PLOS ONE: [sortOrder=DATE_NEWEST_FIRST, sort=Date, newest first, q=subject:"Nephrology"]PLOShttps://journals.plos.org/plosone/webmaster@plos.orgaccelerating the publication of peer-reviewed sciencehttps://journals.plos.org/plosone/search/feed/atom?sortOrder=DATE_NEWEST_FIRST&sort=Date,+newest+first&unformattedQuery=subject:%22Nephrology%22All PLOS articles are Open Access.https://journals.plos.org/plosone/resource/img/favicon.icohttps://journals.plos.org/plosone/resource/img/favicon.ico2024-03-29T09:31:24ZNational clinical and financial outcomes associated with acute kidney injury following esophagectomy for cancerAyesha P. NgNikhil ChervuCorynn BrancheSyed Shahyan BakhtiyarMehrab MarzbanPaul A. TostePeyman Benharash10.1371/journal.pone.03008762024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Ayesha P. Ng, Nikhil Chervu, Corynn Branche, Syed Shahyan Bakhtiyar, Mehrab Marzban, Paul A. Toste, Peyman Benharash</p>
Background <p>Esophagectomy is a complex oncologic operation associated with high rates of postoperative complications. While respiratory and septic complications have been well-defined, the implications of acute kidney injury (AKI) remain unclear. Using a nationally representative database, we aimed to characterize the association of AKI with mortality, resource use, and 30-day readmission.</p> Methods <p>All adults undergoing elective esophagectomy with a diagnosis of esophageal or gastric cancer were identified in the 2010–2019 Nationwide Readmissions Database. Study cohorts were stratified based on presence of AKI. Multivariable regressions and Royston-Parmar survival analysis were used to evaluate the independent association between AKI and outcomes of interest.</p> Results <p>Of an estimated 40,438 patients, 3,210 (7.9%) developed AKI. Over the 10-year study period, the incidence of AKI increased from 6.4% to 9.7%. Prior radiation/chemotherapy and minimally invasive operations were associated with reduced odds of AKI, whereas public insurance coverage and concurrent infectious and respiratory complications had greater risk of AKI. After risk adjustment, AKI remained independently associated with greater odds of in-hospital mortality (AOR: 4.59, 95% CI: 3.62–5.83) and had significantly increased attributable costs ($112,000 vs $54,000) and length of stay (25.7 vs 13.3 days) compared to patients without AKI. Furthermore, AKI demonstrated significantly increased hazard of 30-day readmission (hazard ratio: 1.16, 95% CI: 1.01–1.32).</p> Conclusions <p>AKI after esophagectomy is associated with greater risk of mortality, hospitalization costs, and 30-day readmission. Given the significant adverse consequences of AKI, careful perioperative management to mitigate this complication may improve quality of esophageal surgical care at the national level.</p>Inoculation of Pan02 cells produces tumor nodules in mouse pancreas: Characterization of a novel orthotopic pancreatic ductal adenocarcinoma tumor model for interventional studiesJames I. GriffinXinyue ChenLuqi DuanQingxin MuRodney J. Y. Ho10.1371/journal.pone.03007232024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by James I. Griffin, Xinyue Chen, Luqi Duan, Qingxin Mu, Rodney J. Y. Ho</p>
Preclinical models of cancer are vital for assessing and predicting efficacies and toxicities of novel treatments prior to testing in human subjects. Current pancreatic tumor models exhibit variable growth rates, unpredictable tumor size after implantation in non-native tissues, or require surgical implantation. Surgical implantation in the pancreas may produce not only unpredictable tumor uptake but could also elicit additional inflammatory responses. In searching for a pancreatic carcinoma cell that can be introduced into a mouse via simple injection, we found that Pan02, a murine ductal pancreatic adenocarcinoma derived from a pancreatic lesion of a C57BL/6 mouse, inoculated peritoneally can consistently produce pancreatic tumors. This intraperitoneal, but not intravenous, introduction of Pan02 cells leads to the attachment and growth of Pan02 in the pancreas before spreading to other tissues. Time-course tissue analysis indicates that the Pan02 cells first find, infiltrate, and grow within the pancreas, producing a pancreatic tumor model. This model appears to mimic pancreatic cancer development in humans and is the first reported use of Pan02 cells to produce orthotopic pancreatic and metastatic neoplasms in a mouse model without the need for tumor implantation within matrices or survival surgeries. This orthotopic pancreatic tumor model, with consistent tumor uptake, synchronized tumor development and survival, and predictable outcomes may enable and accelerate the preclinical evaluation of treatment candidates for pancreatic cancer.The accuracy of different calculation methods when identifying handgrip strength asymmetry among middle-aged and older Chinese adultsYilin WangJing WangBinyou WangJing FuXiaoyan Chen10.1371/journal.pone.02994692024-03-28T14:00:00Z2024-03-28T14:00:00Z<p>by Yilin Wang, Jing Wang, Binyou Wang, Jing Fu, Xiaoyan Chen</p>
At present, there is no uniform standard mean of identifying handgrip strength (HGS) asymmetry based on maximum or average HGS values. Therefore, this study aimed to explore the accuracy of different calculation methods in the evaluation of HGS asymmetry. Using the maximum reading of two trials from both hands (Method A) as the reference standard, the accuracy of the HGS asymmetry identified by the average value of two trials of both hands (Method B) was determined by using various indicators, including specificity, sensitivity, the area under the receiver operating characteristic curve (AUC), positive, and negative predictive values. Overall, 12,163 individuals were included in this study, of whom 47.61% (5791/12,163) were male. The percentages of individuals with HGS asymmetry differed as a function of age and sex when using these two different methods. When employing Method A, 38.52%, 41.57%, and 44.57% of males 45 ≤ age<60, 60 ≤ age<80, and ≥ 80 years of age exhibited HGS asymmetry as compared to 40.78%, 39%, and 39.63% of females. Using Method B, the corresponding proportions were 41.69%, 42.5%, and 40% in males and 42.01%, 41.18%, and 40.55% in females, respectively. When compared to Method A, Method B was found to be effective in identifying HGS asymmetry, with AUC values ranging from 0.844 to 0.877. However, there was only moderate agreement between the two methods in assessing HGS asymmetry. Specifically, the Kappa values for the two Methods were 0.692, 0.694, and 0.766 in males aged 45 to 60, 60 to 80, and 80 years and above, respectively. For females, the Kappa values were 0.674, 0.661, and 0.751, respectively. These results demonstrated that the maximal or average HGS values from two trials using both hands has a significant impact on the consequent identification of HGS asymmetry.Association of anti-diabetic drugs and covid-19 outcomes in patients with diabetes mellitus type 2 and chronic kidney disease: Nationwide registry analysisJelena DimnjakovićTamara BublePero IvankoTamara PoljičaninSandra Karanović ŠtambukHana BrborovićOgnjen Brborović10.1371/journal.pone.03010562024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Jelena Dimnjaković, Tamara Buble, Pero Ivanko, Tamara Poljičanin, Sandra Karanović Štambuk, Hana Brborović, Ognjen Brborović</p>
Introduction <p>Patients with diabetes mellitus type 2 and chronic kidney disease (T2DM-CKD) have a 5 times higher risk of developing severe SARS-CoV-2 infection than those without these 2 diseases. The goal of this study is to provide information on T2DM-CKD and COVID-19 outcomes, with an emphasis on the association with anti-diabetic medications.</p> Methodology <p>Study is designed as a retrospective cohort analysis covering the years 2020 and 2021. Data from the National Diabetes Registry (CroDiab) were linked to hospital data, primary healthcare data, Causes of Death Registry data, the SARS-CoV-2 vaccination database, and the SARS-CoV-2 test results database. Study outcomes were cumulative incidence of SARS-CoV-2 positivity, COVID-19 hospitalizations, and COVID-19 deaths. For outcome predictors, logistic regression models were developed.</p> Results <p>Of 231 796 patients with diabetes mellitus type 2 in the database, 7 539 were T2DM-CKD (3.25%). The 2-year cumulative incidences of all three studies’ outcomes were higher in T2DM-CKD than in diabetes patients without CKD (positivity 18.1% vs. 14.4%; hospitalization 9.7% vs. 4.2%; death 3.3% vs. 1.1%, all p<0.001). For COVID-19 hospitalization, protective factors were SGLT-2 inhibitors use (OR 0.430; 95%CI 0.257–0.719) and metformin use (OR 0.769; 95% CI 0.643–0.920), risk factors were insulin use (1.411; 95%CI 1.167–1.706) and sulfonylureas use (OR 1.226; 95% CI 1.027–1.464). For SARS-CoV-2 positivity protective factors were SGLT-2 inhibitors (0.607; 95% CI 0.448–0.823), repaglinide use (OR 0.765; 95% CI 0.593–0.986) and metformin use (OR 0.857; 95% CI 0.770–0.994). DPP-4 inhibitors showed a non-significant decrease in risk for COVID-19 death (OR 0.761; 95% CI 0.568–1.019).</p> Conclusion <p>T2DM-CKD are heavily burdened by COVID-19 disease. Our results suggest no association between antidiabetic drugs and COVID-19 death outcome while SGLT-2 and metformin show to be protective against COVID-19 hospitalization and infection, repaglinide against infection, and insulin and sulfonylureas show to be risk factors for COVID-19 hospitalization and infection. Further research in T2DM-CKD is needed.</p>Association of spironolactone use with risk of urinary tract cancer in the general population: A matched population-based cohort studyLiang-Cheng ChenHsuan-Ju YangBen-Hui YuMoon-Sing LeeHon-Yi LinWen-Yen ChiouDai-Wei LiuFeng-Chun HsuChia-Hui ChewShih-Kai Hung10.1371/journal.pone.03003912024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Liang-Cheng Chen, Hsuan-Ju Yang, Ben-Hui Yu, Moon-Sing Lee, Hon-Yi Lin, Wen-Yen Chiou, Dai-Wei Liu, Feng-Chun Hsu, Chia-Hui Chew, Shih-Kai Hung</p>
Purpose <p>The correlation between spironolactone usage and cancer risk has sparked interest. The objective of this study is to examine the association between spironolactone use and the incidence of urinary tract cancer in the general population.</p> Methods <p>We conducted a matched population-based cohort study. The study population was obtained from the Taiwan National Health Insurance Research Database (TNHIRD) during the period from 2000 to 2016. The multivariate Cox proportional hazard model was performed to examine the impact of spironolactone use on the risk of urinary tract cancer. A total of 8,608 individuals exposed to spironolactone were exact matched by 1:1 ratio with unexposed controls on factors including age, gender, comorbidities, CCI scores and socioeconomic status. The incidences of urinary tract cancer, including prostate, renal and bladder cancer, were estimated in both spironolactone exposed and non-exposed cohorts.</p> Results <p>After adjusting for confounding variables, the multivariate Cox regression analysis showed no significant association between spironolactone exposure and urinary tract cancer incidence, including bladder (adjusted hazard ratio [aHR] = 1.19, 95% confidence interval [CI] = 0.72–1.96, p = 0.50), renal (aHR = 1.75, 95% CI = 0.99–3.07, p = 0.053), and prostate cancer (aHR = 0.67, 95% CI = 0.43–1.04, p = 0.07). When the population was stratified into low (cumulative dose < = 29,300 mg) and high (cumulative dose >29,300 mg) dose of spironolactone, only high dose of spironolactone use was significantly associated with a reduced risk of prostate cancer (aHR = 0.45, 95% CI = 0.23–0.89, p = 0.02), while being associated with an elevated risk of renal cancer (aHR = 2.09, 95% CI = 1.07–4.08, p = 0.03). However, no clear cumulative dose-response relationship was observed in theses associations.</p> Conclusions <p>High cumulative dose of spironolactone may be potentially associated with a decreased incidence of prostate cancer and an increased incidence of renal cancer, while no significant association was observed with bladder cancer incidence. However, given the lack of support from the dose-response pattern, the available evidence is inconclusive to establish a definitive association between spironolactone use and urinary tract cancer.</p>Risk factors for catheter-associated bloodstream infection in hemodialysis patients: A meta-analysisHuajie GuoLing ZhangHua HeLili Wang10.1371/journal.pone.02997152024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Huajie Guo, Ling Zhang, Hua He, Lili Wang</p>
Objective <p>This meta-analysis aimed to elucidate the risk factors contributing to catheter-associated bloodstream infection in hemodialysis patients.</p> Methods <p>Comprehensive literature searches were conducted in both English and Chinese databases, which encompassed PubMed, Cochrane Library, Embase, CNKI, Wanfang Data, VIP Database and China Biomedical Literature Database. The search timeframe extended from each database’s inception to March 8, 2023. Two independent researchers executed literature screening, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Statistical analysis of the data was performed using RevMan 5.3 software, facilitating the identification of significant risk factors associated with catheter-related bloodstream infections in hemodialysis patients. This meta-analysis is registered with PROSPERO under the registration number CRD42023406223.</p> Results <p>Forty-nine studies were incorporated into this meta-analysis, from which 22 risk factors were examined. Through the analysis, 17 risk factors exhibited statistical significance (<i>P</i> < 0.05): age (OR = 1.52, 95% CI [0.49, 4.68]), diabetes (OR = 2.52, 95% CI [1.95, 3.25]), kidney disease (OR = 3.45, 95% CI [1.71, 6.96]), history of catheter-associated infection (OR = 2.79, 95% CI [1.96, 3.98]), hypertension (OR = 1.43, 95% CI [1.08, 1.91]), dialysis duration (OR = 3.06, 95% CI [1.70, 5.50]), catheter placement site (OR = 1.91, 95%CI [1.35, 2.70]), catheter duration (OR = 2.06, 95% CI [1.17, 3.60]), number of catheterizations (OR = 4.22, 95% CI [3.32, 5.37]), catheter types (OR = 3.83, 95% CI [2.13, 6.87]), CD4<sup>+</sup> cells (OR = 0.33, 95% CI [0.18, 0.63]), albumin (ALB, OR = 2.12, 95% CI [1.15, 3.91]), C-reactive protein (CRP, OR = 1.73, 95% CI [1.47, 2.03]), hemoglobin (Hb, OR = 1.48, 95% CI [0.54, 4.07]), procalcitonin (PCT, OR = 1.05, 95% CI [1.03, 1.06]), inadequate hand hygiene (OR = 5.32, 95% CI [1.07, 26.37]), and APACHE II scores (OR = 2.41, 95% CI [1.33, 4.37]).</p> Conclusion <p>This meta-analysis suggests that age, diabetes, kidney disease, history of catheter-associated infection, hypertension, dialysis duration, catheter placement site, catheter duration, number of catheterizations, catheter type, CD4<sup>+</sup> cells, albumin, C-reactive protein, hemoglobin, procalcitonin, inadequate hand hygiene, and APACHE II scores significantly influence the incidence of catheter-associated bloodstream infection in hemodialysis patients.</p>Sex-related differences in pre-dialysis trajectories and dialysis initiation: A French nationwide retrospective studyMaxime RaffrayLouise BourasseauCécile VigneauCécile CouchoudClémence BéchadeFrançois GlowackiSahar Bayaton behalf of the REIN registry10.1371/journal.pone.02996012024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Maxime Raffray, Louise Bourasseau, Cécile Vigneau, Cécile Couchoud, Clémence Béchade, François Glowacki, Sahar Bayat, on behalf of the REIN registry </p>
Background <p>In the last two decades, sex and gender differences have been documented in chronic kidney disease (CKD) management, including access to renal replacement therapy and its outcomes. The objectives of this study were to 1) compare the pre-dialysis healthcare utilization in men and women, and 2) examine the sex-specific factors associated with emergency dialysis start.</p> Methods <p>Adult patients with CKD who started dialysis in France in 2015 were extracted from the Renal Epidemiology and Information Network registry. Patients were matched to the French National Health Data System database to extract healthcare utilization data for the 2 years before dialysis start. Frequencies and monthly rates of consultations and hospitalizations were compared between men and women. Logistic regression analyses were performed separately in the two groups.</p> Results <p>Among the 8856 patients included, 3161 (35.7%) were women. Median age (71 years) and estimated glomerular filtration rate (8.1 and 7.7 ml/min for men and women) were similar between groups at dialysis start. Monthly consultations rates with a general practitioner and nephrology-related care were similar between women and men. Some sex-specific differences were found: higher frequencies of consultations with a psychiatrist in women and more frequent hospitalizations for circulatory system diseases in men. Emergency dialysis start rate was 30% in both groups. Emergency dialysis start was associated with acute nephropathy, compared with slowly progressive nephropathy, in women but not in men (OR = 1.48, p<0.01 vs 1.15, p = 0.18).</p> Conclusions <p>This study found similar quantitative pre-dialysis healthcare utilization in men and women. To better understand sex/gender differences in CKD care trajectories, future research should focus on patients with CKD who are unknown to nephrology services, on patients receiving conservative care and on the sex/gender-specific mechanisms underlying care decision-making.</p>Work disability and employment status among advanced chronic kidney disease patientsShing Shen BayLydia KamaruzamanRozita MohdShamsul Azhar Shah10.1371/journal.pone.02973782024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Shing Shen Bay, Lydia Kamaruzaman, Rozita Mohd, Shamsul Azhar Shah</p>
Introduction <p>Chronic kidney disease (CKD) is a major public health issue with significant socioeconomic impacts. In Malaysia, the prevalence of CKD in 2018 was 15%. Complications of CKD such as anaemia, mineral bone disease, and infections led to frequent hospitalizations resulting in work disability and unemployment. To date, there is no data of employment status of CKD patients in Malaysia.</p> Methods <p>A cross-sectional study of patients with advanced CKD (stage 4 and 5 non-dialysis) treated in our centre. We interviewed those aged 18 to 60 years old who were selected based on random sampling of their employment status and associated factors. Work disabilities and quality of life were assessed using work productivity and activity impairment (WPAI-GH) questionnaire and kidney disease and quality of life (KDQOL-36) questionnaire. These questionnaires were assisted by the main investigators to aid participants in facilitating their response process.</p> Result <p>A total of 318 patients recruited, 53.5% were males, with a mean age of 49.0 ± 9.0 years old. The main cause of CKD was diabetes (67.0%) followed by hypertension (11.3%). Majority of them were obese (55.3%) with a mean body mass index of 28.81 ± 6.3 kg/m<sup>2</sup>. The mean household income was RM 4669.50 ± 3034.75 (USD1006.27 ± 653.99). The employment rate was 50% (n = 159). 86% of the unemployed patients were in B40 income category. Multiple Logistic Regression was performed on the significant factors affecting employment status showed one year increase in age increased 6.5% odds to be unemployed. Female and dyslipidaemia had 2.24- and 2.58-times higher odds respectively to be unemployed. Meanwhile, patients with tertiary level of education were 81% less odds to be unemployed. Patients with advanced CKD had a mean percentage of 24.35 ± 15.23 work impairment and 13.36 ± 32.34 mean percentages of face absenteeism due to the disease burden. Furthermore, patients who were unemployed had significant perceived symptoms and problem lists, effects, and burden of kidney disease (p<0.01) and showed poor mental and physical composites (p<0.01) as compared with those who were employed.</p> Conclusion <p>The employment rate of advanced CKD patients was low with half of patients lost their jobs due to the disease burden and had poor mental and physical composites of quality of life. This raises the concern for financial support for long term renal replacement therapy.</p>Why do people sell their kidneys? A thematic synthesis of qualitative evidenceBijaya ShresthaLuechai SringernyuangManash ShresthaBinita ShresthaAnuska AdhikariDev Ram SunuwarShiva Raj MishraBipin Adhikari10.1371/journal.pgph.00030152024-03-27T14:00:00Z2024-03-27T14:00:00Z<p>by Bijaya Shrestha, Luechai Sringernyuang, Manash Shrestha, Binita Shrestha, Anuska Adhikari, Dev Ram Sunuwar, Shiva Raj Mishra, Bipin Adhikari</p>
Globally, demands for the kidneys have surpassed supply both living and deceased donors. High demands relative to the availability have made the kidney one of the most saleable human organs. The main objective was to explore the drivers of kidney selling. Literature related to kidney selling and its drivers was explored in three databases including MEDLINE (PubMed), Scopus (Elsevier), and JSTOR covering the period from 1987 to 2022. A total of 15 articles were selected, which underwent thematic analysis. Investigators independently assessed the articles for relevance and study quality to synthesize the data. The thematic analysis involved a critical approach to understanding the reasons for kidney selling by examining power disparities and social inequities. Kidney selling and the underlying reasons for it showed similarities across various geographic regions. Several factors were identified which increased individuals’ vulnerability for kidney selling. At the micro level, poverty and illiteracy emerged as significant factors. Lack of financial safety nets obliged family to resort to kidney selling which helped to alleviate poverty, resolve debt, and other urgent financial issues. Nonetheless, the revenues from kidney selling were also used to purchase luxury items (diverting away from investing in livelihood expenses) such as buying motorbikes, mobile phones and televisions. Family, and gender responsibilities also played roles in kidney selling such as obligations related to paying dowry made parents particularly vulnerable. Surprisingly, a few victims of kidney selling later adopted kidney brokering role to support their livelihood. Kidney selling was further fostered by lack of stringent policy to regulate and monitor background checks for kidney transplantation. There were myriad factors that affected individual’s vulnerability to kidney selling which stemmed from micro (poverty, illiteracy), meso (weak legal system, lacking stringent institutional policy, regulatory framework) and macro (social inequalities, corruption, organ shortage, insufficient health infrastructure) levels.Impact of extracorporeal membrane oxygenation-related complications on in-hospital mortalityEunae ByunPil Je KangSung Ho JungSeo Young ParkSang Ah LeeTae-Won KwonYong-Pil Cho10.1371/journal.pone.03007132024-03-25T14:00:00Z2024-03-25T14:00:00Z<p>by Eunae Byun, Pil Je Kang, Sung Ho Jung, Seo Young Park, Sang Ah Lee, Tae-Won Kwon, Yong-Pil Cho</p>
Introduction <p>Although extracorporeal membrane oxygenation (ECMO) is a well-established treatment for supporting severe cardiopulmonary failure, the morbidity and mortality of patients requiring ECMO support remain high. Evaluating and correcting potential risk factors associated with any ECMO-related complications may improve care and decrease mortality. This study aimed to assess the predictors of ECMO-related vascular and cerebrovascular complications among adult patients and to test the hypothesis that ECMO-related complications are associated with higher in-hospital mortality rates.</p> Methods <p>This single-center, retrospective study included 856 ECMO runs administered via cannulation of the femoral vessels of 769 patients: venoarterial (VA) ECMO (<i>n</i> = 709, 82.8%) and venovenous (VV) ECMO (<i>n</i> = 147, 17.2%). The study outcomes included the occurrence of ECMO-related vascular and cerebrovascular complications and in-hospital death. The association of ECMO-related complications with the risk of in-hospital death was analyzed.</p> Results <p>The incidences of ECMO-related vascular and cerebrovascular complications were 20.2% and 13.6%, respectively. The overall in-hospital mortality rate was 48.7%: 52.8% among VA ECMO runs and 29.3% among VV ECMO runs. Multivariable analysis indicated that age (<i>P</i> < 0.01), cardiopulmonary cerebral resuscitation (<i>P</i> < 0.01), continuous renal replacement therapy (<i>P</i> < 0.01), and initial platelet count [<50×10<sup>3</sup>/μL (<i>P</i> = 0.02) and 50–100(×10<sup>3</sup>)/μL (<i>P</i> < 0.01)] were associated with an increased risk of in-hospital death. ECMO-related vascular and cerebrovascular complications were not independently associated with higher in-hospital mortality rates for VA or VV ECMO runs.</p> Conclusion <p>ECMO-related vascular and cerebrovascular complications were not associated with an increased risk of in-hospital death among adult patients.</p>Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical frameworkAlan J. M. BrnabicSarah E. CurtisJoseph A. JohnstonAlbert LoAnthony J. ZagarIlya LipkovichZbigniew KadziolaMegan H. MurrayTimothy Ryan10.1371/journal.pone.03007082024-03-22T14:00:00Z2024-03-22T14:00:00Z<p>by Alan J. M. Brnabic, Sarah E. Curtis, Joseph A. Johnston, Albert Lo, Anthony J. Zagar, Ilya Lipkovich, Zbigniew Kadziola, Megan H. Murray, Timothy Ryan</p>
Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies–which was statistically significant for the comparison with teriflunomide–this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.Comparison of EKFC, Pakistani CKD-EPI and 2021 Race-Free CKD-EPI creatinine equations in South Asian CKD population: A study from Pakistani CKD community cohortAqsa SafdarWaqas AkramMahtab Ahmad KhanDanish TahirMuhammad Hammad Butt10.1371/journal.pone.03004282024-03-21T14:00:00Z2024-03-21T14:00:00Z<p>by Aqsa Safdar, Waqas Akram, Mahtab Ahmad Khan, Danish Tahir, Muhammad Hammad Butt</p>
Introduction <p>South Asian individuals possess a high risk of chronic kidney disease. There is a need to study, evaluate, and compare the newly suggested glomerular filtration rate (eGFR) equations for accurate CKD diagnosis, staging, and drug dosing. This study aimed to (1) evaluate the European Kidney Function Consortium (EKFC), Pakistani CKD-EPI<sub>,</sub> and 2021 Race-Free CKD-EPI creatinine equation in the South Asian population with CKD and (2) to examine the expected implications on both CKD classification as well as End Stage Renal Disease (ESRD) prevalence across these equations in South Asian population.</p> Methods <p>We carried out a cross-sectional investigation on 385 participants, a CKD cohort ≥ 18 years, at Allama Iqbal Medical College, Jinnah Hospital, Lahore. Serum creatinine was measured by Jaffe’s method and rGFR was measured by inulin clearance.</p> Results <p>Pakistani CKD-EPI has a lower median difference at -1.33 ml/min/1.73<i>m</i><sup>2</sup> elevated precision (IQR) at 2.33 (-2.36, -0.03) and higher P30 value at 89.35% than 2021 CKD-EPI and EKFC equations. The mean difference (ml/min/1.73<i>m</i><sup>2</sup>), 95% agreement limits (ml/min/1.73<i>m</i><sup>2</sup>) of CKD-EPI <sub>PK</sub>: -1.18, -6.14, 2021 CKD-EPI: -5.98, -13.24 and EKFC: -5.62, -13.01 (P <0.001). These equations highly correlated to rGFR (P <0.001). An upward re-classification in GFR categories was shown by 2021 CKD-EPI and EKFC compared to the Pakistani CKD-EPI equation. However, there was an exception regarding the G5 category, where an elevated count of 217 (56.36%) was shown for CKD-EPI <sub>PK</sub>. The prevalence of ESRD was seen in entire age groups and prevailed among females more than in males overall equations.</p> Conclusions <p>Pakistani CKD-EPI exhibited outstanding performance, while 2021 CKD-EPI and EKFC demonstrated poor performances and could not show an adequate advantage for both CKD classification and prevalence of ESRD compared to Pakistani CKD-EPI. Therefore, Pakistani CKD-EPI appears optimal for this region and warrants future validation in other South Asian countries. In contrast, suitable measures must be implemented in Pakistani laboratories.</p>Association of daytime napping with incidence of chronic kidney disease and end-stage kidney disease: A prospective observational studyQinjun LiYing ShanJingchi LiaoLing WangYanling WeiLiang DaiSen KanJianqing ShiXiaoyan HuangGuoyuan Lu10.1371/journal.pone.02983752024-03-21T14:00:00Z2024-03-21T14:00:00Z<p>by Qinjun Li, Ying Shan, Jingchi Liao, Ling Wang, Yanling Wei, Liang Dai, Sen Kan, Jianqing Shi, Xiaoyan Huang, Guoyuan Lu</p>
Background and aims <p>Few studies have examined the relationship between daytime napping and risk of kidney diseases. We aimed to investigate the association of daytime napping with the incidence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We also examined whether sleep duration modified the association of nap with CKD or ESKD.</p> Methods <p>We recruited 460,571 European middle- to older-aged adults without prior CKD or ESKD between March 13, 2006, and October 1, 2010, in the UK Biobank. Sleep behavior data were obtained through questionnaires administered during recruitment. The analysis of the relationship between napping and the occurrence of CKD and ESKD utilized Cox proportional hazards regression models. The modification role of sleep duration on the effect of nap on CKD and ESKD was also examined.</p> Results <p>After a mean follow-up of 11.1 (standard deviation 2.2) years, we observed 28,330 incident CKD cases and 927 ESKD cases. The daytime napping was associated with incident CKD (P for trend = .004). After fully adjusted, when compared with participants who did not take nap, those in sometimes and usually nap groups had higher risk of CKD. Nevertheless, the available evidence did not support a link between daytime napping and ESKD (P for trend = .06). Simultaneously, there was insufficient evidence suggesting that sleeping duration modified the association of daytime napping with incident CKD or ESKD.</p> Conclusion <p>Daytime napping was associated with an increased risk of CKD. However, the absence of conclusive evidence did not indicate a connection between daytime napping and ESKD.</p>Mice with renal-specific alterations of stem cell-associated signaling develop symptoms of chronic kidney disease but surprisingly no tumorsAdam MyszczyszynOliver PoppSeverine KunzAnje SporbertSimone JungLouis C. PenningAnnika FendlerPhilipp MertinsWalter Birchmeier10.1371/journal.pone.02829382024-03-21T14:00:00Z2024-03-21T14:00:00Z<p>by Adam Myszczyszyn, Oliver Popp, Severine Kunz, Anje Sporbert, Simone Jung, Louis C. Penning, Annika Fendler, Philipp Mertins, Walter Birchmeier</p>
Previously, we found that Wnt and Notch signaling govern stem cells of clear cell kidney cancer (ccRCC) in patients. To mimic stem cell responses in the normal kidney <i>in vitro</i> in a marker-unbiased fashion, we have established tubular organoids (tubuloids) from total single adult mouse kidney epithelial cells in Matrigel and serum-free conditions. Deep proteomic and phosphoproteomic analyses revealed that tubuloids resembled renewal of adult kidney tubular epithelia, since tubuloid cells displayed activity of Wnt and Notch signaling, long-term proliferation and expression of markers of proximal and distal nephron lineages. In our wish to model stem cell-derived human ccRCC, we have generated two types of genetic double kidney mutants in mice: Wnt-β-catenin-GOF together with Notch-GOF and Wnt-β-catenin-GOF together with a most common alteration in ccRCC, Vhl-LOF. An inducible Pax8-rtTA-LC1-Cre was used to drive recombination specifically in adult kidney epithelial cells. We confirmed mutagenesis of β-catenin, Notch and Vhl alleles on DNA, protein and mRNA target gene levels. Surprisingly, we observed symptoms of chronic kidney disease (CKD) in mutant mice, but no increased proliferation and tumorigenesis. Thus, the responses of kidney stem cells in the tubuloid and genetic systems produced different phenotypes, i.e. enhanced renewal versus CKD.Interpretable machine learning-based individual analysis of acute kidney injury in immune checkpoint inhibitor therapyMinoru SakuragiEiichiro UchinoNoriaki SatoTakeshi MatsubaraAkihiko UedaYohei MineharuRyosuke KojimaMotoko YanagitaYasushi Okuno10.1371/journal.pone.02986732024-03-19T14:00:00Z2024-03-19T14:00:00Z<p>by Minoru Sakuragi, Eiichiro Uchino, Noriaki Sato, Takeshi Matsubara, Akihiko Ueda, Yohei Mineharu, Ryosuke Kojima, Motoko Yanagita, Yasushi Okuno</p>
Background <p>Acute kidney injury (AKI) is a critical complication of immune checkpoint inhibitor therapy. Since the etiology of AKI in patients undergoing cancer therapy varies, clarifying underlying causes in individual cases is critical for optimal cancer treatment. Although it is essential to individually analyze immune checkpoint inhibitor-treated patients for underlying pathologies for each AKI episode, these analyses have not been realized. Herein, we aimed to individually clarify the underlying causes of AKI in immune checkpoint inhibitor-treated patients using a new clustering approach with Shapley Additive exPlanations (SHAP).</p> Methods <p>We developed a gradient-boosting decision tree-based machine learning model continuously predicting AKI within 7 days, using the medical records of 616 immune checkpoint inhibitor-treated patients. The temporal changes in individual predictive reasoning in AKI prediction models represented the key features contributing to each AKI prediction and clustered AKI patients based on the features with high predictive contribution quantified in time series by SHAP. We searched for common clinical backgrounds of AKI patients in each cluster, compared with annotation by three nephrologists.</p> Results <p>One hundred and twelve patients (18.2%) had at least one AKI episode. They were clustered per the key feature, and their SHAP value patterns, and the nephrologists assessed the clusters’ clinical relevance. Receiver operating characteristic analysis revealed that the area under the curve was 0.880. Patients with AKI were categorized into four clusters with significant prognostic differences (p = 0.010). The leading causes of AKI for each cluster, such as hypovolemia, drug-related, and cancer cachexia, were all clinically interpretable, which conventional approaches cannot obtain.</p> Conclusion <p>Our results suggest that the clustering method of individual predictive reasoning in machine learning models can be applied to infer clinically critical factors for developing each episode of AKI among patients with multiple AKI risk factors, such as immune checkpoint inhibitor-treated patients.</p>