biopsy (124 participants with chronic kidney disease [CKD], 43 participants with acute kidney injury [AKI]) and 58 clinicians were included in this study. CKD participants and clinicians had low etiology concordance for the 2 leading causes of CKD: diabetes (k = 0.358) and hypertension (k = 0.081). At 28 days postbiopsy, 46 (84%) participants reported that the biopsy affected their understanding of their diagnosis, and 21 (38%) participants reported that the results of the biopsy affected their medications. Participants also shared biopsy impressions in free-text responses, including impacts on lifestyle and concurrent condition management. The biopsy positively shifted clinician perceptions of the procedure's clinical management benefits, while perceptions of prognostic value decreased and diagnostic ratings remained unchanged. Limitations: Our study did not have demographic data of clinicians and could not provide insight into postbiopsy experiences for participants who did not respond to follow-up surveys. Conclusions: Participant perspectives of the personal implications of kidney biopsy can be integrated into shared decision-making between clinicians and patients. Enhanced biopsy reports and interactions between nephrologists and pathologists could augment the management and prognostic value of kidney biopsies. Plain-Language Summary: The utility of kidney biopsy is debated among clinicians, and patients' perspectives are even less explored. To address these gaps, we synthesized perspectives from clinicians and patient participants of the Kidney Precision Medicine Project (KPMP). Both before and after biopsy, clinicians were surveyed on how the procedure affected their clinical management, diagnosis, and prognosis. After biopsy, participants shared how the procedure affected their diagnosis, medication, and lifestyle changes. Clinicians and patients shared an appreciation for the biopsy's impact on medical management but diverged in their takeaways on diagnosis and prognosis. These findings highlight the need for greater collaboration between patients and clinicians, particularly as they navigate shared decision-making when considering kidney biopsy.

Serum Metabolomic Markers of Dairy Consumption: Results from the Atherosclerosis Risk in Communities Study and the Bogalusa Heart Study.

BACKGROUND: Dairy consumption is related to chronic disease risk; however, the measurement of dairy consumption has largely relied upon self-report. Untargeted metabolomics allows for the identification of objective markers of dietary intake. OBJECTIVES: We aimed to identify associations between dietary dairy intake (total dairy, low-fat dairy, and high-fat dairy) and serum metabolites in 2 independent study populations of United States adults. METHODS: Dietary intake was assessed with food frequency questionnaires. Multivariable linear regression models were used to estimate cross-sectional associations between dietary intake of dairy and 360 serum metabolites analyzed in 2 subgroups of the Atherosclerosis Risk in Communities study (ARIC; n = 3776). Results from the 2 subgroups were meta-analyzed using fixed effects meta-analysis. Significant meta-analyzed associations in the ARIC study were then tested in the Bogalusa Heart Study (BHS; n = 785). RESULTS: In the ARIC study and BHS, the mean age was 54 and 48 years, 61% and 29% were Black, and the mean dairy intake was 1.7 and 1.3 servings/day, respectively. Twenty-nine significant associations between dietary intake of dairy and serum metabolites were identified in the ARIC study (total dairy, n = 14; low-fat dairy, n = 10; high-fat dairy, n = 5). Three associations were also significant in BHS: myristate (14:0) was associated with high-fat dairy, and pantothenate was associated with total dairy and low-fat dairy, but 23 of the 27 associations significant in the ARIC study and tested in BHS were not associated with dairy in BHS. CONCLUSIONS: We identified metabolomic associations with dietary intake of dairy, including 3 associations found in 2 independent cohort studies. These results suggest that myristate (14:0) and pantothenate (vitamin B5) are candidate biomarkers of dairy consumption.

Metabolomics of Dietary Intake of Total, Animal, and Plant Protein: Results from the Atherosclerosis Risk in Communities (ARIC) Study.

Background: Dietary consumption has traditionally been studied through food intake questionnaires. Metabolomics can be used to identify blood markers of dietary protein that may complement existing dietary assessment tools. Objectives: We aimed to identify associations between 3 dietary protein sources (total protein, animal protein, and plant protein) and serum metabolites using data from the Atherosclerosis Risk in Communities Study. Methods: Participants' dietary protein intake was derived from a food frequency questionnaire administered by an interviewer, and fasting serum samples were collected at study visit 1 (1987-1989). Untargeted metabolomic profiling was performed in 2 subgroups (subgroup 1: n = 1842; subgroup 2: n = 2072). Multivariable linear regression models were used to assess associations between 3 dietary protein sources and 360 metabolites, adjusting for demographic factors and other participant characteristics. Analyses were performed separately within each subgroup and meta-analyzed with fixed-effects models. Results: In this study of 3914 middle-aged adults, the mean (SD) age was 54 (6) y, 60% were women, and 61% were Black. We identified 41 metabolites significantly associated with dietary protein intake. Twenty-six metabolite associations overlapped between total protein and animal protein, such as pyroglutamine, creatine, 3-methylhistidine, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Plant protein was uniquely associated with 11 metabolites, such as tryptophan betaine, 4-vinylphenol sulfate, N-δ-acetylornithine, and pipecolate. Conclusions: The results of 17 of the 41 metabolites (41%) were consistent with those of previous nutritional metabolomic studies and specific protein-rich food items. We discovered 24 metabolites that had not been previously associated with dietary protein intake. These results enhance the validity of candidate markers of dietary protein intake and introduce novel metabolomic markers of dietary protein intake.

Serum Metabolites and Kidney Outcomes: The Atherosclerosis Risk in Communities Study.

Rationale & Objective: Novel metabolite biomarkers of kidney failure with replacement therapy (KFRT) may help identify people at high risk for adverse kidney outcomes and implicated pathways may aid in developing targeted therapeutics. Study Design: Prospective cohort. Setting & Participants: The cohort included 3,799 Atherosclerosis Risk in Communities study participants with serum samples available for measurement at visit 1 (1987-1989). Exposure: Baseline serum levels of 318 metabolites. Outcomes: Incident KFRT, kidney failure (KFRT, estimated glomerular filtration rate <15 mL/min/1.73 m2, or death from kidney disease). Analytical Approach: Because metabolites are often intercorrelated and represent shared pathways, we used a high dimension reduction technique called Netboost to cluster metabolites. Longitudinal associations between clusters of metabolites and KFRT and kidney failure were estimated using a Cox proportional hazards model. Results: Mean age of study participants was 53 years, 61% were African American, and 13% had diabetes. There were 160 KFRT cases and 357 kidney failure cases over a mean of 23 years. The 314 metabolites were grouped in 43 clusters. Four clusters were significantly associated with risk of KFRT and 6 were associated with kidney failure (including 3 shared clusters). The 3 shared clusters suggested potential pathways perturbed early in kidney disease: cluster 5 (15 metabolites involved in alanine, aspartate, and glutamate metabolism as well as 5-oxoproline and several gamma-glutamyl amino acids), cluster 26 (6 metabolites involved in sugar and inositol phosphate metabolism), and cluster 34 (21 metabolites involved in glycerophospholipid metabolism). Several individual metabolites were also significantly associated with both KFRT and kidney failure, including glucose and mannose, which were associated with higher risk of both outcomes, and 5-oxoproline, gamma-glutamyl amino acids, linoleoylglycerophosphocholine, 1,5-anhydroglucitol, which were associated with lower risk of both outcomes. Limitations: Inability to determine if the metabolites cause or are a consequence of changes in kidney function. Conclusions: We identified several clusters of metabolites reproducibly associated with development of KFRT. Future experimental studies are needed to validate our findings as well as continue unraveling metabolic pathways involved in kidney function decline.

P Granules Protect RNA Interference Genes from Silencing by piRNAs.

P granules are perinuclear condensates in C. elegans germ cells proposed to serve as hubs for self/non-self RNA discrimination by Argonautes. We report that a mutant (meg-3 meg-4) that does not assemble P granules in primordial germ cells loses competence for RNA-interference over several generations and accumulates silencing small RNAs against hundreds of endogenous genes, including the RNA-interference genes rde-11 and sid-1. In wild type, rde-11 and sid-1 transcripts are heavily targeted by piRNAs and accumulate in P granules but maintain expression. In the primordial germ cells of meg-3 meg-4 mutants, rde-11 and sid-1 transcripts disperse in the cytoplasm with the small RNA biogenesis machinery, become hyper-targeted by secondary sRNAs, and are eventually silenced. Silencing requires the PIWI-class Argonaute PRG-1 and the nuclear Argonaute HRDE-1 that maintains trans-generational silencing of piRNA targets. These observations support a "safe harbor" model for P granules in protecting germline transcripts from piRNA-initiated silencing.

A randomized controlled clinical trial comparing guided with nonguided implant placement: A 3-year follow-up of implant-centered outcomes.

STATEMENT OF PROBLEM: Implant-based prosthetic solutions can be time consuming. If implants can be placed successfully with a guide, surgery time can be reduced. PURPOSE: The purpose of this randomized controlled clinical trial was to assess implant outcomes, both clinical and radiological, comparing guided with nonguided implant placement after 3 years of follow-up. MATERIAL AND METHODS: A total of 314 implants were placed in 72 jaws (60 participants). The jaws were randomly assigned to 1 of the 6 treatment groups: Materialise Universal/mucosa (Mat Mu), Materialise Universal/bone (Mat Bo), Facilitate/mucosa (Fac Mu), Facilitate/bone (Fac Bo), freehand navigation (Freehand), and a pilot-drill template (Templ). Radiographic and clinical parameters (bone loss, pocket probing depth, bleeding on probing, and plaque scores) were recorded at the time of implant placement, prosthesis installment (baseline), and 1-year, 2-year, and 3-year follow-up. Analysis was performed using a linear mixed model, and correction for simultaneous hypothesis was made according to Sidak (α=.05). RESULTS: Three participants left the study before the 3-year follow-up; hence, 302 implants in 69 jaws were included in this study. None of the implants failed. The mean marginal bone loss after the third year of loading was 0.7 ±1.3 mm for the guided surgery group and 0.5 ±0.6 mm for the control group. No significant intergroup or follow-up period differences were observed (P>.05). In the guided surgery groups, the mean number of surfaces with bleeding on probing and plaque at 3-year follow-up was 1.7 ±1.5 and 1.7 ±1.7, respectively; for the control groups, this was 1.6 ±1.4 and 1.6 ±1.6, respectively. The mean pocket probing depth was 3.0 ±1.3 mm for the guided group and 2.6 ±1.0 mm for the control group. No significant differences were found (P>.1). CONCLUSIONS: Within the limitation of this study, no statistically significant differences could be found between the guided group and the control group at the 3-year follow-up.

Randomized controlled trial comparing immediate loading with conventional loading using cone-anchored implant-supported screw-retained removable prostheses: A 2-year follow-up clinical trial.

STATEMENT OF PROBLEM: Implant-based prosthetic solutions can be time consuming. If implants can be loaded immediately, treatment time can be reduced. PURPOSE: The purpose of this prospective randomized controlled trial was to monitor the survival rate of Ankylos implants, comparing conventional with immediate loading by using abutments with the SynCone concept for screw-retained removable prostheses in the edentulous maxilla. MATERIAL AND METHODS: A total of 90 implants were placed in 15 study participants. The participants were randomly assigned to the immediate or conventional loading treatment group. Radiographic and clinical parameters were recorded at the time of permanent prosthesis installment and at 1- and 2-year follow-up examinations, and participants' satisfaction was measured by using questionnaires before and after prosthesis installation. A linear mixed model was used to measure differences. RESULTS: One implant in the conventional group was lost during abutment placement; hence, 89 implants could be followed for 2 years. Approximately 90% of these implants showed no bone loss or even bone gain at 1 and 2 years follow-up. Mean values for the immediate group were, respectively, 0.09 ±0.35 mm and 0.13 ±0.38 mm and 0.01 ±0.41 mm and -0.06 ±0.32 mm for the conventional method. No significant differences (P=.053) were found in bone level alterations between the groups. For all participants, the mean number of surfaces (4 per implant) with bleeding on probing (BoP) and plaque were 0.76 ±0.81 and 0.16 ±0.42 at 1 year follow-up and 0.44 ±0.66 and 0.02 ±0.15, respectively, at the second-year follow-up. The mean pocket probing depths were 2.05 ±0.54 mm at 1 year and 2.18 ±0.64 mm at 2 years. For both groups, a significant rise in satisfaction and quality of life was observed (P≤.001) at 1 and 2 years compared with pretreatment. CONCLUSIONS: Ankylos implants placed in the edentulous maxilla, immediately or conventionally loaded by a detachable prosthesis, showed favorable bone-level preservation after 2 years of follow-up. No significant differences could be found between the immediate and conventional groups. A significant increase in quality of life was observed for both loading modes.

Guided Implant Surgery in the Edentulous Maxilla: A Systematic Review.

PURPOSE: This systematic review verified the usefulness/limitations of static surgical guides during implant surgery in the edentulous maxilla. The PICO question was: "Does the use of digitally generated surgical guides vs conventional techniques affect the following outcomes: surgical complications, implant complications, prosthesis complications, implant survival, prosthesis survival, economics, patient satisfaction, and maintenance intervention?" MATERIALS AND METHODS: The electronic searches retrieved 2,588 unique articles from which eventually 36 full-text articles were read for eligibility. Because no randomized controlled clinical trials could be found, the PICO question had to be reformulated, now only looking to the outcome of digitally generated surgical guides without comparison with conventional techniques. RESULTS: Although long-term data are lacking, the outcome of implants placed with a static guide and of the prosthetic reconstruction seems similar to that expected from conventional techniques. The number of surgical complications with guided surgery is negligible. Guided flapless implant surgery offers slightly more comfort for the patient; however, the economic benefits are unclear. CONCLUSION: Implant therapy via static surgical guides in the maxilla is predictable, with slightly more comfort for the patient but with only minor economic advantages.