www.kidney-international.

org clinical trial

Q3
A randomized multicenter trial on a lung
ultrasound–guided treatment strategy in patients
1
2
on chronic hemodialysis with high cardiovascular 54
55
3 Q1
risk 56
4 57
5 Q58 Carmine Zoccali1,2, Claudia Torino3, Francesca Mallamaci3, Pantelis Sarafidis4, Aikaterini Papagianni4, 58
6 Robert Ekart5, Radovan Hojs5, Marian Klinger6, Krzysztof Letachowicz7, Danilo Fliser8, 59
7 Sarah Seiler-Mußler8, Fabio Lizzi8, Andrzej Wiecek9, Agata Miskiewicz9, Kostas Siamopoulos10, 60
8 61
9
Olga Balafa10, Itzchak Slotki11,12, Linda Shavit11,12, Aristeidis Stavroulopoulos13,14, Adrian Covic15, 62
10 Dimitrie Siriopol15, Ziad A. Massy16,17, Alexandre Seidowsky16,17, Yuri Battaglia18, 63
11 Alberto Martinez-Castelao19,20, Carolina Polo-Torcal19,20, Marie-Jeanne Coudert-Krier21, 64
12 Patrick Rossignol22,23, Enrico Fiaccadori24, Giuseppe Regolisti24, Thierry Hannedouche23,25, 65
13 Thomas Bachelet26, Kitty J. Jager27, Friedo W. Dekker28, Rocco Tripepi3, Giovanni Tripepi3, 66
14 Q4 Luna Gargani29, Rosa Sicari29, Eugenio Picano29 and Gérard Michel London23,30 67
15 68
16 Q5Q6 1Renal Research Institute, New York, New York, USA; 2Associazione Ipertensione Nefrologia e Trapianto Renale, Reggio Cal, Italy; 3Institute 69
Q7
17 of Clinical Physiology–Reggio Cal Unit, National Research Council, Reggio Calabria, Italy; 4Department of Nephrology, Aristotle University 70
18 Q8 of Thessaloniki, Thessaloniki, Greece; 5University Clinical Centre Maribor, Maribor, Slovenia; 6University of Opole, Opole, Poland; 7Wroclaw 71
19 Q9Q10 Medical University, Wroclaw, Poland; 8Saarland University Hospital, Homburg, Germany; 9University of Silesia in Katowice, Katowice, 72
Q11
Q12Q13 Poland; 10University Hospital of Ioannina, Ioannina, Greece; 11Shaare Zedek Medical Center, Jerusalem, Israel; 12Faculty of Medicine,
20 Q14Q15
73
Q16Q17 Hebrew University of Jerusalem, Jerusalem, Israel; 13IASIO Hospital–General Clinic of Kallithea, Kallithea, Greece; 14Athens Kidney Institute
21 Q18 74
Q19Q20 NEPHROEXPERT, Athens, Greece; 15Dr. C. I. Parhon Hospital, Iasi, Romania; 16Ambroise Pare University Hospital, Assistance Publique–
22 75
Q21Q22 Hôpitaux de Paris, Paris-Ile-de France-Ouest University, Boulogne Billancourt, Paris, France; 17Centre Epidémiologie et Santé Publique,
23 76
Institut National de la Santé et de la Recherche Médicale (INSERM) U1018, Team 5, Villejuif, France; 18Division of Nephrology and Dialysis,
24 Q23Q24 St. Anna University Hospital, Ferrara, Italy; 19Bellvitge’s University Hospital-Hospitalet, Barcelona, Spain; 20Red de Investigación Renal,
77
25 Q25
Q26Q27 Instituto Salud Carlos III, Madrid, Spain; 21Association Lorraine de Traitement de l’Insuffisance Rénale, Nancy, France; 22Université de
78
26 Lorraine, Centre D’Investigation Clinique Plurithématique–INSERM 1433–Centre Hospitalier Régional Universitaire de Nancy, INSERM 79
27 Q28Q29 U1116, Vandœuvre-lès-Nancy, France; 23FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists) Network, Nancy, France; 80
28 Q30 24
Department of Medicine and Surgery and Nephrology Unit, University Hospital Parma, Parma, Italy; 25University Hospital of Strasbourg, 81
29 Q31Q32 and School of Medicine, Strasbourg, France; 26Clinique Saint-Augustin-CTMR, ELSAN, Bordeaux, France; 27Department of Clinical 82
30 Q33 Epidemiology, Biostatistics, and Bio-informatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 83
28
31 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands; 29Institute of Clinical Physiology–Pisa, 84
32 Q34Q35 National Research Council, Pisa, Italy; and 30Centre Hospitalier F.H. Manhès, Fleury-Mérogis, France 85
33 86
34 87
35 88
36 Lung congestion is a risk factor for all-cause and outcomes. A total of 367 patients were enrolled: 183 in the 89
37 cardiovascular mortality in patients on chronic active arm and 180 in the control arm. In the active arm, the 90
38 hemodialysis, and its estimation by ultrasound may be pre-dialysis lung scan was used to titrate ultrafiltration 91
39 useful to guide ultrafiltration and drug therapy in this during dialysis and drug treatment. Three hundred and 92
40 population. In an international, multi-center randomized seven patients completed the study: 152 in the active arm 93
41 controlled trial (NCT02310061) we investigated whether a and 155 in the control arm. During a mean follow-up of 94
42 lung ultrasound-guided treatment strategy improved a 1.49 years, lung congestion was significantly more 95
43 composite end point (all-cause death, non-fatal myocardial frequently relieved in the active (78%) than in the control 96
44 infarction, decompensated heart failure) vs usual care in (56%) arm and the intervention was safe. The primary 97
45 patients receiving chronic hemodialysis with high composite end point did not significantly differ between 98
46 cardiovascular risk. Patient-Reported Outcomes the two study arms (Hazard Ratio 0.88; 95% Confidence 99
47 (Depression and the Standard Form 36 Quality of Life Interval: 0.63-1.24). The risk for all-cause and cardiovascular 100
48 Questionnaire, SF36) were assessed as secondary hospitalization and the changes of left ventricular mass and 101
49 function did not differ among the two groups. A post hoc 102
50 Correspondence: Carmine Zoccali, Associazione Ipertensione Nefrologia e analysis for recurrent episodes of decompensated heart 103
51 Trapianto Renale c/o CNR-IFC, Clinical Epidemiology of Renal Diseases and failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 104
52 Q36 Hypertension, 89124, Reggio Calabria, Italy. E-mail: carmine.zoccali@tin.it 0.41-0.97) showed a risk reduction for these outcomes in 105
53 Received 14 May 2021; revised 1 July 2021; accepted 8 July 2021 the active arm. There were no differences in patient- 106

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107 reported outcomes between groups. Thus, in patients on informed consent. An international independent Data Safety 163
108 chronic hemodialysis with high cardiovascular risk, a Monitoring Committee monitored patient safety 164
109 treatment strategy guided by lung ultrasound effectively 165
110 relieved lung congestion but was not more effective than Trial participants 166
111 usual care in improving the primary or secondary end To set up the trial, an Internet-based platform was created and an Q38 167
open call to all members of the European Cardiovascular and Renal
112 points of the trial. 168
Medicine (EURECAm) working group of the European Renal As-
113 Kidney International (2021) -, -–-; https://doi.org/10.1016/ sociation and the European Society of Dialysis and Transplantation
169
114 j.kint.2021.07.024
(ERA-EDTA) was made. Investigators representing 24 European 170
115 KEYWORDS: cardiovascular risk; chronic kidney failure; ESRD; heart failure renal units expressed an interest for the trial and entered in the study Q39 171
116 hemodialysis; lung congestion; lung ultrasound platform the clinical data of patients potentially eligible for the study. 172
117 Copyright ª 2021, Published by Elsevier, Inc., on behalf of the International Six renal units were dropped for organizational problems, leaving 18 173
Society of Nephrology.
118 participating renal units. 174
119 To be enrolled into the trial, patients had to be >18 years of age, 175
120 on hemodialysis >3 months prior to study day 1, and have a high- 176

V
121 risk cardiovascular profile: that is, a history of myocardial infarction 177
olume overload is a leading risk factor for death and
122 with or without ST elevation or unstable angina, acute coronary 178
cardiovascular events in patients with chronic kidney
syndrome documented by electrocardiogram recordings, and cardiac
123 failure who are maintained on chronic dialysis,1 troponins or stable angina pectoris with documented coronary artery
179
124 particularly in those with myocardial ischemia and heart disease by prior coronary angiography or electrocardiography or HF 180
125 failure (HF), which represent a substantial fraction (about with dyspnea class III-IV according to New York Heart Association 181
126 30%–40%)2 of this population. Early identification of volume functional classification. Exclusion criteria were cancer or other 182
127 overload may prevent cardiovascular complications in these advanced noncardiac disease or comorbidity (e.g., end-stage liver 183
128 patients, but clinical signs of volume expansion are inade- failure) imposing a poor short-term prognosis, active infections or 184
129 quate to reliably identify patients at risk and to monitor them relevant intercurrent disease, and inadequate lung scanning and 185
130 over time.3 However, reliable, standard techniques for echocardiographic studies. An echocardiographic study was per- 186
131 measuring extracellular or circulating (blood) volume applied formed in all participants to document anatomical (LV hypertrophy) 187
132 or functional (or both) alterations of the LV. 188
in clinical practice do not convey information on funda-
133 mental heart function parameters that determine the indi- 189
Lung US
134 vidual hemodynamic tolerance to volume excess and the 190
Lung water assessment by chest US is a quick (w5 minutes) and easy
135 response to ultrafiltration: that is, left ventricular (LV) filling to learn technique that requires just a 2-hour training session. A
191
136 pressure and LV function. Extravascular lung water is criti- detailed description of the technique and its validation in patients on 192
137 cally dependent on these parameters and represents a proxy of hemodialysis is described elsewhere.5 Nephrologists and cardiologists 193
138 both circulating volume and LV filling pressure and function4 of participating units were trained by a remote Internet-based pro- 194
139 and may therefore be a better criterion to identify patients at a gram and, after training, all of them were certified by the lung US 195
140 higher risk of adverse clinical outcomes and to monitor the expert of the trial (LG) who acted also as study trainer.8 All centers 196
141 effect of therapy aimed at preventing these outcomes. A fast participating to the trial were provided a handheld US machine (VS 197
142 (<5 minute), easy to learn, simple, and inexpensive technique scan, General Electric) to be used during the trial. 198
143 that measures extravascular lung water by using standard 199
144 Intervention 200
ultrasound (US) machines has been validated in patients on
Patients were randomized to a lung US–guided treatment policy or
145 dialysis.5 Lung US is applied to monitor treatment of to standard clinical care. Given the nature of the intervention,
201
146 decompensated HF.6,7 Whether systematic measurement of treatment assignment was not blinded. In patients randomized to the
202
147 lung water by this technique may translate into better clinical active arm of the study, lung US was performed by nephrologists 203
148 outcomes in patients with chronic kidney failure has never before and after hemodialysis session and the predialysis lung scan 204
149 been tested. was used to titrate ultrafiltration (UF) during dialysis and drug 205
150 The aim of this randomized clinical trial is that of testing a treatment. In patients in this arm with moderate to severe lung 206
151 treatment policy guided by extravascular lung water mea- congestion (>15 lung comets predialysis; see Supplementary 207
152 surements by US to prevent all-cause death, decompensated Figure S1) lung US was repeated at least once a week until the 208
153 HF, and nonfatal myocardial infarction in high-risk patients treatment goal (<15 US-B lines) was achieved and once a month Q40 209
154 on hemodialysis with myocardial ischemia or HF as thereafter. Depending on the severity of lung congestion, specific 210
155 weight reduction targets were suggested to nephrologists of partici- 211
compared to standard care based on clinical signs and
pating centers.9 The same (monthly) monitoring frequency was Q41
156 symptoms. 212
adopted also in patients without or with mild pulmonary congestion
157 213
at baseline (<15 US-B lines). Furthermore, the use of the technique
158 METHODS was allowed whenever its application was deemed useful to assume 214
159 The Lung Water by Ultrasound-Guided Treatment in Hemodialysis clinical decisions by attending physicians. Patients in the active arm 215
160 Q37 Patients (LUST) trial is registered in ClinicalTrials.gov (identifier: of the study without evidence of lung congestion at baseline who 216
161 NCT02310061). The study was approved by the institutional review developed pulmonary congestion (i.e., clinical signs or >15 US-B 217
162 board at each study site, and all participants provided written lines or both) during the trial received the same treatment 218

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219 contemplated for those with lung congestion at baseline.9 The Methods against bias 275
220 treatment goal was pursued by UF intensification realized either by Randomization (permuted blocks of random length) stratified by 276
221 lengthening the duration of dialysis or by extradialysis sessions, ac- center was made at the coordinating center and communicated to 277
222 cording to individual tolerance and feasibility. If the treatment goal participating centers by e-mail or telephone. 278
was not achieved within the first 3 to 4 weeks or intolerance to UF
223 279
supervened, adjustment of drug treatment was considered including Study outcomes
224 280
the introduction or dose adjustments of drugs of proven efficacy for The main study endpoint was a composite of all-cause death,
225 cardiovascular prevention in patients on hemodialysis along the al- nonfatal myocardial infarction, or decompensated HF. The second- 281
226 gorithm of a consensus document by Kidney Disease: Improving ary clinical endpoints of the trial were all-cause and cardiovascular 282
227 Global Outcomes10 (see Supplementary Table S1). Other cardio- hospitalizations and changes in echocardiographic parameters 283
228 vascular and noncardiovascular medications were maintained un- including LV mass index, left atrial volume index, ejection fraction, 284
229 changed or appropriately adapted in relationship to the individual and the Early diastolic trans mitral flow velocity (E) to early diastolic 285
230 needs. mitral annular tissue velocity (e0 ). In the trial we also collected in- 286
231 Patients in the control arm of the study were followed up and formation on patient-reported outcomes (Depression and the 287
232 managed with standard criteria according to current recommenda- Standard Form 36 Quality of Life Questionnaire, SF36) and 2 288
233 tions (implying optimization of fluids volume control based on questionnaires collected by doctors (Berlin Questionnaire and Kar- 289
clinical criteria and the use of carvedilol, angiotensin-converting nofsky score).
234 290
enzyme inhibitors or sartans whenever deemed necessary) and the
235 291
use of lung US was not allowed in these patients. Sample size, study power
236 In addition to peridialysis measurements in the active arm of the A total sample size of 500 patients (250 per group) was expected
292
237 trial, lung US recordings were made in both arms during the baseline to provide approximately 80% power to detect a difference in the 293
238 visit and in subsequent visits at 6, 12, and 24 months by a cardiol- primary endpoint with an assumed type 1 error rate of 0.05, 2- 294
239 ogist blind to study intervention. During the same visits patients of sided. We estimated that the 2-year event rate for the composite 295
240 both groups underwent echocardiography. endpoint would be 45% in the usual care group and 30% (a 33% 296
241 The occurrence of clinical events was accurately registered in the risk reduction) in the arm with the lung US–guided intervention. 297
242 Internet platform of the trial in both study arms, and the platform According to protocol, all patients were to be followed for 24 298
243 was actively surveilled by an investigator at the coordinating center months after randomization. For the analysis of the primary, 299
244 (CT). In the case of doubt, clinical events were adjudicated by an composite endpoint and all-cause and cardiovascular hospitaliza- 300
external panel of physicians unaware of the allocation of patients into tions (secondary endpoints), we analyzed the data by the Kaplan-
245 301
the trial. Meier method and the univariate Cox’s regression hazard ratio Q42
246 302
247 303
248 304
249 305
Flow of patients in the LUST trial
250 306
251 307
252 363 randomized* 308
253 309
254 310
255 183 Randomized to receive Lung–US 180 Randomized to receive usual care
311
256 guided intervention All received the allocated intervention 312
257 All received the allocated intervention 313
258 31 Withdrawn 25 Withdrawn
314
259 21 Lost to follow-up 19 Lost to follow-up 315
260 6 Withdrawn by site investigator 6 Withdrawn by site investigator 316
4 Transferred 3 Transferred
261 317
262 318
263 319
264 152 Completed the study 155 Completed the study 320
265 97 Underwent the 4 study visits 90 Underwent the 4 study visits 321
266 51 Died 59 Died 322
4 Transplanted 6 Transplanted
267 323
268 324
269 183 Included in the primary analysis 180 Included in the primary analysis 325
270 326
271 327
272 *The number of patients screened for eligibility is unavailable 328
273 Figure 1 | CONSORT flow diagram for patients in the Lung Water by Ultrasound-Guided Treatment in Hemodialysis Patients (LUST) 329
274 trial. US, ultrasound. Q51 330

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331 (HR) was considered as the main estimate of the effect of the Table 1 | Main demographic, somatometric, and clinical Q53
387
332 intervention. Missing baseline categorical variables were replaced characteristics in patients as divided according to the study 388
333 with the mean or median value, as appropriate. The effect of the interventions 389
334 allocation arm on the number of US-B lines and on echocar- 390
Active arm Control arm
diographic parameters was investigated by linear mixed models. (n [ 183) (n [ 180)
335 391
After the publication of the protocol at ClinicalTrials.gov, 2 studies
336 Age, yr 70  10 70  11 392
reporting a benefit of lung US–guided treatment strategies in
337 BMI, kg/m2 26  5 26  5 393
patients with HF were published.11,12 For this reason, we also
338 Male sex 127 (69) 128 (71) 394
made separate secondary analyses (post hoc) of recurrent episodes Current smokers 23 (13) 27 (15)
339 of decompensated heart failure and repeated cardiovascular events Diabetics 74 (40) 73 (41)
395
340 as well as post hoc analyses of the individual components of the On antihypertensive treatment 138 (75) 136 (76) 396
341 composite endpoint. Cardiovascular events were prespecified and Dialysis vintage, mo 51 (22–141) 59 (27–166) 397
342 listed in the study platform. These included a series of events Acute CS or stable angina 135 (74) 124 (69) 398
demanding hospitalization including myocardial infarction, acute Myocardial infarction 92 (50) 90 (50)
343 Atrial fibrillation 47 (26) 45 (25) 399
344 coronary syndrome, coronary artery graft or coronary angioplasty, Heart failure 69 (38) 85 (47) 400
345 decompensated HF, atrial fibrillation or flutter, other arrhythmias, NYHA functional class III-IV 61 (33) 69 (38) 401
cardiac arrest or sudden death, stroke, transient ischemic attack, Stroke 25 (14) 16 (9)
346 402
de novo peripheral vascular disease, peripheral arteries angioplasty Peripheral vascular disease 50 (27) 53 (29)
347 Systolic/diastolic BP, mm Hg 138  25/71  15 136  24/70  12 403
or stenting, amputation, and vascular surgery. Total (recurrent)
348 episodes of decompensated HF and total cardiovascular events LVM indexed by height, g/m 51.0 (42.7–61.3) 50.2 (41.9–60.7) 404
349 Ejection fraction, % 60 (55–65) 57 (52–61) 405
were expressed as events per 100 person-years. The impact of the
E/e0 11.2 (8.3–14.4) 10.8 (7.8–15.0)
350 study intervention on these secondary (post hoc) analyses was 406
Biochemistry
351 analyzed by the zero inflated binomial regression, which is a Cholesterol, mmol/l 4.1  1.2 3.9  1.1 407
352 method for modeling count variables with excessive zeros and for Hemoglobin, g/l 111  15 112  15 408
353 overdispersed count-based variables.13 No effect of the interven- Albumin, g/l 38  6 39  7 409
tion on these metrics was registered. All analyses were based on CRP, mg/l 4.3 (2.0–10.0) 5.0 (2.4–13.3)
354 Calcium, mmol/l 2.2  0.2 2.2  0.2
410
355 the principle of intention to treat and were performed using SPSS 411
Phosphate, mmol/l 1.6  0.5 1.5  0.4
356 version 24 (IBM Corp) and STATA 16 (StataCorp). The threshold 412
BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; CS, coronary Q54
for statistical significance was 2-sided with a type 1 error rate of
357 syndrome; E/e’, early diastolic transmitral flow velocity (E) to early diastolic mitral 413
0.05. annular tissue velocity (e’); LVM, left ventricular mass; NYHA, New York Heart
358 414
Association.
359 Values are mean  SD, median (interquartile range), or n (%), as appropriate. 415
360 RESULTS 416
361 At the time we started the trial, the interest of nephrologists 417
362 for the technique was modest and most nephrologists felt that Medical treatment by strategy and follow-up 418
363 the same technique was complex and time-consuming, which Patients randomized to the lung US–guided strategy under- 419
364 slowed the recruitment rate. After a 4.5-year recruitment went 4103 predialysis and an equal number of postdialysis 420
365 period, considering the slow recruitment rate, patient lung US recordings made by attending nephrologists (on 421
366 enrollment was stopped when 363 of the 500 planned patients average 24  17 for each measurement per patient). In the 422
367 (77%) had been enrolled in the trial. Final study visits for all lung US studies blindly made by cardiologists in coincidence 423
368 patients still actively participating in the trial had to be of the four prefixed visits of the trial, patients in the active 424
369 completed prior to the database lock (July 10, 2020). arm had a decline in the number of US-B lines (baseline: 15; 425
370 95% confidence interval [CI]: 12–19; study end: 9; 95% CI: Q45 426
371 Study patients 5–12) while those in the control arm (from 16 [95% CI: 13– 427
372 Three hundred and sixty-three patients were randomized 20] to 30 [95% CI: 20–39]) had an increase in US-B lines 428
373 (lung US–guided therapy: 183; standard care: 180) at 18 (Figure 2a). Data analysis by linear mixed models showed that 429
374 Q43 renal units in Europe between March 1, 2013, and December the allocation arm was a strong modifier of the evolution of 430
375 31, 2017 (The CONSORT flow diagram is presented in US-B lines across the trial (P ¼ 0.002) (Figure 2b). Accord- 431
376 Q44 Figure 1). All patients but 1 were of Caucasian descent and ingly, the number of patients who achieved the treatment 432
377 for legal reasons race could not be specified for the 54 target (<15 US-B lines) was higher (P < 0.001) in the active 433
378 French patients of the trial. The groups were generally well (n ¼ 117; 78%) than in the control (n ¼ 85; 56%) arm. 434
379 balanced with respect to baseline characteristics (Table 1). Adjustment of the antihypertensive therapy along the pre- 435
380 As the study enrolled patients on hemodialysis who were at specified treatment algorithm was performed in 21 patients in 436
381 high cardiovascular risk, the study population was charac- the US-B lines group and in 10 patients in the usual care 437
382 terized a high prevalence of major cardiovascular comor- group (P ¼ 0.045) and the corresponding total number of 438
383 bidities (Table 1). Most patients were receiving adjustments was 38 and 15, respectively. The incidence rate 439
384 pharmacologic therapy for hypertension and cardiovascular was 14.1 adjustments per 100 person-years in the first and 5.5 440
385 comorbidities with no difference between the 2 groups adjustments per 100 person-years in the second group (P ¼ 441
386 (Supplementary Table S2). 0.001). 442

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443 Number of US-B

45
a 499
444 lines–real data 40 Usual care 500
(mean, 95% CI) Lung US
445 35 501
446 30 502
447 25 503
448 20 504
449 15 505
450 10 506
451 5 507
452 0 508
0 6 12 24
453 Number of US-B 45
509
454 lines–estimated
40
b Usual care
510
by LMM P = 0.002
455 (mean, 95% CI) 35 Lung US 511
456 30
512
457 25
513
458 20
514
459 15
515
460 10
516
461 5
517
462 0
518
463 0 6 12 24 519
No. at risk
464 Lung-US–guided 183 154 131 62 520
Usual care 180 155 132 69
465 521
466 Figure 2 | Trend of US-B lines in the active and control group. (a) Data are mean and 95% confidence interval (CI). (b) Data (mean and Q52 522
467 95% CI) are data fitted by the linear mixed model (LMM). The I value was derived from the LMM and indicates that the allocation arm modified 523
the evolution of US-B lines across the trial. US, ultrasound.
468 524
469 Predialysis systolic blood pressure (lung US group: base- of secondary endpoints, including the echocardiographic pa- 525
470 line: 138  25 mm Hg, last study visit: 139  26 mm Hg; rameters (left atrial volume, LV mass index, ejection fraction, 526
471 usual care group: baseline: 136  24 mm Hg, last study visit: and the E/e0 ) (Supplementary Table S3), and the risk for all- 527
472 137  21 mm Hg), postdialysis systolic blood pressure (lung cause and cardiovascular hospitalizations were similar in the 528
473 US group: baseline: 131  25 mm Hg, last study visit: 129  2 arms (all-cause hospitalizations: HR: 1.03; 95% CI: 0.77– 529
474 25 mm Hg; usual care group: baseline: 130  25 mm Hg, last 1.36; P ¼ 0.86; cardiovascular hospitalizations: HR: 1.02; 95% 530
475 study visit: 132  23 mm Hg), predialysis body weight (lung CI: 0.71–1.46; P ¼ 0.92). Death occurred in 51 patients (28%) 531
476 US group: baseline: 76  16 kg, last study visit: 76  16 kg; in the lung US–guided group and in 59 (33%) in the usual 532
477 usual care group: baseline: 74  16 kg, last study visit: 73  care group (HR: 0.89; 95% CI: 0.61–1.29; P ¼ 0.53). The time 533
478 17 kg), and postdialysis body weight (lung US group: baseline: to the first episode of myocardial infarction and decom- 534
479 74  16 kg, last study visit: 74  16 kg; usual care group: pensated HF did not significantly differ between the 2 groups 535
480 baseline: 72  15 kg, last study visit: 72  17 kg) did not (Table 2). A post hoc, secondary analysis of the total number of 536
481 change across the trial. repeated episodes of decompensated HF and repeated cardio- 537
482 vascular events in the 2 groups (Figure 414) showed a signifi- 538
483 Safety cant reduction in the incidence rate for these outcomes in the 539
484 The intervention was safe, and the risk of dialysis hypotension lung US arm as compared to those in the usual care arm 540
485 Q46 was less in the active arm of the trial (Table 2). Other possible (Table 3). 541
486 adverse effects of the intervention including vascular access 542
487 (AV fistula or graft) problems and intradialysis and extra- 543
Other secondary analyses
488 dialysis arrhythmia did not differ between the 2 groups. 544
489 Secondary analyses on patient-reported outcomes (Depres- 545
490 Study outcomes
sion and the Standard Form 36 Quality of Life Questionnaire, 546
491 During a mean follow-up of 1.49  0.72 years the main SF36) as well as the results of 2 additional questionnaires 547
492 composite endpoint occurred in 62 patients (34%) in the lung collected by doctors (Berlin Questionnaire and Karnofsky 548
493 US–guided therapy arm and in 71 patients (39%) in the control score) are reported in Supplemental Table S4). No effect of 549
494 arm and the HR was statistically not significant (HR: 0.88; 95% the intervention on these metrics was registered. 550
495 CI: 0.63–1.24, P ¼ 0.47) (Figure 3). No effect modification by 551
496 Q47 age, gender, diabetes, ischemic heart disease, HF, systolic blood DISCUSSION 552
497 pressure, and ejection fraction (Supplementary Figure S2) nor The primary finding of this study is that in patients at on 553
498 by center (Supplementary Figure S3) was found. The analysis hemodialysis who are at high risk for cardiovascular events, a 554

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555 Q55 Table 2 | XXX for a combined endpoint, including mortality, time to an 611
556 Rates of adverse events urgent visit, and hospitalization for worsening HF, but mor- 612
557 of interest Lung US arm Usual care arm P value tality did not differ between the 2 groups. In another trial in 613
558 Dialysis hypotension 858; 320 (300–342) 1292; 473 (448–500) <0.001
244 patients with chronic HF randomized to lung US–guided 614
559 Total episodes of 31; 11.6 (7.8–16.4) 34; 12.5 (8.6–17.4) 0.76 in addition to physical examination–guided therapy or to 615
560 arrhythmia on and off physical examination–guided therapy alone,12 a marked 616
561 dialysis across the trial reduction (56%) for the risk of hospitalization for acute 617
Vascular access 25; 9.3 (6.0–13.7) 19; 7.0 (4.2–10.9) 0.34
562 problems decompensated HF was registered but again no difference in 618
563 mortality was registered between the 2 study arms. 619
Values are total number and incidence rate; events  100 person-years (95% con-
564 fidence interval). In the LUST study, the intervention reduced markedly the 620
565 degree of lung congestion, which is per se a condition pre- 621
566 strategy of guiding therapy based on lung US successfully and disposing to pulmonary edema, and the proportion of pa- 622
567 safely reduced lung congestion in the active arm of the trial tients achieving the target level of lung water (<15 US-B 623
568 but this strategy was not more effective than a usual care lines) was substantially higher in the active arm of the trial 624
569 strategy in reducing the composite endpoint of time to death (78%) than in the control arm (56%). Similarly, intensifica- 625
570 or myocardial infarction or decompensated HF. tion of concomitant antihypertensive therapies occurred more 626
571 In a trial in 123 patients hospitalized for HF randomized to frequently in the active arm. B-lines reduction was achieved 627
572 either standard follow-up or to a lung US–guided diuretic with a smooth lung decongestion, as witnessed by the 628
573 therapy,11 patients in the active arm had a 48% risk reduction reduction of number of hypotensive episodes during dialysis 629
574 630
575 631
576 Primary endpoint (composite of death, myocardial infarction, or 632
577 de novo decompensated heart failure) 633
578 634
Endpoint
579 Probability 635
580 636
0.6
581 637
582 0.5 638
583 Usual care 639
0.4 Lung–US guided
584 640
585 0.3 641
586 642
0.2
587 643
588 0.1 644
589 0
645
590 0 2 4 6 8 10 12 14 16 18 20 22 24 646
591 Months since randomization 647
No. at risk
592 Lung–US guided 183 161 154 148 140 133 126 118 113 105 99 92 59 648
Usual care 180 166 157 150 143 133 124 119 106 98 94 88 61
593 649
594 Death 650
All-cause mortality
595 Probability 651
596 0.4
652
597 653
Usual care
598 Lung–US guided
654
0.3
599 655
600 656
601 0.2 657
602 658
603 0.1 659
604 660
0
605 661
0 2 4 6 8 10 12 14 16 18 20 22 24
606 Months since randomization
662
607 No. at risk 663
608 Lung–US guided 183 165 159 154 145 137 131 124 120 114 106 99 62 664
Usual care 180 168 163 155 147 140 132 129 118 112 106 99 69
609 665
610 Figure 3 | Kaplan-Meier cumulative curves for the primary endpoint. US, ultrasound. 666

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 C Zoccali et al.: Lung ultrasound–guided treatment in high-risk kidney failure patients clinical trial

667 active arm of the trial (6 hemodialysis treatments per week) 723
668 but increased in the control arm (3 hemodialysis treatments 724
669 per week). Notwithstanding the efficacy and the safety of the 725
670 lung US–guided treatment strategy in relieving lung conges- 726
671 tion, the risk reduction (12%) observed in the active arm of 727
672 the trial for the composite endpoint was largely nonsignificant 728
673 as were the changes in echocardiographic parameters. Only in 729
674 a post hoc analysis stimulated by 2 trials in patients with 730
675 HF11,12 did we observed a risk reduction for repeated episodes 731
676 of decompensated HF and cardiovascular events (Figure 4). 732
677 The difference observed in this post hoc analysis is difficult to 733
678 interpret and may be a pure chance effect. However, it is 734
679 possible that because the decongestion process was slow and 735
680 maximized at the end of the trial, it may take a long time for 736
681 this process to have an impact on clinical outcomes. In the 737
682 frequent hemodialysis trial no effect of hemodialysis inten- 738
683 sification on mortality was observed during the trial,16 while a 739
684 marked reduction (46%; range: 10%–90%) in the death risk 740
685 was registered in a secondary analysis made 3.6 years (range: Q48 741
686 1.5–5.3 years) after randomization.17 In a LUST substudy 742
687 including also patients on hemodialysis who were non-high- 743
688 risk hypertensive, the lung US–guided strategy safely reduced 744
689 48-hour ambulatory blood pressure.18 In any case, the anal- 745
690 ysis of the total number of events (decompensated HF and 746
691 cardiovascular events in general) is a secondary analysis and 747
692 as such has just a hypothesis-generating value. 748
693 This study has important limitations making the results 749
694 inconclusive as for the primary endpoint. First, at the time of 750
695 the study design there was no previous trial testing lung US, 751
696 neither in chronic kidney failure nor in other conditions. 752
697 Available information in observational studies suggested a 753
698 substantial benefit of fluid overload correction. Indeed in a 754
699 previous multicenter cohort study by us19 the risk of death 755
700 (adjusted for New York Heart Association functional class and 756
701 Figure 4 | Cumulative (repeated) episodes of decompensated other risk factors) of patients with severe lung congestion was 757
702 heart failure (HF) (a) and cardiovascular events (b). Data plotting 4.2-fold (HR:4.20; 95% CI: 2.45–7.23) higher than that in 758
was done according to Nelson’s hazard plotting method.14
703 patients with milder forms of lung congestion or no 759
704 congestion and the corresponding risk for cardiac events was 760
705 in the lung US group. In spite of these changes, body weight 3.2 higher (HR: 3.20; 95% CI: 1.75–5.88). Ex post, the 33% 761
706 did not change in either group. A similar phenomenon was risk reduction we hypothesized was unrealistic. Observational 762
707 noted in the frequent hemodialysis trial,15 where both pre- studies are a suboptimal source of information to make 763
708 dialysis and postdialysis body weight remained constant in quantitative inferences on the expected effect of experimental 764
709 both arms of the study while total body water decreased in the interventions. Extending the observation of patients to the 765
710 766
711 767
712 Table 3 | XXX Q56
768
713 Secondary analyses Lung US arm n (%); (95% CI) Usual care arm n (%); (95% CI) HR (95% CI) P value 769
714 770
Deaths 51 (28); (22–35) 59 (33); (26–40) 0.89 (0.61–1.29) 0.53
715 First myocardial infarction 16 (9); (5–14) 10 (6); (3–10) 1.61 (0.73–3.55) 0.24 771
716 First episode of decompensated HF 12 (7); (3–11) 19 (11); (6–16) 0.64 (0.31–1.32) 0.23 772
717 n; Incidence rate per 100 n; Incidence rate per 100 773
718 person-years (95% CI) person-years (95% CI) IRR (95% CI) P value 774
719 Total (recurrent) episodes of decompensated HF 15; 5.6 (3.1–9.2) 24; 8.8 (5.6–13.1) 0.37 (0.15–0.93) 0.035a
775
720 Total (recurrent) cardiovascular events 127; 47.3 (39.4–56.3) 157; 57.5 (48.9–67.2) 0.63 (0.41–0.97) 0.038a 776
721 CI, confidence interval; HF, heart failure; HR, hazard ratio; IRR, incidence rate ratio; US, ultrasound.
777
722 a
Zero-inflated binomial regression. 778

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 clinical trial C Zoccali et al.: Lung ultrasound–guided treatment in high-risk kidney failure patients

779 posttrial period and, more importantly, a second trial We thank the following clinicians (nephrologists and 835
780 adopting a protocol similar to LUST and a metanalysis of this cardiologists) for their collaboration in the LUST trial: Eric Abergel 836
(Bordeaux, France); Jawad Atrash (Jerusalem, Israel); Caroline Bidault
781 trial with ours are needed to obtain conclusive results about (Paris, France); Marie Blinn (Homburg/Saar, Germany); Astrid
837
782 the usefulness of lung US for guiding therapy in high-risk Breitbart (Hannover, Germany); Albane Brodin-Sartorius (Paris, 838
783 patients on hemodialysis. Second, we did not achieve the France); Maciej Bulanowski (Katowice, Poland); Carola Cademartiri 839
784 enrollment targets planned for the trial. However, the data (Parma, Italy); Loutradis N. Charalampos (Thessaloniki, Greece); Nelly 840
785 analysis of enrolled patients (n ¼ 383; 77% of the planned Castin (Nancy, France); Faty Diallo (Paris, France); Paola Di Marco, 841
Eric Prinz (Strasbourg, France); Tommaso Di Motta (Parma, Italy);
786 study population) showed a largely nonsignificant difference Philipp Ege (Homburg/Saar, Germany); Andreu Foraster, Alex Ruiz-
842
787 between the 2 arms of the trial. Third, because of the type of Mayoral, and Gustavo Villalobos (Barcelona, Spain); Klaudia 843
788 the intervention, the study was unblinded, which could have Gieszczyk-Strózik (Katowice, Poland); Nicolas Girerd (Nancy, France); 844
789 generated bias. Fourth, a possible favorable effect of the Anna Gozdzik (Wroclaw, Poland); Gunnar Henrik Heine (Homburg/ 845
790 intervention was observed only in exploratory secondary Saar, Germany); Barbara Krunic (Maribor, Slovenia); Nicolas 846
Mansecal (Paris, France); Sylvain Marchais (Manhès, Fleury Mérogis,
791 analyses considering recurring episodes of decompensated HF France); François Marchal (Bordeaux, France); Edoardo Melilli
847
792 and recurring cardiovascular events. Even though biologically (Barcelona, Spain); Katarzyna Mizia (Katowice, Poland); Mihai 848
793 plausible, these effects are merely hypothesis-generating. Onofriescu (Iasi, Romania); Bruno Marc Pannier (Manhès, Fleury 849
794 Additional trials need to be done to prove the usefulness of Mérogis, France); Konstantinos Pappas (Ioannina, Greece); Carolina 850
795 lung US in this population. Polo (Barcelona, Spain); Giuseppe Regolisti (Parma, Italy); Radu 851
Andy Sascau (Iasi, Romania); Franco Schito (Parma, Italy); Alexandre
796 In conclusion, in patients on hemodialysis who are at high Seidowsky (Paris, France); Tomas Serrato (Manhès, Fleury Mérogis,
852
797 cardiovascular risk, a strategy of lung US-guided therapy France); Linda Shavit (Jerusalem, Israel); Sophie Vallance (Nancy, 853
798 safely reduced congestion but was not more effective than a France); Eve Vilaine (Paris, France); Gustavo Villalobos (Barcelona, 854
799 usual care strategy in improving the primary (composite) Spain); Tanya Weitsman (Jerusalem, Israel); Stephen Zewinger 855
800 endpoint of the LUST trial. (Homburg/Saar, Germany); and Christos Zounis (Kallithea, Greece). 856
We thank the independent Data Safety Monitoring Committee
801 members: Dr. Michel Kessler (nephrologist, Nancy, France); Renaud
857
802 DISCOSURE Fay (statistician, Nancy, France); Michele Emdin (cardiologist, Pisa, 858
803 CZ and FM received lecture fees from Amgen in 2019.LG Italy); Dr. Yohann Bernard and Nadine Petitpain of the Nancy Regional 859
804 received fees from General Electric Healthcare, Philips and University Hospital Center, which sponsored the trial in the 860
805 French centers; and Dr. Xavier Lepage of the Nancy Centre 861
Healthcare, and Caption Health outside the submitted work.
d’Investigation Clinique.
806 AW received fees from GlaxoSmithKline, personal fees from 862
807 Astellas, and fees from AstraZeneca outside the submitted 863
808 work. PR received fees from Ablative Solutions, AstraZeneca, SUPPLEMENTARY MATERIAL 864
809 Bayer, Boehringer-Ingelheim, Corvidia, CVRx, Fresenius, G3P Supplementary File (PDF) 865
810 Figure S1. Treatment algorithm according to the number of US-B 866
(stocks), Grunenthal, Idorsia, KBP, Novartis, NovoNordisk,
lines.
811 Relypsa, Sanofi, Sequana Medical, Servier, Stealth Peptides, 867
Figure S2. Effect modification by age, sex, heart failure, ejection
812 Vifor, and Vifor Fresenius Medical Care Renal Pharma outside fraction, and study site of the effect of the lung US–guided policy on
868
813 the submitted work; and is a cofounder of CardioRenal. ZAM the composite endpoint (all-cause death, nonfatal myocardial 869
814 received grants and other support from Amgen, Sanofi- infarction, and decompensated HF). 870
815 Genzyme, and Baxter; grants from the French government, Figure S3. Effect modification by center. 871
816 MSD, GSK, Lilly, FMC, and Outsuka; and other support from Table S1. Cardiovascular drugs administration in patients where the 872
817 treatment goal (<15 US-B lines/comets) is not achieved by UF alone. 873
Daichi and Astellas outside the submitted work. KJJ received
Table S2. Pharmacological treatment at baseline in the 2 study
818 fees from Fresenius Medical Care outside the submitted work. 874
groups.
819 All the other authors declared no competing interests. Table S3. Echocardiographic parameters in the 2 study arms. (Left)
875
820 Unadjusted data. (Right) Data fitted according to the linear mixed 876
821 DATA AVAILABILITY STATEMENT model. 877
822 Individual deidentified participant data whereupon the main Table S4. Secondary analyses on patient-reported outcomes 878
823 (Depression and the Standard Form 36 Quality of Life Questionnaire, 879
results of the trial described in this manuscript are based will
824 SF36) of 3 additional questionnaires collected by doctors (the Sub- 880
be shared with interested investigators. The data will become jective Global Assessment score, the Berlin Questionnaire, and the
825 available 3 months after the publication of this study, and data 881
Karnofsky score).
826 access will end after 2 years. Interested investigators should Table S5. Berlin Questionnaire proportion of patients classified at Q49
882
827 contact the first author of the study for explaining the hy- high risk for sleep apnea according to the Berlin Questionnaire score. 883
828 potheses they intend to test, the methods they will apply, and 884
829 to obtain the study data. 885
830 REFERENCES 886
831 1. Zoccali C, Mallamaci F. Mapping progress in reducing 887
ACKNOWLEDGMENTS cardiovascular risk with kidney disease. Clin J Am Soc Nephrol.
832 The authors are members of the EURECAm working group of the 2018;13:1432–1434.
888
833 Q57 ERA-EDTA and the LUST trial was funded in 2013 by a grant of the 2. Zoccali C, Bolignano D, Mallamaci F. Left ventricular hypertrophy in 889
834 ERA-EDTA (no number for the grant is available). chronic kidney disease. In: Turner NN, Lameire N, Goldsmith DJ, et al., 890

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891 eds. Oxford Textbook of Nephrology. 4th ed. Oxford, UK: Oxford University 11. Rivas-Lasarte M, Álvarez-García J, Fernández-Martínez J, et al. Lung 920
892 Press; 2019:1–68. ultrasound-guided treatment in ambulatory patients with heart failure: a 921
893 3. Torino C, Gargani L, Sicari R, et al. The agreement between auscultation randomized controlled clinical trial (LUS-HF study). Eur J Heart Fail. 922
894 and lung ultrasound in hemodialysis patients: the LUST study. Clin J Am 2019;21:1605–1613. 923
895 Soc Nephrol. 2016;11:2005–2011. 12. Marini C, Fragasso G, Italia L, et al. Lung ultrasound-guided therapy 924
896 4. Agricola E, Bove T, Oppizzi M, et al. “Ultrasound comet-tail images”: a reduces acute decompensation events in chronic heart failure. Heart. 925
897 marker of pulmonary edema: a comparative study with wedge pressure 2020;106:1934–1939. 926
898 and extravascular lung water. Chest. 2005;127:1690–1695. 13. Jahn-Eimermacher A. Comparison of the Andersen-Gill model with 927
899 5. Mallamaci F, Benedetto FA, Tripepi R, et al. Detection of pulmonary Poisson and negative binomial regression on recurrent event data. 928
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902 6. Picano E, Scali MC, Ciampi Q, et al. Lung ultrasound for the cardiologist. 1969;1:27–52. 931
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904 7. Platz E, Solomon SD, McMurray JJV. Lung ultrasound: monitoring on nutrition and body composition: Frequent Hemodialysis Network 933
905 congestion in patients with heart failure. Eur J Heart Fail. 2019;21:1614– Trial. Kidney Int. 2012;82:90–99. 934
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907 8. Gargani L, Sicari R, Raciti M, et al. Efficacy of a remote web-based lung per week versus three times per week (FHN). N Engl J Med. 2010;363: 936
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909 project. Nephrol Dial Transplant. 2016;31:1982–1988. 17. Chertow GM, Levin NW, Beck GJ, et al. Long-term effects of frequent in- 938
910 9. LUST Study User Manual. p. 11–12. Available at: https://lust. center hemodialysis. J Am Soc Nephrol. 2016;27:1830–1836. 939
911 nefroepidemiologiarc.eu/manuals/User_manual%20november%208th% 18. Loutradis C, Sarafidis PA, Ekart R, et al. The effect of dry-weight reduction 940
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