medRxiv - Nephrology最新文献

{"title":"COVID-19-associated acute renal failure in critically ill patients correlates with microthrombosis and renal loss of thrombomodulin","authors":"Matilda Koskinen, Elisabet Englund, Gül Gizem Korkut, Angelina Schwarz, Marie Jeansson","doi":"10.1101/2024.03.18.24304157","DOIUrl":"https://doi.org/10.1101/2024.03.18.24304157","url":null,"abstract":"Critically ill COVID-19 patients have a high degree of acute kidney injury which develops in up to 85% of patients. We have previously shown that circulating levels of angiopoietin-2 increased in critically ill COVID-19 patients correlated to kidney injury, coagulopathy, and mortality. Furthermore, our experiments showed a causal effect on coagulopathy from angiopoietin-2 binding and inhibition of thrombomodulin mediated anticoagulation. In the current study we hypothesize that renal microthrombi may be a mechanism for reduced renal function in critically ill COVID-19 patients, and that local dysregulation of thrombomodulin and angiopoietin-2 may be involved.\u0000To investigate our hypothesis, we utilized postmortem kidney tissue from seven COVID-19 patients treated at the intensive care unit. We evaluated kidney function, thrombosis, tubular injury, fibrosis, glomerulosclerosis, glomerular size as well as renal expression of thrombomodulin and angiopoietin-2. Proximity ligation assay was utilized to evaluate the presence of angiopoietin-2 binding to thrombomodulin. Normal kidney tissue came from the healthy part of six nephrectomies due to cancer.\u0000Our experiments show renal thrombosis in 6/7 COVID-19 patients, on average 14.7 (6.9-22.5) thrombi per mm2. Most COVID-19 kidneys had extensive kidney injury, especially tubular necrosis, but also glomerular enlargement, glomerulosclerosis, and tubulointerstitial fibrosis which in some cases most likely resulted from underlying disease. Thrombomodulin expression was reduced in glomeruli and peritubular capillaries in kidneys from COVID-19 patients, whereas no change was found for angiopoietin-2.\u0000In summary, our study describes a high degree of acute renal failure, renal microthrombosis, and loss of thrombomodulin in postmortem tissue from critically ill COVID-19 patients.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140171689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human kidney-derived tubular organoid, tubuloid, recapitulates cellular senescence, inflammation and fibrosis by repeated-cisplatin treatment","authors":"Yuki Nakao, Yutaro Mori, Makiko Mori, Shintaro Mandai, Tamami Fujiki, Hiroaki Kikuchi, Fumiaki Ando, Koichiro Susa, Takayasu Mori, Yuma Waseda, Soichiro Yoshida, Yasuhisa Fujii, Eisei Sohara, Shinichi Uchida","doi":"10.1101/2024.03.17.24304404","DOIUrl":"https://doi.org/10.1101/2024.03.17.24304404","url":null,"abstract":"Kidney organoids derived from human pluripotent stem cells have been an attracting pathophysiological model recapitulating the response of human kidney to drugs in recent years. Here, we have developed an alternative way to make more homogeneous epithelial-like structures called ″tubuloid″ based on primary human renal proximal tubular epithelial cells (hRPTECs) cultured from human resected kidneys and tested their efficacy by administering cisplatin at three concentrations of 0.2, 2.0, and 20.0 μg/mL. Tubuloids showed highly differentiated structures composed of proximal tubular epithelial cells with expression of LTL and LRP2/Megalin. Treatment of tubuloids with cisplatin increased γH2AX, a marker for DNA damage, in a dose-dependent manner. Kidney Injury Molecule-1 (KIM-1), a marker of kidney injury, and cleaved caspase-3, a marker for apoptotic signals were expressed due to cisplatin treatment. Repeated administration of cisplatin resulted in upregulation of the cellular senescence marker p16 and enhanced expression of inflammatory cytokines IL-1β and IL-6, indicating an induced senescence-associated secretory phenotype (SASP). Myofibroblast activation was also induced by the supernatant collected from cisplatin-treated tubuloids, which could reflect renal fibrosis. Thus, we succeeded in establishing a model of cisplatin-induced kidney injury based on tubuloids using hRPTECs. Tubuloids have the potential to serve as a novel pathological model and can be utilized to simulate the response of renal epithelial cells to toxins and therapeutic agents. Given its capability to replicate cellular senescence, SASP and the fibrosis, tubuloids could potentially serve as a pathophysiological model for chronic kidney disease (CKD), which is known for fibrosis as a final common pathological pathway.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140171684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning for classifying chronic kidney disease and predicting creatinine levels using at-home measurements","authors":"Brady Metherall, Anna K. Berryman, Georgia S. Brennan","doi":"10.1101/2024.03.15.24304364","DOIUrl":"https://doi.org/10.1101/2024.03.15.24304364","url":null,"abstract":"Background: Chronic kidney disease (CKD) is a global health concern with early detection playing a pivotal role in effective management. Machine learning models demonstrate promise in CKD detection, yet the impact on detection and classification using different sets of clinical features remains under-explored.\u0000Methods: In this study, we focus on CKD classification and creatinine prediction using three sets of features; at-home, monitoring, and laboratory. We employ artificial neural networks (ANNs) and random forests (RFs) on a dataset of 400 patients with 25 input features, which we divide into three feature sets. Using 10-fold cross-validation, we calculate metrics such as accuracy, true positive rate (TPR), true negative rate (TNR), and mean squared error.\u0000Results: Our results reveal RF achieves superior accuracy (92.5%) in at-home CKD classification over ANNs (82.9%). ANNs achieve a higher TPR (92.0%) but a lower TNR (67.9%) compared with RFs (90.0% and 95.8%, respectively). For monitoring and laboratory features, both methods achieve accuracies exceeding 98%. The R2 score for creatinine regression is approximately 0.3 higher with laboratory features than at-home features. Feature importance analysis identifies key clinical variables hemoglobin and blood urea, and key comorbidities hypertension and diabetes mellitus, in agreement with previous studies.\u0000Conclusions: Machine learning models, particularly RFs, exhibit promise in CKD diagnosis and highlight significant features in CKD detection. Moreover, such models may assist in screening a general population using at-home features---potentially increasing early detection of CKD, thus improving patient care and offering hope for a more effective approach to managing this prevalent health condition.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140171952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adherence to a healthful plant-based diet and risk of chronic kidney disease among individuals with diabetes: A prospective cohort study","authors":"Alysha S. Thompson, Anna Tresserra-Rimbau, Amy Jennings, Nicola P. Bondonno, Catharina J. Candussi, Joshua K. O'Neill, Claire Hill, Martina Gaggl, Aedin Cassidy, Tilman Kuhn","doi":"10.1101/2024.03.14.24304283","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304283","url":null,"abstract":"Background: Chronic kidney disease (CKD) is highly prevalent among people with diabetes. While identifying modifiable risk factors to prevent a decline in kidney function among those living with diabetes is pivotal, there is limited evidence on dietary risk factors for CKD. In this study we examined the associations between healthy and less healthy plant-based diets (PBDs) and the risk of CKD among those with diabetes, and to identify potential underlying mechanisms. Methods: We conducted a prospective analysis among 7,747 UK Biobank participants with prevalent diabetes. Multivariable Cox proportional hazard regression models were used to examine the associations between healthful and unhealthful PBDs and the risk of CKD. Causal mediation analyses were further employed to explore the underlying mechanisms of the observed associations. Results: Among 7,747 study participants with diabetes, 1,030 developed incident CKD over 10.2 years of follow-up. Higher adherence to a healthy PBD was associated with a 24% lower CKD risk (HRQ4 versus Q1: 0.76 [95%CI: 0.63-0.92], ptrend = 0.002), while higher adherence to an unhealthy PBD was associated with a 35% higher risk (HRQ4 versus Q1: 1.35 [95%CI: 1.11-1.65], ptrend = 0.006). The observed associations were predominantly mediated by markers of body fatness (proportion mediated: 11-25%) and kidney function (23-89%). Conclusions: In this prospective cohort study of middle-aged adults with diabetes, adherence to a healthy PBD was associated with lower CKD risk, whereas adherence to an unhealthy PBD was associated with a higher CKD risk. Associations were primarily mediated by markers of lower body fatness and improved kidney function.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary Clusterin is a biomarker of renal epithelial senescence and predicts human kidney disease progression","authors":"David P Baird, Maximilian Reck, Ross Campbell, Marie-Helena Docherty, Matthieu Vermeren, Andy Nam, Wei Yang, Nathan Schurman, Claire Williams, Jamie P Traynor, Patrick B Mark, Katie Mylonas, Jeremy Hughes, Laura Denby, Bryan Conway, David Ferenbach","doi":"10.1101/2024.03.14.24303997","DOIUrl":"https://doi.org/10.1101/2024.03.14.24303997","url":null,"abstract":"Cellular senescence drives organ fibrosis and ageing, and accumulating evidence supports the ability of senescence-depleting drugs to improve outcomes in experimental models of disease. The lack of non-invasive biomarkers represents a major obstacle to the design of human trials of candidate senolytics. On samples from 51 patients with chronic kidney disease (CKD), we performed liquid chromatography mass spectrometry (LC-MS) analysis of urine samples alongside immunofluorescence staining of paired kidney biopsies for p21, Ki67, and CD10+Pancytokeratin as senescence, proliferation and pan-epithelial cell markers respectively. Only Urinary Clusterin (uClusterin) correlated tightly with p21+ epithelial senescence in vivo (rho >0.5, p<0.001) and was upregulated in the in vitro SASP atlas. This was validated in a second cohort of matched urine and kidney samples from n=53 participants, with uClusterin predicting levels of senescence after adjusting for renal function, age and albuminuria. In spatial transcriptomic data from n=13 CKD patients, Clusterin colocalised with senescence marker CDKN1A. In a larger cohort of n=322 participants, elevated levels of uClusterin predicted CKD progression (defined as reaching ESKD or >40% reduction in renal function) after adjusting for baseline eGFR, albuminuria, age, systolic blood pressure (SBP) and sex. uClusterin levels represents a surrogate for histological quantification of p21+Ki67- senescent renal epithelia and predicts outcomes in human kidney disease independent of existing clinical risk factors.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140153175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global burden of renal anemia in 204 countries and territories, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021","authors":"Feifan Chu, Jinzhong Ji, Yuning Ma, Qing Guan, Lumin Chen, Zujie Chen, Qiwei Ji, Mingxin Sun, Hui Zhang, Haihan Song, Xiuquan Lin, Hao Zhou","doi":"10.1101/2024.03.12.24304162","DOIUrl":"https://doi.org/10.1101/2024.03.12.24304162","url":null,"abstract":"Background: Renal anemia, one of the causes of anemia, has inflicted a certain degree of loss on global health. However, there are no comprehensive analyses on the burden of renal anemia yet. This study aims to comprehensively evaluate the age-standardized prevalence and Years Lived with Disability (YLDs) burden and trends of renal anemia across different sexes, ages, countries, and regions from 1990 to 2021. Methods: We analyzed the prevalence and YLDs of renal anemia from 1990 to 2021 across different sexes, ages, countries, and regions. We also examined the relationship between the burden of renal anemia in various regions and the Human Development Index (HDI). Further analyses included the changes in the rank of renal anemia among causes of anemia from 1990 to 2021. Finally, we conducted health inequality analysis, frontier analysis, and APC (age-period-cohort) model analysis on the burden of renal anemia. Results: In 2021, the global prevalence of renal anemia across all age groups was 0.82% (95% uncertainty interval [UI] 0.73 - 0.91), equivalent to 63.92 million (59.61 - 71.81) prevalent cases, resulting in 1.70 million (1.13 - 2.43) years lived with disability (YLDs), showing an increase compared to 1990. In recent years, renal anemia has risen in rank among causes of anemia. The burden of renal anemia varies significantly across different age groups and regions, with particularly severe burdens observed among populations over sixty years of age in Central Europe, Eastern Europe, Central Asia, South Asia, Southeast Asia, southern Latin America, and North American countries. A series of analyses based on the HDI revealed the following: descriptive analysis indicated a positive correlation between the prevalence of renal anemia and HDI; cross-national inequality analysis showed an increasing disparity in prevalence and YLDs between high HDI and low HDI countries, with higher burdens in high HDI countries; although with low prevalence, frontier analysis revealed considerable opportunities to reduce the age-standardized YLDs in the Low and medium of HDI spectrum; APC analysis suggested significant differences in the prevalence of renal anemia in high HDI regions (not very high HDI regions) compared to middle and low HDI regions across age, period, and cohort analyses. Conclusions: Although the global burden of anemia is decreasing, renal anemia remains a significant health issue, especially among older populations in mid and high-development countries. Targeted programs should be implemented, starting with enhancing diagnosis and treatment in specific regions and populations. The development of new medications should also be considered.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140128707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Reassessment of Sodium Correction Rates and Hospital Length of Stay Accounting for Admission Diagnosis","authors":"Eric Gottlieb, Leo Anthony Celi","doi":"10.1101/2024.03.08.24303993","DOIUrl":"https://doi.org/10.1101/2024.03.08.24303993","url":null,"abstract":"Background\u0000Recent studies have challenged assumptions about slow correction of severe hyponatremia and have shown that rapid correction is associated with shorter hospital length of stay. However, the confounding effect of admission diagnosis has not been fully explored. The objective of this study was to determine whether rapid correction is still associated with shorter length of stay when controlling for admission diagnosis. Methods\u0000This retrospective cohort study is based on the Medical Information Mart for Intensive Care, including data from both MIMIC-III (2001-2012) and MIMIC-IV (2008-2019). Patients were identified who presented to the hospital with initial sodium <120 mEq/L and were categorized according to total sodium correction achieved in the first day (<6 mEq/L; 6-10 mEq/L; >10 mEq/L). Linear regression was used to assess for an association between correction rate and hospital length of stay, and to determine if this association was significant when controlling for admission diagnosis classifications based on diagnosis related groups (DRGs). Results\u0000There were 636 patients included in this study. Median [IQR] hospital length of stay was 7 [4, 11] days. Patients had a median [IQR] initial sodium value of 117 [114, 118] mEq/L and final sodium value of 124 [119, 128] mEq/L. In a univariate linear regression, the highest rate of correction (>10 mEq/L) was associated with a shorter length of stay than a moderate rate of correction (coef. -2.363, 95% CI [-4.710, -0.017], p=0.048), but the association was not significant when controlling for admission diagnosis group (coef. -1.685, 95% CI [-3.836, 0.467], p=0.125). Conclusions\u0000Faster sodium correction was not associated with shorter length of stay when controlling for admission diagnosis categories, suggesting that the disease state confounds this association. While some patients may be discharged earlier if sodium is corrected more rapidly, others may not benefit or may be harmed by this strategy.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140097245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nephroprotective effects of cilastatin in people at risk of acute kidney injury: A systematic review and meta-analysis","authors":"Dilaram Acharya, Fannar Ghanim, Tyrone G Harrison, Tayler D Scory, Nusrat Shommu, Paul Ronksley, Meghan J Elliott, David Collister, Matthew T James","doi":"10.1101/2024.03.06.24303823","DOIUrl":"https://doi.org/10.1101/2024.03.06.24303823","url":null,"abstract":"Background: Cilastatin is an inhibitor of drug metabolism in the proximal tubule of the kidney that demonstrates nephroprotective effects in animal models. Cilastatin has been in clinical use since the 1980s in combination with the antibiotic imipenem to prevent imipenem degradation, which has enabled studies testing the effect of cilastatin on kidney outcomes in observational studies and clinical trials This systematic review and meta-analysis was undertaken to evaluate the nephroprotective effects of cilastatin among people susceptible to acute kidney injury (AKI).\u0000Methods: We systematically searched MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Trials registry to November 2023 for observational studies or trials that compared kidney outcomes with cilastatin, either alone or as combination imipenem-cilastatin, compared to an inactive or active control group not treated with cilastatin. Two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. Treatment effects were estimated using random effects models and heterogeneity was reported using the I2 statistic.\u0000Results: We identified 10 studies (five RCTs, n=535 patients; 5 observational studies n=6,198 participants) that met the inclusion criteria, including studies with comparisons of imipenem-cilastatin to an inactive control as well as those with comparisons to alternate antibiotics among patients being treated for bacterial infections. Based on results from 5 studies, imipenem-cilastatin significantly reduced the incidence of AKI (pooled odds ratio [OR] 0.42 [95% CI 0.26 to 0.69]; I2 48%), with consistent results observed from randomized trials (two trials, OR 0.12 [95% CI, 0.02 to 0.73]; I2 0%) and observational studies (four studies, OR 0.46 [95% CI, 0.28 to 0.78]; I2 62%). Based on results from six studies, kidney function was also better with imipenem-cilastatin than comparators (weighted mean difference in serum creatinine -0.14 mg/dL [95% CI -0.22 to 0.07]; I2 0%). There was no statistically significant difference in all-cause mortality with imipenem-cilastatin treatment compared to comparators (pooled OR 0.60 [95% CI, 0.12 to 3.03]; I2 73%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies.\u0000Conclusion: Patients at risk of AKI treated with imipenem-cilastatin less frequently developed AKI and had better short-term kidney function than those receiving control or comparator antibiotics. Larger clinical trials with less risk of bias are needed to establish the efficacy of cilastatin for AKI prevention.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140075352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-trait Analysis of GWAS for circulating FGF23 Identifies Novel Network Interactions Between HRG-HMGB1 and Cardiac Disease in CKD","authors":"Farzana Perwad, Elvis Akwo, Nicholas Vartanian, Larry J Suva, Peter Friedman, Cassiane Robinson-Cohen","doi":"10.1101/2024.03.04.24303051","DOIUrl":"https://doi.org/10.1101/2024.03.04.24303051","url":null,"abstract":"Background: Genome-wide association studies (GWAS) have identified numerous genetic loci associated with mineral metabolism (MM) markers but have exclusively focused on single-trait analysis. In this study, we performed a multi-trait analysis of GWAS (MTAG) of MM, exploring overlapping genetic architecture between traits, to identify novel genetic associations for fibroblast growth factor 23 (FGF23).\u0000Methods: We applied MTAG to genetic variants common to GWAS of 5 genetically correlated MM markers (calcium, phosphorus, FGF23, 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH)) in European-ancestry subjects. We integrated information from UKBioBank GWAS for blood levels for phosphate, 25(OH)D and calcium (n=366,484), and CHARGE GWAS for PTH (n=29,155) and FGF23 (n=16,624). We then used functional genomics to model interactive and dynamic networks to identify novel associations between genetic traits and circulating FGF23.\u0000Results: MTAG increased the effective sample size for all MM markers to n=50,325 for FGF23. After clumping, MTAG identified independent genome-wide significant SNPs for all traits, including 62 loci for FGF23. Many of these loci have not been previously reported in single-trait analyses. Through functional genomics we identified Histidine-rich glycoprotein (HRG) and high mobility group box 1(HMGB1) genes as master regulators of downstream canonical pathways associated with FGF23. HRG-HMGB1 network interactions were also highly enriched in left ventricular heart tissue of a cohort of deceased hemodialysis patients. Conclusion: Our findings highlight the importance of MTAG analysis of MM markers to boost the number of genome-wide significant loci for FGF23 to identify novel genetic traits. Functional genomics revealed novel networks that inform unique cellular functions and identified HRG-HMGB1 as key master regulators of FGF23 and cardiovascular disease in CKD. Future studies will provide a deeper understanding of genetic signatures associated with FGF23 and its role in health and disease.","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140044600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient preferences and priorities for the design of an acute kidney injury prevention trial: Findings from a consensus workshop","authors":"Meghan J Elliott, Kirsten Fiest, Shannan Love, Dale Birdsell, Maureena Loth, Heather Dumka, Benny Ranna, Nusrat Shommu, Eleanor Bentrud, Sarah Gil, Dilaram Acharya, Tyrone G Harrison, Neesh Pannu, Matthew T James","doi":"10.1101/2024.03.04.24303721","DOIUrl":"https://doi.org/10.1101/2024.03.04.24303721","url":null,"abstract":"Background: Hospitalized patients who develop acute kidney injury (AKI) as a result of nephrotoxic medication exposure are at high risk of adverse outcomes, such as prolonged hospitalization, chronic kidney disease, and cardiovascular events. High-quality clinical trials are needed to establish the safety and efficacy of potential therapies to prevent AKI. Incorporation of the preferences of people with lived experience into trial design can increase the feasibility, acceptability, and relevance of trials.\u0000Objective: The purpose of this consensus workshop was to identify patient and caregiver priorities for recruitment, intervention delivery, and outcomes of a clinical trial of cilastatin to prevent nephrotoxic AKI, which will be integrated into development of the trial protocol.\u0000Design: Consensus workshop using a modified nominal group technique (NGT) approach. Setting: We conducted a half-day hybrid in-person/virtual workshop at the University of Calgary in December 2023 to engage participants from across Alberta, Canada. Participants: Eligible participants included adults with experience of or caring for someone with AKI, chronic kidney disease, or risk factors for AKI (e.g., diabetes, critical care hospitalization).\u0000Methods: With reference to vignettes (i.e., patient scenarios) and a question guide, experienced facilitators led a series of small- and large-group discussions focused on the following 3 topic areas related to clinical trial design: (1) consent and recruitment; (2) intervention delivery; and (3) trial outcomes. In a final prioritization exercise, participants voted on their top 3 preferences within each topic area, which were categorized as high, medium, or low priority. We analyzed transcripts from small- and large-group discussions inductively using conventional content analysis to elaborate on prioritization results.\u0000Results: Thirteen individuals participated in the consensus workshop, including 11 patients and 2 caregivers. In the voting exercise for consent and recruitment, participants prioritized use of technological means for identifying eligible participants (i.e., technology enabled pre-screening) and involvement of family members in the consent process. For intervention delivery, participants prioritized the importance of measures to facilitate intervention administration (e.g., intravenous cannula placement) and providing support for return visits. For trial outcomes, participants identified short and long-term kidney-related and other clinical outcomes (e.g., AKI, chronic kidney disease, cardiovascular events) as top priorities. Analysis of discussion transcripts largely reinforced voting results and provided additional insight into preferences for care team and family involvement in trial-related decisions, participants desire to avert AKI and implications of allocation to a placebo arm, and their varied experiences of AKI and critical illness.\u0000Limitations: The short duration of group discussions and hybrid in-perso","PeriodicalId":501513,"journal":{"name":"medRxiv - Nephrology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140034680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}