Pavithra Sakthivel, Alyaa Mostafa, Olalekan Lee Aiyegbusi
Abstract Background Most patients with end-stage renal disease (ESRD) are managed with dialysis and less commonly kidney transplantation. However, not all are suitable for or desire either of these renal replacement therapies. Conservative management (CM) is an option. However, the selection of CM is often not easy for patients and clinicians. The aim of this systematic review is to identify the key factors that influence the selection of CM for ESRD. Methods Medline, Embase, PsychINFO, and CINAHL Plus were systematically searched from inception to September 10, 2021. Titles/abstracts and full texts were independently screened by two reviewers. Reference lists of included articles were searched. An update search via PubMed was conducted on August 10, 2023. A narrative synthesis of review findings was conducted. Results At the end of the screening process, 15 qualitative and 8 survey articles were selected. Reference checking yielded no additional relevant studies. Main themes were: (i) Patient-specific factors; (ii) Clinician-specific factors; (iii) Organisational factors; and (iv) National and international factors. Patient-specific factors were awareness and perceptions of CM and dialysis, beliefs about survival, preferred treatment outcomes and influence of family/caregivers and clinicians. Clinician-specific factors included perceptions of CM as ‘non-intervention’, perceptions of clinician role in the decision-making process, and confidence and ability to initiate sensitive treatment discussions. Relationships with and involvement of other healthcare professionals, time constraints, and limited clinical guidance were also important factors. Conclusions An improvement in the provision of education regarding CM for patients, caregivers, and clinicians is essential. Robust studies are required to generate crucial evidence for the development of stronger recommendations and guidance for clinicians.
{"title":"Factors that influence the selection of conservative management for end stage renal disease – a systematic review","authors":"Pavithra Sakthivel, Alyaa Mostafa, Olalekan Lee Aiyegbusi","doi":"10.1093/ckj/sfad269","DOIUrl":"https://doi.org/10.1093/ckj/sfad269","url":null,"abstract":"Abstract Background Most patients with end-stage renal disease (ESRD) are managed with dialysis and less commonly kidney transplantation. However, not all are suitable for or desire either of these renal replacement therapies. Conservative management (CM) is an option. However, the selection of CM is often not easy for patients and clinicians. The aim of this systematic review is to identify the key factors that influence the selection of CM for ESRD. Methods Medline, Embase, PsychINFO, and CINAHL Plus were systematically searched from inception to September 10, 2021. Titles/abstracts and full texts were independently screened by two reviewers. Reference lists of included articles were searched. An update search via PubMed was conducted on August 10, 2023. A narrative synthesis of review findings was conducted. Results At the end of the screening process, 15 qualitative and 8 survey articles were selected. Reference checking yielded no additional relevant studies. Main themes were: (i) Patient-specific factors; (ii) Clinician-specific factors; (iii) Organisational factors; and (iv) National and international factors. Patient-specific factors were awareness and perceptions of CM and dialysis, beliefs about survival, preferred treatment outcomes and influence of family/caregivers and clinicians. Clinician-specific factors included perceptions of CM as ‘non-intervention’, perceptions of clinician role in the decision-making process, and confidence and ability to initiate sensitive treatment discussions. Relationships with and involvement of other healthcare professionals, time constraints, and limited clinical guidance were also important factors. Conclusions An improvement in the provision of education regarding CM for patients, caregivers, and clinicians is essential. Robust studies are required to generate crucial evidence for the development of stronger recommendations and guidance for clinicians.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"43 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136034338","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}
Emilio Rodrigo, Luis F Quintana, Teresa Vázquez-Sánchez, Ana Sánchez-Fructuoso, Anna Buxeda, Eva Gavela, Juan M Cazorla, Sheila Cabello, Isabel Beneyto, María O López-Oliva, Fritz Diekmann, José M Gómez-Ortega, Natividad Calvo Romero, María J Pérez-Sáez, Asunción Sancho, Auxiliadora Mazuecos, Jordi Espí-Reig, Carlos Jiménez, Domingo Hernández
ABSTRACT Background Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN. Methods We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. ‘Tubulo-interstitial inflammation’ (TII) was defined when ‘t’ or ‘i’ were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL). Results A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119–4.910, P = .024) independently of other histologic and clinical variables. Conclusions In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.
免疫球蛋白A肾病(IgAN)是肾移植受者中最常见的复发疾病，其复发会降低移植物的存活率。复发时的几个变量与移植物丢失的高风险相关。临床或亚临床炎症的存在与肾移植丢失的高风险相关，但尚不清楚它如何影响复发性IgAN患者的预后。方法我们进行了一项多中心回顾性研究，包括活检证实IgAN复发的肾移植受者，其中有Banff和Oxford分类评分。当t或i≥2时定义为“小管间质炎症”(TII)。主要终点是进展为慢性肾脏疾病(CKD)第5期或死亡检查-移植物丢失(CKD5/DCGL)。结果共纳入119例IgAN复发肾移植受者，其中23例出现TII。中位随访时间为102.9个月，39例(32.8%)患者达到CKD5/DCGL。TII与CKD5/DCGL的高风险相关(3年18.0% vs 45.3%， log-rank为7.588,P = 0.006)。多因素分析后，TII与CKD5/DCGL的风险相关(HR 2.344, 95% CI 1.119-4.910, P = 0.024)，独立于其他组织学和临床变量。结论:在IgAN复发的肾移植受者中，TII有助于增加CKD5/DCGL的风险，独立于先前已知的变量。我们建议在临床变量中加入TII和牛津分类，以确定移植物丢失风险增加的复发性IgAN患者，这些患者可能受益于强化免疫抑制或特异性IgAN治疗。
{"title":"Tubulo-interstitial inflammation increases the risk of graft loss after the recurrence of IgA nephropathy","authors":"Emilio Rodrigo, Luis F Quintana, Teresa Vázquez-Sánchez, Ana Sánchez-Fructuoso, Anna Buxeda, Eva Gavela, Juan M Cazorla, Sheila Cabello, Isabel Beneyto, María O López-Oliva, Fritz Diekmann, José M Gómez-Ortega, Natividad Calvo Romero, María J Pérez-Sáez, Asunción Sancho, Auxiliadora Mazuecos, Jordi Espí-Reig, Carlos Jiménez, Domingo Hernández","doi":"10.1093/ckj/sfad259","DOIUrl":"https://doi.org/10.1093/ckj/sfad259","url":null,"abstract":"ABSTRACT Background Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN. Methods We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. ‘Tubulo-interstitial inflammation’ (TII) was defined when ‘t’ or ‘i’ were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL). Results A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119–4.910, P = .024) independently of other histologic and clinical variables. Conclusions In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"939 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136079274","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}
Karl Emil Nelveg-Kristensen, Bo Madsen, Mark McClure, Nanna Bruun, Cecilie Lyngsø, Hans Dieperink, Jon Waarst Gregersen, Elizabeth Krarup, Per Ivarsen, Christian Torp-Pedersen, Martin Egfjord, Wladimir Szpirt, Nicholas Carlson
ABSTRACT Background Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries. Methods All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival. Results We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998–2004: 0.50 (SD 0.2), 2005–2011: 0.80 (SD 0.4), 2012–2018: 1.4 (SD 0.5); P = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients <45, 45–75 and >75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998–2004: 0.47 (SD 0.13), 2005–2011: 0.16 (SD 0.07), 2012–2018: 0.46 (SD 0.07); P = .035]. The 5-year mortality was 26.8% and mortality remained stable over time (P = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45–11.3], P < .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48–1.41), P = .50]. Conclusion The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients.
{"title":"Age and time-dependent increase in incident anti-glomerular basement membrane (anti-GBM) disease: a nation-wide cohort study","authors":"Karl Emil Nelveg-Kristensen, Bo Madsen, Mark McClure, Nanna Bruun, Cecilie Lyngsø, Hans Dieperink, Jon Waarst Gregersen, Elizabeth Krarup, Per Ivarsen, Christian Torp-Pedersen, Martin Egfjord, Wladimir Szpirt, Nicholas Carlson","doi":"10.1093/ckj/sfad261","DOIUrl":"https://doi.org/10.1093/ckj/sfad261","url":null,"abstract":"ABSTRACT Background Epidemiologic assessments of anti-glomerular basement membrane (GBM) disease have been challenging due to its rare occurrence. We examined changes in the incidence and outcomes from 1998 to 2018 using nationwide healthcare registries. Methods All patients with incident anti-GBM disease were identified using the International Classification of Diseases, 10th Revision code DM31.0A. Controls were matched 4:1 on birthyear and sex using exposure density sampling. Log link regression adjusted for time, age and sex was applied to model survival. Results We identified 97 patients with incident anti-GBM disease, corresponding to an incidence of 0.91 cases/million/year [standard deviation (SD) 0.6]. The incidence increased over time [1998–2004: 0.50 (SD 0.2), 2005–2011: 0.80 (SD 0.4), 2012–2018: 1.4 (SD 0.5); P = .02] and with age [0.76 (SD 0.4), 1.5 (SD 1.04) and 4.9 (SD 2.6) for patients &lt;45, 45–75 and &gt;75 years]. The median age was 56 years (interquartile range 46) and 51.6% were female. Dialysis was required in 58.4%, 61.9% and 62.9% of patients at day 30, 180 and 360, respectively. The 1-year kidney survival probability was 0.38 (SD 0.05) and exhibited time-dependent changes [1998–2004: 0.47 (SD 0.13), 2005–2011: 0.16 (SD 0.07), 2012–2018: 0.46 (SD 0.07); P = .035]. The 5-year mortality was 26.8% and mortality remained stable over time (P = .228). The risk of death was greater than that of the matched background population {absolute risk ratio [ARR] 5.27 [confidence interval (CI) 2.45–11.3], P &lt; .001}, however, it was comparable to that of patients with anti-neutrophil cytoplasmic antibody–associated vasculitis (AAV) requiring renal dialysis at presentation [ARR 0.82 (CI 0.48–1.41), P = .50]. Conclusion The incidence of anti-GBM disease increased over time, possibly related to temporal demographic changes. Mortality remained high and was comparable with an age- and sex-matched cohort of dialysis-dependent AAV patients.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"20 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136178134","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}
Titus Andrian, Anca Stefan, Ionut Nistor, Adrian Covic
Abstract Vitamin K supplementation has been considered recently as a potential treatment for addressing vascular calcification in chronic kidney disease patients. We conducted a systematic review and meta-analysis to summarize the impact of vitamin K supplementation in dialysis patients. Electronic databases were searched for clinical randomized trials among patients treated with vitamin K. Random effects models were performed and risk of bias was evaluated with Cochrane tools and search was conducted until 15 of September 2023. Eleven trials comprising 830 patients (both adult and pediatric, mainly hemodialysis) compared vitamin K with different controls: lower doses of vitamin K, standard care or placebo. Vitamin K supplementation had no effect on mortality. Vitamin K administration improved vitamin K levels and led to lower levels of dp-uc-MGP and moderately increased Calcium levels (0,18 [0,04–0,32]). Vitamin K1 proved more potency in reducing dp-uc-MGP (SMD −1,64 [−2,05, −1,23] vs. −0,56 [−0,82, −0,31]) and also raised serum vitamin K levels in comparison with vitamin K2 (5,69 [3,43, 7,94]) vs. 2,25 [−2.36, 6,87]). While it did not have a proved benefit in changing calcification scores (−0,14 [−0,37–+0,09]), vitamin K proved to be a safe product. There was some concern with bias. Vitamin K supplementation has no impact on mortality and did not show significant benefit in reversing calcification scores. Vitamin K1 improved vitamin K deposits and lowered dp-uc-MGP which is a calcification biomarker more than vitamin K2. As it proved to be a safe product, additional randomized well-powered studies with improved treatment regimens are needed to establish the true impact of vitamin K in dialysis patients.
{"title":"Vitamin K supplementation impact in dialysis patients – a systematic review and meta-analysis of randomized trials","authors":"Titus Andrian, Anca Stefan, Ionut Nistor, Adrian Covic","doi":"10.1093/ckj/sfad255","DOIUrl":"https://doi.org/10.1093/ckj/sfad255","url":null,"abstract":"Abstract Vitamin K supplementation has been considered recently as a potential treatment for addressing vascular calcification in chronic kidney disease patients. We conducted a systematic review and meta-analysis to summarize the impact of vitamin K supplementation in dialysis patients. Electronic databases were searched for clinical randomized trials among patients treated with vitamin K. Random effects models were performed and risk of bias was evaluated with Cochrane tools and search was conducted until 15 of September 2023. Eleven trials comprising 830 patients (both adult and pediatric, mainly hemodialysis) compared vitamin K with different controls: lower doses of vitamin K, standard care or placebo. Vitamin K supplementation had no effect on mortality. Vitamin K administration improved vitamin K levels and led to lower levels of dp-uc-MGP and moderately increased Calcium levels (0,18 [0,04–0,32]). Vitamin K1 proved more potency in reducing dp-uc-MGP (SMD −1,64 [−2,05, −1,23] vs. −0,56 [−0,82, −0,31]) and also raised serum vitamin K levels in comparison with vitamin K2 (5,69 [3,43, 7,94]) vs. 2,25 [−2.36, 6,87]). While it did not have a proved benefit in changing calcification scores (−0,14 [−0,37–+0,09]), vitamin K proved to be a safe product. There was some concern with bias. Vitamin K supplementation has no impact on mortality and did not show significant benefit in reversing calcification scores. Vitamin K1 improved vitamin K deposits and lowered dp-uc-MGP which is a calcification biomarker more than vitamin K2. As it proved to be a safe product, additional randomized well-powered studies with improved treatment regimens are needed to establish the true impact of vitamin K in dialysis patients.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135767278","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}
Syeda Tayyaba Rehan, Eman Ali, Farea Eqbal, Muhammad Nadeem Ahsan, Muhammad Sohaib Asghar
{"title":"Meta Analysis on Efficacy and Safety of Rituximab versus Tacrolimus for Nephrotic Syndrome in Pediatric age group","authors":"Syeda Tayyaba Rehan, Eman Ali, Farea Eqbal, Muhammad Nadeem Ahsan, Muhammad Sohaib Asghar","doi":"10.1093/ckj/sfad263","DOIUrl":"https://doi.org/10.1093/ckj/sfad263","url":null,"abstract":"","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135853468","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}
ABSTRACT Maintenance hemodialysis patients suffer from multiple comorbidities and treatment-related complications. A personalized approach to hemodialysis prescription could reduce some of these burdens by preventing complications such as excessive changes in blood pressure, arrhythmias, post-dialysis fatigue and decreased quality of life. A patient-centered approach to dialysate electrolyte concentrations represents one such opportunity. In addition to modifications in dialysate electrolyte concentrations, consideration of individual factors such as patients’ serum concentrations, medication profiles, nutritional status and comorbidities is critical to tailoring hemodialysis prescriptions to optimize patient outcomes. The development of personalized dialysis treatment depends on the collection of comprehensive patient data, advances in technology, resource allocation and patient involvement in decision-making. This review discusses how the treatment of maintenance hemodialysis patients could benefit from individualized changes in certain dialysis fluid components.
{"title":"Personalizing electrolytes in the dialysis prescription: what, why and how?","authors":"R Gulsah Dilaver, T Alp Ikizler","doi":"10.1093/ckj/sfad210","DOIUrl":"https://doi.org/10.1093/ckj/sfad210","url":null,"abstract":"ABSTRACT Maintenance hemodialysis patients suffer from multiple comorbidities and treatment-related complications. A personalized approach to hemodialysis prescription could reduce some of these burdens by preventing complications such as excessive changes in blood pressure, arrhythmias, post-dialysis fatigue and decreased quality of life. A patient-centered approach to dialysate electrolyte concentrations represents one such opportunity. In addition to modifications in dialysate electrolyte concentrations, consideration of individual factors such as patients’ serum concentrations, medication profiles, nutritional status and comorbidities is critical to tailoring hemodialysis prescriptions to optimize patient outcomes. The development of personalized dialysis treatment depends on the collection of comprehensive patient data, advances in technology, resource allocation and patient involvement in decision-making. This review discusses how the treatment of maintenance hemodialysis patients could benefit from individualized changes in certain dialysis fluid components.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135853470","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":"Reconsidering the Role of the IL-23/IL-17 Immune Axis in Idiopathic Nephrotic Syndrome Pathogenesis","authors":"Giuseppe Salfi","doi":"10.1093/ckj/sfad264","DOIUrl":"https://doi.org/10.1093/ckj/sfad264","url":null,"abstract":"","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"112 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135853473","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}
Sita Arjune, Martin R Späth, Simon Oehm, Polina Todorova, Stefan J Schunk, Katharina Lettenmeier, Seung-Hun Chon, Malte P Bartram, Philipp Antczak, Franziska Grundmann, Danilo Fliser, Roman-Ulrich Müller
ABSTRACT Backgound Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging–based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future. Methods In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction. Results ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients (PKD1: 2304 ± 5119; PKD2: 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R2 of all models examined (∼0.5). Conclusion uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractiv
常染色体显性多囊肾病(ADPKD)是最常见的遗传性肾脏疾病，可导致成年期肾功能的稳定丧失。由于病程多变，因此有必要确定病情进展迅速的患者，这些患者将从靶向治疗和干预中获益最多。目前，基于磁共振成像的肾脏体积测量是用于此目的的最常用工具。可容易定量测定的生物标志物，可用于预测肾功能的丧失，但尚未在临床实践中建立。糖蛋白Dickkopf 3 (DKK3)在应激时在肾小管上皮中分泌，并通过Wnt信号通路促进小管间质纤维化，最近被描述为评估肾功能丧失风险的生物标志物，但尚未对ADPKD进行研究。本研究旨在首次了解DKK3是否确实可以改善未来ADPKD的预后预测。方法采用酶联免疫吸附试验(ELISA)测定184例AD(H)型PKD患者和47例健康对照者尿液中DKK3 (uDKK3)水平。使用多元线性回归来检验这些值在结果预测中的潜力。结果ADPKD患者uDKK3值明显高于对照组(平均1970±5287 vs 112±134.7 pg/mg肌酐)。此外，uDKK3随着Mayo分级(a /B 1262±2315 vs D/E 3104±7627 pg/mg肌酐)的增加而稳步增加，Mayo分级是ADPKD进展的最佳生物标志物。uDKK3也与估计的肾小球滤过率(eGFR)相关。PKD1突变患者的uDKK3水平高于PKD2患者(PKD1: 2304±5119;PKD2: 506.6±526.8 pg/mg肌酐)。单变量线性回归显示uDKK3是未来eGFR斜率估计的重要预测因子。在多元线性回归中，该效应在同时包含高度调整后的肾脏总容积和/或eGFR的模型中不显著。然而，将copeptin水平和copeptin与uDKK3之间的相互作用项添加到模型中，这三个变量的预测值都很显著，并且在所有模型中R2最高(~ 0.5)。结论uDKK3与ADPKD患者的Mayo分型有明显相关性。uDKK3水平与肾功能相关，这可能表明uDKK3也预测了该群体肾功能的不成比例损失。有趣的是，我们发现在我们的预测模型中copeptin和uDKK3之间存在相互作用，与之前的模型相比，包含这两个变量及其相互作用项的最佳模型可以很好地解释eGFR斜率的方差。考虑到这些分析中的患者数量有限，需要进一步的研究来证实结果。尽管如此，uDKK3似乎是未来改善ADPKD预后预测的一个有吸引力的候选者。
{"title":"DKK3 as a potential novel biomarker in patients with autosomal polycystic kidney disease","authors":"Sita Arjune, Martin R Späth, Simon Oehm, Polina Todorova, Stefan J Schunk, Katharina Lettenmeier, Seung-Hun Chon, Malte P Bartram, Philipp Antczak, Franziska Grundmann, Danilo Fliser, Roman-Ulrich Müller","doi":"10.1093/ckj/sfad262","DOIUrl":"https://doi.org/10.1093/ckj/sfad262","url":null,"abstract":"ABSTRACT Backgound Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging–based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future. Methods In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction. Results ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients (PKD1: 2304 ± 5119; PKD2: 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R2 of all models examined (∼0.5). Conclusion uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractiv","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135853469","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}
Sebastian Sewerin, Charlotte Aurnhammer, Cene Skubic, Kaja Blagotinšek Cokan, Jera Jeruc, Damjana Rozman, Frederick Pfister, Katalin Dittrich, Brigitte Mayer, Ria Schönauer, Friederike Petzold, Jan Halbritter
Abstract Background Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic EYA1 variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT). BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored. Methods Through thorough phenotyping and exome sequencing, we studied one family with disease presentation in at least four generations in both clinical and genetic terms. Functional investigation of the single associated EYA1 variant c.1698+1G>A included splice site analysis and assessment of EYA1 distribution in patient-derived fibroblasts. The candidate modifier gene CYP51A1 was evaluated by histopathological analysis of murine CYP51A1+/− kidneys. As the gene encodes the enzyme Lanosterol 14α-demethylase, we assessed sterol intermediates in patient blood samples as well. Results The EYA1 variant c.1698+1G>A resulted in functional deletion of the EYA domain by exon skipping. The EYA domain mediates protein-protein interactions between EYA1 and co-regulators of transcription. EYA1 abundance was reduced in the nuclear compartment of patient-derived fibroblasts, suggesting impaired nuclear translocation of these protein complexes. Within the affected family, renal phenotypes spanned from normal kidney function in adulthood to chronic kidney failure in infancy. By analyzing exome sequencing data for variants segregating with an effect on the kidney, we identified a canonical splice site alteration in CYP51A1 as the strongest candidate variant, potentially playing a role as genetic modifier. Conclusions In this study, we demonstrate pathogenicity of EYA1 c.1698+1G>A, propose a mechanism for dysfunction of mutant EYA1, and conjecture CYP51A1 as a potential genetic modifier of renal involvement in BOR syndrome.
{"title":"Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome","authors":"Sebastian Sewerin, Charlotte Aurnhammer, Cene Skubic, Kaja Blagotinšek Cokan, Jera Jeruc, Damjana Rozman, Frederick Pfister, Katalin Dittrich, Brigitte Mayer, Ria Schönauer, Friederike Petzold, Jan Halbritter","doi":"10.1093/ckj/sfad260","DOIUrl":"https://doi.org/10.1093/ckj/sfad260","url":null,"abstract":"Abstract Background Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic EYA1 variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT). BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored. Methods Through thorough phenotyping and exome sequencing, we studied one family with disease presentation in at least four generations in both clinical and genetic terms. Functional investigation of the single associated EYA1 variant c.1698+1G&gt;A included splice site analysis and assessment of EYA1 distribution in patient-derived fibroblasts. The candidate modifier gene CYP51A1 was evaluated by histopathological analysis of murine CYP51A1+/− kidneys. As the gene encodes the enzyme Lanosterol 14α-demethylase, we assessed sterol intermediates in patient blood samples as well. Results The EYA1 variant c.1698+1G&gt;A resulted in functional deletion of the EYA domain by exon skipping. The EYA domain mediates protein-protein interactions between EYA1 and co-regulators of transcription. EYA1 abundance was reduced in the nuclear compartment of patient-derived fibroblasts, suggesting impaired nuclear translocation of these protein complexes. Within the affected family, renal phenotypes spanned from normal kidney function in adulthood to chronic kidney failure in infancy. By analyzing exome sequencing data for variants segregating with an effect on the kidney, we identified a canonical splice site alteration in CYP51A1 as the strongest candidate variant, potentially playing a role as genetic modifier. Conclusions In this study, we demonstrate pathogenicity of EYA1 c.1698+1G&gt;A, propose a mechanism for dysfunction of mutant EYA1, and conjecture CYP51A1 as a potential genetic modifier of renal involvement in BOR syndrome.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"118 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135853478","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}
Liangying Gan, Li Xing, Yan Xu, Linghui Zhou, Hong Jiang, Xiuli Sun, Tianjun Guan, Ping Luo, Junxia Wang, Fuyun Sun, Zhiyong Guo, Minghao Guo, Ju Gao, Gang Wei, Wen Zhong, Yongchun Zhou, Li Zuo
ABSTRACT Background The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD). Methods This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference −1.17 mg/dl (95% CI −1.694 to −0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor. Conclusions Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.
{"title":"Tenapanor in Chinese patients with ESRD on haemodialysis with hyperphosphatemia: a randomised, Phase 3 trial","authors":"Liangying Gan, Li Xing, Yan Xu, Linghui Zhou, Hong Jiang, Xiuli Sun, Tianjun Guan, Ping Luo, Junxia Wang, Fuyun Sun, Zhiyong Guo, Minghao Guo, Ju Gao, Gang Wei, Wen Zhong, Yongchun Zhou, Li Zuo","doi":"10.1093/ckj/sfad216","DOIUrl":"https://doi.org/10.1093/ckj/sfad216","url":null,"abstract":"ABSTRACT Background The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD). Methods This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference −1.17 mg/dl (95% CI −1.694 to −0.654, P &lt; .001). More patients receiving tenapanor achieved a serum phosphorous level &lt;5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor. Conclusions Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.","PeriodicalId":18987,"journal":{"name":"NDT Plus","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136212947","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}
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