Plasma Proteins associated with Chronic Histopathologic Lesions on Kidney Biopsy.

BACKGROUND: The severity of chronic histopathologic lesions on kidney biopsy is independently associated with higher risk of progressive chronic kidney disease (CKD). Because kidney biopsies are invasive, identification of blood markers that report on underlying kidney histopathology has the potential to enhance CKD care. METHODS: We examined the association between 6592 plasma protein levels measured by aptamers and the severity of interstitial fibrosis and tubular atrophy (IFTA), glomerulosclerosis, arteriolar sclerosis, and arterial sclerosis among 434 participants of the Boston Kidney Biopsy Cohort. For proteins significantly associated with at least one histologic lesion, we assessed renal arteriovenous protein gradients among 21 individuals who had undergone invasive catheterization and assessed the expression of the cognate gene among 47 individuals with single cell RNA sequencing data in the Kidney Precision Medicine Project. RESULTS: In models adjusted for estimated glomerular filtration rate (eGFR), proteinuria, and demographic factors, we identified 35 proteins associated with one or more chronic histologic lesions, including 20 specific for IFTA, 8 specific for glomerulosclerosis, and 1 specific for arteriolar sclerosis. In general, higher levels of these proteins were associated with more severe histologic score and lower eGFR. Exceptions included testican-2 and NELL1, which were associated with less glomerulosclerosis and IFTA, respectively, and higher eGFR; notably, both of these proteins demonstrated significantly higher levels from artery to renal vein, demonstrating net kidney release. In the Kidney Precision Medicine Project, 13 of the 35 protein hits had cognate gene expression enriched in one or more cell types in the kidney, including podocyte expression of select glomerulosclerosis markers (including testican-2) and tubular expression of several IFTA markers (including NELL1). CONCLUSIONS: Proteomic analysis identified circulating proteins associated with chronic histopathologic lesions, some of which have concordant site-specific expression within the kidney.

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.

Pulsed Photothermal Therapy of Solid Tumors as a Precondition for Immunotherapy.

Photothermal therapy (PTT) refers to the use of plasmonic nanoparticles to convert electromagnetic radiation in the near infrared region to heat and kill tumor cells. Continuous wave lasers have been used clinically to induce PTT, but the treatment is associated with heat-induced tissue damage that limits usability. Here, the engineering and validation of a novel long-pulsed laser device able to induce selective and localized mild hyperthermia in tumors while reducing the heat affected zone and unwanted damage to surrounding tissue are reported. Long-pulsed PTT induces acute necrotic cell death in heat affected areas and the release of tumor associated antigens. This antigen release triggers maturation and stimulation of CD80/CD86 in dendritic cells in vivo that primes a cytotoxic T cell response. Accordingly, long-pulsed PTT enhances the therapeutic effects of immune checkpoint inhibition and increases survival of mice with bladder cancer. Combined, the data promote long-pulsed PTT as a safe and effective strategy for enhancing therapeutic responses to immune checkpoint inhibitors while minimizing unwanted tissue damage.

Stage-Based Detection Methods and Recurrence Patterns for Cutaneous Melanoma.

Melanoma surveillance guidelines vary. Melanoma recurrence patterns and detection methods were examined. Resected melanoma patients were reviewed. Recurrence detection included patient complaint (PC), physical exam (PE), cross-sectional imaging (CSI), and ultrasound (US). 276 patients were included: 131 stage I, 83 stage II, and 62 stage III. Recurrence rates were 8%, 24%, and 27%, respectively. For stage I patients, 46% of recurrences were local, 18% regional, and 36% distant. Patient complaint identified 55% of recurrences, PE 36%, and CSI 9%. For stage II, 20% of recurrences were local, 20% regional, and 60% distant. Patient complaint identified 35% of recurrences, PE 20%, and CSI 45%. For stage III, 6% of recurrences were local, 53% regional, and 41% distant. Patient complaint identified 17% of recurrences, PE 12%, CSI 59%, and US 12%. Average time to recurrence by stage was 23.7, 24.6, and 17.7 months, respectively. H&P for all melanoma patients and CSI for higher stages are effective surveillance strategies.

Subcapsular sinus macrophages maximize germinal center development in non-draining lymph nodes during blood-borne viral infection.

Lymph node (LN) germinal centers (GCs) are critical sites for B cell activation and differentiation. GCs develop after specialized CD169+ macrophages residing in LN sinuses filter antigens (Ags) from the lymph and relay these Ags into proximal B cell follicles. Many viruses, however, first reach LNs through the blood during viremia (virus in the blood), rather than through lymph drainage from infected tissue. How LNs capture viral Ag from the blood to allow GC development is not known. Here, we followed Zika virus (ZIKV) dissemination in mice and subsequent GC formation in both infected tissue-draining and non-draining LNs. From the footpad, ZIKV initially disseminated through two LN chains, infecting LN macrophages and leading to GC formation. Despite rapid ZIKV viremia, non-draining LNs were not infected for several days. Non-draining LN infection correlated with virus-induced vascular leakage and neutralization of permeability reduced LN macrophage attrition. Depletion of non-draining LN macrophages significantly decreased GC B cells in these nodes. Thus, although LNs inefficiently captured viral Ag directly from the blood, GC formation in non-draining LNs proceeded similarly to draining LNs through LN sinus CD169+ macrophages. Together, our findings reveal a conserved pathway allowing LN macrophages to activate antiviral B cells in LNs distal from infected tissue after blood-borne viral infection.

The anatomic basis of leptomeningeal metastasis.

Leptomeningeal metastasis (LM), or spread of cancer to the cerebrospinal fluid (CSF)-filled space surrounding the central nervous system, is a fatal complication of cancer. Entry into this space poses an anatomical challenge for cancer cells; movement of cells between the blood and CSF is tightly regulated by the blood-CSF barriers. Anatomical understanding of the leptomeninges provides a roadmap of corridors for cancer entry. This Review describes the anatomy of the leptomeninges and routes of cancer spread to the CSF. Granular understanding of LM by route of entry may inform strategies for novel diagnostic and preventive strategies as well as therapies.

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Efficacy of prophylactic use of intraoperative vancomycin powder in preventing surgical site infection in neurological surgeries in Irrua, Nigeria: A randomized controlled study.

PURPOSE: The objective was to determine the efficacy of intraoperative vancomycin powder in preventing SSIs in neurological surgeries. METHODS: A prospective randomized controlled study of patients who had clean cranial and non-implant spine surgeries at the Irrua Specialist Teaching Hospital, Irrua, Nigeria from February 1, 2021 to January 31, 2022. Patients were randomized into two groups. Group A patients had prophylactic intraoperative vancomycin powder applied to the surgical bed before wound closure while group B patients did not. Patients in both groups were followed up for 30 days post-operatively for evidence of SSI. The occurrence of SSIs was determined using clinical and laboratory parameters. Baseline characteristics, operative details, rates of wound infection, and microbiological data for each case were recorded. Data was analyzed using Statistical Package for Scientific Solution (SPSS) version 23 software. RESULTS: Forty-two patients were randomized into 2 groups of 21 patients each. The age range of the patients was 20 to 80 years. The majority of the patients were males (32 out of 42). The mean age of patients in group A was 48.05 ± 17.03 years, while group B had a mean age of 45.95 ± 19.14 years. The mean Body Mass Index of patients in groups A and B were 23.92 ± 5.21 and 23.21 ± 3.99 respectively. Seven out of 21 patients (33.3 %) in the control group ( group B) had superficial SSIs while no patient in the experimental group had SSI, p-value < 0.05. The organisms cultured were Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. CONCLUSION: Intraoperative vancomycin powder was effective in reducing the rate of SSIs following neurological surgeries and without adverse drug reactions.

Macrophage Ontogeny, Phenotype, and Function in Ischemia Reperfusion-Induced Injury and Repair.

AKI is characterized by a sudden, and usually reversible, decline in kidney function. In mice, ischemia-reperfusion injury (IRI) is commonly used to model the pathophysiologic features of clinical AKI. Macrophages are a unifying feature of IRI as they regulate both the initial injury response as well as the long-term outcome following resolution of injury. Initially, macrophages in the kidney take on a proinflammatory phenotype characterized by the production of inflammatory cytokines, such as CCL2 (monocyte chemoattractant protein 1), IL-6, IL-1 ß , and TNF- α . Release of these proinflammatory cytokines leads to tissue damage. After resolution of the initial injury, macrophages take on a reparative role, aiding in tissue repair and restoration of kidney function. By contrast, failure to resolve the initial injury results in prolonged inflammatory macrophage accumulation and increased kidney damage, fibrosis, and the eventual development of CKD. Despite the extensive amount of literature that has ascribed these functions to M1/M2 macrophages, a recent paradigm shift in the macrophage field now defines macrophages on the basis of their ontological origin, namely monocyte-derived and tissue-resident macrophages. In this review, we focus on macrophage phenotype and function during IRI-induced injury, repair, and transition to CKD using both the classic (M1/M2) and novel (ontological origin) definition of kidney macrophages.

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C.

BACKGROUND: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. OBJECTIVE: To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. DESIGN: Population-based cohort study. SETTING: Stockholm, Sweden, 2010 to 2019. PARTICIPANTS: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. MEASUREMENTS: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. RESULTS: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. LIMITATION: No GFR measurements. CONCLUSION: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. PRIMARY FUNDING SOURCE: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.

Cancer vaccines in the clinic.

Vaccines are an important tool in the rapidly evolving repertoire of immunotherapies in oncology. Although cancer vaccines have been investigated for over 30 years, very few have achieved meaningful clinical success. However, recent advances in areas such antigen identification, formulation development and manufacturing, combination therapy regimens, and indication and patient selection hold promise to reinvigorate the field. Here, we provide a timely update on the clinical status of cancer vaccines. We identify and critically analyze 360 active trials of cancer vaccines according to delivery vehicle, antigen type, indication, and other metrics, as well as highlight eight globally approved products. Finally, we discuss current limitations and future applications for clinical translation of cancer vaccines.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Staged circumferential lumbar fusions have less intraoperative complications and shorter operative time with no difference in 30-, 90-, and 1-year complications: a propensity-matched cohort analysis of 190 patients.

BACKGROUND CONTEXT: Circumferential lumbar fusions (cLFs) are becoming more common with increasing and more minimally invasive anterior access techniques. Staging allows reassessment of indirect decompression and alignment prior to the posterior approach, and optimization of OR time management. Safety of staging has been well documented in deformity surgery but has yet to be delineated in less extensive, degenerative cLFs. PURPOSE: The purpose of this study is to compare perioperative complications and outcomes between staged versus single-anesthetic circumferential fusions in the lumbar spine. STUDY DESIGN: Propensity-matched comparative observational cohort. PATIENT SAMPLE: Patients who underwent cLFs for lumbar degenerative disease. OUTCOME MEASURES: In-hospital, 30-day, 90-day, and 1-year complications. METHODS: From 123 patients undergoing single-anesthetic and 154 patients undergoing staged cLF, 95 patients in each group were propensity-matched based on age, sex, BMI, ASA score, smoking, revision, and number of levels. We compared perioperative, 30-day, 90-day, and 1-year complications between the two cohorts. RESULTS: Mean days between stages was 1.58. Single-anesthetic cLF had longer total surgery time (304 vs 240 minutes, p<.001) but shorter total PACU total time (133 vs 196 minutes, p<.001). However, there was no difference in total anesthesia time (368 vs 374 minutes, p=.661) and total EBL (357 vs 320cc, p=.313). Intraoperative complications were nine incidental durotomies in the single-anesthetic and one iliac vein injury in the staged group (9% vs 1%, p=.018). There was no difference of in-hospital (38 vs 31, p=.291), 30-day (16 vs 23, p=.281), 90-day (10 vs 15, p=.391), 1-year complications (9 vs 12, p=.644), and overall cumulative 1-year complications (54 vs 56, p=.883) between the two cohorts. CONCLUSIONS: There is a decrease in total surgical time and intraoperative complications during staged compared with single-anesthetic cLF with no difference in in-hospital, 30-day, 90-day, and 1-year complications between approaches.

Accuracy of GFR estimating equations based on creatinine, cystatin C or both in routine care.

BACKGROUND: New equations to estimate glomerular filtration rate based on creatinine (eGFRcr), cystatin C (eGFRcys) or both (eGFRcr-cys) have been developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the European Kidney Function Consortium (EKFC). There is a need to evaluate the performance of these equations in diverse European settings to inform implementation decisions, especially among people with key comorbid conditions. METHODS: We performed a cross-sectional study including 6174 adults referred for single-point plasma clearance of iohexol in Stockholm, Sweden, with 9579 concurrent measurements of creatinine and cystatin C. We assessed the performance of the CKD-EPI 2009/2012/2021, EKFC 2021/2023, revised Lund-Malmö (RLM) 2011 and Caucasian, Asian, Pediatric and Adult (CAPA) 2014 equations against measured GFR (mGFR). RESULTS: Mean age was 56 years, median mGFR was 62 mL/min/1.73 m2 and 40% were female. Comorbid conditions were common: cardiovascular disease (30%), liver disease (28%), diabetes (26%) and cancer (26%). All eGFRcr-cys equations had small bias and P30 (the percentage of estimated values within 30% of mGFR) close to 90%, and performed better than eGFRcr or eGFRcys equations. Among eGFRcr equations, CKD-EPI 2009 and CKD-EPI 2021 showed larger bias and lower P30 than EKFC 2021 and RLM. There were no meaningful differences in performance across eGFRcys equations. Findings were consistent across comorbid conditions, and eGFRcr-cys equations showed good performance in patients with liver disease, cancer and heart failure. CONCLUSIONS: In conclusion, eGFRcr-cys equations performed best, with minimal variation among equations in this Swedish cohort. The lower performance of CKD-EPI eGFRcr equations compared with EKFC and RLM may reflect differences in population characteristics and mGFR methods. Implementing eGFRcr equations will require a trade-off between accuracy and uniformity across regions.

Opioid-sparing Anesthesia Decreases In-hospital and 1-year Postoperative Opioid Consumption Compared With Traditional Anesthesia: A Propensity-matched Cohort Study.

STUDY DESIGN: Propensity-matched cohort. OBJECTIVE: The aim of this study was to determine if opioid-sparing anesthesia (OSA) reduces in-hospital and 1-year postoperative opioid consumption. SUMMARY OF BACKGROUND DATA: The recent opioid crisis highlights the need to reduce opioid exposure. We developed an OSA protocol for lumbar spinal fusion surgery to mitigate opioid exposure. MATERIALS AND METHODS: Patients undergoing lumbar fusion for degenerative conditions over one to four levels were identified. Patients taking opioids preoperatively were excluded. OSA patients were propensity-matched to non-OSA patients based on age, sex, smoking status, body mass index, American Society of Anesthesiologists grade, and revision versus primary procedure. Standard demographic and surgical data, daily in-hospital opioid consumption, and opioid prescriptions 1 year after surgery were compared. RESULTS: Of 296 OSA patients meeting inclusion criteria, 172 were propensity-matched to non-OSA patients. Demographics were similar between cohorts (OSA: 77 males, mean age=57.69 yr; non-OSA: 67 males, mean age=58.94 yr). OSA patients had lower blood loss (326 mL vs. 399 mL, P =0.014), surgical time (201 vs. 233 min, P <0.001) emergence to extubation time (9.1 vs. 14.2 min, P< 0.001), and recovery room time (119 vs. 140 min, P =0.0.012) compared with non-OSA patients. Fewer OSA patients required nonhome discharge (18 vs. 41, P =0.001) compared with the non-OSA cohort, but no difference in length of stay (90.3 vs. 98.5 h, P =0.204). Daily opioid consumption was lower in the OSA versus the non-OSA cohort from postoperative day 2 (223 vs. 185 morphine milligram equivalents, P =0.017) and maintained each day with lower total consumption (293 vs. 225 morphine milligram equivalents, P =0.003) throughout postoperative day 4. The number of patients with active opioid prescriptions at 1, 3, 6, and 12 months postoperative was statistically fewer in the OSA compared with the non-OSA patients. CONCLUSIONS: OSA for lumbar spinal fusion surgery decreases in-hospital and 1-year postoperative opioid consumption. The minimal use of opioids may also lead to shorter emergence to extubation times, shorter recovery room stays, and fewer discharges to nonhome facilities.

Cigarette Smoking and Risk of Hospitalization With Acute Kidney Injury: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Smoking is a modifiable risk factor for various adverse events. However, little is known about the association of smoking with the incidence of acute kidney injury (AKI) in the general population. This study investigated the association of cigarette smoking with the risk of AKI. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 14,571 participants (mean age 55±6 years, 55% women, and 25% Black participants) from the ARIC study visit 1 (1987-1989) followed through December 31, 2019. EXPOSURE: Smoking parameters (status, duration, pack-years, intensity, and years since cessation). OUTCOME: Incident hospitalization with AKI, defined by a hospital discharge with a diagnostic code relevant to AKI. ANALYTICAL APPROACH: Multivariable Cox regression models. RESULTS: Over a median follow-up period of 26.3 years, 2,984 participants had an incident hospitalization with AKI. Current and former smokers had a significantly higher risk of AKI compared to never smokers after adjusting for potential confounders (HR, 2.22 [95% CI, 2.02-2.45] and 1.12 [1.02-1.23], respectively). A dose-response association was consistently seen for each of smoking duration, pack-years, and intensity with AKI (eg, HR, 1.19 [95% CI, 1.16-1.22] per 10 years of smoking). When years since cessation were considered as a time-varying exposure, the risk of AKI associated with smoking compared with current smokers began to decrease after 10 years, and became similar to never smokers at 30 years (HR for≥30 years, 1.07 [95% CI, 0.97-1.20] vs never smokers). LIMITATIONS: Self-reported smoking measurements and missing outpatient AKI cases. CONCLUSIONS: In a community-based cohort, all smoking parameters were robustly associated with the risk of AKI. Smoking cessation was associated with decreased risk of AKI, although the excess risk lasted up to 30 years. Our study supports the importance of preventing smoking initiation and promoting smoking cessation for the risk of AKI. PLAIN-LANGUAGE SUMMARY: Smoking is a behavior that is associated with many negative health effects. It is not well understood how smoking relates to the occurrence of acute kidney injury (AKI) in the community. In this study, we looked at data from a group of 14,571 adults who were followed for 26 years to see how different aspects of smoking (such as whether someone smoked, how long they smoked for, how many cigarettes they smoked per day, and whether they quit smoking) were related to AKI. We found that smoking was strongly linked to an increased risk of AKI. This risk decreased after 5-10 years of quitting smoking, but the excess risk lasted up to 30 years. This study shows the importance of preventing people from starting smoking and to encourage smokers to quit to reduce their risk of AKI.

The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care.

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Plasma Biomarkers and Incident CKD Among Individuals Without Diabetes.

Rationale & Objective: Biomarkers of kidney disease progression have been identified in individuals with diabetes and underlying chronic kidney disease (CKD). Whether or not these markers are associated with the development of CKD in a general population without diabetes or CKD is not well established. Study Design: Prospective observational cohort. Setting & Participants: In the Atherosclerosis Risk in Communities) study, 948 participants were studied. Exposures: The baseline plasma biomarkers of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), soluble urokinase plasminogen activator receptor (suPAR), tumor necrosis factor receptor 1 (TNFR-1), tumor necrosis factor receptor 2 (TNFR-2), and human cartilage glycoprotein-39 (YKL-40) measured in 1996-1998. Outcome: Incident CKD after 15 years of follow-up defined as ≥40% estimated glomerular filtration rate decline to <60 mL/min/1.73 m2 or dialysis dependence through United States Renal Data System linkage. Analytical Approach: Logistic regression and C statistics. Results: There were 523 cases of incident CKD. Compared with a random sample of 425 controls, there were greater odds of incident CKD per 2-fold higher concentration of KIM-1 (OR, 1.49; 95% CI, 1.25-1.78), suPAR (OR, 2.57; 95% CI, 1.74-3.84), TNFR-1 (OR, 2.20; 95% CI, 1.58-3.09), TNFR-2 (OR, 2.03; 95% CI, 1.37-3.04). After adjustment for all biomarkers, KIM-1 (OR, 1.42; 95% CI, 1.19-1.71), and suPAR (OR, 1.86; 95% CI, 1.18-2.92) remained associated with incident CKD. Compared with traditional risk factors, the addition of all 6 biomarkers improved the C statistic from 0.695-0.731 (P < 0.01) and using the observed risk of 12% for incident CKD, the predicted risk gradient changed from 5%-40% (for the 1st-5th quintile) to 4%-44%. Limitations: Biomarkers and creatinine were measured at one time point. Conclusions: Higher levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with higher odds of incident CKD among individuals without diabetes. Plain-Language Summary: For people with diabetes or kidney disease, several biomarkers have been shown to be associated with worsening kidney disease. Whether these biomarkers have prognostic significance in people without diabetes or kidney disease is less studied. Using the Atherosclerosis Risk in Communities study, we followed individuals without diabetes or kidney disease for an average of 15 years after biomarker measurement to see if these biomarkers were associated with the development of kidney disease. We found that elevated levels of KIM-1, suPAR, TNFR-1, and TNFR-2 were associated with the development of kidney disease. These biomarkers may help identify individuals who would benefit from interventions to prevent the development of kidney disease.