Pub Date : 2024-08-09DOI: 10.1053/j.ajkd.2024.06.017
Keith P McCullough, Hal Morgenstern, Hugh C Rayner, Friedrich K Port, Michel Y Jadoul, Tadao Akizawa, Ronald L Pisoni, William H Herman, Bruce M Robinson
<p><strong>Rationale & objective: </strong>Case-mix adjusted hemodialysis mortality has decreased since 1998. Many factors that influence mortality may have contributed to this trend, and these associations may differ by continental region. We studied changes in hemodialysis facility practices over time and their potential role in mediating changes in patient survival.</p><p><strong>Study design: </strong>Observational prospective cohort study.</p><p><strong>Setting & participants: </strong>Adult hemodialysis patients treated in 500 hemodialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) between 1999 and 2015 in the United States, Japan, and 4 European countries: Germany, Italy, Spain, and the United Kingdom.</p><p><strong>Predictors: </strong>Four practice measures at each facility: the percentages of patients with Kt/V≥1.2, interdialytic weight gain [IDWG]<5.7%, phosphorus<6mg/dL, and using arteriovenous fistulas (AVFs).</p><p><strong>Outcome: </strong>Patient survival.</p><p><strong>Analytical approach: </strong>Mediation analyses, adjusted for case mix, were conducted using 3-year study phase as the exposure and facility practice measures as potential mediators.</p><p><strong>Results: </strong>In Europe, we observed a 13% improvement in overall case-mix adjusted survival per decade. Trends in facility practice measures, especially Kt/V and phosphorus, explained 10% improvement in case-mix survival per decade, representing 77% (10% explained of 13% improvement) of the observed improvement. In Japan, 73% of the observed 12%/decade improvement in case-mix adjusted survival could be attributed to facility practices, especially Kt/V and IDWG. In the United States, 56% of the observed 47%/decade improvement in case-mix adjusted survival could be attributed to facility practices, especially AVF use and phosphorus control.</p><p><strong>Limitations: </strong>Unmeasured changes in the characteristics of the patient population over this period may confound the observed associations.</p><p><strong>Conclusions: </strong>The improvements in adjusted hemodialysis patient survival in Europe, Japan, and the United States from 1999 to 2015 can be largely explained by improvements in specific facility practices. Future changes in patient survival may be responsive to further evolution in the implementation of common clinical practices.</p><p><strong>Plain-language summary: </strong>Case-mix adjusted survival of patients treated with hemodialysis has improved over the last 2 decades in the United States, Japan, and Europe. Some of this improvement can be explained by region-specific changes in 4 dialysis practices, namely increases in the proportions of patients achieving (1) Kt/V≥1.2, (2) serum phosphorus levels<6mg/dL, (3) interdialytic weight gain<5.7% of body weight, and/or (4) use of arteriovenous fistulas as vascular access, with the magnitude varying according to region-specific trends in these practices. These
{"title":"Explaining International Trends in Mortality on Hemodialysis Through Changes in Hemodialysis Practices in the Dialysis Outcomes and Practice Patterns Study (DOPPS).","authors":"Keith P McCullough, Hal Morgenstern, Hugh C Rayner, Friedrich K Port, Michel Y Jadoul, Tadao Akizawa, Ronald L Pisoni, William H Herman, Bruce M Robinson","doi":"10.1053/j.ajkd.2024.06.017","DOIUrl":"10.1053/j.ajkd.2024.06.017","url":null,"abstract":"<p><strong>Rationale & objective: </strong>Case-mix adjusted hemodialysis mortality has decreased since 1998. Many factors that influence mortality may have contributed to this trend, and these associations may differ by continental region. We studied changes in hemodialysis facility practices over time and their potential role in mediating changes in patient survival.</p><p><strong>Study design: </strong>Observational prospective cohort study.</p><p><strong>Setting & participants: </strong>Adult hemodialysis patients treated in 500 hemodialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) between 1999 and 2015 in the United States, Japan, and 4 European countries: Germany, Italy, Spain, and the United Kingdom.</p><p><strong>Predictors: </strong>Four practice measures at each facility: the percentages of patients with Kt/V≥1.2, interdialytic weight gain [IDWG]<5.7%, phosphorus<6mg/dL, and using arteriovenous fistulas (AVFs).</p><p><strong>Outcome: </strong>Patient survival.</p><p><strong>Analytical approach: </strong>Mediation analyses, adjusted for case mix, were conducted using 3-year study phase as the exposure and facility practice measures as potential mediators.</p><p><strong>Results: </strong>In Europe, we observed a 13% improvement in overall case-mix adjusted survival per decade. Trends in facility practice measures, especially Kt/V and phosphorus, explained 10% improvement in case-mix survival per decade, representing 77% (10% explained of 13% improvement) of the observed improvement. In Japan, 73% of the observed 12%/decade improvement in case-mix adjusted survival could be attributed to facility practices, especially Kt/V and IDWG. In the United States, 56% of the observed 47%/decade improvement in case-mix adjusted survival could be attributed to facility practices, especially AVF use and phosphorus control.</p><p><strong>Limitations: </strong>Unmeasured changes in the characteristics of the patient population over this period may confound the observed associations.</p><p><strong>Conclusions: </strong>The improvements in adjusted hemodialysis patient survival in Europe, Japan, and the United States from 1999 to 2015 can be largely explained by improvements in specific facility practices. Future changes in patient survival may be responsive to further evolution in the implementation of common clinical practices.</p><p><strong>Plain-language summary: </strong>Case-mix adjusted survival of patients treated with hemodialysis has improved over the last 2 decades in the United States, Japan, and Europe. Some of this improvement can be explained by region-specific changes in 4 dialysis practices, namely increases in the proportions of patients achieving (1) Kt/V≥1.2, (2) serum phosphorus levels<6mg/dL, (3) interdialytic weight gain<5.7% of body weight, and/or (4) use of arteriovenous fistulas as vascular access, with the magnitude varying according to region-specific trends in these practices. These ","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1053/j.ajkd.2024.06.011
Elodie Speyer, Charlotte Tu, Jarcy Zee, Ricardo Sesso, Antonio A Lopes, Emilie Moutard, Abdou Y Omorou, Bénédicte Stengel, Fredric O Finkelstein, Roberto Pecoits-Filho, Natalia Alencar de Pinho, Ronald L Pisoni
<p><strong>Rationale & objective: </strong>Recent evidence suggests people with nondialysis chronic kidney disease (ND-CKD) experience a substantial burden of symptoms, but informative large-scale studies have been scarce. We assessed the prevalence of symptoms and the association of overall symptom burden with quality of life in patients with moderate to severe CKD.</p><p><strong>Study design: </strong>Cross-sectional study.</p><p><strong>Setting & participants: </strong>4,430 patients with ND-CKD stages 3-5 enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, and the United States between 2013 and 2021.</p><p><strong>Exposure: </strong>13 individual patient-reported symptoms from the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire and an overall symptom burden score (low, intermediate, and high).</p><p><strong>Outcome: </strong>Physical and mental component summary scores (PCS and MCS) of the KDQOL-SF.</p><p><strong>Analytical approach: </strong>Adjusted prevalence ratios and generalized estimating equations.</p><p><strong>Results: </strong>Patients (mean age, 68 years; 40% women; mean baseline estimated glomerular filtration rate [eGFR], 30mL/min/1.73m<sup>2</sup>) were very much to extremely bothered by numerous symptoms ("soreness in muscles," 23%; "washed out or drained," 21%; "cramps, shortness of breath, dry skin, diminished sex life, or numbness in hands or feet," 14%-17%). The adjusted prevalences of "cramps," "washed out or drained," "lack of appetite," "nausea/upset stomach," and "sex life" were greater with more severe CKD and in women (except for "sex life"). A high overall symptom burden was more common in women, in France, and in patients with severe albuminuria and various comorbidities, but not with lower eGFR. The PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high versus low overall symptom burden.</p><p><strong>Limitations: </strong>Generalizability limited to patients under nephrology care, residual confounding, and inaccurate Brazilian translation of some symptoms.</p><p><strong>Conclusions: </strong>The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD.</p><p><strong>Plain-language summary: </strong>Little is known about symptoms in patients with non-dialysis-dependent chronic kidney disease (ND-CKD). In the Chronic Kidney Disease Outcomes and Practice Patterns Study, which enrolled 4,430 patients with CKD stages 3-5 in Brazil, France, and the United States, patients most often reported soreness in muscles, feeling washed out or drained, cramps, shortness of breath, dry skin, altered sex life, and numbness in hands or feet. Cramps, feeling washed out or drained, lack of appetite, and nausea were more often reported at lower levels of kidney function. Th
{"title":"Symptom Burden and Its Impact on Quality of Life in Patients With Moderate to Severe CKD: The International Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).","authors":"Elodie Speyer, Charlotte Tu, Jarcy Zee, Ricardo Sesso, Antonio A Lopes, Emilie Moutard, Abdou Y Omorou, Bénédicte Stengel, Fredric O Finkelstein, Roberto Pecoits-Filho, Natalia Alencar de Pinho, Ronald L Pisoni","doi":"10.1053/j.ajkd.2024.06.011","DOIUrl":"10.1053/j.ajkd.2024.06.011","url":null,"abstract":"<p><strong>Rationale & objective: </strong>Recent evidence suggests people with nondialysis chronic kidney disease (ND-CKD) experience a substantial burden of symptoms, but informative large-scale studies have been scarce. We assessed the prevalence of symptoms and the association of overall symptom burden with quality of life in patients with moderate to severe CKD.</p><p><strong>Study design: </strong>Cross-sectional study.</p><p><strong>Setting & participants: </strong>4,430 patients with ND-CKD stages 3-5 enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, and the United States between 2013 and 2021.</p><p><strong>Exposure: </strong>13 individual patient-reported symptoms from the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire and an overall symptom burden score (low, intermediate, and high).</p><p><strong>Outcome: </strong>Physical and mental component summary scores (PCS and MCS) of the KDQOL-SF.</p><p><strong>Analytical approach: </strong>Adjusted prevalence ratios and generalized estimating equations.</p><p><strong>Results: </strong>Patients (mean age, 68 years; 40% women; mean baseline estimated glomerular filtration rate [eGFR], 30mL/min/1.73m<sup>2</sup>) were very much to extremely bothered by numerous symptoms (\"soreness in muscles,\" 23%; \"washed out or drained,\" 21%; \"cramps, shortness of breath, dry skin, diminished sex life, or numbness in hands or feet,\" 14%-17%). The adjusted prevalences of \"cramps,\" \"washed out or drained,\" \"lack of appetite,\" \"nausea/upset stomach,\" and \"sex life\" were greater with more severe CKD and in women (except for \"sex life\"). A high overall symptom burden was more common in women, in France, and in patients with severe albuminuria and various comorbidities, but not with lower eGFR. The PCS and MCS scores were 13.4 and 7.7 points lower, respectively, for high versus low overall symptom burden.</p><p><strong>Limitations: </strong>Generalizability limited to patients under nephrology care, residual confounding, and inaccurate Brazilian translation of some symptoms.</p><p><strong>Conclusions: </strong>The high symptom burden observed in this large cohort of ND-CKD patients across 3 diverse countries and its strong association with poorer health-related quality of life should inform clinical management of and clinical research in CKD.</p><p><strong>Plain-language summary: </strong>Little is known about symptoms in patients with non-dialysis-dependent chronic kidney disease (ND-CKD). In the Chronic Kidney Disease Outcomes and Practice Patterns Study, which enrolled 4,430 patients with CKD stages 3-5 in Brazil, France, and the United States, patients most often reported soreness in muscles, feeling washed out or drained, cramps, shortness of breath, dry skin, altered sex life, and numbness in hands or feet. Cramps, feeling washed out or drained, lack of appetite, and nausea were more often reported at lower levels of kidney function. Th","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1053/j.ajkd.2024.06.012
Gabriel Cojuc-Konigsberg, Alberto Guijosa, Alberto Moscona-Nissan, Alberto Nordmann-Gomes, Vianca Anabel Canaviri-Flores, Alan Braverman-Poyastro, Regina de la Fuente-Ramírez, Denisse Tinajero-Sánchez, Alejandra de Las Fuentes Cepeda, Andrés Noyola-Pérez, Rafael Lozano, Ricardo Correa-Rotter, Juan C Ramírez-Sandoval
<p><strong>Rationale & objective: </strong>Almost 80% of individuals with chronic kidney disease (CKD) reside in low- and middle-income countries (LMICs) and are potentially underrepresented in randomized controlled clinical trials (RCTs). We assessed the global distribution of RCTs comparing pharmacological treatments for CKD over the past 2 decades, as well as the magnitude and evolution of participation by LMICs.</p><p><strong>Study design: </strong>Systematic review.</p><p><strong>Setting & study populations: </strong>RCTs evaluating pharmacological interventions in adults with CKD.</p><p><strong>Selection criteria for studies: </strong>RCTs published between 2003-2023 and indexed in MEDLINE.</p><p><strong>Data extraction: </strong>Each trial was reviewed and extracted independently by 2 investigators with disagreements settled by consensus or a third reviewer.</p><p><strong>Analytical approach: </strong>RCT participation of World Bank-defined income groups and geographic regions were described, and the representation indices (RI) according to RCT participants and estimated CKD prevalences were calculated. RCTs were also categorized as global, regional, or national in scope.</p><p><strong>Results: </strong>Among 7,760 identified studies, we included 1,366 RCTs conducted in 84 countries with 301,158 participants. National, regional, and global RCTs represented 85.4%, 3.5%, and 11.1% of studies, respectively. LMICs were included in 34.7% of RCTs. No RCTs included participants from low-income countries, and lower-middle-income countries participated in 13.2%. Of participants from RCTs with available information, 25.4% (n=64,843 of 255,237) were from LMICs. According to the RI, 6 LMICs were overrepresented (>1.25), 7 were adequately represented (0.75-1.25), and 26 were underrepresented (<0.75). Most global CKD RCTs (80.2%) included LMICs; however, LMIC participants constituted only 32.9% of the global trial population. We observed a positive trend in LMIC inclusion over time, rising from 22.9% (n=71of 310) in 2003-2007 to 45.5% (n=140of 308) in 2018-2023.</p><p><strong>Limitations: </strong>The use of an income-group dichotomy, exclusion of nonrandomized studies of intervention, and studies identified in 1 database.</p><p><strong>Conclusions: </strong>Despite an increase in participation over the past 2 decades, individuals with CKD from LMICs remain significantly underrepresented in RCTs. These findings suggest that increased efforts are warranted to increase LMIC representation in pharmacological CKD RCTs.</p><p><strong>Plain-language summary: </strong>Chronic kidney disease (CKD) substantially affects people from low- and middle-income countries (LMICs). However, the participation of these countries in randomized controlled trials (RCTs) remains uncertain. To assess the global distribution and representation of these countries in kidney disease research, we reviewed 1,366 CKD drug RCTs published from 2003-2023, conducted in 84 countries involv
{"title":"Representation of Low- and Middle-Income Countries in CKD Drug Trials: A Systematic Review.","authors":"Gabriel Cojuc-Konigsberg, Alberto Guijosa, Alberto Moscona-Nissan, Alberto Nordmann-Gomes, Vianca Anabel Canaviri-Flores, Alan Braverman-Poyastro, Regina de la Fuente-Ramírez, Denisse Tinajero-Sánchez, Alejandra de Las Fuentes Cepeda, Andrés Noyola-Pérez, Rafael Lozano, Ricardo Correa-Rotter, Juan C Ramírez-Sandoval","doi":"10.1053/j.ajkd.2024.06.012","DOIUrl":"10.1053/j.ajkd.2024.06.012","url":null,"abstract":"<p><strong>Rationale & objective: </strong>Almost 80% of individuals with chronic kidney disease (CKD) reside in low- and middle-income countries (LMICs) and are potentially underrepresented in randomized controlled clinical trials (RCTs). We assessed the global distribution of RCTs comparing pharmacological treatments for CKD over the past 2 decades, as well as the magnitude and evolution of participation by LMICs.</p><p><strong>Study design: </strong>Systematic review.</p><p><strong>Setting & study populations: </strong>RCTs evaluating pharmacological interventions in adults with CKD.</p><p><strong>Selection criteria for studies: </strong>RCTs published between 2003-2023 and indexed in MEDLINE.</p><p><strong>Data extraction: </strong>Each trial was reviewed and extracted independently by 2 investigators with disagreements settled by consensus or a third reviewer.</p><p><strong>Analytical approach: </strong>RCT participation of World Bank-defined income groups and geographic regions were described, and the representation indices (RI) according to RCT participants and estimated CKD prevalences were calculated. RCTs were also categorized as global, regional, or national in scope.</p><p><strong>Results: </strong>Among 7,760 identified studies, we included 1,366 RCTs conducted in 84 countries with 301,158 participants. National, regional, and global RCTs represented 85.4%, 3.5%, and 11.1% of studies, respectively. LMICs were included in 34.7% of RCTs. No RCTs included participants from low-income countries, and lower-middle-income countries participated in 13.2%. Of participants from RCTs with available information, 25.4% (n=64,843 of 255,237) were from LMICs. According to the RI, 6 LMICs were overrepresented (>1.25), 7 were adequately represented (0.75-1.25), and 26 were underrepresented (<0.75). Most global CKD RCTs (80.2%) included LMICs; however, LMIC participants constituted only 32.9% of the global trial population. We observed a positive trend in LMIC inclusion over time, rising from 22.9% (n=71of 310) in 2003-2007 to 45.5% (n=140of 308) in 2018-2023.</p><p><strong>Limitations: </strong>The use of an income-group dichotomy, exclusion of nonrandomized studies of intervention, and studies identified in 1 database.</p><p><strong>Conclusions: </strong>Despite an increase in participation over the past 2 decades, individuals with CKD from LMICs remain significantly underrepresented in RCTs. These findings suggest that increased efforts are warranted to increase LMIC representation in pharmacological CKD RCTs.</p><p><strong>Plain-language summary: </strong>Chronic kidney disease (CKD) substantially affects people from low- and middle-income countries (LMICs). However, the participation of these countries in randomized controlled trials (RCTs) remains uncertain. To assess the global distribution and representation of these countries in kidney disease research, we reviewed 1,366 CKD drug RCTs published from 2003-2023, conducted in 84 countries involv","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-02DOI: 10.1053/j.ajkd.2024.06.010
{"title":"Continuous Kidney Replacement Therapy in Pediatric Intensive Care Unit: Little People, Big Gaps","authors":"","doi":"10.1053/j.ajkd.2024.06.010","DOIUrl":"10.1053/j.ajkd.2024.06.010","url":null,"abstract":"","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0272638624008667/pdfft?md5=1d95a5d332c21b81869dda366d94e0cc&pid=1-s2.0-S0272638624008667-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1053/j.ajkd.2024.05.017
Jonathon Mitchell, Michael R Ehmann, Scott Levin, Xihan Zhao, Steven Menez, Chirag R Parikh, Eili Y Klein, Jeremiah S Hinson
{"title":"Patterns in Emergency Clinician Management of Acute Kidney Injury.","authors":"Jonathon Mitchell, Michael R Ehmann, Scott Levin, Xihan Zhao, Steven Menez, Chirag R Parikh, Eili Y Klein, Jeremiah S Hinson","doi":"10.1053/j.ajkd.2024.05.017","DOIUrl":"10.1053/j.ajkd.2024.05.017","url":null,"abstract":"","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1053/j.ajkd.2024.05.018
Francisco Pereira Gonçalves, Isabel Tavares, Roberto Silva, Ana Teresa Nunes, Luciano Pereira, Andreia Campos, Joel Pinto, Ana Lopes, Marta Simões, Manuela Grazina, Agnes B Fogo, João Paulo Oliveira
Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency.
{"title":"Homozygosity for a Rare FASTKD2 Variant Resulting in an Adult Onset Autosomal Recessive Mitochondrial Podocytopathy.","authors":"Francisco Pereira Gonçalves, Isabel Tavares, Roberto Silva, Ana Teresa Nunes, Luciano Pereira, Andreia Campos, Joel Pinto, Ana Lopes, Marta Simões, Manuela Grazina, Agnes B Fogo, João Paulo Oliveira","doi":"10.1053/j.ajkd.2024.05.018","DOIUrl":"10.1053/j.ajkd.2024.05.018","url":null,"abstract":"<p><p>Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency.</p>","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1053/j.ajkd.2024.05.016
Ellen Dobrijevic, Anita van Zwieten, Andrew J Grant, Clement T Loy, Jonathan C Craig, Armando Teixeira-Pinto, Germaine Wong
<p><strong>Rationale & objective: </strong>Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear.</p><p><strong>Study design: </strong>Two-sample Mendelian randomization (MR).</p><p><strong>Setting & participants: </strong>Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329).</p><p><strong>Exposure: </strong>eGFR and UACR.</p><p><strong>Outcome: </strong>Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence.</p><p><strong>Analytical approach: </strong>Univariable and multivariable MR conducted for all outcomes.</p><p><strong>Results: </strong>The mean eGFR and median UACR were 91.4mL/min/1.73m<sup>2</sup> and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m<sup>2</sup> and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR.</p><p><strong>Limitations: </strong>To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification.</p><p><strong>Conclusions: </strong>Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death.</p><p><strong>Plain-language summary: </strong>Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian rand
{"title":"Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study.","authors":"Ellen Dobrijevic, Anita van Zwieten, Andrew J Grant, Clement T Loy, Jonathan C Craig, Armando Teixeira-Pinto, Germaine Wong","doi":"10.1053/j.ajkd.2024.05.016","DOIUrl":"10.1053/j.ajkd.2024.05.016","url":null,"abstract":"<p><strong>Rationale & objective: </strong>Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear.</p><p><strong>Study design: </strong>Two-sample Mendelian randomization (MR).</p><p><strong>Setting & participants: </strong>Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329).</p><p><strong>Exposure: </strong>eGFR and UACR.</p><p><strong>Outcome: </strong>Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence.</p><p><strong>Analytical approach: </strong>Univariable and multivariable MR conducted for all outcomes.</p><p><strong>Results: </strong>The mean eGFR and median UACR were 91.4mL/min/1.73m<sup>2</sup> and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m<sup>2</sup> and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR.</p><p><strong>Limitations: </strong>To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification.</p><p><strong>Conclusions: </strong>Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death.</p><p><strong>Plain-language summary: </strong>Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian rand","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1053/j.ajkd.2024.05.015
Hye-Sun Park, Sang Ho Park, Yeseul Seong, Hyo Jeong Kim, Hoon Young Choi, Hyeong Cheon Park, Jong Hyun Jhee
<p><strong>Rationale & objective: </strong>The association of long-term cumulative blood pressure (BP) loads with the risk of incident chronic kidney disease (CKD) remains a matter of debate. This study investigated this association among healthy Korean adults with normal kidney function.</p><p><strong>Study design: </strong>Prospective cohort study.</p><p><strong>Setting & participants: </strong>We analyzed 5,221 participants without CKD in the Korean Genome and Epidemiology Study. Cumulative systolic and diastolic BP (SBP and DBP) loads were calculated as the ratios of the areas under the curve (AUC) for SBP≥120mm Hg or≥80mm Hg for DBP divided by the AUC for all SBP or DBP measurements during the exposure period. These AUCs were categorized into 4 groups: group 0 (reference), cumulative BP load of 0 and groups 1-3, tertiles of cumulative BP loads.</p><p><strong>Outcome: </strong>Primary end point was incident CKD defined as a composite of an estimated glomerular filtration rate (eGFR) below 60mL/min/1.73m<sup>2</sup> or proteinuria greater than 1+on dipstick examination for at least 2 consecutive measurements≥90 days apart.</p><p><strong>Analytical approach: </strong>Multivariable Cox proportional hazards regression to estimate the independent association of cumulative BP loads with incident CKD.</p><p><strong>Results: </strong>Higher cumulative SBP and DBP loads were associated with an increased risk of incident CKD (HR, 1.23 [95% CI, 1.12-1.35] for SBP; and HR, 1.14 [95% CI, 1.04-1.26] for DBP loads for each 1.0-unit greater load). Compared with SBP group 0, groups 2 and 3 were associated with 1.94- and 1.89-fold greater risk of incident CKD. Compared with DBP group 0, groups 2 and 3 were associated with 1.42- and 1.54-fold greater risks. These associations of high cumulative BP loads with an increased risk of incident CKD remained consistent even in the subgroups not taking antihypertensive agents or without prior hypertension diagnosis.</p><p><strong>Limitations: </strong>The assessment of CKD outcomes relied on eGFR and spot urine tests.</p><p><strong>Conclusions: </strong>These findings highlight the association between high cumulative SBP and DBP loads and the occurrence of CKD, even in individuals with normal BP levels.</p><p><strong>Plain-language summary: </strong>Although hypertension is a major risk factor for chronic kidney disease (CKD), most studies have focused on single-point blood pressure (BP) measurements. To explore the association between long-term cumulative BP load and the development of CKD, 5,221 Korean adults with normal kidney function were included in this study. Cumulative systolic BP and diastolic BP load both exhibited a significant association with an increased risk of incident CKD. Notably, the association of cumulative BP loads with elevated risk of incident CKD was evident also in individuals who were not taking antihypertensive agents or who had no previous history of hypertension. These findings underscore
{"title":"Cumulative Blood Pressure Load and Incident CKD.","authors":"Hye-Sun Park, Sang Ho Park, Yeseul Seong, Hyo Jeong Kim, Hoon Young Choi, Hyeong Cheon Park, Jong Hyun Jhee","doi":"10.1053/j.ajkd.2024.05.015","DOIUrl":"10.1053/j.ajkd.2024.05.015","url":null,"abstract":"<p><strong>Rationale & objective: </strong>The association of long-term cumulative blood pressure (BP) loads with the risk of incident chronic kidney disease (CKD) remains a matter of debate. This study investigated this association among healthy Korean adults with normal kidney function.</p><p><strong>Study design: </strong>Prospective cohort study.</p><p><strong>Setting & participants: </strong>We analyzed 5,221 participants without CKD in the Korean Genome and Epidemiology Study. Cumulative systolic and diastolic BP (SBP and DBP) loads were calculated as the ratios of the areas under the curve (AUC) for SBP≥120mm Hg or≥80mm Hg for DBP divided by the AUC for all SBP or DBP measurements during the exposure period. These AUCs were categorized into 4 groups: group 0 (reference), cumulative BP load of 0 and groups 1-3, tertiles of cumulative BP loads.</p><p><strong>Outcome: </strong>Primary end point was incident CKD defined as a composite of an estimated glomerular filtration rate (eGFR) below 60mL/min/1.73m<sup>2</sup> or proteinuria greater than 1+on dipstick examination for at least 2 consecutive measurements≥90 days apart.</p><p><strong>Analytical approach: </strong>Multivariable Cox proportional hazards regression to estimate the independent association of cumulative BP loads with incident CKD.</p><p><strong>Results: </strong>Higher cumulative SBP and DBP loads were associated with an increased risk of incident CKD (HR, 1.23 [95% CI, 1.12-1.35] for SBP; and HR, 1.14 [95% CI, 1.04-1.26] for DBP loads for each 1.0-unit greater load). Compared with SBP group 0, groups 2 and 3 were associated with 1.94- and 1.89-fold greater risk of incident CKD. Compared with DBP group 0, groups 2 and 3 were associated with 1.42- and 1.54-fold greater risks. These associations of high cumulative BP loads with an increased risk of incident CKD remained consistent even in the subgroups not taking antihypertensive agents or without prior hypertension diagnosis.</p><p><strong>Limitations: </strong>The assessment of CKD outcomes relied on eGFR and spot urine tests.</p><p><strong>Conclusions: </strong>These findings highlight the association between high cumulative SBP and DBP loads and the occurrence of CKD, even in individuals with normal BP levels.</p><p><strong>Plain-language summary: </strong>Although hypertension is a major risk factor for chronic kidney disease (CKD), most studies have focused on single-point blood pressure (BP) measurements. To explore the association between long-term cumulative BP load and the development of CKD, 5,221 Korean adults with normal kidney function were included in this study. Cumulative systolic BP and diastolic BP load both exhibited a significant association with an increased risk of incident CKD. Notably, the association of cumulative BP loads with elevated risk of incident CKD was evident also in individuals who were not taking antihypertensive agents or who had no previous history of hypertension. These findings underscore ","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1053/j.ajkd.2024.05.013
Anne-Laure Faucon, Catherine M Clase, Helena Rydell, Milica Uhde, Peter Barany, Marie Evans, Juan-Jesús Carrero
<p><strong>Rationale & objective: </strong>Pruritus is a common but not well-characterized complaint of patients receiving maintenance dialysis. This study sought to quantify the burden of pruritus and its associated adverse health outcomes in this population.</p><p><strong>Study design: </strong>Observational study.</p><p><strong>Setting & participants: </strong>All patients receiving maintenance dialysis in Stockholm, Sweden, during 2005-2021.</p><p><strong>Exposure: </strong>Clinically recognized pruritus defined using International Classification of Diseases, Tenth Revision codes or a prescription for antipruritus treatments (including UV therapy).</p><p><strong>Outcomes: </strong>All-cause mortality, severe infection-related hospitalizations (composite of endocarditis, peritoneal dialysis-related peritonitis, hemodialysis/peritoneal dialysis-related catheter infection, sepsis due to Staphylococcus spp., or skin infection) and incident diagnoses of anxiety/depression and sleep disorders.</p><p><strong>Analytical approach: </strong>Multivariable logistic regression and cause-specific hazards models to analyze factors associated with prevalent and new-onset pruritus, respectively. Multivariable cause-specific hazards models with time-varying exposure were used to explore the association of prevalent and new-onset pruritus with adverse health outcomes.</p><p><strong>Results: </strong>Among 3,281 dialysis recipients (median age, 64 years; 66% men; 69% receiving hemodialysis, 77% with incident dialysis), 456 (14%) had pruritus at enrollment. During a median follow-up of 3.3 (IQR, 1.3-9.2) years, 539 (19%) additional patients experienced pruritus. Older age, female sex, a lower serum albumin level, and higher C-reactive protein, serum calcium, and phosphorus levels were independently associated with pruritus. Compared with patients without pruritus, patients with pruritus were at a higher risk of sleep disorders (adjusted HR, 1.96; 95% CI, 1.60-2.39), developing anxiety/depression (adjusted HR, 1.56; 95% CI, 1.23-1.98), and being hospitalized for severe infections (adjusted HR, 1.36; 95% CI, 1.18-1.57), the latter attributed to higher risk of sepsis and peritoneal dialysis-related peritonitis. There was no detectable association between the development of pruritus and all-cause mortality.</p><p><strong>Limitations: </strong>Potential misclassification bias if pruritus is not clinically recognized, lack of information on pruritus intensity/severity, use of diagnostic codes for exposure and outcome diagnoses.</p><p><strong>Conclusions: </strong>At least one third of patients experience pruritus during their first years undergoing dialysis, and pruritus was consistently associated with adverse health outcomes.</p><p><strong>Plain-language summary: </strong>Pruritus is a common but not well-characterized symptom of patients receiving dialysis. We analyzed data from 3,281 patients receiving maintenance hemodialysis or peritoneal dialysis in the region o
{"title":"Burden of CKD-Associated Pruritus and Adverse Clinical Outcomes in Patients Receiving Dialysis: The Stockholm Creatinine Measurements (SCREAM) Project.","authors":"Anne-Laure Faucon, Catherine M Clase, Helena Rydell, Milica Uhde, Peter Barany, Marie Evans, Juan-Jesús Carrero","doi":"10.1053/j.ajkd.2024.05.013","DOIUrl":"10.1053/j.ajkd.2024.05.013","url":null,"abstract":"<p><strong>Rationale & objective: </strong>Pruritus is a common but not well-characterized complaint of patients receiving maintenance dialysis. This study sought to quantify the burden of pruritus and its associated adverse health outcomes in this population.</p><p><strong>Study design: </strong>Observational study.</p><p><strong>Setting & participants: </strong>All patients receiving maintenance dialysis in Stockholm, Sweden, during 2005-2021.</p><p><strong>Exposure: </strong>Clinically recognized pruritus defined using International Classification of Diseases, Tenth Revision codes or a prescription for antipruritus treatments (including UV therapy).</p><p><strong>Outcomes: </strong>All-cause mortality, severe infection-related hospitalizations (composite of endocarditis, peritoneal dialysis-related peritonitis, hemodialysis/peritoneal dialysis-related catheter infection, sepsis due to Staphylococcus spp., or skin infection) and incident diagnoses of anxiety/depression and sleep disorders.</p><p><strong>Analytical approach: </strong>Multivariable logistic regression and cause-specific hazards models to analyze factors associated with prevalent and new-onset pruritus, respectively. Multivariable cause-specific hazards models with time-varying exposure were used to explore the association of prevalent and new-onset pruritus with adverse health outcomes.</p><p><strong>Results: </strong>Among 3,281 dialysis recipients (median age, 64 years; 66% men; 69% receiving hemodialysis, 77% with incident dialysis), 456 (14%) had pruritus at enrollment. During a median follow-up of 3.3 (IQR, 1.3-9.2) years, 539 (19%) additional patients experienced pruritus. Older age, female sex, a lower serum albumin level, and higher C-reactive protein, serum calcium, and phosphorus levels were independently associated with pruritus. Compared with patients without pruritus, patients with pruritus were at a higher risk of sleep disorders (adjusted HR, 1.96; 95% CI, 1.60-2.39), developing anxiety/depression (adjusted HR, 1.56; 95% CI, 1.23-1.98), and being hospitalized for severe infections (adjusted HR, 1.36; 95% CI, 1.18-1.57), the latter attributed to higher risk of sepsis and peritoneal dialysis-related peritonitis. There was no detectable association between the development of pruritus and all-cause mortality.</p><p><strong>Limitations: </strong>Potential misclassification bias if pruritus is not clinically recognized, lack of information on pruritus intensity/severity, use of diagnostic codes for exposure and outcome diagnoses.</p><p><strong>Conclusions: </strong>At least one third of patients experience pruritus during their first years undergoing dialysis, and pruritus was consistently associated with adverse health outcomes.</p><p><strong>Plain-language summary: </strong>Pruritus is a common but not well-characterized symptom of patients receiving dialysis. We analyzed data from 3,281 patients receiving maintenance hemodialysis or peritoneal dialysis in the region o","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1053/j.ajkd.2024.06.005
{"title":"Yet More Reassurance: Treat-to-Target With Allopurinol or Febuxostat is Safe and Effective in Lowering Serum Urate in People With CKD","authors":"","doi":"10.1053/j.ajkd.2024.06.005","DOIUrl":"10.1053/j.ajkd.2024.06.005","url":null,"abstract":"","PeriodicalId":7419,"journal":{"name":"American Journal of Kidney Diseases","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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