Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders

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说明：

1. 本文初译者非医学专业人士。译文经由浙大二院肾内科牟利军医生详细校对，可作为临床参考和交流之用。
2. 为了便于后续发现问题，持续改进，保留原文英汉对照。不足之处，还请读者(特别是医学专业人士)不吝指正，谢谢！
3. 对于患者，以下内容不构成任何临床建议，亦不承担任何责任，具体诊断治疗请咨询您的医生。

作者：Martin Konrad✉️ [1], Tom Nijenhuis [2], Gema Ariceta [3], Aurelia Bertholet-Thomas [4], Lorenzo A Calo [5], Giovambattista Capasso [6], Francesco Emma [7], Karl P Schlingmann [8], Mandeep Singh [9], Francesco Trepiccione [6], Stephen B Walsh [10], Kirsty Whitton [11], Rosa Vargas-Poussou [12], Detlef Bockenhauer [13]

1. 德国明斯特大学医院普通儿科。Email：konradma@uni-muenster.de
2. 荷兰奈梅亨 Radboud 大学医学中心肾内科。
3. 西班牙巴塞罗那自治大学巴塞罗那瓦尔德希伯伦大学医院肾病儿科。
4. 克劳德伯纳德里昂第一大学, 里昂, 法国.
5. 意大利帕多瓦帕多瓦大学肾脏病学、透析、移植医学系 (DIMED)。
6. 意大利那不勒斯坎帕尼亚大学“Luigi Vanvitelli”医学院转化医学系肾脏科。
7. 意大利罗马 Bambino Gesù 儿童医院 IRCCS，肾脏科儿科专科。
8. 德国明斯特大学医院普通儿科。
9. 英国埃塞克斯郡绍森德大学医院 NHS 信托基金会胎儿医学中心。
10. 英国伦敦大学学院肾脏医学系。
11. 英国伦敦。
12. 乔治·蓬皮杜欧洲医院、巴黎公共援助医院、临床调查中心, 巴黎, 法国；儿童和成人遗传性肾脏疾病参考中心，巴黎，法国。
13. 英国伦敦大学学院肾脏医学系；英国伦敦 NHS 基金会信托大奥蒙德街儿童医院儿科肾脏科。

Kidney International (2021) 99, 324–335; https://doi.org/10.1016/j.kint.2020.10.035 https://www.kidney-international.org/article/S0085-2538(20)31404-6/fulltext31404-6/fulltext) （正式发表版本） Diagnosis and management of Bartter syndrome - 2021.pdf

https://www.erknet.org/guidelines-pathways/tubulopathies/bartter-syndrome （未删减版本） Barttersyndrome_consensus_paper__extended_version.pdf

以下基于Kidney International发表版本翻译

摘要 Abstract

Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.

巴特综合征是一种罕见的遗传性失盐性肾小管疾病，以继发性醛固酮增多伴低钾、低氯性代谢性碱中毒、低至正常血压为特征。其主要致病机制是主要发生在髓袢升支粗段的盐重吸收障碍。该疾病的临床表现存在显著的差异，其遗传异质性来自于迄今为止已描述的5种不同基因。尽管有相当多的表型重叠，但已经证实特定临床特征与基础的分子缺陷之间存在相关性，从而产生基因特异性表型。与很多其他罕见病一样，能指导诊断和治疗性干预的临床研究缺乏。在这份专家共识文件中，作者们总结了目前已知的知识，并提出了评估和提高医疗质量的临床指标。

Keywords：Bartter syndrome，hypokalemic metabolic alkalosis，inherited hypokalemia，salt-losing tubulopathy

关键词：巴特综合征、低钾性代谢性碱中毒、遗传性低钾血症、失盐性肾小管病

正文

The term Bartter syndrome (BS) encompasses different inherited salt-losing tubulopathies characterized by polyuria, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. Five different forms (BS1–5), based on molecular genetics, have been identified to date (Table 1).1

巴特综合征(BS)包括以多尿、低钾血症、低氯性代谢性碱中毒和血压正常的高肾素高醛固酮血症为特征的多种不同的遗传性失盐性肾小管病。基于分子遗传学，迄今为止已确认5种不同类型的BS（BS 1~5)【表1】[1]

【表1】巴特综合征的分子遗传学

Table 1Molecular genetics of Bartter syndrome

OMIM, 在线人类孟德尔遗传病目录 AR, 常染色体隐性遗传 XLR, X-linked recessive X连锁隐性遗传

Clinical characteristics include polyuria, dehydration, failure to thrive, growth retardation, and a medical history of polyhydramnios with premature birth. Hypercalciuria and nephrocalcinosis are typical for some forms. BS is a potentially life-threatening condition necessitating rapid diagnosis and therapy.The primary molecular defect in all types of BS leads to impaired salt reabsorption in the thick ascending limb of the loop of Henle.[2] Regardless of the underlying molecular defect, mutations result in renal tubular salt wasting with activation of the renin-angiotensin system and consequent hypokalemic and hypochloremic metabolic alkalosis. In addition, the tubuloglomerular feedback is altered at the level of the macula densa, which, under physiologic conditions, senses low tubular chloride concentrations in conditions of volume contraction. This activates cyclooxygenases (primarily COX-2) to produce high amounts of prostaglandins (primarily prostaglandin E2), which in turn stimulate renin secretion and aldosterone production, in the attempt to reestablish normal intravascular volume and glomerular perfusion.[3] In BS, the tubuloglomerular feedback is uncoupled because chloride is not reabsorbed in the macula densa owing to the underlying molecular defects. Therefore, cells produce high amounts of prostaglandin E2 regardless of volume status, causing excessive synthesis of renin and aldosterone. This constitutes the rationale for treating BS patients with prostaglandin synthesis inhibitors, which often results in noticeable clinical improvement.[4] [5] [6]

临床特征包括多尿、脱水、发育停滞、生长迟缓以及羊水过多伴早产的病史。高钙尿症和肾钙质沉着症是有一些类型BS的典型表现。BS是一种可能危及生命的疾病，需要快速的诊断和治疗。所有类型BS的主要分子缺陷均会导致髓袢升支粗段盐重吸收功能受损[2]。无论何种基础的分子缺陷，基因突变均导致肾小管盐丢失伴肾素-血管紧张素系统激活，以及随之而来的低钾和低氯性代谢性碱中毒。此外，管球反馈在致密斑水平发生改变。即，在生理条件下，当容量减少时，致密斑可感知到（肾小管腔中的）低氯离子浓度。这会激活环氧合酶（主要是COX-2）产生大量前列腺素（主要是前列腺素E2），进而刺激肾素分泌和醛固酮生成，以试图恢复正常的血容量和肾小球灌注[3]。在BS中，因为基础的分子缺陷，氯离子在致密斑中不会被重吸收，造成管球反馈的机制失灵。因此，无论容量状态如何，细胞都会产生大量前列腺素E2，从而引起肾素和醛固酮的过度合成。这构成了使用前列腺素合成抑制剂治疗BS患者的基本原理，前列腺素合成抑制剂通常会带来明显的临床改善。[4] [5] [6]

Impaired salt reabsorption in the thick ascending limb has 2 additional consequences that are important in BS, namely
(i) a reduction of calcium reabsorption with hypercalciuria and progressive medullary nephrocalcinosis,7,8 and
(ii) a reduction or complete blunting of the osmotic gradient in the renal medulla, causing isosthenuria, i.e., an impaired ability to dilute or concentrate the urine.9
An exception is seen in most patients with BS3, who have a milder defect without hypercalciuria and partial capacity to concentrate the urine.

在BS中，髓袢升支粗段的盐重吸收受损带来2个重要的额外后果，即：

• (i)钙重吸收减少导致的高钙尿症和进行性肾髓质钙质沉着症[7] [8]，和
• (ii)肾髓质中渗透梯度的减少或完全减弱，引起的等渗尿，即尿液稀释或浓缩能力受损[9]。

大多数BS3患者是一个例外情况。他们的缺陷较轻，无高钙尿，并保留了部分尿液浓缩能力。

To date, 5 different causative genes have been identified (Table 1; Figure 1), encoding proteins directly involved in salt reabsorption in the thick ascending limb (BS1–4) or regulating their expression (BS5). The mode of inheritance is autosomal recessive in BS1–410, 11, 12, 13, 14 and X-linked recessive in BS5.15

迄今为止，已经确定了5种不同的致病基因【表1】【图1】，这些基因编码的蛋白直接参与髓袢升支粗段盐重吸收(BS1-4)或调节其表达(BS5)。BS1-4的遗传方式为常染色体隐性遗传[10] [11] [12] [13] [14]，BS5为X连锁隐性遗传[15]。

Figure 1 Pathophysiology of Bartter syndrome.
Schematic model of salt transport in the thick ascending limb and the distal convoluted tubule with associated defects in Bartter syndrome (BS) indicated.

1. In the thick ascending limb, NaCl is reabsorbed by the NaK2Cl cotransporter NKCC2, which is mutated in BS type 1.
2. Here, the potassium ion is recycled into the tubular lumen via the apical potassium channel KCNJ1 (ROMK), which is mutated in BS type 2.
3. In the distal convoluted tubule, NaCl enters the tubular epithelium via the NaCl cotransporter NCC. In both tubular segments, chloride leaves the cell on the basolateral side through chloride-permeable ion channels ClC-Ka and ClC-Kb. A molecular defect of ClC-Kb causes BS type 3. Mutations in either the accessory subunit barttin or a combined defect of both chloride channels ClC-Ka and ClC-Kb result in BS types 4a and 4b.
4. Finally, transient BS type 5 is caused by mutations of MAGE-D2. MAGE-D2 stimulates trafficking by protecting NKCC2 and NCC from intracellular degradation via HSP40 and promotes apical targeting of NKCC2 and NCC via Gs-alpha.[20]

【图1】Bartter综合征的病理生理学

（如图所示）BS相关缺陷的髓袢升支粗段和远曲小管中的盐转运图解模型：

1. 在髓袢升支粗段，NaCl被NaK2Cl共同转运蛋白NKCC2重吸收，NKCC2在BS1型中发生突变。
2. 在此（髓袢升支粗段），钾离子通过顶端侧钾通道KCNJ1(ROMK)再循环到肾小管腔内，ROMK在BS 2型中发生突变。
3. 在远曲小管中，NaCl通过NaCl共同转运蛋白NCC进入小管上皮细胞。在这两个肾小管节段中，，氯离子通过氯离子渗透性离子通道ClC-Ka和ClC-Kb从基底侧离开小管上皮细胞。ClC-Kb的分子缺陷引起BS 3型。辅助亚单位barttin的突变或氯离子通道ClC-Ka和ClC-Kb的联合缺陷导致BS4a和4b型。
4. 最后，一过性BS5型是由MAGE-D2的突变引起的。MAGE-D2通过保护NKCC2和NCC免于被HSP40在细胞内降解来刺激运输，并通过Gs-α促进NKCC2和NCC的顶端靶向定位。[20]

Clinical characteristics, such as severity of biochemical abnormalities, presence of polyhydramnios and preterm delivery, degree of calciuria with or without medullary nephrocalcinosis, and presence of sensorineural deafness show typical gene-specific patterns. Several patients with BS3 have clinical features that are virtually indistinguishable from Gitelman syndrome (GS), another salt-losing tubulopathy.[1]

Most patients with BS receive supplementation with sodium chloride, potassium chloride and fluids that are adjusted individually based on symptoms, tolerability, severity of the tubulopathy, age of the patient and glomerular filtration rate. In addition, nonsteroidal antiinflammatory drugs (NSAIDs) are for most patients a mainstay of treatment,[16] at least during the first years of life (except in transient BS5). The use of other therapies, such as potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, have been reported in the literature, but evidence supporting their efficacy, tolerability, and safety is limited.

临床特征表现出典型的基因特异性模式，如：生化异常的严重程度、是否存在羊水过多和早产、伴或不伴髓质肾钙质沉着的尿钙程度、是否存在感音神经性耳聋等。一些BS3患者的临床特征与另一种失盐性肾小管病Gitelman综合征(GS)几乎无法区分。[1]

大多数BS患者接受氯化钠、氯化钾和液体补充。用量根据症状、耐受性、肾小管病的严重程度、年龄和肾小球滤过率进行个体化调整。此外，非甾体抗炎药(NSAIDs)，对大多数患者的治疗而言，是最重要基础用药[16]。至少在出生后第一年是如此（短暂BS5除外）。文献中已报道其他治疗方案，如保钾利尿剂、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂，但支持其疗效、耐受性和安全性的证据有限。

Despite significant gain in knowledge since the genetic elucidation of these diseases, information on long-term outcome of BS is almost completely lacking. In particular, the risk of chronic renal failure and its potential relationship to prolonged use of NSAIDs, chronic hypokalemia, and chronic hypovolemia is not well documented. Likewise, little information exists on the incidence of secondary hypertension and cardiac arrhythmias. Other open questions include optimal diagnostic approaches, particularly in the neonatal period, and the best therapeutic strategies based on outcome data. Also, the best management of BS during pregnancy has not been established.

自从这些疾病的（致病）基因被阐明以来，尽管获得了相当多的BS知识，但关于BS长期结局方面的信息几乎是完全缺乏的。尤其是慢性肾衰竭的风险，及其与长期使用NSAIDs、慢性低钾血症和慢性血容量不足的潜在关系尚未被充分证实。同样，关于继发性高血压和心律失常发生率的信息也很少。其他悬而未决的问题包括最佳诊断方法，特别是在新生儿期，以及基于结局数据的最佳治疗策略。此外，妊娠期间BS的最佳管理方法也尚未建立。

Therefore, an interdisciplinary group of experts was assembled under the umbrella of the European Rare Kidney Disease Reference Network to develop recommendations for the diagnosis and management of patients with BS (for full version, see Konrad et al.[17]). The recommendations are listed in Box 1, Box 2, Box 3. It is beyond the scope of this executive summary to discuss each recommendation in detail. Instead, we highlight the significant underlying concepts. The recommendations are endorsed by the European Society for Paediatric Nephrology and the Working Group on Inherited Kidney Disorders of the European Renal Association–European Dialysis and Transplantation Association.

因此，我们组建了一个隶属于欧洲罕见肾病指导网络的跨学科专家小组，以制定BS患者诊断和管理的建议（完整版本见Konrad et al.[17]）。这些推荐建议已在【框1】、【框2】、【框3】中列出。详细讨论每项建议超出了本执行摘要的范围。相反，我们旨在强调重要的基本理念。这些建议得到了欧洲儿科肾病学会和欧洲肾脏协会-欧洲透析和移植协会遗传性肾病工作组的支持。

方法 Methods

The consensus process was initiated by European Rare Kidney Disease Reference Network. Two groups were assembled: a consensus core group and a voting panel. The core group comprised specialists for pediatric and adult nephrology, genetics, and obstetrics and a patient representative. The voting group included 36 members with special expertise in Bartter syndrome.

The core group performed a systematic literature review via the PubMed and Cochrane databases through October 15, 2018. The following key MeSH terms were used: Bartter syndrome, inherited hypokalemic alkalosis, SLC12A1, KCNJ1, CLCNKA, CLCNKB, BSND, and MAGED2. The search retrieved 2218 results, and 135 articles were referenced in the full version.[17]

本共识程序由欧洲罕见肾病指导网络发起。成立了两个小组：一个共识核心小组和一个投票小组。核心小组由儿科和成人肾病学、遗传学和产科专家以及一位患者代表组成。投票小组包括36名在BS方面具有专业知识的成员。

核心小组通过PubMed和Cochrane数据库进行了系统性文献综述，截止日期为2018年10月15日。使用了以下关键MeSH术语：巴特综合征、遗传性低钾性碱中毒、SLC12A1、KCNJ1、CLCNKA、CLCNKB、BSND和MAGED2。检索获得了2218条结果，在本论文完整版本中引用了135篇文章。[17]

Initial recommendations were developed during a first meeting by discussion in thematic workgroups and plenary sessions. Evidence and recommendations were graded (whenever possible) according to the method used in the current American Academy of Pediatrics guidelines. [18] [19] A first written draft was compiled and reviewed by the consensus core group. Remaining gaps were identified by a second meeting. Consequently, 2 rounds of anonymous voting were performed using the Delphi method until at least 70% support was reached for each individual recommendation.

在第一次会议期间，通过专题工作组和全体会议的讨论提出了初步建议。根据现行美国儿科学会指南中使用的方法对证据和建议进行分级（尽可能）。[18] [19] 第一份书面草案由共识核心小组汇编并审查后，剩余缺漏在第二次会议确定。最终，每项建议均使用德尔菲法（Delphi method）进行了2轮匿名投票，直到获得至少70%的支持。

诊断 Diagnosis

【框1】巴特综合征诊断建议

See Box 1. For details, see Konrad et al.[17]
详情见Konrad et al. [17]

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框1 巴特综合征诊断建议

Recommendations for diagnosis of Bartter syndrome | | —- | |

产前期 Prenatal period

1. During pregnancy, a diagnosis of (antenatal) BS should be considered in the presence of a polyhydramnios of fetal origin (grade C, weak recommendation).
1. We do not recommend the assessment of electrolytes and/or aldosterone from amniotic fluid for prenatal diagnosis of BS (grade C, moderate recommendation).
1. Molecular genetic testing can be applied for prenatal diagnosis; however, recommendations should be adapted to country-specific ethical and legal standards and communicated with appropriate genetic counseling (grade D, weak recommendation).
1. Whenever genetic testing is unavailable, the assessment of the “Bartter index” (AFP × total protein) in the amniotic fluid might be considered for prenatal diagnosis of BS (grade C, weak recommendation).


1. 在妊娠期间，如果存在胎儿来源的羊水过多，应考虑诊断为（产前型）BS （C级，弱推荐）。
1. 我们不建议通过检测羊水中的电解质和/或醛固酮进行BS的产前诊断（C级，中度推荐）。
1. 分子遗传学检测可应用于产前诊断；但此建议应根据具体国家的伦理和法律标准调整适应，并进行适当的遗传咨询（D级，弱推荐）。
1. 当不能进行基因检测时，可考虑通过测定羊水中的“Bartter指数”（甲胎蛋白 × 总蛋白）进行BS的产前诊断（C级，弱推荐）。

产后期 Postnatal period

1. Postnatally, a diagnosis of BS should be considered in the presence of renal salt wasting, polyuria, rapid weight loss, and signs of dehydration. Failure to thrive, recurrent vomiting, repeated fever, hypochloremic and hypokalemic metabolic alkalosis, and nephrocalcinosis should raise the suspicion of BS beyond the neonatal period (grade C, moderate recommendation),
1. For initial diagnostic work-up, we recommend the following (grade C, moderate recommendation):
1. Evaluation of medical history including polyhydramnios, premature birth, growth failure, and family history.
1. Biochemical parameters: serum electrolytes (sodium, chloride, potassium, calcium, magnesium), acid-base status, renin, aldosterone, creatinine, fractional excretion of chloride, and urinary calcium-creatinine ratio.
1. Renal ultrasound to detect medullary nephrocalcinosis and/or kidney stones.
1. We recommend confirming the clinical diagnosis of BS by means of genetic analysis whenever possible (grade B, moderate recommendation).
1. We suggest offering genetic counseling for families with probands with confirmed clinical and/or genetic diagnosis of BS (grade D, weak recommendation).
1. We do not recommend tubular function tests with furosemide or thiazides for patients with suspected BS if genetic testing is accessible (grade D, moderate recommendation).


1. 出生后，出现肾性失盐、多尿、体重迅速减轻和脱水体征时，应考虑BS诊断。新生儿期过后，出现发育停滞、反复呕吐、反复发热、低氯和低钾代谢性碱中毒，以及肾钙质沉着的，应引起对BS的怀疑（C级，中度推荐），
1. 对于初步诊断检查，我们建议如下（C级，中度建议）：
1. 病史评价，包括羊水过多、早产、生长停滞和家族史。
1. 生化参数：血清电解质（钠、氯、钾、钙、镁）、酸碱状态、肾素、醛固酮、肌酐、尿氯排泄分数和尿钙/尿肌酐比值。
1. 肾脏超声检测髓质肾钙质沉着症和（或）肾结石。
1. 我们建议尽可能通过基因分析确定BS的临床诊断（B级，中度推荐）。
1. 我们建议对临床和/或基因诊断为BS（D级，弱推荐）的先证者家系提供遗传咨询。
1. 如果可进行基因检测，我们不建议对疑似BS的患者通过呋塞米或噻嗪类利尿剂试验进行肾小管功能检查（D级，中度推荐）。

> AFP, alpha fetoprotein 甲胎蛋白; BS, 巴特综合征.

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一般方法 General approach

The diagnosis of BS is primarily based on clinical, biochemical and sonographic findings (Box 1). Even if the different subtypes of BS can usually be characterized clinically (Table 2[20] [21]), we recommend genetic analysis for confirmation.

BS的诊断主要基于临床、生化和超声检查结果【框1】。即使BS的不同亚型通常有不同的临床特点【表2】[20] [21]，我们仍建议做基因分析进行确认。

【表2】 不同类型的BS的主要临床和生化特征

Table 2 Main clinical and biochemical characteristics of different types of Bartter syndrome

CKD, chronic kidney disease 慢性肾病; ESRD end-stage renal disease 终末期肾病; IQR, interquartile range 四分位距（25%~75%）. Data from Komhoff and Laghmani[20] and Legrand et al.[21]

扩展阅读：
UpToDate-遗传性失盐性肾小管病类型-The inherited salt-wasting renal tubulopathies.pdf

产前的诊断检查 Antenatal diagnostic work-up

Early polyhydramnios of fetal origin should raise the clinical suspicion of BS. In principle, there are 2 possible options to confirm the diagnosis: (i) prenatal genetic testing and (ii) biochemical analysis of amniotic fluid. Both measures are invasive and carry the risk of procedure-related complications.

However, whenever prenatal diagnosis is indicated, we consider genetic testing to be the most reliable method. In situations, where prenatal genetic testing is not available or diagnostic, the assessment of the “Bartter index” (total protein × alfa-fetoprotein) may be considered[22]. In larger studies, other parameters, such as high chloride or aldosterone levels, failed to distinguish between amniotic fluid from polyhydramnios related to other causes and control pregnancies[23] [24].

胎儿来源的早期羊水过多应提高临床上对BS可能性的怀疑。原则上，可通过2种可能的手段进行确诊：(i) 产前基因检测，和(ii) 羊水生化分析。这两种措施都是有创的，存在手术相关并发症的风险。

然而，每当有产前诊断指征时，我们认为基因检测是最可靠的方法。在产前基因检测未做或不能诊断的情况下，可考虑评估“Bartter指数”（总蛋白 × α-甲胎蛋白）[22]。在更大规模的研究中，其他参数（如高氯或醛固酮水平）未能将BS与其他原因相关的羊水过多与对照妊娠组相区别[23] [24]。

产后的检查诊断 Postnatal diagnostic work-up

The diagnostic work-up for BS after birth should include a detailed clinical evaluation asking for a family history of pregnancy complicated by polyhydramnios with or without premature birth, and a medical history of polyuria, episodes of dehydration, unexplained fever, failure to thrive, and recurrent vomiting. In children, growth charts are very helpful to assess the development of height and weight. Additional clinical signs may include salt craving, muscle weakness, low blood pressure, and pubertal delay.

Laboratory analysis for suspected BS should include the parameters listed in Box 1. The assessment of urinary prostaglandin excretion (prostaglandin E2) may be helpful, although this procedure is not feasible in a routine clinical setting. For definitive diagnosis, we recommend genetic testing.

出生后，BS的诊断检查应包括：详尽的临床评价；询问妊娠并发羊水过多伴（或不伴）早产的家族史；以及多尿、脱水发作、不明原因发热、发育停滞和反复呕吐的病史。在儿童中，生长曲线图对于评估身高和体重的发育很有帮助。其他的临床体征可能包括嗜盐、肌无力、低血压和青春期延迟。

疑似BS应做的实验室分析包括【框1】中列出的项目。尿前列腺素排泄（前列腺素E2）的评估可能有帮助，但该检查在常规临床条件下难以开展。为了得到明确诊断，我们建议进行基因检测。

不同类型BS的临床特征 Clinical characteristics of different types of BS

Key clinical and biochemical findings in patients with BS are detailed below and in Table 2, with a special focus on gene-specific differences between the known subtypes of BS. For differential diagnosis, see the Differential Diagnosis section below.
BS患者的关键临床和生化检查结果详见下文和【表2】，特别关注BS已知亚型之间的基因特异性差异。关于鉴别诊断，请参见下文的【鉴别诊断】章节。

症状出现年龄 Age at presentation

1. BS causes polyhydramnios, leading to premature birth in the majority of patients.
2. Polyhydramnios typically develops between the 20th and 30th weeks of gestation. Timing and severity vary according to the underlying genetic defect. In BS4 and BS5, polyhydramnios is typically observed earlier than in BS1 and BS2[15] [20] [21] [25] .
3. BS5 always presents antenatally, but symptoms spontaneously resolve typically around the estimated date of delivery.
4. BS3 usually manifests later in life. Nevertheless, a prenatal presentation does not exclude BS3. The vast majority of patients with BS3 are diagnosed after the age of 1 year[26~32]. Patients typically present with failure to thrive, poor weight gain, or polyuria with polydipsia. Less frequent symptoms are related to dehydration. Most patients exhibit salt craving, although this is rarely a presenting symptom.

5. In a minority of cases, the diagnosis of BS is incidental after noticing abnormal laboratory results, discovery of nephrocalcinosis, or family screening.

6. BS引起羊水过多，导致大多数患儿早产。

7. 羊水过多通常在妊娠第20周至第30周期间发生。发生时间和严重程度因基础的遗传缺陷而异。BS4和BS5通常比BS1和BS2更早观察到羊水过多现象[15] [20] [21] [25]。
8. BS5总是在产前出现，但症状通常在预产期前后自发缓解。
9. BS3通常在生长后期表现出来。然而，BS3并不排除产前表现的可能性。绝大多数BS3患者在1岁后确诊[26~32]。患者通常表现为发育停滞、体重难以增加或多尿伴多饮烦渴。较少见脱水相关症状，大多数患者表现出嗜盐，尽管这很少是一种主要症状。
10. 在少数病例中，BS的诊断是在发现实验室检查结果异常、肾钙质沉着或家族史筛查后，偶然发现的。

失盐，血钾/氯/镁，碳酸氢根水平 Salt wasting, plasma potassium, chloride, magnesium, and bicarbonate levels

1. After birth, the first symptom is often hypovolemia from renal salt loss.
2. Hypochloremic and hypokalemic metabolic alkalosis may not be present during the first days of life.
3. Infants with BS2 often have transient neonatal acidosis and hyperkalemia and, on average, hypokalemia and alkalosis are less pronounced during follow-up.
4. In contrast, patients with BS3 and BS4 tend to have the lowest plasma potassium levels and the most pronounced hypochloremic alkalosis.

5. In some patients with BS3, hypomagnesemia may be present.

6. 出生后，首发症状通常为肾性失盐导致的血容量不足。

7. 出生后最初几天可能不会出现低氯和低钾代谢性碱中毒。
8. BS2婴儿常出现一过性的新生儿酸中毒和高钾血症，低钾血症和碱中毒通常在随访时较不明显。
9. 相反，BS3和BS4患者的血钾水平往往最低，低氯性碱中毒最为明显。
10. 在一些BS3患者中，可能出现低镁血症。

尿钙和肾钙质沉着症 Calciuria and nephrocalcinosis

1. Hypercalciuria with subsequent nephrocalcinosis occurring after 1–2 months of life is a typical feature of BS1 and BS2. Although computerized tomography provides more accurate assessment of renal calcifications than renal ultrasound, it is associated with radiation burden and thus should be reserved for clinical situations where there is a direct therapeutic consequence, e.g., localization of stones in obstructive uropathy which may occur in rare cases in BS.
2. In contrast, patients with BS3 and BS4 usually have normocalciuria, although hypercalciuria may occur.
3. Interestingly, hypocalciuria has also been reported in patients with BS3, and these patients mimic the phenotype of GS.

4. In transient BS5, hypercalciuria may be observed, but nephrocalcinosis is a rare finding.

5. 出生1-2个月后，高钙尿以及随后发生的肾钙质沉着症是BS1和BS2的典型特征。与肾脏超声相比，尽管CT检查可更准确地评估肾脏钙质沉着状况，但其涉及到辐射负荷，因此应该保留到出现有直接治疗结果的临床状况时使用。例如用于BS中罕见情况下可能发生的阻塞性尿路病中的结石定位。

6. 相反，BS3和BS4患者通常钙尿正常，但也可能出现高钙尿。
7. 有趣的是，在BS3患者中也报告了低钙尿，这些患者有类似GS的表型。
8. 在一过性BS5中，可能观察到高钙尿，但罕见肾钙质沉着症。

基因检测 Genetic testing

1. We recommend offering genetic testing with the use of a gene panel to all patients with a clinical suspicion of BS. Recommendations for genes to be included in the panel are detailed in Table 331404-6/fulltext#tbl3).
2. The detection of pathogenic variants in genes responsible for BS is crucial to confirm the clinical diagnosis and for genetic counseling.
3. An early genetic diagnosis may help in resolving difficult cases with overlapping phenotypes. In addition, the identification of the genetic defect may prompt screening for and treatment of deafness in patients with BS4 and for avoiding aggressive treatments in transient BS5.
4. Analytical sensitivity in BS is 90%–100%, and clinical sensitivity is ∼75% in children2131404-6/fulltext#bib21),2731404-6/fulltext#bib27),3331404-6/fulltext#bib33) but only 12.5% in adult patients.3431404-6/fulltext#bib34) This difference is possibly related to the broader differential diagnosis (especially abuse of diuretics and laxatives) in adults and the higher proportion of patients with BS3 because the analysis of CLCNKB is technically challenging.
5. Although large rearrangements can be detected by next-generation sequencing, it is recommended to confirm them by a second independent method (e.g., multiplex ligation-dependent probe amplification). Large rearrangements are particularly frequent in the CLCNKB gene but have also been described in KCNJ1, BSND, and MAGED2.1331404-6/fulltext#bib13),2131404-6/fulltext#bib21),3531404-6/fulltext#bib35)
6. Genetic counseling should be offered to any family affected by BS. Counseling should include cascade screening. Testing relatives is particularly useful to identify heterozygous female carriers in families with an index case carrying a MAGED2 mutation.

7. Prenatal diagnosis and preimplantation genetic diagnosis are technically feasible after reliable genetic counseling and may be considered on an individual basis, according to national ethical and legal standards.

8. 我们建议对所有临床疑似BS的患者使用基因组合（panel）方式进行基因检测。Panel中建议包括的基因详见【表3】。

9. BS相关基因中的致病突变的检测对于确定临床诊断和遗传咨询至关重要。
10. 早期基因诊断可能有助于解决表型重叠的疑难病例。此外，基因缺陷的鉴定可能促进对BS4患者进行耳聋筛查和治疗，并避免对一过性的BS5进行过度治疗。
11. BS的基因检测分析敏感性为90%-100%，儿童中的临床敏感性约为75%[21] [27] [33]，但成人患者中的敏感性仅为12.5%[34]。34这种差异可能与成人中更广泛的鉴别诊断（尤其是利尿剂和泻药滥用）以及BS3患者比例更高有关，因为CLCNKB的分析在技术上颇有挑战。
12. 虽然新一代测序可以检测到大片段重排，但建议通过另外独立的方法（如MLPA）进行确认。大片段重排在CLCNKB基因中特别常见，但也可见于KCNJ1、BSND和MAGED2。[13] [21] [35]
13. （医院）应向所有BS患者家庭提供遗传咨询。咨询应包括家系级联筛查。亲属基因检测对于在指示病例（先证者）携带一个MAGED2突变的家系中的女性杂合携带者的鉴别特别有用。
14. 经可靠的遗传咨询后，产前诊断和胚胎植入前遗传学诊断在技术上是可行的。可根据本国伦理和法律标准，视个体情况予以考虑。

【表3】 巴特综合征基因检测中应包括的建议基因

Table 3 Genes recommended to be included in genetic testing for Bartter syndrome

1. ADH, autosomal dominant hypocalcemia 常染色体显性遗传低钙血症
2. AME, apparent mineralocorticoid excess 盐皮质激素假性增多症
3. BS, Bartter syndrome 巴特综合征
4. CCD, congenital chloride diarrhea 先天性失氯性腹泻
5. EAST, epilepsy, ataxia, sensorineural deafness, tubulopathy 癫痫、共济失调、感音神经性耳聋、肾小管病
6. HALD, familial hyperaldosteronism 家族性醛固酮增多症
7. HELIX, hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, xerostomia 少汗、电解质紊乱、泪腺功能障碍、鱼鳞病、口干
8. MIM, Mendelian Inheritance in Man 人类孟德尔遗传（疾病目录）
9. PHA, pseudohypoaldosteronism 假性醛固酮减少症

Listed are genes to be considered in the (differential) diagnosis of BS and therefore should be included in a panel of genes for genetic testing.

a Genes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can biochemically mimic BS.

列出的是BS（鉴别）诊断中考虑的基因，因此应包含在一个基因组合（panel）中进行基因检测。

a 第2-8行中的基因应包括在最小诊断基因组（panel）中，即：BS以及Gitelman综合征的基础基因，GS在临床上可能难以与BS3区分。列表中其他基因，可以与BS存在表型重叠。BS2在新生儿期可与假性醛固酮减少症1型(PHA1)类似。列出的高血压疾病可以在生化检查上与BS类似。

鉴别诊断 Differential Diagnosis

1. The differential diagnosis of BS depends on the age at presentation and the specific context (Table 431404-6/fulltext#tbl4); for details, see Konrad et al.1731404-6/fulltext#bib17)).
2. Polyhydramnios due to excessive fetal polyuria is virtually always caused by BS. There are no reports of other inherited tubular disorders causing severe polyhydramnios. In particular, polyhydramnios is not a feature in severe proximal tubulopathies nor in nephrogenic diabetes insipidus. There are reports of polyhydramnios in infants misdiagnosed with pseudohypoaldosteronism type I, but these cases have later been shown to harbor KCNJ1 mutations underlying BS2.27,36
3. Congenital chloride diarrhea can be confused with BS. Pregnancies are often complicated by polyhydramnios with preterm delivery (usually not severe).37 Postnatally, this disease causes pronounced hypokalemic and hypochloremic metabolic alkalosis secondary to watery diarrhea.
4. Pseudo-Bartter syndrome is occasionally observed in cystic fibrosis because of salt loss in sweat.
5. Presentation beyond infancy, especially in adolescence or even adulthood (most often BS3), makes GS a primary consideration in those patients with hypocalciuria and/or hypomagnesemia. Patients with hepatocyte nuclear factor 1β nephropathy may also present with hypokalemic alkalosis and hypomagnesemia.38 Other rare tubulopathies exhibiting metabolic alkalosis are listed in Table 4.
6. Some patients with BS primarily present with nephrocalcinosis and/or urolithiasis. A young age at onset of kidney stone disease should raise the clinical suspicion of a specific underlying cause, including (incomplete) distal renal tubular acidosis.
7. If the presenting sign is hypokalemia, the initial differential diagnosis is wide. In this context, it is important to distinguish renal from gastrointestinal potassium loss and potassium shifts. If primary hyperaldosteronism and diuretic and/or laxative use or abuse are excluded, the differential diagnosis narrows down to rare tubulopathies (Table 4).

8. Urinary chloride excretion assessed by either fractional chloride excretion or urinary sodium/chloride ratio is helpful to distinguish renal from extrarenal salt losses. In BS, fractional chloride excretion is usually elevated (>0.5%).32

9. BS的鉴别诊断取决于症状出现的年龄和具体情形（【表4】；详情见Konrad et al.）[17]。

10. 由于胎儿多尿导致的羊水过多几乎总是由BS引起。尚无引起严重羊水过多的其他遗传性肾小管疾病的报道。特别是羊水过多不是严重近端小管病的特征，也不是肾性尿崩症的特征。有报道被误诊为假性醛固酮减少症I型的婴儿导致的羊水过多的病例，但这些病例后来被证明存在潜藏于BS2之下的KCNJ1突变。[27] [36]
11. 先天性失氯性腹泻可与BS混淆。妊娠常并发羊水过多伴早产（通常不严重）[37]。出生后，该病可引起水样腹泻继发明显的低钾低氯代谢性碱中毒。
12. 由于汗液中的盐丢失，在囊性纤维化中偶见假性Bartter综合征（症状）。
13. 在低尿钙伴（或不伴）低镁血症的患者中，婴儿期之后出现症状的，尤其是青春期甚至成年期（最常见的是BS3）的，使GS成为首要的诊断考虑。肝细胞核因子1β肾病患者也可出现低钾性碱中毒和低镁血症[38]。其他表现代谢性碱中毒症状的罕见肾小管病列于【表4】。
14. 部分BS患者主要表现为肾钙质沉着和（或）尿石症。发病年龄较小的肾结石病例，应提高存在某种特定的基础病因的临床怀疑，包括（不完全性）远端肾小管酸中毒。
15. 如果表现体征为低钾血症，初期鉴别诊断的范围较大。在这种情况下，区分肾脏还是胃肠道钾流失，亦或是钾（细胞内）转移就非常重要。如果排除了原发性醛固酮增多症和利尿剂和（或）泻药使用或滥用的可能，则鉴别诊断范围就缩小至肾小管罕见病【表4】。
16. 通过氯排泄分数或尿钠/氯比值来评估尿氯排泄（程度）有助于区分肾性和肾外盐消耗。BS的氯排泄分数通常升高(> 0.5%)[32]。

【表4】巴特综合征的鉴别诊断

Table 4 Differential diagnosis of Bartter syndrome

• CF, cystic fibrosis 囊性纤维化
• CKD, chronic kidney disease 慢性肾脏病
• EAST, epilepsy, ataxia, sensorineural deafness, tubulopathy 癫痫、共济失调、感音神经性耳聋、肾小管病
• HELIX, hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, xerostomia 少汗、电解质紊乱、泪腺功能障碍、鱼鳞病、口干
• HNF1B, hepatocyte nuclear factor 1 beta 肝细胞核因子1β
• MODY5, maturity onset diabetes of the young type 5 青少年起病5型成年型糖尿病
• SeSAME, seizures, sensorineural deafness, ataxia, mental retardation, electrolyte imbalance 癫痫发作、感音神经性耳聋、共济失调、精神发育迟滞、电解质失衡

In theory, thick ascending limb and distal convoluted tubule function can be clinically tested by administering loop diuretics or thiazides to better characterize the clinical diagnosis of BS. Diuretic tests, however, are obsolete because they have been surpassed by genetic analysis. It is important to note that there is a potential risk of severe volume depletion in subjects with suspected BS, especially in infancy, because of an exaggerated response to thiazides due to the compensatory up-regulation of salt reabsorption in the distal convoluted tubule.39

Moreover, there remain significant uncertainties about their diagnostic value.39, 40, 41 We therefore advise against routine tubular function testing in patients with BS, in line with the Kidney Disease: Improving Global Outcomes consensus statement on GS.42 Nevertheless, these tests may have a role in individual challenging cases or for research purposes, together with genetic testing, if performed in experienced (tertiary) medical centers.

理论上，在临床上，可使用袢利尿剂或噻嗪类利尿剂，对髓袢升支粗段和远曲小管的功能进行检测，以更好地表征BS的临床诊断。然而，利尿试验已经过时，它们已经被基因分析替代。值得注意的是，在疑似BS受试者中存在严重血容量不足的潜在风险，尤其是在婴儿期，由于远曲小管盐重吸收的代偿性上调，对噻嗪类利尿剂会产生过度反应。[39]

此外，其诊断价值仍存在很大的不确定性。[[39] [40] 41] 因此，和KIDGO的GS专家共识的意见一样[42]，我们也不建议对BS患者进行常规肾小管功能试验。不过，如果在有经验的（三级）医疗中心，在配合基因检测的情况下，开展这些检测项目可能在个别疑难病例（的诊断）中发挥作用，或出于研究目的。

治疗 Therapy

【框2】巴特综合征治疗建议

See Box 1. For details, see Konrad et al.[17]
详情见Konrad et al. [17]

|

框2 巴特综合征治疗建议

Recommendations for therapy of Bartter syndrome | | —- | |

产前期 Prenatal period

1. Before the initiation of therapeutic measures (repeated amniocentesis and/or NSAIDs) aiming at the reduction of amniotic fluid volume, we suggest carefully weighing the intended benefit (prolongation of pregnancy) with the potential risks for the fetus, such as premature closure of the ductus arteriosus or necrotizing enterocolitis (grade D, weak recommendation).
1. Whenever prenatal therapy for the reduction of amniotic fluid is considered, we suggest involving a multidisciplinary team including a maternal-fetal medicine specialist, neonatologist, pediatric nephrologist, and pediatric cardiologist (in case of NSAID therapy) (grade D, weak recommendation).


1. 在开始采取旨在减少羊水量的治疗措施（反复羊膜穿刺术 和/或 NSAIDs）之前，我们建议仔细权衡（妊娠延长的）预期获益与胎儿的潜在风险，如动脉导管过早闭合或坏死性小肠结肠炎（D级，弱推荐）弱推荐）。
1. 当考虑减少羊水的产前治疗时，我们建议由多学科团队参与，包括母胎医学专家、新生儿科医生、儿科肾病学医生和儿科心脏病医生（如果需要使用NSAID治疗的情况下）（D级，弱推荐）。

产后期 Postnatal period

1. We recommend considering pharmacologic doses (5–10 mmol/kg/d) of sodium chloride supplementation in patients with BS (grade C, moderate recommendation).
1. We do not recommend salt supplementation in patients with BS and secondary nephrogenic diabetes insipidus (grade D, weak recommendation).
1. We recommend using potassium chloride if potassium is supplemented (grade C, moderate recommendation).
1. We do not recommend aiming for complete normalization of plasma potassium levels (grade D, weak recommendation).
1. Whenever needed, we recommend using oral magnesium supplements, at best organic magnesium salts owing to their better biovailability (grade D, weak recommendation).
1. We recommend spreading out salt and electrolyte supplements throughout the day as much as possible (grade C, moderate recommendation).
1. We recommend considering treatment with NSAIDs in symptomatic patients with BS, especially in early childhood (grade B, moderate recommendation).
1. We recommend using gastric acid inhibitors together with nonselective cyclooxygenase inhibitors (grade C, moderate recommendation).
1. We suggest optimizing nutritional support to facilitate optimal growth (grade D, weak recommendation).
1. We do not recommend routine use of potassium-sparing diuretics, ACE inhibitors, or angiotensin receptor blockers in BS (grade D, weak recommendation).
1. We do not recommend the use of thiazides to reduce hypercalciuria in BS (grade D, weak recommendation).


1. 我们建议考虑让BS患者按照(5-10 mmol/kg/d)的药物性剂量补充氯化钠（C级，中度推荐）。
1. 我们不建议BS继发肾性尿崩症的患者补充盐（D级，弱推荐）。
1. 如果补充钾，我们建议使用氯化钾（C级，中度推荐）。
1. 我们不建议将血钾水平完全正常作为（治疗）目标（D级，弱推荐）。
1. 根据需要，我们建议口服镁补充剂，最好是有机镁盐，因为具有更好的生物利用度（D级，弱推荐）。
1. 我们建议在一天中分尽可能多次补充盐和电解质（C级，中度推荐）。
1. 我们建议有症状的BS患者考虑使用NSAIDs治疗，特别是在幼儿童期（B级，中度推荐）。
1. 我们建议将胃酸抑制剂与非选择性COX抑制剂一起使用（C级，中度推荐）。
1. 我们建议优化营养支持以促进最佳生长（D级，弱推荐）。
1. 我们不建议BS常规使用保钾利尿剂、ACE抑制剂或血管紧张素受体阻滞剂（D级，弱推荐）。
1. 我们不推荐使用噻嗪类利尿剂来减少BS的高尿钙（D级，弱推荐）。

> ACE, angiotensin-converting enzyme 血管紧张素转换酶

BS, Bartter syndrome 巴特综合征 NSAID, nonsteroidal anti-inflammatory drug 非甾体类抗炎药

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产前治疗 Prenatal therapy

1. Pregnancies complicated by polyhydramnios are at risk of adverse outcomes, especially preterm delivery and complications of premature birth.[[43] 44] Serial amniocenteses are commonly used in the intention of prolonging pregnancies, but the benefits of this strategy have not been evaluated in prospective studies.
2. Maternal treatment with NSAIDs can be considered. Apparent efficacy has been reported in individual cases of polyhydramnios secondary to different causes and in idiopathic polyhydramnios.45 However, the treatment carries significant risks for the fetus, especially of fetal ductus arteriosus constriction. Therefore, close monitoring with the use of fetal echocardiography is mandatory in all cases of maternal NSAID therapy. Other reported complications include neonatal intestinal perforation and necrotizing enterocolitis.[45]
   To date, only a few cases of BS with positive outcome after serial amniocentesis and/or prenatal indomethacin therapy have been reported.[46~49] A substantial publication bias toward favorable outcomes cannot be excluded.
   Given the above-mentioned risks and lack of prospective studies, a formal recommendation cannot be made.

3. If prenatal intervention is considered, a multidisciplinary perinatal team is mandatory, including a maternal-fetal medicine specialist, a neonatologist, a pediatric cardiologist (in case of NSAID therapy), and a pediatric nephrologist.

4. 妊娠并发羊水过多存在不良结局的风险，尤其是早产和早产的并发症。.[[43] 44] 多次羊膜穿刺术通常被用来延长妊娠，但这种策略的获益尚未在前瞻性研究中进行过评估。

5. 可以考虑通过让孕妇使用NSAIDs（对BS胎儿）进行治疗。在各种原因继发和特发性羊水过多的个体病例中报告了明显的疗效。然而，该治疗对胎儿有重大风险，尤其是胎儿动脉导管狭窄。因此，所有接受NSAIDs治疗的孕妇，必须严格使用胎儿超声心动图进行密切监测。有报道的其他并发症包括新生儿肠穿孔和坏死性小肠结肠炎。[45]
   到目前为止，仅有少数BS病例经多次羊膜腔穿刺和（或）产前吲哚美辛治疗后获得良好结局的报道。[46~49] 但无法排除倾向于良好结局的文章发表偏倚。
   鉴于上述风险和缺乏前瞻性研究，我们无法就上述疗法提出正式建议。
6. 如果考虑产前干预，必须组建一个多学科围产期团队，包括母胎医学专家、新生儿科医生、儿科心脏病医生（如果需要使用NSAID治疗的情况下）和儿科肾病学医生。

产后治疗 Postnatal therapy

补盐 Salt supplementation

1. Supplementation with sodium chloride constitutes a physiologic treatment that can support extracellular volume and improve electrolyte abnormalities. At least 5–10 mmol/kg/d has been recommended.[50] Beyond infancy, some of this supplementation may be provided by salt craving and high spontaneous salt intake that is typical for BS.

2. Some patients with BS1 and BS2 have a secondary form of nephrogenic diabetes insipidus.[[51] 52] These patients present a therapeutic dilemma as salt supplementation would worsen polyuria and risk hypernatremic dehydration. We recommend against salt supplementation in patients with hypernatremic dehydration and a concomitant urine osmolality lower than plasma or a history thereof.

3. 补充氯化钠是一种生理性治疗，可支持细胞外容量和改善电解质异常。建议至少补充5-10 mmol/kg/d（=每公斤体重每天补盐290~580毫克）。[50] 婴儿期之后，盐的补充，部分可以通过嗜盐（饮食习惯）和自发的高盐摄入获得，这是BS的典型特征。

4. 部分BS1和BS2患者会继发肾性尿崩症。[[51] 52] 这些患者的治疗存在两难的困境，因为补充盐会加重多尿，并增加高钠性脱水的风险。对于有高钠性脱水，伴随尿渗透压低于血浆或有相关病史的患者，我们不建议补充盐。

补钾 Potassium supplementation

1. If potassium is supplemented, potassium chloride should be used.32 Potassium salts (e.g., citrate) should be avoided because they potentially worsen the metabolic disturbance by aggravating the alkalosis.
2. Hypokalemia in BS can be associated with severe complications, including paralysis, rhabdomyolysis, cardiac rhythm abnormalities, and sudden death.[53] [54] [55]

3. The following recommendation, made for GS[42], applies equally to BS:

   1. Potassium chloride supplements can be administered in water or in a slow-release formulation according to each patient’s preference.
   2. The dose will be titrated according to an individual balance (side-effects vs. symptoms).
   3. Potassium-rich food should be advised, with the caution that some of them contain high amounts of carbohydrates and calories.
   4. The target level for plasma potassium is not exactly known, but a reasonable target level may be 3.0 mmol/l. In GS as well, a level of 3.0 mmol/l has been suggested with the explicit acknowledgement that this may not be achievable in some patients.[42] Realistic target values may be lower for some patients and may also change with time.

4. 如果补钾，应使用氯化钾。应避免使用（枸橼酸钾）等其他钾盐，因为这类钾盐可能会加重碱中毒从而造成更严重的代谢紊乱。

5. BS的低钾血症可能会引起严重的并发症，包括瘫痪、横纹肌溶解、心律失常和猝死。[53] [54] [55]
6. 以下针对GS的建议[42]同样适用于BS：
   1. 根据患者的不同偏好，氯化钾的补充方式可以是水剂或缓释制剂。
   2. 根据个体情况平衡（副作用与症状）进行剂量滴定。
   3. 建议吃富含钾的食物，须注意一些食物含有大量的碳水化合物和卡路里。
   4. 血浆钾的目标值尚不不明确，但合理的目标值可能为3.0 mmol/L。在GS中，已提出3.0 mmol/L的建议值，并明确承认某些患者可能难以达到这一水平。[42]某些患者的实际目标值可能较低，也可能随时间变化。

补镁 Magnesium supplementation

1. If magnesium needs to be supplemented (mainly in patients with BS3), oral administration of magnesium salts should be preferred. It is important to note that organic salts (e.g., aspartate, citrate, lactate) have a higher bioavailability than magnesium oxide or hydroxide.[56] Exact target levels for plasma magnesium in BS are unknown but a level >0.6 mmol/l appears to be reasonable.

2. 如需补充镁（常见于BS3患者），应首选口服镁盐。值得注意的是，有机盐（如：天冬氨酸盐、枸橼酸盐、乳酸盐）的生物利用度高于氧化镁或氢氧化镁[56]。BS血镁的目标值尚未明确，但 > 0.6 mmol/L的水平较为合理。

Because urinary salt and electrolyte losses are continuous, ideal supplementation would be as close to continuous as possible. Infrequent large doses of supplementation will cause rapid changes in blood levels depending on timing of the sample in relation to the last dose. Arguably, large variations in plasma levels may be more detrimental than subnormal but steady levels. We therefore recommend dividing supplementation into as many doses as tolerable for the patient. In infants receiving continuous tube feeds, supplements should be added into the feed.

由于尿液的盐和电解质丢失是持续的，理想的补充方式应尽可能接近持续补充。低频次的大剂量补充将导致血药水平的快速变化，（或高或低）取决于（抽血）样本采集相对于上一次服药的时间。可以认为，血药水平的大幅变化可能比低于正常但稳定的水平更不利。因此，我们建议在患者可接受的情况下，分尽可能多次给药。接受持续管饲的婴儿，应在食物中添加补充剂药物。

非甾体类抗炎药 NSAIDs

1. Pharmacologic suppression of prostaglandin formation addresses the underlying pathophysiology, and multiple clinical observational studies have shown benefit in the form of improved growth and electrolyte profile.[57~60] The use of selective COX-2 inhibitors has also been reported in BS.[6] [61~63] Commonly used NSAIDs in BS are:
   1. indomethacin (1–4 mg/kg/d divided in 3–4 doses),
   2. ibuprofen (15–30 mg/kg daily in 3 doses), and
   3. celecoxib (2–10 mg/kg/d in 2 doses).
2. Currently, there is insufficient evidence to recommend a specific NSAID in BS, and the risks of gastrointestinal and cardiovascular side-effects need to be considered individually. Especially if used in the first few weeks or months of life in premature neonates, the risk of necrotizing enterocolitis should be carefully considered. Euvolemia should be achieved before initiating NSAIDs, because volume status may affect the potential nephrotoxicity.
3. Extended use of NSAIDs for pain is strongly associated with chronic kidney disease.[64] Whether this also applies to patients with BS has been disputed.[65] [66] Indeed, commencement of NSAIDs in BS typically results in clinical improvement, including a stable or even increased glomerular filtration rate, likely reflecting enhanced volume status.[67] Although chronic kidney disease is a common complication of BS, the cause is likely manifold, including premature birth and recurrent episodes of dehydration, so that the specific role of NSAIDs is difficult to determine.

4. There are reports of “tolerance” to NSAIDs over time, as well as of discontinuation of NSAIDs at school age owing to a perceived lack of efficacy.[32] [59] It is unclear whether this is related to insufficient dosing or a change in pathophysiology and whether at some point, the risks of NSAIDs may outweigh the benefits. Chronic use of NSAIDs should be considered carefully in each individual patient, and tapering or cessation may be indicated in stable patients.

5. 药物抑制前列腺素解决了（巴特）根本的病理生理学问题。多项临床观察性研究表明（药物抑制前列腺素后，患者）在生长发育、电解质谱改善等方面均有获益。[57~60] 选择性COX-2抑制剂在BS治疗中也有使用报道。[6] [61~63] BS常用的NSAIDs包括：

   1. 吲哚美辛（1-4 mg/kg/d，分3-4次服用）、
   2. 布洛芬（每日15-30 mg/kg，分3次服用）、
   3. 塞来昔布（2-10 mg/kg/d，分2次服用）。
6. 目前，尚无足够的证据在BS治疗中推荐某一种NSAID。需要根据个体情况，具体考虑胃肠道和心血管副作用的风险。尤其是在早产新生儿出生后最初几周或几个月内使用时，应慎重考虑坏死性小肠结肠炎的风险。开始NSAID治疗前应恢复到血容量正常，因为容量状态可能影响潜在的肾毒性。
7. 长期使用NSAIDs治疗疼痛与慢性肾病密切相关。[64] 这种相关性对于BS患者是否也如此一直存在争议。[65] [66] 事实上，BS在开始NSAIDs治疗后临床（症状）通常都会得到改善，包括稳定或甚至增加的肾小球滤过率，这可能反映了容量状态的增加。[67] 尽管慢性肾病是BS的常见并发症，但病因很可能是多方面的，包括早产和脱水反复发作，因此难以确定是否NSAIDs（对慢性肾病的发生）就有特异性作用。
8. 有报告称NSAIDs随时间推移产生“耐受”，以及由于认为缺乏疗效而在学龄期停用NSAIDs。[32] [59] 尚不明确这是否与剂量不足或病理生理学变化相关，以及NSAIDs的风险是否会在某个时间点超过获益。每位患者都应慎重考虑长期使用NSAIDs，患者如病情稳定可提示逐渐减量或停药。

胃酸抑制剂 Gastric acid inhibitors

1. Indomethacin and ibuprofen are nonselective inhibitors of COX enzymes. In contrast, celecoxib primarily inhibits COX-2.
2. COX-1 is expressed in multiple tissues, and its inhibition is associated with potentially serious side-effects, which have also been reported in patients with BS receiving NSAIDs.
3. Thus, if nonselective COX inhibitors are prescribed, they should be accompanied by gastric acid suppression.

4. If proton pump inhibitors are used, there is a small risk of proton pump inhibitor–associated hypomagnesemia that could compound renal magnesium wasting. Conversion to H2 blockers or other antacids (or to a COX-2 inhibitor) is recommended in those instances.

5. 吲哚美辛和布洛芬是非选择性COX酶抑制剂。相反，塞来昔布主要抑制COX-2。

6. COX-1在多种组织中表达，对COX-1的抑制与某些潜在的严重副作用相关，在接受NSAIDs治疗的BS患者中也有报告。
7. 因此，如果在处方中使用非选择性COX抑制剂，应搭配胃酸抑制（治疗）。
8. 如果使用质子泵抑制剂，有引起较低的质子泵抑制剂相关性低镁血症的风险，可能加重肾性镁丢失。在这些情况下，推荐转换为H2阻滞剂或其他抗酸剂（或COX-2抑制剂）。

支持性治疗 Supportive treatment

1. Growth failure is a common complication of BS and often part of the initial presentation. Dietetic support is important to maximize caloric intake and facilitate optimal growth.

2. Especially in infants and young children, tube feeding may need to be considered. A feeding tube will help not only to achieve adequate caloric intake, but also the administration of salt supplements.

3. 生长障碍是BS的常见并发症，通常是初始症状表现的一部分。饮食支持对最大限度地摄入热量和促进理想生长具有重要作用。

4. 尤其是婴幼儿，可能需要考虑管饲。饲管不仅有助于获得充足的热量摄入，还有助于补充盐。

保钾利尿剂、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂、噻嗪类利尿剂 K-sparing diuretics, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, thiazides

1. The hypokalemic alkalosis of BS is generated in the collecting duct, mediated by aldosterone (reviewed by Kleta and Bockenhauer[1]). Consequently, K-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers can help ameliorate the electrolyte abnormalities in BS, and their use has been reported.[30] [32] [68~70] However, BS is primarily a salt-wasting disorder, and the enhanced sodium reabsorption in the collecting duct is a key compensatory mechanism. Consequently, drugs that inhibit distal sodium reabsorption worsen the salt wasting and risk critical hypovolemia. Arguably, some of the sudden deaths reported in BS may have been caused by hypovolemia rather than hypokalemia.[1] We therefore do not recommend routine use of these drugs. Instead, they should be considered carefully in individual cases and may be indicated in those who have severe symptoms from the electrolyte abnormalities despite maximization of routine treatment with NSAIDs and salt supplements.[71]

2. Thiazides are occasionally used in an attempt to reduce calcium excretion. There are no data on their efficacy in BS. Moreover, compensatory salt reabsorption in the distal convoluted tubule is critical for maintenance of volume homeostasis. Thus, thiazides in BS may lead to life-threating hypovolemia and should not be routinely administered.

3. BS的低钾性碱中毒是在集合管中产生的，由醛固酮介导（由Kleta和Bockenhauer审议[1]）。因此，保钾利尿剂、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂可帮助改善BS的电解质紊乱，已有报告使用。[30] [32] [68~70] 然而，BS主要是一种失盐性疾病，集合管中钠重吸收增加是一种关键的代偿机制。因此，抑制远端钠重吸收的药物会加重盐丢失，并产生严重血容量不足的风险。可以说，BS中报告的一些猝死（病例）可能是由血容量不足而不是低钾血症引起的。[1] 因此我们不推荐常规使用这些药物。相反，（这类药物）在个别病例中应予仔细考虑。对于那些已经按最大剂量常态化使用NSAIDs和盐补充剂，却仍然存在严重的电解质紊乱的患者，可提示使用（这类药物）。[71]

4. 噻嗪类利尿剂偶尔用于减少尿钙排泄。但尚无关于其在BS中疗效的数据。此外，远曲小管的代偿性盐重吸收对于维持容量稳态至关重要。因此，在BS中给与噻嗪类利尿剂可能导致危及生命的低血容量，不应常规使用。

生长激素 Growth hormone

• Growth failure with growth hormone (GH) deficiency in BS has been reported.[28] [32] [72] [73] [74] Whether this is an intrinsic part of the disorder or a secondary complication of altered acid-base and/or electrolyte homeostasis is unclear, but most reports of GH deficiency have concerned patients with BS3, who have the most severe metabolic abnormalities. In addition, elevated systemic prostaglandins may contribute to growth failure. In one report, GH deficiency failed to respond to recombinant human GH supplementation until treatment with a COX inhibitor was commenced.[32] Thus, before commencement of recombinant human GH, optimization of metabolic control should be attempted.

• 已报告BS中生长激素(GH)缺乏导致的生长障碍。[28] [32] [72] [73] [74] 尚不明确这是否疾病的本身的一部分，或是酸碱和/或电解质平衡改变的继发性并发症。但大多数GH缺乏报告与BS3患者有关，BS3的（酸碱）代谢紊乱最严重。此外，全身性的前列腺素水平升高可能加重生长障碍。在一个报道中，GH缺乏（患者）对重组人生长激素补充治疗无反应，直到开始COX抑制剂治疗。[32] 因此，在开始重组人生长激素治疗前，应尝试优化对代谢情况的控制。

随访 Follow-Up

【框3】巴特综合征患者随访建议

See Box 1. For details, see Konrad et al.[17]
详情见Konrad et al. [17]

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框3 巴特综合征患者随访建议

Recommendations for follow-up of patients with Bartter syndrome | | —- | |

就诊频率和设定 Frequency and setting of visits

1. We suggest that patients with BS should be followed in specialized centers with experience in renal tubular disorders to facilitate best medical care (grade D, weak recommendation).
1. We suggest that infants and young children with BS should be seen at least every 3–6 months, depending on severity of clinical problems, to ensure adequate metabolic control, growth, and psychomotor development (grade C, weak recommendation).
1. We suggest that older children with an established therapy and stable condition should be seen at least every 6–12 months (grade C, weak recommendation).
1. We suggest that adult patients should be seen every 6–12 months (grade C, weak recommendation).
1. We suggest evaluating QoL using age-appropriate scales from age 5 years onward at 2-year intervals (grade D, weak recommendation).


1. 我们建议，BS患者应在具有肾小管疾病经验的专科中心接受随访，以便得到最好的医疗服务（D级，弱推荐）。
1. 我们建议，BS婴儿和幼儿，应根据临床问题的严重程度，至少每3-6个月就诊一次，以确保充分的代谢控制、生长和精神运动发育（C级，弱推荐）。
1. 我们建议，已有既定治疗方案且病情稳定的年长儿童应至少每6-12个月进行一次检查（C级，弱推荐）。
1. 我们建议，成人患者应每6-12个月就诊一次（C级，弱推荐）。
1. 我们建议，从5岁开始每隔2年使用适龄量表评估患者生活质量（QoL，Quility of Life)（D级，弱推荐）。

儿童的随访 Follow-up of children

1. At each follow-up visit, we suggest focusing the history and examination on dehydration, degree of polyuria, signs of muscular weakness, growth, and psychomotor development (grade C, weak recommendation).
1. We suggest that biochemical work-up should include acid-base status (either by blood gas or by measurement of venous total CO2), serum electrolytes (including bicarbonate, chloride, and magnesium), renal function, PTH, and urinary calcium excretion (grade C, weak recommendation).
1. We suggest assessing urine osmolality to test for secondary NDI (grade C, weak recommendation).
1. We suggest performing renal ultrasound at least every 12–24 months to monitor nephrocalcinosis, the occurrence of kidney stones, and signs of secondary obstructive uropathy (grade C, weak recommendation).
1. For children with growth retardation despite intensified efforts for metabolic control (optimization of NSAID and salt supplementation including potassium chloride), we suggest considering growth hormone deficiency (grade C, weak recommendation).


1. 我们建议，每次随访时，将病史和检查的重点放在脱水、多尿程度、肌无力体征、生长和精神运动发育方面（C级，弱推荐）。
1. 我们建议，生化检查应包括酸碱状态（通过血气或通过测量静脉总CO2）、血清电解质（包括碳酸氢根、氯和镁）、肾功能、甲状旁腺素(PTH)和尿钙排泄（C级，弱推荐）。
1. 我们建议，评估尿渗透压以检测继发性肾性尿崩症（NDI）（C级，弱推荐）。
1. 我们建议，至少每12-24个月进行一次肾脏超声检查，以监测肾钙质沉着、肾结石的发生和继发性梗阻性尿路病的征兆（C级，弱推荐）。
1. 我们建议，对于尽管已加强代谢控制力度（优化NSAID和盐补充剂，包括氯化钾），但仍然生长迟缓的儿童，应考虑生长激素缺乏症（C级，弱推荐）。

成人的随访 Follow-up of adults

1. At each follow-up visit, we suggest focusing the history and examination on dehydration, degree of polyuria, signs of muscular weakness, fatigue, and palpitations (grade C, weak recommendation).
1. We suggest that biochemical work-up should include acid-base status (either by blood gas or by measurement of venous total CO2), serum electrolytes (including bicarbonate, chloride, and magnesium), renal function, PTH, urinary calcium excretion, and microalbuminuria (grade C, weak recommendation).
1. We recommend performing renal ultrasound at least every 12–24 months to monitor nephrocalcinosis, the occurrence of kidney stones, and signs of secondary obstructive uropathy (grade C, weak recommendation).
1. We suggest performing further cardiology work-up in patients complaining of palpitations or syncope (grade C, weak recommendation).
1. For pregnant women or those planning to become pregnant, we suggest the timely institution of a joint management plan involving nephrology and obstetrics (grade C, weak recommendation).


1. 我们建议，在每次随访时，将病史和检查的重点放在脱水、多尿程度、肌无力体征、疲乏和心悸方面（C级，弱推荐）。
1. 我们建议，生化检查应包括酸碱状态（通过血气或测量静脉CO2总量）、血清电解质（包括碳酸氢根、氯和镁）、肾功能、甲状旁腺素（PTH）、尿钙排泄和微量白蛋白尿（C级，弱推荐）。
1. 我们建议，至少每12-24个月进行一次肾脏超声检查，以监测肾钙质沉着、肾结石的发生和继发性梗阻性尿路病的征兆（C级，弱推荐）。
1. 我们建议，对主诉心悸或晕厥的患者进行进一步的心内科检查（C级，弱推荐）。
1. 我们建议，对于孕妇或计划怀孕的妇女，及时制定涉及肾内科和产科的联合管理计划（C级，弱推荐）。

> BS, Bartter syndrome 巴特综合征;

NDI, nephrogenic diabetes insipidus; 肾性尿崩症 NSAID, nonsteroidal antiinflammatory drug 非甾体类抗炎药; PTH, parathyroid hormone 甲状旁腺素; QoL, quality of life 生活质量.

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In BS, clinical and biochemical features and complications vary widely depending on the underlying molecular defect and individual patient.

1. Treatment and follow-up should be tailored to the patient on the basis of clinical manifestation, medical history, stage of development, molecular defect, and the clinician’s expert judgement in close contact with the patient’s local health care provider. In addition, according to age and/or genotype, other professions might be involved such as dieticians, social workers, psychologists, endocrinologists, and otolaryngologists.
2. At each follow-up visit, specific clinical features should be addressed and biochemical work-up performed (Box 3).
3. In children, there is also special emphasis on growth and pubertal development.
4. Adverse effects of NSAIDs should be looked for. In case of intercurrent illness, it has to be kept in mind that NSAIDs may prevent fever and thus mask the severity of infectious diseases.
5. Renin and aldosterone levels may be helpful in assessing the adequacy of NSAID treatment.
6. During follow-up, the routine assessment of quality of life with the use of age-specific standardized questionnaires would be highly desirable. The first small case series in patients with salt-losing tubulopathies showed that quality of life scores are directly influenced by different biochemical parameters, such as aldosterone or potassium, and thus may help to define better therapeutic targets in the future.[75]

BS（患者）的临床和生化特征以及并发症差异很大，这取决于根本的分子缺陷和患者个体情况的不同。

1. 治疗和随访，应根据临床表现、病史、发育阶段、分子缺陷，以及与患者当地医疗机构保持密切联系的临床专家的判断，为患者量身定制。此外，根据年龄和/或基因型，可能需要其他专业人士的参与，如营养师、社会工作者、心理学家、内分泌科医生和耳鼻喉科医生。
2. 在每次随访时，应设法解决具体的临床特征，并进行生化检查（【框3】）。
3. 在儿童（患者）中，还特别强调生长和青春期发育情况。
4. 应检查（有无）NSAIDs的不良反应。以防发生并发疾病，必须记住NSAIDs可抑制发热，从而掩盖传染性疾病的严重程度。
5. 肾素和醛固酮水平可能有助于评估NSAID治疗（剂量）是否充分。
6. 在随访期间，使用适龄的标准化问卷对生活质量进行常规评估是非常必要的。首个在失盐性肾小管病患者中开展的小型病例系列研究显示，生活质量评分直接受到不同生化参数的影响，如：醛固酮或钾，因此（生活质量评分）可能有助于在未来定义更好的治疗靶点。[75]

长期结局和并发症 Long-term outcomes and complications

1. Data on long-term outcomes in BS are sparse.
2. Whereas nephrocalcinosis and hypercalciuria are present in the majority of patients (except BS3), the prevalence of symptomatic urolithiasis in BS appears to be relatively low.[30]
3. Nephrotic-range proteinuria has been reported in BS patients.[28] [32] [76] When renal biopsies are performed, they often show diffuse glomerular and tubulointerstitial lesions with enlarged glomeruli and focal segmental glomerulosclerosis.[30]
4. Chronic kidney disease is common in BS, and patients with BS1 and BS4 may have more severe chronic kidney disease progression than those with BS2 and BS3.[30] [65] In addition to the molecular defect itself (especially in BS4), other risk factors potentially contributing to chronic kidney injury could be premature birth/low birth weight, nephrocalcinosis, chronic dehydration state, progressive proteinuria related to hyperfiltration due to renin-angiotensin system activation, and treatment with NSAIDs. In BS patients, there seems to be no correlation between serum potassium levels and estimated glomerular filtration rate.[30] [77] Some patients progress to end-stage kidney disease, but exact data are lacking.

5. A few kidney transplantations have been reported in the literature.[30] [78~84] In all cases, electrolyte abnormalities and polyuria were corrected and recurrent disease was not observed.

6. 关于BS长期结局的数据很少。

7. 尽管大多数患者（BS3除外）存在肾钙质沉着和高钙尿，但BS中有症状的尿结石的发病率似乎相对较低。[30]
8. 在BS患者中已报告了肾病范围蛋白尿。[28] [32] [76]进行肾活检时，常表现为弥漫性肾小球和肾小管间质病变，伴肾小球增大和局灶节段性肾小球硬化。[30]
9. 慢性肾病在BS中比较常见，BS1和BS4患者的慢性肾病进展可能比BS2和BS3患者更严重。[30] [65] 除了分子缺陷本身（尤其是在BS4中），其他潜在导致慢性肾损伤的风险因素可能包括：早产/低出生体重、肾钙质沉着、慢性脱水状态、由肾素-血管紧张素系统激活引起的高滤过相关的进行性蛋白尿和NSAIDs治疗。在BS患者中，血清钾水平与估算肾小球滤过率(eGFR)之间似乎无相关性。[30] [77] 部分患者进展为终末期肾病，但缺乏确切的数据。
10. 文献中已报道少数肾移植病例。[30] [78~84] 在所有病例中，电解质紊乱和多尿症均得到纠正，未观察到疾病复发。

心内科检查/麻醉/运动 Cardiac work-up/anesthesia/sports

1. Hypokalemia with or without additional hypomagnesemia prolongs the QT interval, which could lead to an increased risk of ventricular arrhythmias. Isolated reports on cardiac arrhythmias, long QT interval, and sudden death have been reported in BS patients,[53] [85] [86] so electrocardiography should be performed at rest to assess rhythm and QT-interval duration. A further cardiology work-up, as previously recommended for GS,[42] is indicated when patients complain of palpitations or syncope (e.g., Holter, stress electrocardiography), or if electrocardiographic abnormalities persist despite attempted improvement of the biochemical abnormalities.[87]
2. Drugs slowing sinus rhythm or influencing the QT interval, such as negative chronotropic drugs, or drugs potentially inducing or exacerbating hypomagnesemia, such as proton-pump inhibitors, macrolides, fluorchinolones, gentamicin, or antiviral drugs, should be carefully considered.
3. Caution should be taken when patients with BS undergo anesthesia. Hypokalemia and hypomagnesemia can potentiate the effects of anesthetic agents, such as neuromuscular blockade during general anesthesia and adrenaline in regional blockade. However, there is no definitive evidence to suggest safe preoperative plasma potassium levels. In the general population, guidelines suggest aiming for potassium levels >3.0 mmol/l (magnesium >0.5 mmol/l).[88]

4. There is no evidence suggesting that participation in sports is deleterious. In any case, volume depletion should be prevented and additional salt or electrolytes, or both, may help. However, strenuous exercise or competition practice should be considered carefully, particularly in cases with a history of cardiac manifestations or prolonged QT interval.

5. 低钾血症伴或不伴低镁血症可延长QT间期，这可能会增加室性心律失常的风险。在BS患者中已有心律失常、长QT间期和猝死的个别报告，[53] [85] [86] 因此应在静息状态下进行心电图检查，以评估节律和QT间期持续时间。当患者主诉心悸或晕厥，或者尽管尝试改善生化异常但心电图异常仍然持续时，需要进行进一步的心脏病学检查（如：动态心电图、负荷心电图），先前的GS指南[42] 也是这样推荐。[87]

6. 应慎重考虑减慢窦性心律或影响QT间期的药物，如：负性变时性药物，或可能诱导或加重低镁血症的药物，如质子泵抑制剂、大环内酯类、氟喹诺酮类、庆大霉素或抗病毒药物。
7. BS患者接受麻醉时应谨慎。低钾血症和低镁血症可增强麻醉剂的作用，如全身麻醉期间的神经肌肉阻滞和区域阻滞中的肾上腺素。然而，尚无确切证据可就安全的术前血浆钾水平提出建议。在一般人群中，指南建议将血钾水平的目标设定为 > 3.0 mmol/L（镁 > 0.5 mmol/L）。[88]
8. 没有证据表明参加运动是有害的。在任何情况下，均应防止容量不足。补充盐或电解质，或两者同时补充，可能有助于避免容量不足。但是，应谨慎参与剧烈运动或比赛，特别是有心脏症状表现或QT间期延长病史的患者。

妊娠注意事项 Pregnancy considerations

1. During normal pregnancy, serum potassium levels decrease by 0.2–0.5 mmol/l around midgestation.[9] [89]
2. In pregnant women with BS, timely institution of a joint management plan involving nephrology and obstetrics as well as appropriate adaptations in therapy is mandatory.
3. During pregnancy, the target level for plasma potassium is unknown, but a level of 3.0 mmol/l has been suggested with the explicit acknowledgement that this may not be achievable in some patients.[42]
4. In patients with BS, the occurrence of hyperemesis gravidarum may be particularly dangerous owing to the subsequent electrolyte disturbances that may necessitate early parenteral fluid and electrolyte supplementation.
5. Pregnant women with BS should be informed about increased requirements of electrolyte supplements, that renin-angiotensin system blockers are contraindicated, and that NSAIDs are discouraged during pregnancy.
6. Monitoring of plasma electrolyte levels is advised during labor. Therefore, delivery in hospital might be considered to reduce risks of maternal complications. The overall outcome for women with BS and their infants described to date is favorable.[90~95]

7. After delivery, the treatment of the mother may return to baseline supplementation.

8. 在正常妊娠期间，血清钾水平在妊娠中期前后下降0.2-0.5 mmol/L。[9] [89]

9. 对于患有BS的孕妇，必须强制要求及时制定包括肾内科和产科的联合管理方案，并对治疗进行适当调整。
10. 妊娠期间，血浆钾的目标值尚未明确。但建议3.0 mmol/L水平，并明确知晓部分患者可能无法达到这一水平。[42]
11. BS患者的妊娠剧吐，由于会引起随后的电解质紊乱，可能特别危险。可能需要尽早进行胃肠外补液和电解质补充。
12. 应告知BS孕妇：增加电解质补充剂量；禁用肾素-血管紧张素系统阻滞剂；并且在妊娠期间不鼓励使用NSAIDs。
13. 建议在分娩期间监测血浆电解质水平。因此，可考虑住院分娩以降低产妇并发症的风险。到目前为止，报道的BS妊娠的母婴结局总体良好。[90~95]
14. 分娩后，母亲的治疗可恢复到基线补充治疗。

患者教育 Patient Education

详见 Konrad et al.[17]

1. Disease-specific education for patients with BS and their families is highly important. Information can be provided through age-appropriate personal education, information leaflets, web-based information, patient-led forums, and patient/family group support events.
2. It is vital that patients know what to do in case of emergency. “Sick day rules” may be helpful in case of intercurrent illness.
3. BS itself and comorbidities resulting from extreme prematurity in a subset of BS patients can compromise school performance. Depending on the country, various measures to support these children may be available and should be used.
4. Work performance may be limited in some patients, e.g., owing to muscle weakness or fatigue. Occupational therapists may assist patients in finding support for their individual situations.

5. Patients may be hesitant to disclose their condition to employers because they are afraid to lose their job. However, patients should be encouraged to share information about the disease, ideally by providing educational material about BS.

6. 对BS患者及其家属进行具体疾病的教育非常重要。可以通过多种方式提供信息，如：适合年龄的个人教育、信息宣传单、网络信息、患者主导的论坛、患者/家庭团体支持活动等。

7. 患者必须知道在紧急情况下该怎么做至关重要。在疾病发作的情况下，“病期规则”可能有帮助。
8. BS疾病本身，和部分BS患者中极度早产导致的合并症可能影响学校表现。根据国家的不同，可能有多种措施帮助这些儿童，这些措施应加以利用。
9. 由于肌无力或疲乏（等原因）一些患者的工作表现可能受到影响。职业治疗师可能可以帮助患者为他们的个体情况寻求支持。
10. 患者可能会因为害怕失去工作，而不愿意向雇主透露自己的病情。但是，应鼓励患者分享关于疾病的信息，理想的方式是（向别人）提供关于BS的教育材料。

结论和观点 Conclusions and Perspectives

The identification of genes involved in BS with the consequent insights into the molecular pathophysiology is relatively recent. Therefore, long-term follow-up data from genetically defined cohorts are limited. This highlights the need for comprehensive patient registries. As more such data become available, our knowledge of the natural history, treatment response, long-term complications, and quality of life will improve and thus directly influence patient management. We therefore anticipate that with time, the recommendations made here will need to be updated and revised.

BS相关基因的鉴定，以及后续对分子病理生理学的深入理解，相对来说还是刚起步。因此，来自基因诊断明确的队列的长期随访数据有限。这凸显出全面患者注册登记的必要性。随着更多此类数据的获得，我们将增加对自然史、治疗反应、长期并发症和生活质量的了解，从而直接影响患者管理。因此，我们预计，随着时间的推移，本文提出的建议将需要更新和修订。

披露 Disclosure

All the authors declared no competing interests.
所有作者都声明没有利益冲突。

致谢 Acknowledgements

The authors thank the European Rare Kidney Disease Reference Network (ERKNet) for launching, organizing, and funding of this initiative, including travel and housing costs for the core group members. The funder had no influence on the content of the consensus. The authors also thank Tanja Wlodkowski, Heidelberg, Germany, for her continuous support concerning the literature search and the panel voting procedures.

作者们感谢欧洲罕见肾病指导网络(ERKNet)发起、组织和资助这一倡议，包括核心组成员的差旅费和住宿费用。资助者对共识的内容没有影响。作者们还感谢Tanja Wlodkowski（德国海德堡）对文献检索和小组投票程序的持续支持。

参考文献 References

https://www.kidney-international.org/article/S0085-2538(20)31404-6/fulltext#secsectitle016531404-6/fulltext#secsectitle0165)