INTRODUCTION

The life-time risk for end stage kidney disease (ESKD)in autosomal dominant polycystic kidney disease(ADPKD) is characterised by high intra- and interfamilial variability[1]. Epidemiological data indicates that only 50% of patients with ADPKD will develop ESKD by the age of 60[2]. This variability in risk for ESKD is likely due to the interaction of genic factors[3] with environmental variables[4] that alter the expressivity of the clinical phenotype[5,6]. Routine tests performed during the initial clinical evaluation of affected patients, such as estimated glomerular filtration rate (eGFR), lack sensitivity as prognostic markers in early disease[7], and other clinical information (such as family history of early-onset of ESKD) do not have precision[8]. The uncertainty in predicting renal prognosis causes tremendous anxiety to patients and their families[9]. Furthermore, the introduction of disease-modifying drugs to treat ADPKD has catalysed an urgent need to identify and validate a panel of reliable and easily measurable clinical, genetic,molecular and imaging biomarkers in predicting the risk for ESKD[10].

The arginine vasopressin (AVP)-cAMP signalling pathway has a central role in the initiation of lifetime growth of kidney cysts in ADPKD[11]. Serum copeptin is a surrogate marker of AVP release[12], and the availability of a sensitive commercially available immunoassay, has led to several cohort studies to evaluate its role as a prognostic biomarker in ADPKD. The role of copeptin as a clinical diagnostic test is also under evaluation in several other diseases including in the differential diagnosis of polyuria-polydipsia (where it is being considered as a replacement for the direct measurement of serum AVP)[13,14], and in the diagnostic evaluation of other disorders (such as acute myocardial infarction[15] and sepsis[16]) where its potential utility is less certain. In this regard, to date, copeptin is not funded for reimbursement for routine measurement in patients in ADPKD in any country, providing an indirect indicator that its value as a prognostic biomarker in this setting has also not been proven and that further data is needed. The aim of this review is to critically evaluate the role of copeptin as a prognostic biomarker of renal outcomes in ADPKD, and if it has potential as a predictive marker of treatment response.

ROLE OF AVP-CAMP SIGNALLING IN THE PATHOGENESIS OF RENAL CYST GROWTH IN ADPKD

The role of AVP in the pathogenesis of ADPKD has been reviewed elsewhere[11], but briefly, it is considered to be the most important factor that determines the postnatal rate of renal cyst growth. The most compelling preclinical evidence to support this hypothesis is that the congenital deficiency of AVP almost completely abrogated the formation of renal cysts in the pck rat[17].Furthermore, in mouse models of PKD, small-molecule vasopressin-receptor antagonists were highly effective in reducing kidney cyst growth[18]. In humans, the evidence is supported by the TEMPO 3:4 and REPRISE trials which collectively showed that tolvaptan (a highly specific vasopressin-receptor antagonist) reduced the rate of increase in total kidney volume (TKV) in earlystage ADPKD and also the decline in renal function in late-stage disease[19,20]. Given its critical importance,it seems logical to consider markers of AVP release as potential biomarkers in ADPKD.

SYNTHESIS, FUNCTION AND DEGRADATION OF COPEPTIN

Synthesis of copeptin

As shown in Figure 1, copeptin is the C-terminal end of the AVP precursor molecule (pre-proAVP), a 164-amino acid peptide consisting of four segments: (1) The signal peptide at the N-terminus (amino acids 1-19); (2) AVP(amino acids 20-28); (3) neurophysin (amino acids 32-124); and (4) copeptin (amino acids 126-164), a 39-aminoacid glycopeptide that makes up the C-terminal part of pro-AVP. As summarised in Table 1, the precursor peptide (pre-proAVP) is produced in two anatomically distinct regions of the hypothalamus.

在全部的患者中,由于多种西药联用出现不良反应的患者有3例,占5%;观察患者的主要临床表现为:头昏、恶心、呕吐等,还有些患者出现了严重的不良反应为:肝、肾功能衰竭等。

Function of copeptin

While the physiological function of AVP is well defined by its effects on tissue-specific receptors (V1a receptor:mediates vasoconstriction and platelet aggregation;V1b receptor: ACTH secretion; and V2 receptor: water balance), the exact role of copeptin in normal physiology is unclear as it has no known receptors. In this regard,copeptin has been hypothesised to function as a chaperone for pre-proAVP release from the magnoceullar neuron, but its role in peripheral tissues (if any) remains unknown. Thus, the literature has considered that copeptin is simply an inert biomarker with no direct role in the pathogenesis kidney cyst formation, but clearly further studies (such as gene knockout experiments in mice) are needed to evaluate this premise.

Degradation of copeptin

Another gap in knowledge is that little is known about the pharmacokinetics and degradation of copeptin.Available data suggests that it is rapidly cleared from the circulation either through the degradation by tissue-bound proteases, renal excretion and/or hepatic metabolism. New data on this topic are likely to emerge in the future and in this regard, a recent study reported that while the release of copeptin in response to elevation in the serum osmolality in healthy individuals was similar to AVP, its decay in the serum was twofold longer than AVP[21]. Understanding the clearance of copeptin also has major implications for interpreting values in the setting of renal impairment, as reduced glomerular filtration is associated with elevated serum copeptin and thereby, confounds its value as a unique prognostic biomarker in ADPKD (as discussed below).

ADVANTAGES AND DISADVANTAGES OF COPEPTIN MEASUREMENT IN THE LABORATORY

It is well known that the laboratory testing of AVP is time-consuming and not practical (primarily because it is rapidly removed from the circulation with a half-life of less than 30 min requiring a large volume of serum) and is unstable in serum[22,23]. On the other hand, copeptin is released in equimolar amounts with AVP[24], is stable for up to 14 d in serum at room temperature; can be rapidly measured (0.5-2.5 h); and requires only 50 L of serum,making it potentially suitable for a high-throughput clinical pathology laboratory[12]. These analytical comparisons in methodology are summarised in Table 2.

The disadvantage of the copeptin assay is that in many countries, including in Australia, the most widely used and validated assay is a sandwich immunoluminometric method by ThermoFisher Scientific which requires purchase of a specific instrument[22]. As there is insufficient evidence for the use of copeptin in routine clinical practice, it is not currently provided by most clinical pathology laboratories and therefore, not readily accessible. Other manufacturers other than Thermo-Fisher Scientific produce in-house ELISA kits[25] to measure copeptin, and this might make it easier to access the assay, but this is suitable for the clinical setting and large numbers of samples need assayed using a standardised technique. In sum, insufficient clinical evidence has not allowed further development of copeptin for clinical use in ADPKD, and the assay remains primarily restricted to the research setting.

MULTIPLE LIFESTYLE FACTORS INFLUENCE THE BASAL LEVELS OF SERUM COPEPTIN

Several lifestyle factors modify the basal level of copeptin in an individual. The most well studied variable isfluid intake. In healthy individuals, a chronic increase in total fluid intake by approximately 1 L/d above baseline reduced serum copeptin from 5.18 to 3.90 pmol/L[26].Similarly, in patients with Stage 3 CKD (n = 28), the median copeptin level was 17 pmol/L and declined to 4.2 pmol/L with fluid intake over a 6-week period[27],confirming that: (1) Patients with CKD have higher levels of copeptin; and (2) increasing fluid intake can attenuate long-term copeptin levels. The type of fluid consumed may also influence the change in copeptin,as preclinical data in rats shows that rehydration with 20% hypertonic fructose increased plasma osmolality,AVP release and oxidative renal injury in rats with mild dehydration, whereas this effect was not seen with plain water[28].

舞罢真香草阁风，瘦筇水月放天踪。有圈太极真成借，无画乾坤妙莫穷。此外可寻桃李圣，眼中谁认古今雄。凭君莫说陈庄句，已费天机浪语中。［3］卷四，36叶

1.1.2 主要试剂 T4 DNA连接酶、Taq DNA聚合酶为Takara(大连)公司产品；质粒提取试剂盒为QIAGEN公司产品；胶回收试剂盒为Promega公司产品；荧光染料Cy3，Cy5为Amersham Pharmacia biotech公司产品；伤寒沙门菌基因组芯片由本实验室制备.

Multiple other factors may influence the basal levels of copeptin. A cross-sectional analysis of the Groningen population-based cohort study (n = 6801) showed that in addition to lowfluid intake, other dietary factors (high sodium, high protein and low potassium), alcohol intake and smoking were all associated with higher serum copeptin levels[29]. However, it is noteworthy that, in contrast to the Groningen study, alcohol suppresses the release of vasopressin from the pituitary gland[30,31].Similarly, smoking is well known to stimulate the release of AVP in the blood plasma. In rabbits, an injection of 0.5 mg/kg of nicotine increased AVP concentrations by nearly 40 times[32]. The relative importance of each of these factors in influencing copeptin levels, and how they should be considered prior to collecting blood for copeptin in individuals, has not been standardized and further studies are required.

BASELINE SERUM COPEPTIN IS NOT DIAGNOSTIC OF ADPKD AND IS STRONGLY CORRELATED WITH RENAL FUNCTION

Several investigators have raised the hypothesis that serum AVP, and therefore copeptin, could be mildly elevated in ADPKD patients compared to the general healthy population[33]. For example, in a small study of 30 patients, the difference in mean serum copeptin was 8.92 pmol/L [inter-quartile range (IQR): 0.66-21.86]in ADPKD patients (eGFR 100 ± 23 mL/min/1.73 m2)compared to 6.08 pmol (IQR 0.92-10.79) in healthy individuals (eGFR 104 ± 12 mL/min/1.73 m2) (P = 0.22).This mild elevation is most likely due to subclinical volume depletion due to increased urinary losses as a result of impaired urinary concentrating ability and nephrogenic diabetes insipidus, as following water deprivation for 14 h, the difference in mean serum copeptin between ADPKD compared to healthy patients become statistically significant (ADPKD: 17.01 pmol/L;IQR 7.94-17.78 vs healthy: 7.75 pmol, IQR 3.81-8.80;P = 0.04)[33]. However, based on published studies,there is little evidence to support that thesefindings are specific or diagnostic of ADPKD. In particular, a recent study showed that: (1) Mean levels of copeptin in ADPKD patients were comparable to patients with other types of CKD, such as IgA nephropathy (ADPKD: 26.6 pmol vs IgA nephropathy: 20.7 pmol/L; P = 0.84)[34,35],and (2) the levels were more strongly correlated with the serum creatinine rather than the specific cause of CKD[35].

IS SERUM COPEPTIN A PROGNOSTIC BIOMARKER OF RENAL OUTCOMES IN ADPKD?

With this background, the remainder of this article will evaluate the specific utility of copeptin as a biomarker in ADPKD. The National Institutes of Health Biomarker Consortium defines a “biomarker” as a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions[36]. More specifically, the two sub-groups that are relevant to the discussion of copeptin and ADPKD are a “prognostic biomarker” (defined as biomarker that identifies the likelihood of a clinical event, recurrence or progression), and a “predictive biomarker” (defined as a biomarker that identifies those who are likely to respond to a treatment than those that are negative for a biomarker). Furthermore, Park and Ahn[37] outlined that the ideal biomarker in ADPKD should fulfil three characteristics: (1) It should correlate with the clinical severity of ADPKD; (2) it should detect patients at high-risk of progression; and (3) short-term changes should predict a clinical endpoint. In addition,validation is the process of assessing the biomarker and its measurement performance characteristics,and determining the range of conditions under which it provides reproducible and accurate data. The assessment of whether serum copeptin fulfils the criteria and validation in ADPKD is limited by the paucity of data,as only 26 articles were identified by a PubMed search using the terms “copeptin” and “ADPKD” (with at least 6 being review articles). Furthermore, many of these studies consist of small sample sizes. Despite this, the available data was analysed to answer two questions.

Are serum and urinary copeptin levels correlated with markers of disease severity?

Several cross-sectional studies show that serum copeptin is positively correlated with TKV and negatively correlated with eGFR. Furthermore, longitudinal studies show that higher copeptin levels had significantly higher TKV and urine osmolality, evidently shown by a study where TKV increased by 71% as copeptin levels increased by 23%[38,39]. Furthermore, a recent study also showed that serum copeptin predicted changes infibromuscular dilatation in patients with ADPKD, an indicator of cardiovascular disease. To date, only one cohort has evaluated the role of urinary copeptin to creatinine ratio, which reported moderate correlations with ht-TKV (r = 0.383, P = 0.008) and eGFR (r =-0.304, P = 0.036) in 50 Japanese patients with ADPKD[40].

Are there any confounding factors that influence the interpretation of serum and urinary copeptin in ADPKD?

Several studies show that copeptin has a strong relationship with eGFR. Corradi et al[35] recently demonstrated that glomerular filtration affects copeptin to a greater extent rather than its correlation to AVP.The authors of a previous study indicated that after the removal of a kidney, the copeptin levels relatively remained stable, however, only GFR had declined by 40%[33,34]. A greater number of nephrons in the body would indicate a relatively higher AVP activity, and hence,a proportional increase in copeptin. The latter, however,opposes this theory, suggesting that perhaps copeptin is only afiltration marker rather than a disease severity marker for ADPKD. Furthermore, it is not known whether eGFR also confounds the level of urinary copeptin[40].

IS SERUM COPEPTIN A PREDICTIVE BIOMARKER OF TREATMENT RESPONSE TO VASOPRESSIN RECEPTOR ANTAGONISTS OR PRESCRIBED FLUID INTAKE IN ADPKD?

Several authors have suggested that higher baseline levels of copeptin could be used as a method to select patients for AVP blocking therapies, such as tolvaptan or prescribedfluid intake[12]. While this is an attractive hypothesis, it has yet to be formally tested and validated. In this regard, it would certainly be possible to perform a post-hoc analysis of the large randomized controlled trials involving tolvaptan to answer this question. Similarly, an ongoing randomized controlled trial of prescribed fluid intake will evaluate the longterm changes in serum copeptin and its effect on the progression of TKV[41].

CONCLUSION

There is strong interest in the role of copeptin as a molecular biomarker in ADPKD. While aligned with the pathogenesis of ADPKD, copeptin seems attractive for this purpose, but many questions remain. The most important question is whether measuring serum copeptin adds extra value over the standard clinical management tools (such as the PRO-PKD score, eGFR,TKV) to predict renal prognosis[42]? If so, does this predict whether patients with elevated copeptin are more likely to respond to therapies that suppress AVP(either or both pharmacological or life-style factors,such as fluid intake)? If these fundamental questions can be answered, other issues can be addressed, such as: What level of copeptin will be effective in attenuating renal cyst growth? How often should copeptin be measured? Should it be evaluated in all patients who present for the first time? What are the confounding factors that might influence interpretation of the data?Does copeptin itself have a direct pathological role in ADPKD? What is the value of measuring urinary copeptin, and how does serum copeptin compare with other markers of the AVP axis, such as urinary cAMP excretion?

Clearly, well designed prospective studies and health economic data will assist in answering these questions and evaluating the role of copeptin in the management of patients with ADPKD. Until this evidence is available,it will be difficult to influence policy-makers and regulatory bodies to utilize this test in the routine clinical care of patients with ADPKD.

亚硝酸盐阻断剂对酱菜中亚硝酸盐含量的影响见表1。据表1可知，加入亚硝酸盐阻断剂的样品中，可以在经过一系列测定之后，与未加入亚硝酸盐阻断剂的样品进行对比分析。经过研究对比结果，进行统计分析可知，加入亚硝酸盐的含量要低[4]。因此，对酱菜进行日常的腌制时，加入适量的亚硝酸盐阻断剂能够有效中和酱菜中的亚硝酸盐含量，对酱菜中的亚硝酸盐含量起到良好的控制效果[26-27]。

REFERENCES

1 Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet 2007; 369: 1287-1301 [PMID: 17434405 DOI: 10.1016/S0140-6736(07)60601-1]

2 Geberth S, Stier E, Zeier M, Mayer G, Rambausek M, Ritz E.More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension. J Am Soc Nephrol 1995; 6: 1643-1648 [PMID: 8749692]

15 Mueller C, Möckel M, Giannitsis E, Huber K, Mair J, Plebani M,Thygesen K, Jaffe AS, Lindahl B; ESC Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association. Use of copeptin for rapid rule-out of acute myocardial infarction. Eur Heart J Acute Cardiovasc Care 2017; 2048872617710791 [PMID:28593800 DOI: 10.1177/2048872617710791]

4 Wang S, Dong Z. Environmental hit on a genetic basis in polycystic kidney disease. Am J Physiol Renal Physiol 2016; 311: F1358-F1359[PMID: 27558561 DOI: 10.1152/ajprenal.00452.2016]

5 Rangan GK, Tchan MC, Tong A, Wong AT, Nankivell BJ. Recent advances in autosomal-dominant polycystic kidney disease.Intern Med J 2016; 46: 883-892 [PMID: 27553994 DOI: 10.1111/imj.13143]

6 Schrier RW, Brosnahan G, Cadnapaphornchai MA, Chonchol M,Friend K, Gitomer B, Rossetti S. Predictors of autosomal dominant polycystic kidney disease progression. J Am Soc Nephrol 2014; 25:2399-2418 [PMID: 24925719 DOI: 10.1681/ASN.2013111184]

7 Brosnahan GM, Abebe KZ, Moore CG, Rahbari-Oskoui FF, Bae KT, Grantham JJ, Schrier RW, Braun WE, Chapman AB, Flessner MF, Harris PC, Hogan MC, Perrone RD, Miskulin DC, Steinman TI, Torres VE; HALT-PKD Trial Investigators. Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials. Am J Kidney Dis 2018; Epub ahead of print [PMID: 29306517 DOI:10.1053/j.ajkd.2017.10.023]

8 Barua M, Cil O, Paterson AD, Wang K, He N, Dicks E, Parfrey P,Pei Y. Family history of renal disease severity predicts the mutated gene in ADPKD. J Am Soc Nephrol 2009; 20: 1833-1838 [PMID:19443633 DOI: 10.1681/ASN.2009020162]

9 Tong A, Rangan GK, Ruospo M, Saglimbene V, Strippoli GF,Palmer SC, Tunnicliffe DJ, Craig JC. A painful inheritance-patient perspectives on living with polycystic kidney disease: thematic synthesis of qualitative research. Nephrol Dial Transplant 2015;30: 790-800 [PMID: 25637642 DOI: 10.1093/ndt/gfv010]

10 Wyatt CM, Le Meur Y. REPRISE: tolvaptan in advanced polycystic kidney disease. Kidney International 2018; 93: 292-295[DOI: 10.1016/j.kint.2017.12.002]

11 van Gastel MDA, Torres VE. Polycystic Kidney Disease and the Vasopressin Pathway. Ann Nutr Metab 2017; 70 Suppl 1: 43-50[PMID: 28614813 DOI: 10.1159/000463063]

A3、A4、B2、B3、C1(无人死亡时)、C2(无人员死亡时)、D1(无人员死亡时)区域为一般风险区域. 风险水平在一定有条件下可接受，需要进一步采取措施予以预防. 其中C1、C2和D1区域发生人员死亡时升级为较大风险区域；

12 Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006; 52: 112-119 [PMID:16269513 DOI: 10.1373/clinchem.2005.060038]

天然气涡轮计量系统如图2所示，一般由涡轮流量计、压力变送器、温度变送器、色谱分析仪、流量计算机5部分组成。涡轮流量计是该计量系统的核心，压力变送器、温度变送器采集输气工况条件下的压力、温度信号。色谱实时在线分析管道中的天然气组分，以确定天然气的压缩因子。流量计算机则将采集到的压力、温度、工况体积流量、气体组分进行运算分析，得到标准状况下的气体体积流量，并用于计量交接，同时保存相应的流量历史数据。

13 Timper K, Fenske W, Kühn F, Frech N, Arici B, Rutishauser J,Kopp P, Allolio B, Stettler C, Müller B, Katan M, Christ-Crain M. Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study. J Clin Endocrinol Metab 2015; 100: 2268-2274 [PMID:25768671 DOI: 10.1210/jc.2014-4507]

14 Winzeler B, Zweifel C, Nigro N, Arici B, Bally M, Schuetz P,Blum CA, Kelly C, Berkmann S, Huber A, Gentili F, Zadeh G,Landolt H, Mariani L, Müller B, Christ-Crain M. Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery. J Clin Endocrinol Metab 2015; 100: 2275-2282 [PMID:25923040 DOI: 10.1210/jc.2014-4527]

3 Persu A, Duyme M, Pirson Y, Lens XM, Messiaen T, Breuning MH, Chauveau D, Levy M, Grünfeld JP, Devuyst O. Comparison between siblings and twins supports a role for modifier genes in ADPKD. Kidney Int 2004; 66: 2132-2136 [PMID: 15569302 DOI:10.1111/j.1523-1755.2004.66003.x]

Moomal Tasneem, Carly Mannix, Annette Wong, Jennifer Zhang, Gopala Rangan, Centre for Transplant and Renal Research, Westmead Institute for Medical Research, the University of Sydney, Sydney 2145, Australia

17 Wang X, Wu Y, Ward CJ, Harris PC, Torres VE. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008; 19: 102-108 [PMID: 18032793 DOI: 10.1681/ASN.2007060688]

18 Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003; 9: 1323-1326 [PMID:14502283 DOI: 10.1038/nm935]

39 Boertien WE, Meijer E, Li J, Bost JE, Struck J, Flessner MF,Gansevoort RT, Torres VE; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease CRISP. Relationship of copeptin, a surrogate marker for arginine vasopressin, with change in total kidney volume and GFR decline in autosomal dominant polycystic kidney disease: results from the CRISP cohort. Am J Kidney Dis 2013; 61: 420-429 [PMID: 23089511 DOI: 10.1053/j.ajkd.2012.08.038]

40 Nakajima A, Lu Y, Kawano H, Horie S, Muto S. Association of arginine vasopressin surrogate marker urinary copeptin with severity of autosomal dominant polycystic kidney disease (ADPKD). Clin Exp Nephrol 2015; 19: 1199-1205 [PMID: 25715868 DOI: 10.1007/s10157-015-1101-7]

21 Fenske WK, Schnyder I, Koch G, Walti C, Pfister M, Kopp P,Fassnacht M, Strauss K, Christ-Crain M. Release and Decay Kinetics of Copeptin vs AVP in Response to Osmotic Alterations in Healthy Volunteers. J Clin Endocrinol Metab 2018; 103: 505-513[PMID: 29267966 DOI: 10.1210/jc.2017-01891]

在异构模式中，随机挑选一些节点，为其配备其他节点两倍通信距离远的发射器。为区别于普通节点，这些节点被称为特殊节点。为了检测特殊节点的设置对网络性能的影响，将其中一小部分节点作为特殊节点进行仿真试验。

22 Morgenthaler NG. Copeptin - Biochemistry and Clinical Diagnostics 1st ed. Bremen: UNI-MED, 2014

23 Dobša L, Cullen Edozien K. Copeptin and its potential role in diagnosis and prognosis of various diseases. Biochemia Medica 2012; 23: 172-190 [DOI: 10.11613/BM.2013.021]

24 de Bree FM, Burbach JP. Structure-function relationships of the vasopressin prohormone domains. Cell Mol Neurobiol 1998; 18:173-191 [PMID: 9535289]

25 Copeptin ELISA Kits. Biocompare: Buyer’s Guide for Life Scientists, 2017

26 Lemetais G, Melander O, Vecchio M, Bottin JH, Enhörning S,Perrier ET. Effect of increased water intake on plasma copeptin in healthy adults. Eur J Nutr 2017; Epub ahead of print [PMID:28578535 DOI: 10.1007/s00394-017-1471-6]

27 Sontrop JM, Huang SH, Garg AX, Moist L, House AA, Gallo K,Clark WF. Effect of increased water intake on plasma copeptin in patients with chronic kidney disease: results from a pilot randomised controlled trial. BMJ Open 2015; 5: e008634 [PMID:26603245 DOI: 10.1136/bmjopen-2015-008634]

渗沥液中悬浮物含量过多，可造成床体孔隙堵塞，堵塞程度因悬浮物自身组成和颗粒粗细的不同而异：有机物含量较多，且颗粒粗大者，容易引起反应床表面结皮，而细小的矿物颗粒则容易穿过表层，使床体内堵塞。堵塞一旦发生，即对床体渗透性能、复氧过程造成严重影响，进而使稳态运行系统失控。因此，渗沥液进入矿化垃圾反应床之前，进行简单的预处理工序十分必要。工程上设置了过滤器来防止矿化床被堵。

37 Park HC, Ahn C. Diagnostic Evaluation as a Biomarker in Patients with ADPKD. Adv Exp Med Biol 2016; 933: 85-103 [PMID:27730437 DOI: 10.1007/978-981-10-2041-4_8]

29 van Gastel MD, Meijer E, Scheven LE, Struck J, Bakker SJ,Gansevoort RT. Modifiable factors associated with copeptin concentration: a general population cohort. Am J Kidney Dis 2015;65: 719-727 [PMID: 25500109 DOI: 10.1053/j.ajkd.2014.10.009]

30 Eisenhofer G, Johnson RH. Effect of ethanol ingestion on plasma vasopressin and water balance in humans. Am J Physiol 1982; 242:R522-R527 [PMID: 7081477]

31 Leppäluoto J, Vuolteenaho O, Arjamaa O, Ruskoaho H. Plasma immunoreactive atrial natriuretic peptide and vasopressin after ethanol intake in man. Acta Physiol Scand 1992; 144: 121-127[PMID: 1533484 DOI: 10.1111/j.1748-1716.1992.tb09276.x]

32 Larose P, Ong H, Januszewicz P, Cantin M, du Souich P.Characterization of the effect of nicotine on vasopressin and atrial natriuretic factor in the rabbit. J Pharmacol Exp Ther 1988; 244:1093-1097 [PMID: 2908045]

33 Zittema D, Boertien WE, van Beek AP, Dullaart RP, Franssen CF,de Jong PE, Meijer E, Gansevoort RT. Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol 2012; 7: 906-913 [PMID: 22516290 DOI: 10.2215/CJN.11311111]

对患者开展心理干预能够，全方位缓解病患内心不良情绪，令其保持乐观心态，面对自身疾病。在此同时，通过科学规划饮食、补充蛋白质等举措，进而全面促进患者心功能恢复，提升疾病治愈率。

34 Zittema D, van den Brand JA, Bakker SJ, Wetzels JF, Gansevoort RT. Copeptin, a surrogate marker for arginine vasopressin,is associated with disease severity and progression in IgA nephropathy patients. Nephrol Dial Transplant 2017; 32: i146-i153[PMID: 28057871 DOI: 10.1093/ndt/gfw391]

35 Corradi V, Martino F, Gastaldon F, Scalzotto E, Caprara C,Fortunato A, Pinaffo G, Marchetti C, Fabbi F, Giavarina D, Ferrari F, Rosner MH, Ronco C. Copeptin levels and kidney function in ADPKD: case-control study. Clin Nephrol 2016; 86: 147-153[PMID: 27487355 DOI: 10.5414/CN108894]

36 Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.Clin Pharmacol Ther 2001; 69: 89-95 [PMID: 11240971 DOI:10.1067/mcp.2001.113989]

28 García-Arroyo FE, Cristóbal M, Arellano-Buendía AS, Osorio H, Tapia E, Soto V, Madero M, Lanaspa MA, Roncal-Jiménez C,Bankir L, Johnson RJ, Sánchez-Lozada LG. Rehydration with soft drink-like beverages exacerbates dehydration and worsens dehydration-associated renal injury. Am J Physiol Regul Integr Comp Physiol 2016; 311: R57-R65 [PMID: 27053647 DOI:10.1152/ajpregu.00354.2015]

38 Meijer E, Bakker SJ, Halbesma N, de Jong PE, Struck J, Gansevoort RT. Copeptin, a surrogate marker of vasopressin, is associated with microalbuminuria in a large population cohort. Kidney Int 2010; 77:29-36 [PMID: 19847155 DOI: 10.1038/ki.2009.397]

19 Boertien WE, Meijer E, de Jong PE, ter Horst GJ, Renken RJ,van der Jagt EJ, Kappert P, Ouyang J, Engels GE, van Oeveren W,Struck J, Czerwiec FS, Oberdhan D, Krasa HB, Gansevoort RT.Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function. Am J Kidney Dis 2015; 65: 833-841 [PMID: 25600953 DOI: 10.1053/j.ajkd.2014.11.010]

在网络迅猛发展的当今社会，依托信息技术推动智慧农业发展，在农业精细化管理模式应用过程中，经过依托发达的网络技术，能够大幅提高农业经营管理收益，经过运用发达的定位技术等，能够实现播种、施肥等农业活动的机械化、智能化。依托网络构建一种直接销售的全新形式，可以构建互联网销售体系，依托信息技术整合农产品信息，借助网络技术，实现对农产品质量的追踪监测，最终实现农业的科学化生产与运营。

20 Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367: 2407-2418 [PMID: 23121377 DOI: 10.1056/NEJMoa1205511]

41 Wong ATY, Mannix C, Grantham JJ, Allman-Farinelli M,Badve SV, Boudville N, Byth K, Chan J, Coulshed S, Edwards ME, Erickson BJ, Fernando M, Foster S, Haloob I, Harris DCH,Hawley CM, Hill J, Howard K, Howell M, Jiang SH, Johnson DW, Kline TL, Kumar K, Lee VW, Lonergan M, Mai J, McCloud P, Peduto A, Rangan A, Roger SD, Sud K, Torres V, Vliayuri E,Rangan GK. Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENTADPKD). BMJ Open 2018; 8: e018794 [PMID: 29358433 DOI:10.1136/bmjopen-2017-018794]

“直译+意译”是将最主要的中心义素直译，然后选择其他有区别性特征的义素修饰、限定或补充这个中心义素(同上：246)。美国权威影视杂志《综艺》(Variety)就采取了这种译法，将其译为“the force”，后面再加上“mystic powers”加以解释，这种译法可能更能被西方读者所接受理解。The force本身来源于广受西方观众喜爱的影视作品《星球大战》，与“洪荒之力”有异曲同工之妙。可以说，“the force”更符合西方读者的认知语境和文化语境，是一种成功的译法。

42 Corradi V, Gastaldon F, Caprara C, Giuliani A, Martino F, Ferrari F, Ronco C. Predictors of rapid disease progression in autosomal dominant polycystic kidney disease. Minerva Med 2017; 108:43-56 [PMID: 27701376 DOI: 10.23736/S0026-4806.16.04830-8]