Article

Ramipril and Cardiovascular Outcomes in Patients on

Maintenance Hemodialysis
The ARCADIA Multicenter Randomized Controlled Trial

Piero Ruggenenti,1,2 Manuel Alfredo Podestà ,1,2 Matias Trillini,1 Annalisa Perna,1 Tobia Peracchi,1 Nadia Rubis,1
Davide Villa,1 Davide Martinetti ,1 Monica Cortinovis,1 Patrizia Ondei,2 Carmela Giuseppina Condemi,2
Carlo Maria Guastoni,3 Agnese Meterangelis,4 Antonio Granata,5 Emanuele Mambelli,6 Sonia Pasquali,7
Due to the number of
Simonetta Genovesi,8,9 Federico Pieruzzi,8,9 Silvio Volmer Bertoli,10 Goffredo Del Rosso,11 Maurizio Garozzo,12
contributing authors,
Angelo Rigotti,13 Claudio Pozzi,14 Salvatore David,15 Giuseppe Daidone,16 Giulio Mingardi,17 Giovanni Mosconi,18 the affiliations are
Andrea Galfré,19 Giorgio Romei Longhena,20 Alfonso Pacitti,21 Antonello Pani,22 Jorge Hidalgo Godoy,1,23 listed at the end of
Hans-Joachim Anders,24 and Giuseppe Remuzzi,1 on behalf of the ARCADIA Study Organization* this article.

Abstract Correspondence: Prof.

Giuseppe Remuzzi,
Background and objectives Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and Istituto di Ricerche
mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme Farmacologiche Mario
inhibitor ramipril in patients on maintenance hemodialysis. Negri IRCCS, Centro
Anna Maria Astori,
Design, setting, participants, & measurements In this phase 3, prospective, randomized, open-label, blinded end Science and
Technology Park
point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left Kilometro Rosso, Via
ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were Stezzano 87, 24126
randomized to ramipril (1.25–10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both Bergamo, Italy. Email:
titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point giuseppe.remuzzi@
marionegri.it
was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the
single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for
symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass
index. All outcomes were evaluated up to 42 months after randomization.

Results At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%)
reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P50.80).
Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline:
216.3 g/m2; 95% confidence interval, 229.4 to 23.1), but did not significantly affect the other secondary outcomes.
Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%).
Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies
on ramipril (four were fatal), compared with none in controls.

Conclusions Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance
hemodialysis.

Clinical Trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug
Regulating Authorities Clinical Trials Database number 2008–003529–17.
CJASN 16: 575–587, 2021. doi: https://doi.org/10.2215/CJN.12940820

Introduction cardiovascular events that are effective in the gen-

Cardiovascular disease is the primary cause of morbidity
and mortality in patients with kidney failure (1). Avail-
able studies report an annual incidence of cardiovascular
events averaging 16% (2), an event rate that is two to ten
times higher than in the general population (3–6).
Because most trials focusing on cardiovascular
events did not include patients with kidney failure,
it is currently unknown whether pharmacologic in-
terventions for primary and secondary prevention of
eral population can be generalized to patients on
maintenance hemodialysis. Moreover, trials aimed
at testing other interventions such as statins, which
significantly reduce cardiovascular mortality in the
general population (7), failed to detect any signifi-
cant cardioprotective effect in patients on mainte-
nance hemodialysis (8).
Renin-angiotensin system (RAS) inhibitors have
been consistently shown to reduce the risk of major

www.cjasn.org Vol 16 April, 2021 Copyright © 2021 by the American Society of Nephrology 575
576 CJASN
cardiovascular events in the general population and in
patients with CKD (9–13). However, most trials focusing on
RAS inhibition excluded patients with kidney failure
because of concerns about hypotension, hyperkalemia,
and residual kidney function deterioration (14). Data
from retrospective studies pointed toward beneficial effects of
angiotensin-converting enzyme (ACE) inhibitors on cardio-
vascular morbidity and mortality in patients on maintenance
hemodialysis (15–18). However, these encouraging findings
were challenged by results from the Fosinopril in Dialysis
(FOSIDIAL) trial, which showed some evidence of cardio-
protection for ACE inhibitor treatment, but failed to detect a
statistically significant treatment effect on the incidence of
cardiovascular events (2). This could explain why registry
data indicate that RAS inhibitors are currently used in less
than half of patients on dialysis, despite their high cardiovas-
cular risk (1). Results of the FOSIDIAL trial, however, should be
considered in the context of its relatively short follow-up, which
resulted in a lower than expected incidence of cardiovascu-
lar events.
To further investigate the potential role of ACE inhibitors
in this high-risk population, we designed a prospective,
randomized, open label, blinded endpoint (PROBE) trial to
evaluate whether, at comparable blood pressure control,
ACE inhibitor therapy more effectively than non-RAS
inhibitor therapy reduces CArdiovascular morbidity and
mortality in chronic DIAlysis patients with left ventricular
hypertrophy and/or arterial hyppertension (ARCADIA).
Materials and Methods
Study Design
This was a phase 3, multicenter, parallel, prospective,
randomized, open-label, blinded end point trial funded by
the Agenzia Italiana del Farmaco, Ministero della Salute
(Rome, Italy). It was conducted in 28 Italian centers,
coordinated and monitored by the Clinical Research Center
for Rare Diseases “Aldo e Cele Daccò” of the Istituto di
Ricerche Farmacologiche Mario Negri IRCCS (Istituto di
Ricovero e Cura a Carattere Scientifico) in Bergamo, Italy.
The trial was approved by the relevant local ethics
committees. All participants provided written informed
consent in compliance with the Declaration of Helsinki.
Data were documented on site into dedicated electronic
case report forms and centralized into the database of the
coordinating center. For full details on the study, including
the study protocol, supplemental figures/tables, and study
organization, please see Supplemental Appendices 1–9.
Participants
We included patients aged .18 years who had been on
hemodialysis two or three times per week for at least 6
months, with hypertension (predialysis systolic and/or
diastolic BP .140/90 mm Hg, or postdialysis systolic and/
or diastolic BP .130/80 mm Hg, or ongoing antihyperten-
sive therapy) and/or left ventricular hypertrophy (defined
as cardiac mass index .130 g/m2 for men and .100 g/m2
for women) within 3 months of enrollment. The main
exclusion criteria were chronic or intradialytic hypoten-
sion, ACE inhibitor and angiotensin II receptor blocker
use for other indications, serum potassium .6.0 mmol/L
in those on hemodialysis twice a week, arrhythmias, and
cardiovascular events within 3 months of enrollment.
Patients with established contraindications were not
assessed for study participation.
Randomization and Procedures
After a 1-month wash-out period from previous RAS
inhibitor therapy and stratification by center and diabetes
status, an independent statistician (G. A. Giuliano, see
ARCADIA Study Organization in Supplemental Appendix
3) at the sponsoring institution allocated participants by
block-size randomization (1:1) to ramipril or non-RAS
inhibitor therapy according to a web-based, computer-
generated randomization list created using SAS version 9.2.
Ramipril was started at 1.25 mg/d and uptitrated to
2.5 mg/d, 5 mg/d, and then to 10 mg/d, according to
BP control and tolerability. BP was monitored to achieve
and maintain a predialysis target BP of ,140/90 mm Hg
and postdialysis target BP of ,130/80 mm Hg in both
treatment arms. Additional treatment with non-RAS-in-
hibiting antihypertensive agents was allowed, to achieve
the BP targets according to standardized guidelines pro-
vided in the study protocol (Supplemental Appendix 6).
Clinical and laboratory parameters, and data about dialysis
procedure and efficiency, were evaluated before and after
the first dialysis of the week at baseline and every 3 months
thereafter. Echocardiography was performed during the
first interdialytic day of the week by the same local
operators at baseline and at 1 and 2 years after random-
ization, using the same device (Supplemental Appendix 7).
Outcomes
Blinded end point reports were reviewed by an End
Point Committee, which included one cardiologist and two
nephrologists. An independent Safety Committee period-
ically conducted unblinded reviews of serious adverse
events (SAEs) and non-SAEs. The primary end point was a
composite of cardiovascular death, myocardial infarction,
or stroke. Death from cardiac and vascular causes was
defined according to the 2014 American College of Cardi-
ology/American Heart Association Clinical Data Stan-
dards and comprised sudden cardiac death attributions
and deaths from heart failure, stroke, cardiovascular
procedures, and complications of pulmonary embolism,
mesenteric ischemia, or peripheral artery disease (19).
Myocardial infarction and stroke were defined as pre-
viously described (20,21). Secondary end points included
the single components of the combined end point, and
hospitalizations for symptomatic fluid overload, new-onset
or recurrence of atrial fibrillation in participants with sinus
rhythm, and thrombosis/stenosis of the arteriovenous
fistula. All of these outcomes were assessed up to 42 months
from randomization. For combined end points, only one
event per participant (whichever occurred first) was in-
cluded in the final analysis. Changes in cardiac mass index
were evaluated at 1 and 2 years after randomization.
Safety
SAEs and non-SAEs, including those possibly related to
the study treatment, such as hypotension, disturbances of
cardiac rhythm and electrical conduction possibly related
to hyperkalemia, cough, and anemia requiring the
CJASN 16: 575–587, April, 2021
introduction or uptitration of erythropoietin therapy, were
recorded up to 42 months from randomization. Potassium
levels were monitored before each dialysis session during
the first week after randomization or after treatment dose
uptitration, at each planned visit thereafter, and whenever
deemed clinically appropriate.
Sample Size and Statistical Analyses
On the basis of the FOSIDIAL study (2), 52.5% of
participants on conventional therapy were expected to
reach the combined primary end point, and ACE in-
hibitor therapy was expected to reduce this figure to at
least 35%. To give the trial an 80% power to detect this
reduction by a two-side test with a type 1 error of 5%,
and accounting for a 5% dropout rate, 133 participants
per group needed to be included.
All outcomes were assessed by intention-to-treat analyses.
The Kaplan–Meier method was used to plot the probability to
achieve efficacy end points. Cox proportional hazard regression
models were performed, and results were expressed as hazard
ratios (HRs) and 95% confidence intervals (95% CIs). According
to predefined criteria, analyses were adjusted for age, sex,
previous cardiovascular events or RAS inhibitor therapy,
and diabetes status and/or left ventricular hypertrophy at
3154 patients in participating centers
314 patients assessed for eligibility
269 patients randomized
140 assigned to Ramipril therapy
11 Reaching fatal outcome end point
13 Death (other reason)
12 Reaching a nonfatal end point
(followed by 2 non-CV deaths)
1 Nonfatal adverse event
1 Lost to follow-up
23 Kidney transplant
7 Withdrawal of consent
2 Other reasons
140 included in the primary
efficacy analysis
Figure 1. | Study flow diagram. CV, cardiovascular.
Ramipril in Patients on Hemodialysis, Ruggenenti et al. 577
inclusion. The primary adjusted model did not include the
study site because of the low number of participants enrolled
in several centers. Additional exploratory models were also
built to include smoking habit at baseline, which was found to
be the strongest characteristic associated with the primary
outcome at univariable analysis. Exploratory analyses were
conducted to assess the effects of ramipril on the primary end
point of the FOSIDIAL trial, and the incidence of the primary
composite end point in diabetic and nondiabetic participants.
All end points were evaluated after censoring of participants
who underwent kidney transplantation, died from noncardio-
vascular causes, withdrew consent, or moved out of the study
area during the follow-up. Changes in continuous efficacy
variables were evaluated by analysis of covariance, including
treatment and baseline measurements. Adverse events were
classified using the Medical Dictionary for Regulatory Activ-
ities system (version 17.1). Data were analyzed by SAS (version
9.4) and STATA (version 15) and were presented as number
(%), mean6SD, or median (interquartile range), as appropriate.
All P values were two-sided.
Results
Forty-five of the 314 patients assessed for eligibility did
not meet the selection criteria. From July 2009 to February
9 withdrew consent
24 did not fulfill eligibility criteria
2 kidney transplant
3 unsatisfactory adherence
1 protocol violation
4 death
2 adverse events
129 assigned to no Ramipril therapy
18 Reaching fatal outcome end point
9 Death (other reason)
6 Reaching a nonfatal end point
(followed by 2 CV and 1 non-CV deaths)
1 Nonfatal adverse event
1 Lost to follow-up
21 Kidney transplant
7 Withdrawal of consent
0 Other reasons
129 included in the primary
efficacy analysis
578 CJASN

2014, 140 of the 269 included participants were randomized
to ramipril, and 129 were randomized to non-RAS in-
hibition therapy (Figure 1). Baseline characteristics and
concomitant medications were balanced between the two
treatment arms. However, the proportion of participants
with previous cardiovascular events, diabetes, and smoking
habit tended to be higher in the ramipril group (Table 1,
Supplemental Table 1 in Supplemental Appendix 1). In the
ramipril arm, the study treatment was uptitrated to the full
dose of 10 mg/d in 43 (31%) participants, and the average

Table 1. Baseline characteristics of people treated with maintenance hemodialysis who were enrolled in a prospective, randomized
clinical trial comparing the effects of ramipril versus nonrenin-angiotensin system inhibition therapy on major cardiovascular events

Characteristic Overall, N5269 Ramipril, n5140 Non-RAS Inhibitor, n5129

Age, yr 64614 64612 62614

Male sex, n (%) 181 (67) 99 (71) 82 (64)
White, n (%) 254 (94) 133 (95) 121 (94)
Current or former smoker, n (%) 112 (42) 70 (50) 42 (33)
Predialysis BMI, kg/m2 25.364.3 25.664.4 25.064.2
Systolic BP before dialysis, mm Hg 144619 145619 143620
Diastolic BP before dialysis, mm Hg 76613 75613 76613
Systolic BP after dialysis, mm Hg 142622 145622 138622
Diastolic BP after dialysis, mm Hg 76615 78616 75614
Arterial hypertension, n (%) 268 (100) 140 (100) 128 (99)
Left ventricular hypertrophy, n (%) 178 (66) 95 (68) 83 (64)
Residual diuresis, L/da 1.060.7 1.060.6 0.960.7
Residual diuresis .500 ml, n (%)a 48/78 (62) 28/41 (68) 20/37 (54)
Duration of dialysis, mo 34 [15–68] 30 [15–63] 37 [13–76]
Prior transplant, n (%) 37 (14) 15 (11) 22 (17)
Equilibrated Kt/V 1.160.3 1.160.2 1.160.3
Interdialytic weight change, kg 2.561.0 2.661.1 2.561.0
Dialysis type, n (%)
Low-flux hemodialysis 86 (32) 47 (34) 39 (30)
High-flux hemodialysis 74 (28) 41 (29) 33 (26)
Hemodiafiltration 105 (39) 51 (36) 54 (42)
N/A 4 (1) 1 (1) 3 (2)
Dialysis frequency, n (%)
Twice/wk 36 (13) 21 (15) 15 (12)
Three times/wk 230 (86) 118 (84) 112 (87)
N/A 3 (1) 1 (1) 2 (2)
Vascular access, n (%)
AVF 226 (84) 114 (81) 112 (87)
AVG 13 (5) 8 (6) 5 (4)
CVC 27 (10) 17 (12) 10 (8)
N/A 3 (1) 1 (1) 2 (2)
Previous cardiovascular history, n (%) 99 (37) 56 (40) 43 (33)
Coronary 58 (22) 34 (24) 24 (19)
Cerebrovascular 22 (8) 11 (8) 11 (9)
Peripheral artery disease 48 (18) 27 (19) 21 (16)
Gastrointestinal ischemia 2 (1) 1 (1) 1 (1)
Diabetes mellitus, n (%) 65 (24) 37 (26) 28 (22)
Total cholesterol, mg/dl 153 [132–183] 148 [129–181] 159 [132–188]
HDL, mg/dl 39 [31–48] 40 [29–48] 39 [32–49]
LDL, mg/dl 80 [62–104] 75 [58–103] 84 [66–106]
Triglycerides, mg/dl 143 [106–192] 133 [104–185] 153 [112–196]
Hemoglobin, g/dl 11.261.3 11.361.2 11.161.3
Hematocrit, % 3564 3564 3464
Serum potassium, mEq/L 5.360.8 5.360.8 5.360.8
C-reactive protein, mg/dl 0.76 [0.23–3.0] 1.05 [0.29–2.63] 0.60 [0.20–3.20]
Other antihypertensive agents, n (%)
Diuretics 128 (48) 74 (53) 54 (42)
Calcium-channel blockers 139 (52) 77 (55) 62 (48)
b-blockers 139 (52) 69 (49) 70 (54)
Lipid-lowering agents, n (%)
Statins 90 (33) 47 (34) 43 (33)
Omega-3 fatty acid 24 (9) 12 (9) 12 (9)
Fibrates 1 (0) 1 (1) 0 (0)
Antiplatelet drugs, n (%) 163 (61) 89 (64) 74 (57)
Antithrombotic agents, n (%) 53 (20) 23 (16) 30 (23)

Data expressed as mean6SD or median [interquartile range] for continuous variables, and number (%) for dichotomous and poly-
chotomous variables. Total percentages may exceed 100% because of rounding. RAS, renin-angiotensin system; BMI, body mass index;
N/A, not available; AVF, arteriovenous fistula; AVG, arteriovenous graft; CVC, central venous catheter.
a
Data available in a subset of participants.
CJASN 16: 575–587, April, 2021
daily ramipril dose during the follow-up was 4.462.3 mg.
The last follow-up visit was completed in April 2016. During
follow-up, 20 participants withdrew from the study because
of adverse events (n52), consent withdrawal (n514), loss to
follow-up (n52), or other reasons (n52).
Primary Outcome
During a median follow-up of 33 (IQR, 17–42) months, 23
participants on ramipril (16%) and 24 on non-RAS inhibitor
therapy (19%) reached the primary composite end point.
The event rate was similar between treatment groups
(HRcrude, 0.93; 95% CI, 0.52 to 1.64; P50.80), and the overall
effect did not reach statistical significance even after
adjustment for predefined covariates (Figure 2, Table 2).
Secondary Outcomes
The hazard for the first occurrence of either cardiovas-
cular death, nonfatal acute myocardial infarction, or non-
fatal stroke considered as single end points was similar
between treatment groups, even after adjusting for pre-
defined covariates (Figure 3, A–C).
During the observation period, ten participants on
ramipril (7%) and 17 on non-RAS inhibitor therapy (13%)
had new-onset or recurrent atrial fibrillation. After adjust-
ing for predefined covariates, ramipril use was associated
with a 55% reduction in the risk of atrial fibrillation
(HRcrude, 0.53; 95% CI, 0.24 to 1.17 and HRadjusted, 0.45;
95% CI, 0.20 to 0.99) (Supplemental Figure 1A in
Supplemental Appendix 2). The incidence of hospitaliza-
tion for symptomatic fluid overload was similar in the two
groups, as was the risk of arteriovenous fistula stenosis or
thrombosis (Table 2, Supplemental Figures 1, B and C and 2
in Supplemental Appendix 2).
0.40
Proportion of participants who reached
Ramipril vs Non-RAS inhibition
the primary composite end point
HRCrude
HRAdjusted
0.30
0.20
0.10
0.00
0 6
Patients at risk
Ramipril 140 128
Non-RAS inhibit. 129 115
Figure 2. | Cumulative incidence of the primary composite outcome. Kaplan–Meier survival curves showing the risk of progression to the
primary composite end point of cardiovascular death, acute myocardial infarction, or stroke in the ramipril group and non-RAS inhibitor group.
Hazard ratios (crude and adjusted for age, sex, previous cardiovascular events or RAS inhibitor therapy, and presence of diabetes and left
ventricular hypertrophy at inclusion) are reported in the figure. Only one event from the composite end point per participant, whichever occurred
first, was included in the analysis. The number of participants at risk is shown in the bottom table. Blue line indicates the ramipril group; red line
indicates the non-RAS inhibitor group. HR, hazard ratio; RAS, renin-angiotensin system.
Ramipril in Patients on Hemodialysis, Ruggenenti et al. 579
At baseline and throughout the follow-up, pre- and post-
dialysis BP values were comparable between groups (Figure 4,
A and B, Table 1). Despite similar BP control between
treatment groups, cardiac mass index decreased significantly
from 135.2639.6 g/m2 at baseline to 126.9636.3 g/m2 at
1 year (P50.02) and to 124.8634.5 g/m2 at 2 years of
follow-up (P50.02) in the ramipril group, whereas this
index did not change appreciably in the control arm
(Figure 4C). Changes in cardiac mass index were signif-
icantly different between treatment groups at 1 year
(P50.02), whereas the difference was only borderline
significant at 2 years (P50.09) (Figure 4C, Supplemental
Table 2 in Supplemental Appendix 1).
Exploratory and Subgroup Analyses
Exploratory analyses for the primary and secondary
outcomes examining adjustment for smoking habit in
addition to predefined covariates provided results consis-
tent with those obtained from the primary adjusted model
(Supplemental Table 3 in Supplemental Appendix 1).
During the study, 34 participants on ramipril (24%) and
43 on non-RAS inhibitor therapy (33%) progressed to the
explorative composite end point of cardiovascular death,
myocardial infarction, unstable angina, stroke, coronary
artery revascularization, hospitalization for fluid overload,
or resuscitated cardiac arrest, which was very similar to
that used in the FOSIDIAL trial as the primary outcome (2)
(HRcrude, 0.72; 95% CI, 0.46 to 1.12). After adjustment for
relevant covariates, ramipril use resulted in a 40% re-
duction in the risk of reaching this composite end point
(Supplemental Figure 3 in Supplemental Appendix 2).
Regardless of treatment allocation, the risk of progres-
sion to the primary composite end point of cardiovascular
0.93 (0.52 to 1.64), P=0.80
0.81 (0.46 to 1.46), P=0.49
Non-RAS inhibition
(Events: n=24)
Ramipril
(Events: n=23)
12 18 24 30 36 42
months
110 98 89 73 55 45
106 98 88 71 59 45
580 CJASN
Table 2. Primary and secondary outcomes
Ramipril,
Outcome
n5140, n (%)
Primary outcome
Composite (cardiovascular death, nonfatal 23 (16)
myocardial infarction, nonfatal stroke)
Secondary outcomes
Cardiovascular death 11 (8)
Nonfatal acute myocardial infarction 8 (6)
Nonfatal stroke 4 (3)
New-onset or recurrence of atrial fibrillation 10 (7)
Hospitalization for fluid overload 10 (7)
Stenosis or thrombosis of the 28 (20)
arteriovenous fistula
RAS, renin-angiotensin system; HR, hazard ratio; 95% CI, 95% confidence interval.
death, nonfatal myocardial infarction, or nonfatal stroke
was significantly higher in participants with diabetes than
in those without diabetes (HRcrude, 2.73; 95% CI, 1.54 to
4.84). However, no significant interaction was found be-
tween treatment allocation and prespecified subgroups on
the risk of progression to the primary composite end point
(Supplemental Figure 4 in Supplemental Appendix 2).
Safety
Ninety-one participants on ramipril (65%) and 86 (67%)
on non-RAS inhibitor therapy had at least one SAE
(P50.80). Twenty participants on ramipril (14%) and nine
controls (7%) developed cancer. Gastrointestinal malig-
nancy was reported in six participants on ramipril, which
was fatal in four cases, compared with none in the control
group (P50.03) (Table 3).
The proportion of participants on ramipril (13%) and
controls (14%) who developed hyperkalemia (serum po-
tassium .6 mEq/L) during the study period was virtually
identical (P50.86), and predialysis serum potassium was
comparable between groups at all time points (Figure 4D).
Thirty-one controls (24%) received an RAS inhibitor during
the follow-up for ensuing specific indications. In the
ramipril group, 58 participants (41%) permanently discon-
tinued the study drug during follow-up: 37 (26%) because
of adverse events, 14 (10%) because of consent withdrawal,
and seven (5%) because of poor adherence or other reasons.
In the ramipril group, 57 participants had symptomatic
hypotension (41%) and 21 had cough (15%), compared
with 15 (12%) and nine (7%) participants in the control
group (P,0.001 and P50.05, respectively). In all partic-
ipants, these events were transient and nonserious, except
for one participant who required hospitalization be-
cause of two episodes of hypotension, which fully
resolved within 48 hours. A summary of non-SAEs in
both allocation groups is reported in Supplemental
Table 4 in Supplemental Appendix 1.
Discussion
In this randomized controlled trial, ramipril did not
appreciably affect the risk of reaching the primary com-
posite end point of cardiovascular death, myocardial
Non-RAS
Ramipril versus Non-RAS P
Inhibitor, n5129,
Inhibitor, HRCrude (95% CI) Value
n (%)
24 (19) 0.93 (0.52 to 1.64) 0.80
17 (13) 0.63 (0.30 to 1.35) 0.23
5 (4) 1.52 (0.50 to 4.66) 0.46
2 (2) 1.94 (0.35 to 10.57) 0.45
17 (13) 0.53 (0.24 to 1.17) 0.12
15 (12) 0.60 (0.27 to 1.34) 0.22
19 (15) 1.47 (0.82 to 2.63) 0.20
infarction, or stroke, compared with non-RAS inhibitor
therapy, in patients on maintenance hemodialysis with
hypertension and/or left ventricular hypertrophy. Because
the event rate was consistently lower than anticipated, the
ARCADIA study was not sufficiently powered to detect a
significant difference in the primary outcome, and there-
fore a cardioprotective effect of ramipril in this population
cannot be definitively excluded.
Nevertheless, secondary analyses revealed that ramipril
therapy reduced the cardiac mass index at 1 year after
randomization, an effect that was not observed in the
control group despite similar BP control. This finding is
consistent with previous studies indicating that RAS in-
hibition ameliorates left ventricular hypertrophy in pa-
tients with hypertension or diabetes who are not on
dialysis (22,23).
These results are similar to those described in the
Hypertension in hemoDialysis Patients treated with Ate-
nolol or Lisinopril (HDPAL) trial (24), which showed a
significant reduction in left ventricular hypertrophy in
patients on hemodialysis who were at high cardiovascular
risk, after treatment with lisinopril for 12 months. How-
ever, the HDPAL trial also demonstrated a similar effect on
left ventricular mass with atenolol, and showed that
allocation to this b-blocker could improve cardiovascular
outcomes compared with RAS inhibition, an effect that was
largely attributed to the steeper BP reduction obtained with
this drug. Such results may be explained by the fact that
86% of HDPAL participants were Black: this feature is of
major clinical relevance because sympathetic dysfunction,
rather than RAS activation, seems to play a pivotal role in
the pathogenesis of hypertension in the Black population
(25,26). Because BP reduction has protective effects against
the development of left ventricular hypertrophy, the effect
on cardiac remodeling mediated by more effective BP
control in the atenolol group could have counterbalanced
the direct effect of RAS inhibition in the lisinopril group.
Conversely, patients enrolled in the ARCADIA study
were mostly White (94%), had less severe hypertension
at baseline, and achieved target BP values throughout
the study period independent of treatment allocation.
The consistent reduction in left ventricular hypertrophy
observed with ramipril suggests that RAS inhibition may
CJASN 16: 575–587, April, 2021 Ramipril in Patients on Hemodialysis, Ruggenenti et al. 581

A 0.20 Non-RAS inhibition

Ramipril vs Non-RAS inhibition

Proportion of participants with

HRCrude 0.63 (0.30 to 1.35), P=0.23 (Events: n=17)

cardiovascular death
HRAdjusted 0.52 (0.24 to 1.13), P=0.10

0.10

Ramipril
(Events: n=11)

0.00
0 6 12 18 24 30 36 42
months
Patients at risk
Ramipril 140 128 110 98 89 73 55 45
Non-RAS inhibit. 129 115 106 98 88 71 59 45
nonfatal acute myocardial infarction

B 0.10
Ramipril vs Non-RAS inhibition
Proportion of participants with

Ramipril
HRCrude 1.52 (0.50 to 4.66), P=0.46 (Events: n=8
HRAdjusted 1.40 (0.45 to 4.38), P=0.56

0.05

Non-RAS inhibition
(Events: n=5)

0.00
0 6 12 18 24 30 36 42
months
Patients at risk
Ramipril 140 128 110 98 89 73 55 45
Non-RAS inhibit. 129 115 106 98 88 71 59 45

C 0.10
Ramipril vs Non-RAS inhibition
Proportion of participants with

HRCrude 1.94 (0.35 to 10.57), P=0.45

HRAdjusted 1.86 (0.34 to 10.28), P=0.48
nonfatal stroke

Ramipril
(Events: n=4)
0.05

Non-RAS inhibition
0.00 (Events: n=2)

0 6 12 18 24 30 36 42
months
Patients at risk
Ramipril 140 128 110 98 89 73 55 45
Non-RAS inhibit. 129 115 106 98 88 71 59 45

Figure 3. | Risk of progression to the single components of the primary composite end point, according to treatment arm. Kaplan–Meier
survival curves showing the risk of the first occurrence of either (A) cardiovascular death, (B) nonfatal acute myocardial infarction, or (C) nonfatal
stroke, considered as single end points in the ramipril group and non-RAS inhibition group. Hazard ratios (crude and adjusted for age, sex,
previous cardiovascular events or RAS inhibitor therapy, and presence of diabetes and left ventricular hypertrophy at inclusion) are reported in the
three panels. The number of participants at risk is shown in the bottom table. Blue line indicates the ramipril group; red line indicates the non-RAS
inhibitor group.
582 CJASN

A B
150 150
Predialysis blood pressure (mmHg)

Predialysis blood pressure (mmHg)

140 140
130 130
120 120
110 110
100 100
90 90
80 80
70 70
60 60
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42
months months

C D
160 p = 0.02 6.0

Predialysis serum potassium (mEq/L)

p = 0.09
150
Cardiac Mass Index (g/m2)

140 5.5
130 * *
120
5.0
110
100
4.5
90
80
Baseline 1 year 2 years
4.0
Patients 136 125 87 89 58 63 0 6 12 18 24 30 36 42
months

Figure 4. | Pre- and postdialysis systolic and diastolic BP over time (A and B), cardiac mass index at baseline and at 1 and 2 years after
randomization (C), and serum potassium levels over time (D) in the two treatment groups. All data are expressed as mean6SEM. Blue
indicates ramipril and red indicates non-RAS inhibitor therapy. *P,0.05 versus baseline; P values for between-groups comparisons are
reported in the figure.

have a protective effect on cardiac remodeling in White
patients on maintenance hemodialysis through a mech-
anism that is at least partially independent of BP changes (27).
Reduction of left ventricular hypertrophy could also
partly explain the marginal reduction of new-onset or
recurrent atrial fibrillation observed in participants allo-
cated to ramipril. Left ventricular hypertrophy determines
a rise in end-diastolic pressure, which drives left atrial
enlargement and is associated with the risk of atrial
fibrillation (28). In line with our findings, RAS inhibition
decreased the rate of atrial fibrillation recurrence in the
general population (29), and observational studies also
described a protective effect of ACE inhibitors in patients
on maintenance hemodialysis (30).
In exploratory analyses, ramipril had a consistent
beneficial effect on a broader composite outcome similar
to that used in the FOSIDIAL trial, reducing the hazard
of reaching this end point by 40% compared with non-
RAS inhibition. Although a direct comparison would be
limited by the inherent differences between the two
trials, it is interesting to note that the effect of ramipril
seemed to be larger compared with that of fosinopril
on this outcome, and may therefore be useful to guide
future studies.
Ramipril treatment was associated with an excess risk of
hypotension and, to a remarkably lower extent, cough. All
events, however, were transient and nonserious, except for
two episodes of symptomatic hypotension observed in one
patient. Notably, serum potassium levels and the incidence of
severe hyperkalemia were comparable between treatment
groups throughout the follow-up. Indeed, ACE-inhibitor-
induced changes on serum potassium are largely mediated
by treatment effect on tubular handling of ultrafiltered
potassium (31), a mechanism that should not play any role
in patients with kidney failure without residual kidney
function. On the other hand, these findings could be partly
explained by the low mean dose of ramipril achieved by
study participants and by the relatively high dropout rate,
which do not allow us to rule out an effect of the drug at
maximal doses on serum potassium levels. Although our
results alleviate some of the concerns for severe hyperkalemia
in patients on maintenance hemodialysis treated with ram-
ipril, additional studies are required to ascertain the effect of
ACE inhibitors on potassium levels in this population.
CJASN 16: 575–587, April, 2021 Ramipril in Patients on Hemodialysis, Ruggenenti et al. 583

Table 3. Number (percent) of serious adverse events occurring for the first time in single participants, according to treatment arm

Overall, n5269, Ramipril, n5140, Non-RAS Inhibitor, n5129,

Serious Adverse Events
n (%) n (%) n (%)

Fatal events 56 (21) 26 (19) 30 (23)

Cardiovascular 31 (12) 11 (8) 20 (16)
Cancer 8 (3) 7 (5) 1 (1)
Gastrointestinal cancer 4 (2) 4 (3) 0 (0)
Infections 8 (3) 3 (2) 5 (4)
Other 9 (3) 5 (4) 4 (3)
Nonfatal cardiovascular events 108 (40) 47 (34) 61 (47)
Stroke/myocardial infarction 20 (7) 13 (9) 7 (5)
Unstable angina 11 (4) 4 (3) 7 (5)
Fluid overload 33 (12) 12 (9) 21 (16)
Atrial fibrillation 10 (4) 3 (2) 7 (5)
Coronary and peripheral artery revascularization 39 (15) 16 (11) 23 (18)
Hemodialysis vascular access thrombosis/ 30 (11) 13 (9) 17 (13)
interventions
Other nonfatal events 111 (41) 62 (44) 49 (38)
Infections 67 (25) 35 (25) 32 (25)
Cancer 22 (7) 14 (10) 8 (6)
Gastrointestinal cancer 2 (1) 2 (1) 0 (0)
Gastrointestinal 23 (9) 15 (11) 8 (6)
Blood and metabolic 9 (3) 5 (4) 4 (3)
Other 39 (15) 21 (15) 18 (14)
Any cardiovascular event 122 (45) 54 (39) 68 (53)
Any cancer 29 (11) 20 (14) 9 (7)
Gastrointestinal cancer 6 (2) 6 (4) 0 (0)
Any event 177 (66) 91 (65) 86 (67)

RAS, renin-angiotensin system.

In our study, the incidence of cancer was higher than in
the average dialysis population (32). The incidence of
malignancy was more than two-fold higher in participants
on ramipril compared with controls, and, even more
concerning, seven fatal cancers were observed in the
ramipril group compared with only one in the control
group. Cancer was not a prespecified efficacy parameter,
and the possibility of a chance effect may therefore be high.
However, the excess risk of cancer was almost fully driven
by the six gastrointestinal malignancies, all of which
clustered in the ramipril arm, suggesting the possibility
of a common pathogenic mechanism.
Notably, ACE inhibitors reduce the catabolism of kinins
such as bradykinin and substance P (33,34) and increase the
expression of inducible and constitutive bradykinin recep-
tors (35). Kinins have been shown to induce cell pro-
liferation and stimulate cancer growth, effects that are
amplified by enhanced expression of kinin receptors. These
molecules also have proangiogenic properties and have
been implicated in cancer survival, invasion, and metasta-
sis (33,36). The above mechanisms could explain the excess
cancer risk in patients receiving ACE inhibitors recently
observed in a population-based cohort study (37). These
effects could be amplified in patients on dialysis because
hemodialysis activates the kallikrein-kinin system, en-
hances bradykinin production (38,39), promotes oxidative
stress and inflammation (40,41), and is per se associated
with excess cancer risk (42,43). At present, it is impossible
to confirm or disprove a causal relationship between
ramipril and malignancy in patients on maintenance
hemodialysis. The reason pertaining to a specific increase
in gastrointestinal cancers in this context is unknown.
The major limitation of our trial was the relatively small
sample size because of resource constraints typical of
academic studies. The number of observed events was
lower than expected from results of the FOSIDIAL trial (2),
which reduced the power of statistical analyses. A run-in
phase to exclude patients prone to intradialytic hypoten-
sion or other drug-related adverse events was not planned,
which explains the high rates of drug discontinuation
owing to side effects. Moreover, uptitration to the maximal
dose was achieved only in a minority of patients. The
prospective, randomized, open-label, blinded end point
design of the study may have also contributed to the poor
adherence we observed, because allocation was open-label.
This may have reduced the power of the study, but this
approach better reflected real-life clinical practice, making
results more easily applicable in routine medical care (44).
Similar considerations apply to the choice of not including
ambulatory BP-monitoring targets among selection criteria
of the study, despite this being currently considered as one
of the most reliable methods for defining hypertension in
patients on hemodialysis. Because patient intolerance,
unavailability, and reimbursement restrictions in several
countries have limited the widespread implementation of
such a technique (45), our data are more closely applicable
to real-world clinical practice. The involvement of a large
number of dialysis units from different Italian regions was
a major strength of the study, which further increased data
generalizability.
In conclusion, we failed to detect any protective effects of
ramipril against a composite end point of cardiovascular
death, myocardial infarction, or stroke in patients on
maintenance hemodialysis with hypertension and/or left
584 CJASN
ventricular hypertrophy, but a definitive conclusion on this
matter could not be reached because of the low event rate
observed. The protective effect of ramipril on the devel-
opment and progression of left ventricular hypertrophy,
and on new-onset and recurrent atrial fibrillation, are
novel findings that could be tested in future ad hoc trials.
Possible effects on cancer, in particular from the gastro-
intestinal tract, and their underlying mechanisms, are
worth investigating.
Disclosures
H.-J. Anders reports employment with Klinikum der Universitat
Munchen and consultancy agreements with AstraZeneca, Bayer,
Boehringer, GlaxoSmithKline, Janssen, Novartis, NOXXON, Pre-
vipharma, and Secarna. S.V. Bertoli reports employment with Ne-
phrology and Dialysis Unit, Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS) Multimedica, Sesto S. Giovanni (Milan). M.
Cortinovis reports employment with Istituto di Ricerche Farm-
acologiche Mario Negri IRCCS. S. David reports employment with
University of Parma, Italy. M. Garozzo reports employment with
Azienda Sanitaria Provinciale di Catania, Ospedale Santa Marta e
Santa Venera di Acireale. S. Genovesi reports honoraria with As-
traZeneca. A. Granata reports employment with Department of
Nephrology and Dialysis, “Cannizzaro” Hospital, Catania, Italy;
and serving as a scientific advisor or member of Journal Ultrasound
and World Journal of Nephrology. C.M. Guastoni reports employment
with Azienda Socio-Sanitaria Territoriale (ASST) Ovest Milanese
Legnano General Hospital. E. Mambelli reports employment
with Unit of Nephrology, Dialysis and Hypertension, Azienda
Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi,
Bologna. D. Martinetti reports employment with Istituto di Ri-
cerche Farmacologiche Mario Negri IRCCS. G. Mingardi reports
employment with Humanitas Gavazzeni Bergamo. G. Mosconi
reports employment with Hospital Forlì. A. Pani reports em-
ployment with Department of Medical Sciences and Public
Health, University of Cagliari, and Department of Nephrology,
Dialysis and Transplantation, “San Michele” Hospital, Azienda
Ospedaliera “G. Brotzu” Cagliari; serving as a scientific advisor
or membership of BMC Nephrology and Journal of Nephrology; and
serving as a European Renal Association-European Dialysis and
Transplant Association (ERA-EDTA) Member, Italian Society of
Nephrology. T. Peracchi reports employment with Istituto di
Ricerche Farmacologiche Mario Negri IRCCS. A. Perna reports
employment with Istituto di Ricerche Farmacologiche Mario
Negri IRCCS, Bergamo, Italy. F. Pieruzzi reports employment
with Università degli Studi di Milano Bicocca; honoraria from
Amicus Therapeutics, Chiesi, Sanofi-Genzyme, and Takeda – Shire;
and serving as a member of the Scientific Committee of the Italian
Association of Fabry Patients (AIAF) and as a Council Member of the
Lombardy section of the Italian Society of Nephrology. C. Pozzi
reports employment with Insalus Clinic-Lecco. G. Remuzzi reports
employment with Istituto di Ricerche Farmacologiche Mario Negri
IRCCS; speaker honorarium/travel reimbursements from Akebia
Therapeutics, Alexion Pharmaceuticals, Alnylam, Boehringer In-
gelheim, Catalyst Biosciences, Handok, Inception Sciences Canada,
Janssen Pharmaceutical, and Omeros (no personal remuneration
is accepted, compensations are paid to his institution for research
and educational activities); honoraria from Akebia Therapeutics,
Alexion Pharmaceuticals Inc, Alnylam, Boehringer Ingelheim,
Catalyst Biosciences, Handok Inc, Inception Sciences Canada,
Janssen Pharmaceutical, and Omeros; and serving as a member of
numerous editorial boards of scientific medical journals. A. Rigotti
reports employment with Os. Infermi Rimini. All remaining authors
have nothing to disclose.
Funding
The study was funded by Agenzia Italiana del Farmaco, Ministero
della Salute (grant number FARM 6WE4PP).
Acknowledgments
The authors thank the participants in the ARCADIA study, the
trial investigators, nephrologists, nurses, and regulatory affairs staff
of all participating centers (listed in Supplemental Material in order
of included patients) for their invaluable assistance; and the labo-
ratory staff, trial monitors, data managers, statisticians, and ev-
eryone at the Clinical Research Center for Rare Diseases Aldo e Cele
Daccò of the Istituto di Ricerche Farmacologiche Mario Negri IRCCS
for their efforts in making this study feasible.
The authors also thank the Istituto di Ricerche Farmacologiche
Mario Negri IRCCS for sponsoring the trial and the Scientific Writing
Academy (SWA) for including this manuscript among its 2018
projects. SWA is a project endorsed by the Istituto di Ricerche
Farmacologiche Mario Negri IRCCS, and sponsored by Fondazione
della Comunità Bergamasca Onlus (Bergamo), Fluorseals S.p.a.
(Grumello del Monte, Bergamo), and the Italian Society of Ne-
phrology, and aims to teach the tools necessary to succeed in pub-
lishing scientific papers in international journals to researchers and
physicians from all over the world. The authors thank the following SWA
2018 participants for their valuable discussions during the preparation of
this manuscript: Dr. Babajide Aderoju Gbadegesin (Nigeria), Dr. Jorge
Hidalgo Godoy (Chile), Dr. Julian A. Marschner (Germany), Dr. Bolanle
Aderonke Omotoso (Nigeria), Dr. Samuel Ayokunle Dada (Nigeria),
Dr. Manish Subedi (Nepal), Dr. Valeria Corradetti, Dr. Valentina Fanny
Leone, Dr. Monica Locatelli, Dr. Manuel Alfredo Podestà, Dr. Francesca
Testa, Dr. Matias Trillini, and Dr. Elisabetta Valoti (all in Italy). Prof.
H.-J.Andersservedastutorforthis effort.Nomedicalwriterwas involved
in the preparation of the manuscript.
Sanofi Italia SpA (Milano, Italy) freely supplied the study drug,
but had no role in study design and conduction, and data handling,
analysis and reporting.
Data Sharing Statement
Sharing of individual participant data with third parties was not
specifically included in the informed consent of the study, and
unrestricted diffusion of such data may pose a potential threat of
revealing participants’ identities, as permanent data anonymization
was not carried out (patient records were instead deidentified per
protocol during the data retention process). To minimize this risk,
individual participant data that underlie the results reported in this
article will be available after 3 months and up to 5 years from article
publication. Researchers shall submit a methodologically sound
proposal to Dr. A. Perna (annalisa.perna@marionegri.it), Head of
the Laboratory of Biostatistics of the Department of Renal Medicine
of the Istituto di Ricerche Farmacologiche Mario Negri IRCCS. To
gain access, data requestors will need to sign a data access agreement
and obtain the approval of the local ethics committee.
Supplemental Material
This article contains the following supplemental material online at
http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.
12940820/-/DCSupplemental.
Supplemental Appendix 1. Supplemental tables.
Supplemental Appendix 2. Supplemental figures.
Supplemental Appendix 3. ARCADIA study organization.
CJASN 16: 575–587, April, 2021
Supplemental Appendix 4. Members of the Scientific Writing
Academy 2018.
Supplemental Appendix 5. CONSORT checklist.
Supplemental Appendix 6. Study protocol.
Supplemental Appendix 7. Guidelines for cardiovascular analyses.
Supplemental Appendix 8. Ethics approval document.
Supplemental Appendix 9. Sample size amendment.
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Received: August 7, 2020 Accepted: February 15, 2021
*The ARCADIA Study Organization members are Giuseppe Re-
muzzi, Patrizia Ondei, Carmela Giuseppina Condemi, Stefano Rota,
Carlo Maria Guastoni, Nicoletta Bellotti, Anna Lisa Neri, Valentina
Martina, Barbara Gidaro, Antonia Stasi, Agnese Meterangelis, Sal-
vatrice Tamburello, Maria Alessandra Riva, Emanuela Cortinovis,
Antonio Granata, Benedetta Salamone, Elena Mancini, Elisa Persici,
Elena Sestigiani, Emanuele Mambelli, Sonia Pasquali, Achiropita
Bovino, Andrea Stella, Simonetta Genovesi, Paolo Fabbrini, Erika
Casiraghi, Silvio Volmer Bertoli, Silvia Tedoldi, Giada Bigatti,
Goffredo Del Rosso, Rosella Malandra, Dario Sassone, Maurizio
Garozzo, Giovanni Giorgio Battaglia, Angelo Rigotti, Davide Cer-
retani, Stefano Bini, Claudio Pozzi, Enzo Corghi, Salvatore David,
Chiara Cantarelli, Valentina Blanco, Giuseppe Daidone, Gianni
Ottaviano, Giulio Mingardi, Stefano Rota, Giovanna Franca Ledda,
Giovanni Mosconi, Loretta Zambianchi, Piergiorgio Bolasco, An-
drea Galfrè, Stefano Murtas, Ugo Teatini, Giorgio Romei Longhena,
Alfonso Pacitti, Paola Inguaggiato, Antonello Pani, Giuliana Dessì,
Francesco Scolari, Sergio Bove, Mario Cozzolino, Meri Pedone,
Marco Farina, Francesco Barbisoni, Renzo Scanziani, Gennaro
Santorelli, Donatella Spotti, Maria Teresa Sciarrone Alibrandi,
Ferruccio Conte, Francesca Stefani, Salvatore Badalamenti, Rossella
Valentino, Nadia Rubis, Wally Calini, Olimpia Diadei, Alessandro
Villa, Davide Villa, Davide Martinetti, Sergio Carminati, Giovanni
Antonio Giuliano, Annalisa Perna, Francesco Peraro, Tobia Per-
acchi, Piero Ruggenenti, Matias Trillini, Manuel Alfredo Podestà,
Paola Boccardo, Sara Peracchi, Esteban Porrini, Ettore Sabadini, and
Francesco Peraro.
P.R., M.A.P., H.-J.A., and G.R. contributed equally as first and last
authors, respectively.
Published online ahead of print. Publication date available at
www.cjasn.org.
See related editorial, “Therapeutic Options to Improve
Cardiovascular Outcomes with Long-Term Hemodialysis,” on
pages 511–513.
CJASN 16: 575–587, April, 2021 Ramipril in Patients on Hemodialysis, Ruggenenti et al. 587

AFFILIATIONS

1
Department of Renal Medicine, Clinical Research Centre for Rare Diseases “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri
IRCCS, Bergamo, Italy
2
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
3
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Ovest Milanese, Ospedali di Legnano e Magenta, Milano, Italy
4
Unit of Nephrology and Dialysis, Policlinico San Pietro, Ponte San Pietro, Bergamo, Italy
5
Unit of Nephrology and Dialysis, Azienda Ospedaliera per l’Emergenza “Cannizzaro,” Catania, Italy
6
Unit of Nephrology, Dialysis and Hypertension, Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi, Bologna, Italy
7
Unit of Nephrology and Dialysis, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
8
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Monza, Ospedale San Gerardo, Monza, Italy
9
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy.
10
Unit of Nephrology and Dialysis, Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Sesto San Giovanni, Milano, Italy
11
Unit of Nephrology and Dialysis, Ospedale Giuseppe Mazzini, Teramo, Italy
12
Unit of Nephrology and Dialysis, Presidio Ospedaliero S. Marta e S. Venera, Acireale, Catania, Italy
13
Unit of Nephrology and Dialysis, Ospedale Infermi, Rimini, Italy
14
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Nord Milano-Ospedale Bassini, Cinisello Balsamo, Milano, Italy
15
Department of Nephrology and Dialysis, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
16
Unit of Nephrology and Dialysis, Ospedale Umberto I, Siracusa, Italy
17
Unit of Nephrology and Dialysis, Humanitas Gavazzeni, Bergamo, Italy
18
Unit of Nephrology and Dialysis, Ospedale “Morgagni-Pierantoni,” Forlı̀, Italy
19
Unit of Nephrology and Dialysis, Azienda Sanitaria Locale 8, Cagliari, Italy
20
Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Rhodense-Ospedale Garbagnate Milanese, Milano, Italy
21
Unit of Nephrology and Dialysis, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
22
Unit of Nephrology and Dialysis, Department of Reproduction, Genitourinary and Kidney Disease and Kidney Transplantation, Azienda
Ospedaliera Brotzu, Cagliari, Italy
23
Institute of Medicine, Universidad Austral de Chile, Valdivia, Chile
24
Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilians Universität Munich, Munich, Germany