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Seasonal variations in the association between proteinuria, CKD, and kidney failure. 蛋白尿、慢性肾脏病和肾衰竭之间关系的季节性变化。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-21 DOI: 10.1093/ndt/gfae278
Takayuki Kawaoka, Yusuke Sakaguchi, Tatsufumi Oka, Yuta Asahina, Koki Hattori, Yohei Doi, Nobuhiro Hashimoto, Yasuo Kusunoki, Satoko Yamamoto, Masafumi Yamato, Ryohei Yamamoto, Isao Matsui, Masayuki Mizui, Jun-Ya Kaimori, Yoshitaka Isaka

Background and hypothesis: Proteinuria exhibits seasonal fluctuations, decreasing in summer and increasing in winter. It is unknown whether the association between proteinuria and the risk of kidney failure varies by season.

Methods: The Osaka Consortium for Kidney Disease Research (OCKR) database contained retrospective data from 15 367 patients with estimated glomerular filtration rates of 10-60 mL/min/1.73m2, who were referred to the Department of Nephrology at five clinical centers in Japan, between 2010 and 2021. Multivariate Cox models were used to examine the associations of urinary protein-to-creatinine ratio (UPCR) in summer (UPCRsummer) and winter (UPCRwinter) with kidney failure defined as initiation of kidney replacement therapy. LASSO was used to compare the strength of the association between UPCRsummer and UPCRwinter with respect to kidney failure. We also assessed whether seasonal fluctuations in UPCR were associated with kidney failure.

Results: The median [interquartile range] UPCRwinter was 0.89 [0.22, 2.69] g/gCre, 46% higher than UPCRsummer (0.61 [0.16, 1.87] g/gCre). During a median follow-up of 3.0 years, 1 585 patients developed kidney failure. In time-dependent Cox models, UPCRwinter showed a higher hazard of kidney failure (1.66 per 1-standard deviation [SD] increase; 95% confidence interval [CI], 1.60-1.73) than UPCRsummer (1.45 per 1-SD increase; 95%CI, 1.41-1.48). LASSO identified that UPCRwinter was more strongly associated with kidney failure than UPCRsummer. Furthermore, higher % changes in UPCRwinter relative to UPCRsummer was associated with a higher hazard of kidney failure.

Conclusions: Proteinuria in winter exhibited stronger associations with kidney failure than that in summer. Seasonal fluctuations in UPCR should not be overlooked in the management of CKD to make reasonable clinical decisions.

背景和假设:蛋白尿呈季节性波动,夏季减少,冬季增加。蛋白尿与肾衰竭风险之间的关系是否因季节而异尚属未知:大阪肾脏病研究联合会(OCKR)数据库中包含了 15 367 名患者的回顾性数据,这些患者的估计肾小球滤过率为 10-60 mL/min/1.73m2,他们在 2010 年至 2021 年期间被转诊到日本五个临床中心的肾脏科。研究人员使用多变量 Cox 模型研究了夏季(UPCRsummer)和冬季(UPCRwinter)尿蛋白肌酐比值(UPCR)与肾衰竭(定义为开始肾脏替代治疗)的相关性。我们使用 LASSO 方法比较了夏季和冬季尿蛋白肌酐比值与肾衰竭的关联强度。我们还评估了 UPCR 的季节性波动是否与肾衰竭有关:UPCRwinter 的中位数[四分位距]为 0.89 [0.22, 2.69] g/gCre,比 UPCRsummer(0.61 [0.16, 1.87] g/gCre)高出 46%。在中位 3.0 年的随访期间,有 1 585 名患者出现了肾衰竭。在时间依赖性 Cox 模型中,UPCRwinter 的肾衰竭风险(每增加 1 个标准差 [SD] 为 1.66;95% 置信区间 [CI],1.60-1.73)高于 UPCRsummer(每增加 1 个标准差为 1.45;95% 置信区间 [CI],1.41-1.48)。LASSO 发现,与 UPCRsummer 相比,UPCRwinter 与肾衰竭的相关性更强。此外,UPCR冬季相对于UPCR夏季的百分比变化越大,肾衰竭的风险越高:结论:冬季蛋白尿与肾衰竭的相关性高于夏季。结论:冬季蛋白尿比夏季蛋白尿与肾衰竭的关联性更强。在治疗慢性肾功能衰竭时,不应忽视 UPCR 的季节性波动,以便做出合理的临床决策。
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引用次数: 0
Neutralizing the IL-7Rα limits injury in experimental ANCA-associated glomerulonephritis. 中和 IL-7Rα 可限制实验性 ANCA 相关性肾小球肾炎的损伤。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-21 DOI: 10.1093/ndt/gfae276
Maliha A Alikhan, Kazuya Kishimoto, Limy Wong, Peemapat Prakongtham, Alana Auden, Kim M O'Sullivan, Juli Jaw, A Richard Kitching

Background and hypothesis: Increased T cell IL-7Rα signaling is associated with a poorer prognosis in ANCA-associated vasculitis. These studies examined the functional role of IL-7Rα (CD127) in experimental glomerulonephritis mediated by anti-MPO T cell autoimmunity. We hypothesized that T cells would express IL-7Rα in the kidney and that blocking the function of IL-7Rα, without cellular depletion, would be protective.

Methods: Mice were immunised with mouse MPO, then low-dose sheep anti-mouse basement membrane (BM) globulin was administered to trigger glomerulonephritis. Flow cytometry and RNA-sequencing characterised intrarenal CD127+ expressing CD4+ and CD8+ T cells in mice with anti-MPO glomerulonephritis. To assess the functional role of IL-7Rα, mice with established anti-MPO autoimmunity were treated with anti-IL-7Rα antibodies.

Results: Control ovalbumin-immunized mice given anti-BM globulin developed minimal injury, while MPO-immunised mice given anti-BM globulin developed albuminuria with glomerular and tubulointerstitial injury. Numbers of intrarenal IL-7Rα+ (CD127+) CD4+ and CD8+ T cells were increased in mice with anti-MPO glomerulonephritis. There were 3 738 and 2 726 genes differentially expressed between intrarenal CD127¯PD-1+ and CD127+PD-1¯ CD8+ and CD4+ T cells, respectively, with substantially overlapping differentially expressed genes between CD8+ and CD4+ T cells. Both CD127¯PD-1+ CD8+ and CD4+ T cells were enriched for previously described T cell exhaustion signatures associated with prognosis in autoimmune disease. As effector memory T cells drive inflammation, we blocked the IL-7Rα after inducing anti-MPO autoimmunity. Anti-IL-7Rα antibodies limited histological injury, and reduced albuminuria numbers of glomerular and interstitial leukocytes, with reduced intrarenal chemokine and pro-inflammatory cytokine expression.

Conclusions: Intrarenal effector memory and exhausted CD4+ and CD8+ T cells are present in experimental anti-MPO glomerulonephritis. Neutralising effector T cells via the IL-7Rα after the induction of autoimmunity limits intrarenal inflammation and disease. IL-7Rα may be a therapeutic target in ANCA-associated vasculitis.

背景和假设:T细胞IL-7Rα信号的增加与ANCA相关性血管炎较差的预后有关。这些研究考察了 IL-7Rα (CD127) 在抗 MPO T 细胞自身免疫介导的实验性肾小球肾炎中的功能作用。我们假设 T 细胞会在肾脏中表达 IL-7Rα,而阻断 IL-7Rα 的功能(不消耗细胞)会起到保护作用:方法:用小鼠MPO免疫小鼠,然后注射低剂量羊抗小鼠基底膜(BM)球蛋白诱发肾小球肾炎。流式细胞术和 RNA 序列分析了抗 MPO 肾小球肾炎小鼠肾内 CD127+ 表达 CD4+ 和 CD8+ T 细胞的特征。为了评估IL-7Rα的功能作用,用抗IL-7Rα抗体治疗已建立抗MPO自身免疫的小鼠:结果:给予抗丙种球蛋白的卵清蛋白免疫对照组小鼠损伤极小,而给予抗丙种球蛋白的MPO免疫小鼠则出现白蛋白尿,并伴有肾小球和肾小管间质损伤。抗MPO肾小球肾炎小鼠肾内IL-7Rα+(CD127+)CD4+和CD8+T细胞数量增加。肾内CD127¯PD-1+和CD127+PD-1¯ CD8+和CD4+T细胞之间分别有3 738和2 726个基因差异表达,CD8+和CD4+T细胞之间的差异表达基因基本重叠。CD127¯PD-1+ CD8+和CD4+T细胞都富集了先前描述的与自身免疫性疾病预后相关的T细胞衰竭特征。由于效应记忆T细胞驱动炎症,我们在诱导抗MPO自身免疫后阻断了IL-7Rα。抗IL-7Rα抗体限制了组织学损伤,减少了肾小球和肾间质白细胞的白蛋白尿数量,降低了肾内趋化因子和促炎细胞因子的表达:结论:在实验性抗MPO肾小球肾炎中存在肾小球内效应记忆和衰竭的CD4+和CD8+T细胞。在诱导自身免疫后,通过 IL-7Rα 中和效应 T 细胞可限制肾内炎症和疾病。IL-7Rα可能是ANCA相关性血管炎的治疗靶点。
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引用次数: 0
Determination of urine volume and glomerular filtration rate using d-serine and d-asparagine. 使用 d-丝氨酸和 d-天冬酰胺测定尿量和肾小球滤过率。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-21 DOI: 10.1093/ndt/gfae279
Ryo Tanaka, Shinsuke Sakai, Ayumu Taniguchi, Masataka Kawamura, Yoko Higa-Maegawa, Soichi Matsumura, Shota Fukae, Shigeaki Nakazawa, Shihoko Kimura-Ohba, Masaru Horio, Shiro Takahara, Ryoichi Imamura, Norio Nonomura, Masayuki Mizui, Yoshitaka Isaka, Yoichi Kakuta, Tomonori Kimura

Background and hypothesis: Measurement of glomerular filtration rate (GFR) is subject to inaccurate urine collection. Clearances of d-serine and d-asparagine, rare enantiomers of amino acids, are the measures of GFR since they are almost free of tubular secretion and reabsorption. We hypothesize that d-serine and d-asparagine can accurately determine urine volume and GFR.

Methods: This cross-sectional observational study included 209 living kidney transplant donors and recipients for whom GFR was measured using the clearance of inulin. Assuming that urine excretions of d-serine and d-asparagine are constant and using urine levels of d-serine and d-asparagine from each urine collection, an equation for estimated urine volume (eUV) was established. Based on the eUV, the abnormal urine volume was replaced with an estimate with which the GFR was re-evaluated.

Result: Clearances of d-serine and d-asparagine were minor in proportional biases when compared with that of creatinine. Using 627 urine collection, the equation for eUV (mL/min) was established as 21.88/urine d-Ser (0.40 + 0.20 × log10(urine d-Asn)). Using eUV, we identified 20 instances where urine collection volumes varied significantly from the estimated values. After replacement with eUV, measured GFR (mGFR) was corrected to adjusted mGFR, which was within approximately 20 mL/min/1.73m2 of the mGFR.

Conclusion: d-Serine and d-asparagine are nearly completely excreted in urine after glomerular filtration, enabling the estimation of urine volume and correct mGFR. Besides reflecting GFR, d-serine and d-asparagine can be used to estimate urine volume. By applying the eUV method, mGFR determined using clearance methods becomes more accurate.

背景和假设:肾小球滤过率(GFR)的测量受尿液收集不准确的影响。d-丝氨酸和d-天冬酰胺是氨基酸的稀有对映体,由于它们几乎不受肾小管分泌和重吸收的影响,因此它们的清除率是衡量肾小球滤过率的标准。我们假设 d-丝氨酸和 d-天冬酰胺能准确测定尿量和 GFR:这项横断面观察性研究包括 209 名活体肾移植供体和受体,他们的 GFR 都是通过菊粉的清除率来测量的。假设尿液中 d-丝氨酸和 d-天冬酰胺的排泄量是恒定的,并利用每次尿液采集中 d-丝氨酸和 d-天冬酰胺的尿液水平,建立了估算尿量(eUV)的方程。根据 eUV,用估计值代替异常尿量,并据此重新评估 GFR:结果:与肌酐相比,d-丝氨酸和 d-天冬酰胺的清除率在比例偏差上较小。通过收集 627 次尿液,得出 eUV(毫升/分钟)的计算公式为:21.88/尿液 d-Ser (0.40 + 0.20 × log10(尿液 d-Asn))。通过使用 eUV,我们确定了 20 个尿液收集量与估计值有显著差异的实例。结论:d-丝氨酸和 d-天冬酰胺经肾小球滤过后几乎完全从尿液中排出,因此可以估算尿量并正确计算 mGFR。除了反映肾小球滤过率,d-丝氨酸和 d-天冬酰胺还可用于估算尿量。应用 eUV 方法后,使用清除率方法测定的 mGFR 将变得更加准确。
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引用次数: 0
Ethical considerations on the use of big Data and Artificial Intelligence in kidney research from the ERA ethics committee. ERA 伦理委员会关于在肾脏研究中使用大数据和人工智能的伦理考虑。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-21 DOI: 10.1093/ndt/gfae267
Wim Van Biesen, Jadranka Buturovic Ponikvar, Monica Fontana, Peter Heering, Mehmet S Sever, Simon Sawhney, Valerie Luyckx

In the current paper, we will focus on requirements to ensure big data can advance the outcomes of our patients suffering from kidney disease. The associated ethical question is whether and how we as a nephrology community can and should encourage the collection of big data of our patients. We identify some ethical reflections on the use of big data, and their importance and relevance. Furthermore, we balance advantages and pitfalls and discuss requirements to make legitimate and ethical use of big data possible. The collection, organization and curation of data come upfront in the pipeline prior to any analyses. Great care must therefore be taken to ensure quality of the data at this stage, to avoid the garbage in garbage out problem and suboptimal patient care as a consequence of such analyses. Access to the data should be organized so that correct and efficient use of data is possible. This means that data must be stored safely, so that only those entitled to do so can access them. At the same time, those who are entitled to access the data should be able to do so in an efficient way, so as not to hinder relevant research. Analysis of observational data is itself prone to many errors and biases. Each of these biases can finally result in provision of low-quality medical care. Secure platforms should therefore also ensure correct methodology is used to interpret the available data. This requires close collaboration of a skilled workforce of experts in medical research and data scientists. Only then will our patients be able to benefit fully from the potential of AI and big data.

在本文中,我们将重点讨论如何确保大数据能够促进肾病患者的治疗效果。与此相关的伦理问题是,作为肾脏病学界,我们是否能够以及应该如何鼓励收集患者的大数据。我们确定了使用大数据的一些伦理思考及其重要性和相关性。此外,我们还平衡了优势和缺陷,并讨论了合法、合乎伦理地使用大数据的要求。在进行任何分析之前,数据的收集、组织和整理都是最重要的工作。因此,在这一阶段必须格外注意确保数据的质量,以避免出现垃圾进垃圾出的问题,并避免此类分析导致病人护理效果不佳。对数据的访问应该有条不紊,以便正确有效地使用数据。这就意味着必须安全地储存数据,只有有权这样做的人才能访问这些数据。同时,有权获取数据的人应能够高效地获取数据,以免妨碍相关研究。对观察数据的分析本身容易出现许多错误和偏差。这些偏差最终都可能导致提供低质量的医疗服务。因此,安全平台还应确保使用正确的方法来解释现有数据。这就需要一支由医学研究专家和数据科学家组成的高技能人才队伍密切合作。只有这样,我们的患者才能充分受益于人工智能和大数据的潜力。
{"title":"Ethical considerations on the use of big Data and Artificial Intelligence in kidney research from the ERA ethics committee.","authors":"Wim Van Biesen, Jadranka Buturovic Ponikvar, Monica Fontana, Peter Heering, Mehmet S Sever, Simon Sawhney, Valerie Luyckx","doi":"10.1093/ndt/gfae267","DOIUrl":"https://doi.org/10.1093/ndt/gfae267","url":null,"abstract":"<p><p>In the current paper, we will focus on requirements to ensure big data can advance the outcomes of our patients suffering from kidney disease. The associated ethical question is whether and how we as a nephrology community can and should encourage the collection of big data of our patients. We identify some ethical reflections on the use of big data, and their importance and relevance. Furthermore, we balance advantages and pitfalls and discuss requirements to make legitimate and ethical use of big data possible. The collection, organization and curation of data come upfront in the pipeline prior to any analyses. Great care must therefore be taken to ensure quality of the data at this stage, to avoid the garbage in garbage out problem and suboptimal patient care as a consequence of such analyses. Access to the data should be organized so that correct and efficient use of data is possible. This means that data must be stored safely, so that only those entitled to do so can access them. At the same time, those who are entitled to access the data should be able to do so in an efficient way, so as not to hinder relevant research. Analysis of observational data is itself prone to many errors and biases. Each of these biases can finally result in provision of low-quality medical care. Secure platforms should therefore also ensure correct methodology is used to interpret the available data. This requires close collaboration of a skilled workforce of experts in medical research and data scientists. Only then will our patients be able to benefit fully from the potential of AI and big data.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oral dysbiosis initiates periodontal disease in experimental kidney disease. 口腔菌群失调引发实验性肾病中的牙周病
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-20 DOI: 10.1093/ndt/gfae266
David Randall, Asil Alsam, Julius Kieswich, Susan Joseph, Joseph Aduse-Opoku, Jonathan Swann, Alan Boyde, Graham Davis, David Mills, Kieran McCafferty, Michael Curtis, Muhammed M Yaqoob

Background and hypothesis: It is presently unclear why there is a high prevalence of periodontal disease in individuals living with chronic kidney disease (CKD). Whilst some have argued that periodontal disease causes CKD, we hypothesised that alterations in saliva and the oral microenvironment in organisms with kidney disease may initiate periodontal disease by causing dysbiosis of the oral microbiota.

Methods: Experimental kidney disease was created using adenine feeding and subtotal nephrectomy in rats, and by adenine feeding in mice. Loss of periodontal bone height was assessed using a dissecting microscope supported by micro-CT, light, confocal and electron microscopy, and immunohistochemistry. Salivary biochemistry was assessed using NMR spectroscopy. The oral microbiome was evaluated using culture-based and molecular methods, and the transmissibility of dysbiosis was assessed using co-caging and microbial transfer experiments into previously germ-free recipient mice.

Results: We demonstrate that experimental kidney disease causes a reproducible reduction of alveolar bone height, without gingival inflammation or overt hyperparathyroidism but with evidence of failure of bone formation at the periodontal crest. We show that kidney disease alters the biochemical composition of saliva and induces progressive dysbiosis of the oral microbiota, with microbial samples from animals with kidney disease displaying reduced overall bacterial growth, increased alpha diversity, reduced abundance of key components of the healthy oral microbiota such as Streptococcus and Rothia, and an increase in minor taxa including those from gram-negative phyla Proteobacteria and Bacteroidetes. Co-housing diseased rats with healthy ones ameliorates the periodontal disease phenotype, whilst transfer of oral microbiota from mice with kidney disease causes periodontal disease in germ-free animals with normal kidney function.

Conclusions: We advocate that periodontal disease should be regarded as a complication of kidney disease, initiated by oral dysbiosis through mechanisms independent of overt inflammation or hyperparathyroidism.

背景与假设:目前尚不清楚慢性肾脏病(CKD)患者牙周病发病率高的原因。有些人认为牙周病是导致 CKD 的原因,而我们的假设是,肾病患者唾液和口腔微环境的改变可能会导致口腔微生物群的菌群失调,从而引发牙周病:方法:通过给大鼠喂食腺嘌呤和次全肾切除术,以及给小鼠喂食腺嘌呤,制造实验性肾病。使用解剖显微镜,辅以显微 CT、光镜、共聚焦显微镜和电子显微镜以及免疫组化技术,对牙周骨高度损失进行评估。唾液生物化学采用核磁共振光谱进行评估。使用培养和分子方法对口腔微生物组进行了评估,并使用共笼和微生物转移实验对先前无菌的受体小鼠进行了评估:结果:我们证明,实验性肾病会导致牙槽骨高度重复性降低,但不会引起牙龈炎症或明显的甲状旁腺功能亢进,但有证据表明牙周嵴骨形成失败。我们的研究表明,肾病会改变唾液的生化成分,并诱发口腔微生物群的渐进性菌群失调,肾病动物的微生物样本显示细菌生长总量减少,α多样性增加,健康口腔微生物群的主要成分(如链球菌和罗氏菌)丰度降低,次要类群(包括革兰氏阴性菌门的变形杆菌和类杆菌)增加。将患病大鼠与健康大鼠共同饲养可改善牙周病表型,而将肾病小鼠的口腔微生物群转移到肾功能正常的无菌动物体内则会导致牙周病:我们主张将牙周病视为肾病的一种并发症,由口腔菌群失调引发,其机制与明显的炎症或甲状旁腺功能亢进无关。
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引用次数: 0
Prophylactic 2-week Glecaprevir/Pibrentasvir in Hepatitis C positive to negative kidney transplantation. 在丙型肝炎阳性转阴肾移植中预防性使用 2 周 Glecaprevir/Pibrentasvir。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-20 DOI: 10.1093/ndt/gfae271
Rebecca A Dieter, Aprajita Mattoo, Perry Hotchkis, Ian S Jaffe, Elaina P Weldon, Jonathan C Berger, Nicole M Ali, Robert A Montgomery, Bonnie E Lonze

Background and hypothesis: Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia.

Methods: This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events.

Results: 7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%.

Conclusion: A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.

背景和假设:丙型肝炎病毒(HCV)阳性转阴性肾移植(KT)需要直接作用抗病毒治疗,但最佳治疗时机和疗程仍不明确。我们假设格列卡韦/匹布伦达韦 300/120 毫克(GLE/PIB)的 14 天预防性疗程将安全有效地治疗供体源性 HCV 病毒血症:这是一项前瞻性、单中心、单臂、开放标签试验研究。20名HCV核酸扩增检测呈阳性的已故供肾的成人HCV阴性受者(HCV阳性转阴性)接受了为期14天的GLE/PIB治疗,第一剂在移植前服用。术后第 1、3、7 和 13 天(POD)监测 HCV RNA 病毒载量(VL)。如果在 POD 13 检测不到 VL,则停用 GLE/PIB;如果检测到 VL,则继续使用 GLE/PIB 完成为期 8 周的疗程。治疗后继续进行监测,以确保持续病毒应答(SVR)。主要结果是 14 天预防性 GLE/PIB 的疗效。次要结果包括患者和异体移植存活率、HCV 病毒血症的发生率、时间和清除率以及安全性事件:结果:7/20 例受试者(35%)从未检测到 HCV 病毒血症。只有一名受试者在 POD 13 检测到 VL,但无法量化,并完成了为期 8 周的疗程。所有受试者在治疗后 12 周均获得 SVR,随访 1 年无复发。检测不到 HCV RNA VL 的平均时间为 10.5 (±4.7) 天,平均峰值 VL 为 371 (±715) 拷贝/毫升。患者6个月和1年的存活率分别为100%和95%:14天的预防性GLE/PIB疗程对HCV阳性转阴性的KT是安全有效的,可预防HCV传播或显著降低可检测到传播的患者的VL,使其在2周内快速清除。
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引用次数: 0
The uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) may enhance eryptosis and increase erythrocyte osmotic fragility through potential activation of Piezo1. 尿毒症溶质 3-羧基-4-甲基-5-丙基-2-呋喃丙酸盐(CMPF)可能会通过潜在的 Piezo1 激活作用,促进红细胞渗出和增加红细胞渗透脆性。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-20 DOI: 10.1093/ndt/gfae275
Beatriz Akemi Kondo Van Spitzenbergen, Gabriela Bohnen Andrade, Erika Sousa Dias, Júlia Bacarin Monte Alegre, Gabriela Ferreira Dias, Nadja Grobe, Andrea Novais Moreno-Amaral, Peter Kotanko

Background and hypothesis: In patients with advanced chronic kidney disease (CKD), the lifespan of red blood cells (RBC) is often shortened, a condition attributed to the "uremic milieu." We reported recently that the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) shares structural similarities with Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, whose activation increases calcium influx into cells. Against this backdrop, we hypothesized that CMPF may induce premature RBC death (eryptosis) through prolonged CMPF-induced activation of Piezo1 located on RBC. To test this hypothesis, we explored if CMPF, at concentrations found in uremia, interacts with Piezo1 located on RBC, increases intracellular calcium (icCa2+), and induces eryptosis.

Methods: RBC from healthy individuals were incubated with CMPF or Jedi1 (both at a concentration of 87 µM), in the presence or absence of the Piezo1 inhibitor GsMTx-4 (2 µM). We challenged RBC osmotically through incubation in solutions of NaCl at concentrations between 3.0 and 9.0 g/L and determined their osmotic fragility. Using flow cytometry, we quantified in incubated RBC icCa2+ levels and phosphatidylserine exposure, a cellular marker of eryptosis.

Results: Incubation of RBC with CMPF and Jedi1 significantly increased RBC osmotic fragility, an effect prevented by GsMTx-4. At 6.0 g/L NaCl, incubation with CMPF and Jedi1 increased exposure of phosphatidylserine and elevated icCa2+ levels of RBC, indicating increased eryptosis. Notably, at an isotonic NaCl concentration of 9.0 g/L, CMPF - but not Jedi1 - significantly increased RBC phosphatidylserine exposure and icCa2+ levels; both effects were diminished by GsMTx-4.

Conclusion: Our findings support the hypothesis that CMPF may function as an endogenous activator of Piezo1, increase icCa2+ levels, trigger eryptosis, and, through this pathway, possibly shorten the RBC life span. To what extent these in vitro findings are operative in advanced CKD warrants clinical studies.

背景与假设:在晚期慢性肾病(CKD)患者中,红细胞(RBC)的寿命通常会缩短,这种情况可归因于 "尿毒症环境"。我们最近报告说,尿毒症溶质 3-羧基-4-甲基-5-丙基-2-呋喃丙酸酯(CMPF)与 Jedi1 有着相似的结构,Jedi1 是机械敏感性阳离子通道 Piezo1 的化学激活剂,激活 Piezo1 会增加细胞中的钙离子流入。在此背景下,我们假设 CMPF 可能会通过延长 CMPF 诱导的位于 RBC 上的 Piezo1 的活化时间来诱导 RBC 早死(红细胞沉降症)。为了验证这一假设,我们探讨了在尿毒症中发现的 CMPF 浓度是否会与位于 RBC 上的 Piezo1 相互作用、增加细胞内钙(icCa2+)并诱导红细胞凋亡:在有或没有 Piezo1 抑制剂 GsMTx-4 (2 µM)的情况下,用 CMPF 或 Jedi1(浓度均为 87 µM)培养健康人的红细胞。我们将 RBC 放入浓度为 3.0 至 9.0 克/升的 NaCl 溶液中进行渗透挑战,并测定其渗透脆性。通过流式细胞术,我们对孵育过的 RBC 的 icCa2+ 水平和磷脂酰丝氨酸暴露进行了量化,磷脂酰丝氨酸是红细胞凋亡的细胞标记物:结果:RBC 与 CMPF 和 Jedi1 一起孵育会显著增加 RBC 的渗透脆性,GsMTx-4 能阻止这种效应。在 6.0 g/L NaCl 条件下,与 CMPF 和 Jedi1 一起孵育会增加磷脂酰丝氨酸的暴露,并升高 RBC 的 icCa2+ 水平,这表明红细胞渗出增加。值得注意的是,在等渗 NaCl 浓度为 9.0 g/L 时,CMPF(而非 Jedi1)可显著增加红细胞磷脂酰丝氨酸暴露和 icCa2+ 水平;GsMTx-4 可减弱这两种效应:我们的研究结果支持这样的假设,即 CMPF 可作为 Piezo1 的内源性激活剂,增加 icCa2+ 水平,引发红细胞凋亡,并通过这一途径可能缩短红细胞的寿命。至于这些体外研究结果在晚期慢性肾功能衰竭中的作用程度,还有待临床研究。
{"title":"The uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) may enhance eryptosis and increase erythrocyte osmotic fragility through potential activation of Piezo1.","authors":"Beatriz Akemi Kondo Van Spitzenbergen, Gabriela Bohnen Andrade, Erika Sousa Dias, Júlia Bacarin Monte Alegre, Gabriela Ferreira Dias, Nadja Grobe, Andrea Novais Moreno-Amaral, Peter Kotanko","doi":"10.1093/ndt/gfae275","DOIUrl":"https://doi.org/10.1093/ndt/gfae275","url":null,"abstract":"<p><strong>Background and hypothesis: </strong>In patients with advanced chronic kidney disease (CKD), the lifespan of red blood cells (RBC) is often shortened, a condition attributed to the \"uremic milieu.\" We reported recently that the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) shares structural similarities with Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, whose activation increases calcium influx into cells. Against this backdrop, we hypothesized that CMPF may induce premature RBC death (eryptosis) through prolonged CMPF-induced activation of Piezo1 located on RBC. To test this hypothesis, we explored if CMPF, at concentrations found in uremia, interacts with Piezo1 located on RBC, increases intracellular calcium (icCa2+), and induces eryptosis.</p><p><strong>Methods: </strong>RBC from healthy individuals were incubated with CMPF or Jedi1 (both at a concentration of 87 µM), in the presence or absence of the Piezo1 inhibitor GsMTx-4 (2 µM). We challenged RBC osmotically through incubation in solutions of NaCl at concentrations between 3.0 and 9.0 g/L and determined their osmotic fragility. Using flow cytometry, we quantified in incubated RBC icCa2+ levels and phosphatidylserine exposure, a cellular marker of eryptosis.</p><p><strong>Results: </strong>Incubation of RBC with CMPF and Jedi1 significantly increased RBC osmotic fragility, an effect prevented by GsMTx-4. At 6.0 g/L NaCl, incubation with CMPF and Jedi1 increased exposure of phosphatidylserine and elevated icCa2+ levels of RBC, indicating increased eryptosis. Notably, at an isotonic NaCl concentration of 9.0 g/L, CMPF - but not Jedi1 - significantly increased RBC phosphatidylserine exposure and icCa2+ levels; both effects were diminished by GsMTx-4.</p><p><strong>Conclusion: </strong>Our findings support the hypothesis that CMPF may function as an endogenous activator of Piezo1, increase icCa2+ levels, trigger eryptosis, and, through this pathway, possibly shorten the RBC life span. To what extent these in vitro findings are operative in advanced CKD warrants clinical studies.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells. 脓毒症中的 CD38 结扎可促进肾脏基质细胞中烟酰胺磷酸核糖转移酶介导的 IL-6 生成。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-20 DOI: 10.1093/ndt/gfae269
Yuya Suzuki, Tadashi Otsuka, Yusuke Takahashi, Shingo Maruyama, Alexey Annenkov, Yasuhiro Kanda, Tomoya Katakai, Hirofumi Watanabe, Riuko Ohashi, Yoshikatsu Kaneko, Ichiei Narita

Background and hypothesis: Activated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe sepsis.

Methods: We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently, we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analyzed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and humans.

Results: LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signaling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 mRNA and NAMPT in renal stromal cells and CD38-positive macrophages, respectively.

Conclusion: Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signaling pathways between mice and human sepsis. NAMPT signaling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.

背景与假设:活化的巨噬细胞是驱动脓毒症免疫反应的关键,它表达高水平的 CD38。虽然其配体 CD31 的循环水平在脓毒症中会升高,但 CD38 及其结扎的功能仍然难以捉摸。本研究旨在利用单细胞和单核 RNA 测序(分别为 scRNA-seq 和 snRNA-seq)阐明 CD38 结扎对脓毒症的影响,从而确定治疗严重脓毒症的新靶点:我们对小鼠腹膜免疫细胞进行了scRNA-seq分析,以精确鉴定暴露于脂多糖(LPS)时CD38表达增加的细胞类型。随后,我们在 LPS 诱导的败血症小鼠模型中使用一种成熟的激动型抗 CD38 抗体诱导 CD38 结扎。我们利用肾脏 snRNA 序列分析了其病理生理效应。最后,我们对收集自患者的败血症组织进行了组织学分析,以确保我们的研究结果在小鼠和人类之间的一致性:结果:LPS刺激可上调腹腔巨噬细胞中CD38的表达。CD38结扎会明显加剧LPS诱导的体内炎症,尤其是在肾脏。肾脏 snRNA-seq 分析显示,CD38 结扎可通过源自 CD38 阳性巨噬细胞的烟酰胺磷酸核糖转移酶(NAMPT)信号诱导肾脏基质细胞产生白细胞介素(IL)-6。抑制 NAMPT 能明显改善 LPS 诱导的 IL-6 生成和肾损伤。人体败血症组织的组织学分析表明,肾基质细胞和 CD38 阳性巨噬细胞中的 IL6 mRNA 和 NAMPT 分别上调:我们的研究结果阐明了 CD38 结扎在 LPS 诱导的败血症模型中的意义,并发现了小鼠和人类败血症之间共享的信号通路。本研究中发现的 NAMPT 信号转导可能是减轻与严重败血症相关的全身炎症和肾损伤的新型治疗靶点。
{"title":"CD38 ligation in sepsis promotes nicotinamide phosphoribosyltransferase-mediated IL-6 production in kidney stromal cells.","authors":"Yuya Suzuki, Tadashi Otsuka, Yusuke Takahashi, Shingo Maruyama, Alexey Annenkov, Yasuhiro Kanda, Tomoya Katakai, Hirofumi Watanabe, Riuko Ohashi, Yoshikatsu Kaneko, Ichiei Narita","doi":"10.1093/ndt/gfae269","DOIUrl":"https://doi.org/10.1093/ndt/gfae269","url":null,"abstract":"<p><strong>Background and hypothesis: </strong>Activated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe sepsis.</p><p><strong>Methods: </strong>We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently, we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analyzed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and humans.</p><p><strong>Results: </strong>LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signaling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 mRNA and NAMPT in renal stromal cells and CD38-positive macrophages, respectively.</p><p><strong>Conclusion: </strong>Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signaling pathways between mice and human sepsis. NAMPT signaling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long-term outcomes of IgA nephropathy in China. 中国 IgA 肾病的长期疗效。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-19 DOI: 10.1093/ndt/gfae252
Xue Shen, Pei Chen, Muqing Liu, Lijun Liu, Sufang Shi, Xujie Zhou, Jicheng Lv, Hong Zhang

Background and hypothesis: The long-term prognosis of IgA nephropathy (IgAN) and the optimal target for proteinuria treatment remain controversial. This study, utilizing a large prospective cohort from China, aims to assess the long-term outcomes of IgAN and to explore the definition of proteinuria remission.

Methods: We enrolled 2 141 patients with biopsy-proven IgAN, all with at least 12 months of follow-up, from a prospective IgAN cohort at Peking University First Hospital. We utilized Kaplan-Meier analysis, Cox regression, and an eGFR slope calculated via a linear mixed model to investigate kidney outcomes.

Results: The median (Q1, Q3) baseline proteinuria was 1.26 (0.65, 2.40) g/d, and the estimated GFR was 80 (52, 103) mL/min/1.73m2. After a mean follow-up of 5.8 (±4.4) years, 509 (24%) patients progressed to end-stage kidney disease (ESKD). The median kidney survival time was 12.4 years, the annual event rate of ESKD was 41.1 per 1000 person-years, and the 15-year kidney survival rate was 40%. Time-averaged proteinuria level was strongly associated with kidney failure (adjusted HR: 1.76, 95%CI: 1.65 to 1.88). Restriction cubic spline analysis indicated that the risk of ESKD increases rapidly when time-average proteinuria exceeded 0.5 g/d. There was no significant difference in long-term kidney survival between patients with proteinuria < 0.3 g/d and those with 0.3-0.5 g/d, with both groups demonstrating a better prognosis.

Conclusion: The long-term outcomes for patients with IgAN under current treatment strategies remain poor, with most progressing to ESKD within 15 years. Patients with time-averaged proteinuria ≥ 0.5 g/d experience worse kidney outcomes, challenging the previous view that proteinuria < 1.0 g/d was associated with a low risk of kidney failure.

背景与假设:IgA肾病(IgAN)的长期预后和蛋白尿的最佳治疗目标仍存在争议。本研究利用来自中国的大型前瞻性队列,旨在评估 IgAN 的长期预后,并探讨蛋白尿缓解的定义:方法:我们从北京大学第一医院的前瞻性 IgAN 队列中招募了 2 141 名经活检证实的 IgAN 患者,所有患者均接受了至少 12 个月的随访。我们采用卡普兰-梅耶分析、Cox回归和线性混合模型计算的eGFR斜率来研究肾脏的预后:中位(Q1,Q3)基线蛋白尿为 1.26 (0.65, 2.40) g/d,估计 GFR 为 80 (52, 103) mL/min/1.73m2。平均随访 5.8 (±4.4) 年后,509(24%)名患者发展为终末期肾病(ESKD)。肾脏存活时间中位数为 12.4 年,ESKD 年发生率为每 1000 人年 41.1 例,15 年肾脏存活率为 40%。时间平均蛋白尿水平与肾衰竭密切相关(调整后 HR:1.76,95%CI:1.65 至 1.88)。限制立方样条分析表明,当时间平均蛋白尿超过 0.5 克/天时,ESKD 的风险迅速增加。蛋白尿患者的长期肾脏存活率没有明显差异:在目前的治疗策略下,IgAN 患者的长期预后仍然很差,大多数患者会在 15 年内发展为 ESKD。时间平均蛋白尿≥ 0.5 克/天的患者的肾脏预后较差,这对之前认为蛋白尿
{"title":"Long-term outcomes of IgA nephropathy in China.","authors":"Xue Shen, Pei Chen, Muqing Liu, Lijun Liu, Sufang Shi, Xujie Zhou, Jicheng Lv, Hong Zhang","doi":"10.1093/ndt/gfae252","DOIUrl":"10.1093/ndt/gfae252","url":null,"abstract":"<p><strong>Background and hypothesis: </strong>The long-term prognosis of IgA nephropathy (IgAN) and the optimal target for proteinuria treatment remain controversial. This study, utilizing a large prospective cohort from China, aims to assess the long-term outcomes of IgAN and to explore the definition of proteinuria remission.</p><p><strong>Methods: </strong>We enrolled 2 141 patients with biopsy-proven IgAN, all with at least 12 months of follow-up, from a prospective IgAN cohort at Peking University First Hospital. We utilized Kaplan-Meier analysis, Cox regression, and an eGFR slope calculated via a linear mixed model to investigate kidney outcomes.</p><p><strong>Results: </strong>The median (Q1, Q3) baseline proteinuria was 1.26 (0.65, 2.40) g/d, and the estimated GFR was 80 (52, 103) mL/min/1.73m2. After a mean follow-up of 5.8 (±4.4) years, 509 (24%) patients progressed to end-stage kidney disease (ESKD). The median kidney survival time was 12.4 years, the annual event rate of ESKD was 41.1 per 1000 person-years, and the 15-year kidney survival rate was 40%. Time-averaged proteinuria level was strongly associated with kidney failure (adjusted HR: 1.76, 95%CI: 1.65 to 1.88). Restriction cubic spline analysis indicated that the risk of ESKD increases rapidly when time-average proteinuria exceeded 0.5 g/d. There was no significant difference in long-term kidney survival between patients with proteinuria < 0.3 g/d and those with 0.3-0.5 g/d, with both groups demonstrating a better prognosis.</p><p><strong>Conclusion: </strong>The long-term outcomes for patients with IgAN under current treatment strategies remain poor, with most progressing to ESKD within 15 years. Patients with time-averaged proteinuria ≥ 0.5 g/d experience worse kidney outcomes, challenging the previous view that proteinuria < 1.0 g/d was associated with a low risk of kidney failure.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic testing in a national cohort of adults with chronic kidney disease of unknown origin. 全国不明原因慢性肾病成人队列中的基因检测。
IF 4.8 2区 医学 Q1 TRANSPLANTATION Pub Date : 2024-11-19 DOI: 10.1093/ndt/gfae270
Amber de Haan, Mark Eijgelsheim, Liffert Vogt, Ewout J Hoorn, Joris I Rotmans, Gijs Fortrie, Roos F J Marsman, Tonia C Rothuizen, H Siebe Spijker, Laura R Claus, Constantijn J A M Konings, Femke Waanders, Joan Doornebal, Andrea B Kramer, Aaltje Y Adema, Bert van der Zwaag, Albertien M van Eerde, Nine V A M Knoers, Martin H de Borst

Background and hypothesis: Chronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing.

Methods: In this prospective cohort study, we recruited patients with unexplained CKD (eGFR <60mL/min/1.73 m2 without underlying clinical diagnosis) with onset <50 years who underwent MPS-based multi-gene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent out to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing.

Results: A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients), and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N=71) included genetic illiteracy (53%), difficulties with test selection (51%), and lack of time (43%).

Conclusion: MPS-based multi-gene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset <50 years. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice.

背景和假设:至少有 20% 的慢性肾脏病(CKD)患者的病因不明。大规模平行测序(MPS)可作为不明原因慢性肾脏病患者的重要诊断工具,但来自常规临床实践的前瞻性数据十分有限。我们的目的是在现实世界中确定对不明原因的 CKD 患者进行基于 MPS 的基因组检测的诊断率和相关性。此外,我们还研究了实施基因检测的障碍:在这项前瞻性队列研究中,我们招募了不明原因的 CKD 患者(eGFR 结果):59/340名参与者(17%)发现了诊断变异。最常见的诊断变异位于 NPHP1(13 名患者)、COL4A3(12 名患者)、COL4A4(5 名患者)、COL4A5(6 名患者)和 PAX2(5 名患者)。在 73% 的患者中,基因诊断至少导致了一种临床后果。荷兰肾病专家(71 人)报告的主要障碍包括不了解遗传学知识(53%)、难以选择检测方法(51%)和缺乏时间(43%):结论:在不明原因的慢性肾脏病患者中,17% 的患者通过基于 MPS 的多基因面板检测获得了基因诊断。我们的研究结果支持 MPS 在对发病原因不明的成人慢性肾功能衰竭患者的诊断工作中的相关性。
{"title":"Genetic testing in a national cohort of adults with chronic kidney disease of unknown origin.","authors":"Amber de Haan, Mark Eijgelsheim, Liffert Vogt, Ewout J Hoorn, Joris I Rotmans, Gijs Fortrie, Roos F J Marsman, Tonia C Rothuizen, H Siebe Spijker, Laura R Claus, Constantijn J A M Konings, Femke Waanders, Joan Doornebal, Andrea B Kramer, Aaltje Y Adema, Bert van der Zwaag, Albertien M van Eerde, Nine V A M Knoers, Martin H de Borst","doi":"10.1093/ndt/gfae270","DOIUrl":"https://doi.org/10.1093/ndt/gfae270","url":null,"abstract":"<p><strong>Background and hypothesis: </strong>Chronic kidney disease (CKD) remains unexplained in at least 20% of patients. Massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD, but prospective data from routine clinical practice are limited. We aimed to determine the diagnostic yield and relevance of MPS-based gene panel testing in patients with unexplained CKD in a real-world context. We additionally examined barriers to implementation of genetic testing.</p><p><strong>Methods: </strong>In this prospective cohort study, we recruited patients with unexplained CKD (eGFR <60mL/min/1.73 m2 without underlying clinical diagnosis) with onset <50 years who underwent MPS-based multi-gene panel testing from 11 academic and non-academic hospitals across the Netherlands. In patients with a (likely) pathogenic variant, we verified that the variant likely explained the clinical phenotype. A nationwide online survey was sent out to all Dutch nephrologists and residents to investigate potential barriers for gene panel testing.</p><p><strong>Results: </strong>A diagnostic variant was identified in 59/340 participants (17%). Most common diagnostic variants were in NPHP1 (13 patients), COL4A3 (12 patients), COL4A4 (5 patients), COL4A5 (6 patients), and PAX2 (5 patients). A genetic diagnosis led to at least one clinical consequence in 73% of patients. Main barriers reported by Dutch nephrologists (N=71) included genetic illiteracy (53%), difficulties with test selection (51%), and lack of time (43%).</p><p><strong>Conclusion: </strong>MPS-based multi-gene panel testing yielded a genetic diagnosis in 17% of patients with unexplained CKD. Our findings support the relevance of MPS in the diagnostic workup of adults with unexplained CKD with onset <50 years. Additionally, our results underline the need to improve genetic education among nephrologists to better the implementation of MPS-based diagnostic testing in clinical practice.</p>","PeriodicalId":19078,"journal":{"name":"Nephrology Dialysis Transplantation","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Nephrology Dialysis Transplantation
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