Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

Caterina Dolla; Alberto Mella; Giacinta Vigilante; Fabrizio Fop; Anna Allesina; Roberto Presta; Aldo Verri; Paolo Gontero; Fabio Gobbi; Roberto Balagna; Roberta Giraudi; Luigi Biancone

doi:10.1371/journal.pone.0249552

. 2021 Apr 5;16(4):e0249552. doi: 10.1371/journal.pone.0249552

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

Caterina Dolla ^1,^#, Alberto Mella ^1,^#, Giacinta Vigilante ^1,^#, Fabrizio Fop ¹, Anna Allesina ¹, Roberto Presta ¹, Aldo Verri ², Paolo Gontero ³, Fabio Gobbi ⁴, Roberto Balagna ⁴, Roberta Giraudi ¹, Luigi Biancone ^1,^*

Editor: Frank JMF Dor⁵

PMCID: PMC8021200 PMID: 33819285

Abstract

Background

Pre-existing chronic hypotension affects a percentage of kidney transplanted patients (KTs). Although a relationship with delayed graft function (DGF) has been hypothesized, available data are still scarce and inconclusive.

Methods

A monocentric retrospective observational study was performed on 1127 consecutive KTs from brain death donors over 11 years (2003–2013), classified according to their pre-transplant Mean Blood Pressure (MBP) as hypotensive (MBP < 80 mmHg) or normal-hypertensive (MBP ≥ 80 mmHg, with or without effective antihypertensive therapy).

Results

Univariate analysis showed that a pre-existing hypotension is associated to DGF occurrence (p<0.01; OR for KTs with MBP < 80 mmHg, 4.5; 95% confidence interval [CI], 2.7 to 7.5). Chronic hypotension remained a major predictive factor for DGF development in the logistic regression model adjusted for all DGF determinants. Adjunctive evaluations on paired grafts performed in two different recipients (one hypotensive and the other one normal-hypertensive) confirmed this assumption. Although graft survival was only associated with DGF but not with chronic hypotension in the overall population, stratification according to donor age revealed that death-censored graft survival was significantly lower in hypotensive patients who received a KT from >50 years old donor.

Conclusions

Our findings suggest that pre-existing recipient hypotension, and the subsequent hypotension-related DGF, could be considered a significant detrimental factor, especially when elderly donors are involved in the transplant procedure.

Introduction

Kidney transplantation is the best option for end-stage kidney disease (ESKD) treatment, improving both patients’ survival and quality of life. Even though chronic hypotension significantly affects ESKD patients, few studies limited to specific time-point (i.e., intraoperative hypotension) or subsets (non-heart-beating/young living donors) [1–6] are focused on its potential role in influencing graft outcomes.

At the same time, the definition of hypotension is a matter of debate: for example, low blood pressure without a documented causative factor (“constitutional hypotension”) is a disputed diagnostic entity [7]. Although literature studies generally evaluated mean blood pressure (MBP), no threshold value is universally accepted (ranging from 70 to 90 mmHg), with no consensus on whether this cut-off may vary according to age/gender [7, 8].

However, some reports suggest a higher risk of delayed graft function (DGF) secondary to a hypotension-mediated reduction in renal blood flow [9–11]. DGF, as well-known, negatively affects graft outcomes, including increased short- and long-term morbidity and mortality, allograft immunogenicity, acute rejection, hospitalization rates, and costs [1, 12–14].

Our study aims to investigate the effect of pre-existing recipient hypotension on both DGF and long-term allograft outcomes in kidney transplanted patients (KTs).

Materials and methods

Study design

We performed a retrospective study on 1127 patients who received their KT from brain death donors (DBD) at the Renal Transplant Center “A. Vercellone,” AOU Città Della Salute e Della Scienza Hospital, Turin thorough an observational period of 11 years (from January 2003 to December 2013).

For every patient, blood pressure (BP) was measured using automatically inflated cuffs using a digital monitor; BP evaluation was made by health workers several times for every patient to ensure reliability and avoid values altered by emotionalism. We also considered recent BP data from their dialytic records and measurement in their waiting list schedule for patients not on antihypertensive treatment.

Based on the concordance of current values and clinical diary of the last three pre-transplant months, mean blood pressure (MBP) was calculated using the formula: MBP = [(2*DBP) + SBP]/3.

Because no guideline defines the exact cut-off value in KTs, we set the hypotension threshold at 80 mmHg according to available experiences [4, 9, 10, 15].

Thereafter, patients were divided in hypotensive (MBP < 80 mmHg; n = 65, 5.8%), normotensive (MBP ≥ 80; n = 127, 11.2%) and hypertensive group (MBP ≥ 80 with at least one antihypertensive medication, n = 935, 83%).

Before KT, all patients were on follow-up in their dialysis centers for a minimum of one year; filed medical documentation is available for every patient.

The recipients’ follow-up was performed with scheduled clinical visits or hospital admissions when significant complications occurred. Data were collected from the patients’ charts.

Furthermore, we evaluated donor age, gender, cardiovascular cause of death, hypertension, creatinine, KDPI and estimated glomerular filtration rate (eGFR, CKD-EPI formula) at time of organ procurement, cold ischemia time (CIT), recipient characteristics (age, gender, type of dialysis, hypertension, time spent on dialysis), and available perioperative MBP values at specific time-points (before, at reperfusion, and after surgery).

DGF was defined as the need for hemodialysis (established on a clinical basis) within the first post-transplant week.

The same group of trained pathologists analyzed all available kidney biopsies throughout the study period.

The study was performed in adherence to the last version of the Helsinki Declaration and the Principles of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism. None of the transplant donors was from a vulnerable population; according to Italy legal system (Law no. 91/1999 and Ministry of Health Decrees 8/04/2000-11/4/2008), all adult citizens are offered the possibility (not the obligation) of giving or withdrawing their consent to the donation of organs and tissues after death. In the case of a potential donor (i.e., a person who has been pronounced dead), the re-suscitation team will verify whether the person carries a document containing a statement of intent, or whether such a statement been registered in the online database. If a citizen has not stated his/her intention while alive, the law allows the donor next of kin to withdraw consent to organ removal while death is being ascertained.

All KT recipients signed informed consent, including their permission to have data from their medical records used in research. This study is covered by our Ethical Committee (Comitato Etico Interaziendale A.O.U. Città Della Salute e Della Scienza di Torino—A.O. Ordine Mauriziano—A.S.L. Città di Torino) approval, resolution number 1449/2019 on 11/08/2019 (“TGT observational study”).

Immunosuppressive regimen and perioperative management

Immunosuppressive protocols were homogeneous for the whole study period: induction was mainly conducted with anti-CD25 and steroids; calcineurin inhibitor, mycophenolate mofetil, and steroids were mostly adopted as maintenance immunosuppression. In patients who received KT from extended criteria donors (ECD), calcineurin inhibitors were introduced after functional graft recovery (usually at serum creatinine ≤ 2,5 mg/dL). Steroid dosage was 500 mg, 200 mg, 50 mg, and 20 mg, respectively, on days 1, 2, 3, 4 after KT, with subsequent tapering in 45–60 days.

Management of suboptimal blood pressure during intervention was also similar in the overall population and composed by initial crystalloid infusions with subsequent dopamine adoption (usually 2.5 μg/kg/min) in persistent MBP<80 mmHg.

Statistical analysis

Discrete data were described as percentages and analyzed with the Pearson chi-square test or, for small samples, the Fisher exact test. The odds ratios (OR [CI 95%]) were used to measure relative risk. Continuous variables were described as mean ± standard deviation, when normal, and median (25th; 75th percentile), when non-normally distributed. Mann-Whitney, Kruskal-Wallis, or t-test was used when appropriate. Cumulative graft and patient survival were analyzed by Kaplan-Meier (KM) curves and the Log Rank test. Cox analysis was used for the multivariate model. Relevant variables were checked first in univariate analysis and then including multivariate analysis (logistic regression); for some continuous variables, the cut-off value was set based on ROC curve results. The paired kidney analysis accounts for couples (n = 18) of recipients at their first KT transplanted in our center (one hypotensive and one normal/hypertensive). All statistical analyses were performed using SPSS software (IBM SPSS Statistics, vers. 25.0.0). A significant level for all tests was set at p<0,05.

Results

Characteristics of the studied population and the role of DGF

Table 1 detailed the clinical and demographic characteristics of our population.

Table 1. Clinical and demographic characteristics of the studied population.

Characteristics	All patients (n = 1127)
Recipient gender M/F, n (%)	721 (64) / 406 (36)
Recipient age, yrs	53.8 ± 11,9
Recipient hypertension, n (%)	934 (82.9)
HD, n (%)	880 (78.1)
PD, n (%)	247 (21.9)
Time spent on dialysis, yrs	3.9 (2.7–6.7)
Type of transplantation (SKT/DKT), n (%)	1082 (96) / 45 (4)
Previous KT (0 / ≥ 1), n (%)	972 (86.2) / 155 (13.8)
Donor gender M/F, n (%)	578 (51.3) / 549 (48.7)
Donor age, yrs	57.3 ± 15.6
Donor hypertension, n (%)	544 (48.3)
Donor eGFR (CKD-EPI), mL/min/1.73m²	89 ± 28
Donor death for cardiovascular cause, n (%)	811 (72.0)
KDPI≥85%, n (%)	545 (48.3)
CIT, h	17.0 [14.0–20.3]^*
DGF, n (%)	310 (28.5)^**

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* median [25°-75° percentile]

** evaluated on available data (n = 1088)

sCr: Creatinine; SKT: Single Kidney Transplantation; DKT: Dual Kidney Transplantation; HD: Hemodialysis; PD: Peritoneal Dialysis; DGF: Delayed Graft Function; CIT: cold ischemia time

Briefly, DGF was observed in 310 patients (28.5%); in these KTs, KM curves showed significant (p<0.001) low allograft (at 5 years 71.3% in DGF group vs. 87.9% in no DGF), patient (84% vs. 94.8%) and death-censored graft survival (80.4% vs. 91.6%) (Fig 1).

Fig 1 — Graft, patient, and death-censored graft survival were all reduced in patients who experienced DGF (p<0.001 in all analyses).

As expected, KTs who experienced DGF also had a worse renal function at any follow-up time (Fig 2).

Statistically significant associations with increased DGF risk were noted by univariate analysis for some recipient (age, history of previous KT ≥ 1, hemodialysis) and donor characteristics (age, death for a cardiovascular cause, hypertension, eGFR, CIT) (p = 0.01 for all these variables). As shown in Table 2, the no-DGF group was composed of younger recipients who received KT from younger donors, often without hypertension or death for a cardiovascular cause. Donor eGFR is consequently higher in the no-DGF group and, likewise, CIT is lower than in KTs who experienced DGF.

Table 2. Factors associated with DGF (univariate analysis).

	no DGF (71.5%)	DGF (28.5%)	p
Recipient gender (M/F), %	64,4 / 35,6	61 / 39	0.3
Recipient age, yrs	54 (45–62)	57 (49–75)	0.01
MBP <80 mmHg, %	3,2 / 96,8	12,9 / 87,1	<0.001
PD / HD, %	25.9 / 74.1	10.8 / 89.2	<0.001 [OR for HD, 2.9 (1.9–4.4)]
Time spent on dialysis, yrs	3.3 (1.9–5.8)	5.4 (3.1–7.9)	<0.001
Previous KT (0 / ≥ 1), %	89,5 / 10,5	79,7 / 20,3	< 0.001 [OR, 2.2 (1.5–3.1)]
Donor gender (M/F), %	50,1 / 49,9	53,9 /46,1	0,283
Donor age, yrs	58 (46–69)	63,5 (50–72)	<0.001
Donor cause of death (cardiovascular/trauma/other), %	67,7 / 24,3 / 8	81,4 / 13,1 / 5,5	<0.001
Donor hypertension (no/yes), %	55,9 / 44,1	43,5 / 56,5	< 0.001 [OR, 1.6 (1.2–2.2)]
Donor eGFR, mL/min/1.73m²	93,62 (72,90–110,81)	88,47 (64,26–104,05)	<0.001
CIT, h	16.8 (14.0–20.0)	17.2 (14.7–20.9)	0.01

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MBP: Mean Blood Pressure; HD: Hemodialysis; PD: Peritoneal Dialysis; eGFR: estimated glomerular filtration rate; CIT: cold ischemia time

Interestingly, a close and significant correlation between pre-existing hypotension and DGF was already observed.

Association between pre-existing hypotension and DGF

As shown in Fig 3, DGF incidence was increased in the hypotensive vs. normal-hypertensive group (p<0.001; OR for Hypotension, 4.5; 95% confidence interval [CI], 2.7 to 7.5). This difference remained significant when separating normotensive and hypertensive KTs (Table 3), stressing the importance of a hypotension causative role in DGF occurrence.

Table 3. DGF incidence according to pre-existing blood pressure status.

	no DGF (71.5%)	DGF (28.5%)	P
Hypotensive group	25/65 (38,5%)	40/65 (61,5%)	< 0.01
Normotensive group	93/127 (73,2%)	34/127 (26,8%)
Hypertensive group	660/896 (73,7%)	236/896 (26,3%)

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To confirm the role of hypotension in our population and to reduce the effect of possible confounders variables, we stratified KT characteristics according to blood pressure status (Table 4); groups were quite superimposable except for reduced donor age, longer time spent on dialysis, and a higher percentage of the female gender and previous hemodialytic patients in hypotensive KTs.

Table 4. Characteristics of the studied population according to pre-existing blood pressure status.

	Hypotensive (5.9%)	Normal-hypertensive (94.1%)	p
Recipient gender (M/F), %	47 / 53	65 / 35	0.005
Recipient Age, yrs	51.5 (42–62.25)	55 (46–63)	0.207
PD/HD, %	5.7 / 94.3	23 / 77.0	0.001
Previous KT (0/≥1), %	75.8 / 24.2	86.9 / 13.1	0.016
Donor gender (M/F), %	51.5 / 48.5	51.3 / 48.7	0.999
Donor age, yrs	48 (39–64.25)	60 (48–70)	<0.001
Donor cause of death (cardiovascular/trauma/other), %	68.3 / 25 / 6.7	72.2 / 20.6 / 7.2	0.688
Donor hypertension (no/yes), %	56.1 / 43.9	51.4 / 48.6	0.525
Donor eGFR, ml/min/1.73m²	96.0 (73.8–117.2)	91.8 (69.9–107.7)	0.130
CIT, h	16 (13.5–19.5)	17 (14–20.3)	0.233
Time spent on dialysis, yrs	6.0 (3.4–8.7)	3.8 (2.1–6.6)	<0.001

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HD: Hemodialysis; PD: Peritoneal Dialysis; eGFR: estimated glomerular filtration rate; CIT: cold ischemia time

The significant association between DGF and blood pressure status was confirmed by multivariate analysis including all factors associated with DGF occurrence (Table 5): patients in the hypotensive group had the higher risk of experiencing DGF (OR, 5.4; 95% confidence interval [CI], 2.8 to 10.6).

Table 5. Factors associated with DGF (multivariate analysis).

	P	H.R.	95% C.I. per EXP(B)
	P	H.R.	Inferior	Superior
MBP<80 mmHg	<0.001	5.4	2.8	10.6
Donor death for a cardiovascular cause, n (%)	0.002	1.9	1.3	2.8
Donor age (>60 yrs)	0.008	1.7	1.1	2.4
Time spent on dialysis (≥ 4 yrs)	<0.001	2.1	1.5	2.9
CIT	0.889	1	1	1
Previous KT (≥ 1)	0.078	1.2	0.9	2.4
Recipient age (≥ 50 yrs)	0.220	1.3	0.9	1.9
Dialysis type (HD vs. PD)	<0.001	2.9	1.8	4.8
Donor hypertension	0.195	1.3	0.9	1.8

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MBP: Mean blood pressure; CIT: cold ischemia time; KT: kidney transplant

Hypotension-related DGF may influence death-censored graft survival in KT from elderly donors

Based on the demonstration of an association between pre-existing hypotension and DGF, we consequently investigated the possible long-term effects of blood pressure status on graft and patient survival.

In the KM model, graft, patient, and death-censored survival were similar between groups (Fig 4); similarly, eGFR did not differ between hypotensive and normal-hypertensive KT (Fig 5).

Fig 5 — No difference was noted between the hypotensive and normal-hypertensive groups during the follow-up (p = N.S. at any time-point).

Nevertheless, an association between hypotension and death-censored graft survival emerged considering KTs from elderly donors. Through a stratified analysis by exploiting donor age tertiles (≤50, 51–66 and ≥67 yrs), we found that death-censored graft survival was significantly reduced (p = 0.04) in the hypotensive patients who received KT from a donor > 50 yrs (78% of functioning graft in the hypotensive group at 5 yrs vs. 87.4% in the normal-hypertensive group for donor age 51–66; 58.3% vs. 82% for donor age ≥ 67 yrs, respectively) (Fig 6).

Fig 6 — Death-censored graft survival was reduced in patients with pre-existing hypotension who received a kidney from a donor between 51 and 66 yrs (p = 0.04) or ≥ 67 yrs (p = 0.04).

Multivariate Cox regression analysis demonstrated that DGF and donor age were the only independent risk factors for death-censored graft survival reduction, suggesting the role of hypotension-induced DGF in this scenario (Table 6).

Table 6. Multivariate Cox regression analysis.

	P	H.R.	95% C.I. per EXP(B)
	P	H.R.	Inferior	Superior
MBP<80 mmHg	0.146	1.593	0.851	2.984
DGF	<0.001	2.177	1.599	2.963
Donor age	<0.01	1.037	1.026	1.049

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MBP: Mean blood pressure; DGF: delayed graft function

Pre-existing hypotension is both associated with DGF in paired kidneys and with perioperative hypotension

We also performed a confirmatory analysis investigating KTs among paired kidneys with one hypotensive and one normal-hypertensive recipient, identifying 18 couples treated with the same induction therapy (anti-CD25 antibody and steroids): as for the overall population, DGF incidence was significantly higher in patients with pre-existing hypotension [(66.7% vs. 22.2% in Normal-hypertensive KT; p = 0.02, OR 7.0 (1.6–30.8)] without differences in recipient age, CIT, graft, or patient survival.

Considering perioperative data (available in 917/1127, S1 File, sheet 2), we found a concordance between “historical” hypotension and an MBP<80 mmHg immediately before, during (at reperfusion), or after the surgery (K = 0.616); however, pre-existing hypotension showed a better associated with DGF [OR for perioperative hypotension 2.8 (1.9–4.1)].

Additionally, patients in the hypotension group also had an increased risk of receiving a perioperative fluid administration > 3000 mL (37.9% vs. 13.9% in normal-hypertensive; p<0.001).

Discussion

Renal function is intrinsically related to hemodynamic status. Autoregulation allows kidneys to maintain normal blood flow and glomerular filtration rate between a mean systemic arterial pressure from 80 mmHg to 160 mmHg [16]. However, in the first post-transplant period, some critical stress factors (i.e., ischemia-reperfusion injury, exposure to vasoconstrictors such as calcineurin inhibitors) may impair this system [4, 17], so the effect of hypotension could be further aggravated with a significant reduction in renal blood flow.

However, few studies have specifically investigated the possible consequences of recipient hypotension in graft and patient outcomes, often limiting their considerations to perioperative management or short-term post-transplant period.

In our study, we found that pre-existing chronic hypotension (defined as an MBP<80 mmHg assessed during a three months pre-transplant period) is a crucial detrimental factor because a) it significantly and independently correlates to DGF, also in paired kidney analysis among KTs with discordant blood pressure status (hypotensive vs. normal-hypertensive); b) in KTs from elderly donors it may contribute to a low death-censored graft survival due to hypotension-related DGF; c) it is associated with documented intraoperative hypotensive episodes and perioperative fluid administration > 3000 mL with a better correlation to DGF than perioperative values.

Even though DGF is broadly considered a harmful condition with a significant negative impact on graft and patient survival [18–22], its relationship with hypotension is debated.

In 2000, Boom [1] reported that recipients with MBP below 100 mmHg before transplantation had a doubled risk of DGF. However, the studied population (CIT 29±7 h, donor age 37±14 yrs, recipient age 46±13 yrs) was quite different from standard real-life settings.

Ozdemir et al. [2] associated a systolic blood pressure <120 mmHg to an increased risk of DGF in living-related renal allograft recipients: these data again involved a limited population (KTs from living donors) with a younger age than typically observed in current practice.

Our data are closely related to those reported by Gingell-Littlejohn et al. [11] and Kaufmann et al. [9]. Both studies identified a correlation between intraoperative MBP and DGF occurrence, despite targets and cut-offs varied between studies [any recorded MBP<70 mmHg and an MBP <80 mm Hg at the time of reperfusion, respectively]. As for Webber et al. [4], who adopted our definition observing the highest risk of PNF for patients with MBP <80 mmHg, the high OR identified by multivariate analysis and confirmed in both paired kidneys and perioperative data analyses suggest that, besides being only related to intraoperative hypotension, chronic pre-existing blood pressure status may better describe a high-risk profile of KTs who may develop DGF.

Additionally, to the best of our knowledge, our study is the first to deeply evaluate long-term graft and patient survival stratifying population according to pre-existing blood pressure status and with the absence of confounding factors such as extensive percentage of living donation or donors after cardiac deaths.

We did not find an association between hypotension and graft or patient survival on the overall population and paired kidneys. However, sorting out the population by donor age, hypotensive patients who received KT from a donor >50 yrs had a reduced death-censored graft survival; according to multivariate Cox regression analysis, where only DGF and donor age remain significant, we speculate that DGF-mediated hypotension may particularly exert its negative effect in this frail subset of KTs, identifying a subgroup of patients where targeted blood pressure monitorization acquires the highest importance.

Our results effectively emphasize the need for rational peri- and postoperative fluid management to maintain adequate kidney perfusion without a maximization of cardiac filling; however, as reported in literature and observed in current practice, this target remains a challenge [15]. No guideline or recommendation is to date available for catecholamine choice/dosage [15, 23] as for intraoperative fluid amount and quality [24–26]. On the other hand, the excessive use of inotropes [27] and fluid infusions [9], as observed in our population, were both associated with adverse outcomes. A “goal-directed therapy,” borrowed from critical care experience [28, 29], may represent the optimal approach in this setting, although no studies are currently available in KTs [15].

We acknowledge that our study has some limitations: the retrospective design, the limited number of postoperative data. However, all 1127 patients underwent the same surgical and clinical management and a subsequent strict and continuous monitorization with a precise schedule followed by our team of transplant nephrologists; additionally, the adopted multivariate model and paired kidney analysis reduced the effect of possible confounders.

In conclusion, pre-existing chronic hypotension is the only modifiable condition with a significant and independent association with post-KT DGF occurrence.

Based on our analysis results, we would also highlight the association between hypotension and reduced death-censored graft survival in elderly patients, suggesting that hypotension-mediated DGF may become more critical in the setting of the so-called “suboptimal” donors, stressing the importance of therapeutic strategies implementation in this area.

Allocation and institutional policies should carefully consider patients with pre-existing chronic hypotension primarily when expanded-criteria donors are used, focusing on maximizing patient outcomes through a corresponding system resource implementation.

Supporting information

S1 File. The raw data elaborated in this study are included in supporting information [(sheet 1: Overall population; sheet 2: Perioperative MBP] (last access date 03/10/2021).

(XLSX)

Click here for additional data file.^{(599.3KB, xlsx)}

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0249552.r001

Decision Letter 0

Frank JMF Dor

10 Nov 2020

PONE-D-20-31022

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplant from elderly donors

PLOS ONE

Dear Dr. Biancone,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Biancone et al highlight an important and underreported topic in kidney transplantation. Three expert reviewers from all relevant MDT backgrounds in kidney transplantation have commented on the MS, and have indicated major revisions would be necessary to make the MS publishable in PlosOne. I agree with their assessment. It would need to be rewritten with a clear focus on the primary aim of the study. One of the important points made re: the design of the study is that the recipient BP is particularly important after the reperfusion and we are missing details on perioperative details and BP management. Description of methods needs to be better, and expansion of discussion around the limitations of methodology in relation to the outcome of the analyses is required. The MS would need to be corrected/rewritten by a native english speaker given considerable spelling/grammar errors.

Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact.

Please submit your revised manuscript by Dec 25 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Frank JMF Dor, M.D., Ph.D., FEBS, FRCS

Academic Editor

PLOS ONE

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3.) We note that your study involved analysis of data relating to tissue/organ transplantation. Please provide the following additional information regarding tissue/organ donors for transplantation cases analyzed in your study.

1. Please provide the full name of the source of the transplanted tissue/organs used in the study (the transplantation center name).

2. Please state in your response letter and ethics statement whether the transplant cases for this study involved any vulnerable populations; for example, tissue/organs from prisoners, subjects with reduced mental capacity due to illness or age, or minors.

- If a vulnerable population was used, please describe the population, justify the decision to use tissue/organ donations from this group, and clearly describe what measures were taken in the informed consent procedure to assure protection of the vulnerable group and avoid coercion.

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4. Please indicate whether the donors were previously registered as organ donors.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an extremely interesting study focusing on a neglected but critical aspect of kidney transplantation. Recipient hypotension is in my personal experience the main factor underlying delayed graft function - even more important in practice than cold ischaemic time - yet little in the way of academic study has focused on this area.

The study - a retrospective analysis of >1000 cases analyses associations between recipient BP (assessed in multiple ways) in the period PRIOR to transplantation. In fact the recipient BP is only relevant AFTER reperfusion and this important point could be highlighted in the introduction more prominently. There is however likely to be a high correlation with intra-operative and post-operative blood pressure immediately post transplant and the salient point of the article holds true despite this.

The authors use MAP<80mmHg as the definition of hypotension. That is reasonable based on consensus however this issue has been specifically studied in the perioperative context and ROC curve analysis indicates perioperative BP of 75mmHg or less is the threshold below which DGF becomes significantly more likely (Gingell-Littlejohn et al. Transplant Proc . Jan-Feb 2013;45(1):46-50. doi: 10.1016/j.transproceed.2012.03.058. Epub 2012 Sep 6.) This study is relevant to the article and should be quoted.

The further analyses using paired kidneys and propensity matching add strength to the correlation described. The discussion does not adequately capture the importance of the point made nor the obvious ways in which addressing the issue of recipient hypotension might be attempted. The discussion should consider approaches like goal-directed therapy, inotropes, pressors, specific renal artery flow measurement etc. all of which might be logical approaches to minimise the DGF risk in a hypotensive recipient.

Some further specific points:

The article briefly acknowledges the limitations caused by potential covariance (P19 line 313). This needs expansion. Specifically, the length of time spent on dialysis is a key variable which I am certain would have been available to the authors with a little further work. Specifically this would be an ideal parameter to have applied in the propensity matching in order to address the potential confounding effect. It is well known that chronic HD is associated with hypotension and the absence of this parameter undermines the MVA. This issue should also feature in the discussion as it is unclear how modifiable such a state is in the short period between notification and kidney implantation. If this effect is the main origin of recipient hypotension, strategies to address that in chronic dialysis patients - and their obvious difficulties - should be discussed in the manuscript.

The manuscript appropriately ends on highlighting the danger inherent in allocating older donor kidneys to the hypotensive group.

A further important point worth making relates to the context of recent allocation changes - such as the D4/R4 combination favoured by the new UK scheme since Sept. 2019). Based on the paper's analysis it can be more specifically stated that such transplants are likely to have more DGF, longer stays, more post transplant biopsies and require more resource per case. It is therefore reasonable to conclude that s ystems should provide additional resources to address these inevitable issues BEFORE committing overstretched units to repeatedly undertake such transplants by through allocation policy change.

Table s 2 and 8 would be better presented as graphs

Table 5: several P values appear nonsensical

Reviewer #2: This paper is single center study into association of recipient hypotension with delayed graft outcome and graft survival after kidney transplantation. The major outcome is that recipient hypotension is associated with the risk for DCG and the risk for death censored graft loss in the case of older donors.

While the role of recipient hypotension in kidney transplant outcome merits additional research I feel that the current version of this paper does not add much current knowledge in the field and have a number of comments.

1. The paper does not seem to have a clear focus. While the introduction states that the study intends to analyze the role of recipient hypotension in kidney transplantation the first section of the paper focuses on risk factors for DGF. This section does not add much. I would suggest addressing the role of hypotension and graft outcome directly without the largely confirmatory section on risk factors for DGF.

2. The methods section does not adequately describe the multivariable analysis. A very restricted number of variables is entered in the presented model, although a couple more variables could be included based on the results of the univariable analysis and clinical reasoning (e.g dialysis type). Instead of a thorough multivariable analysis propensity score matching is included. As a bias for receiving a specific treatment is not an issue in this study, I do not understand the rationale for propensity score matching. A more thorough multivariable analysis with the possible addition of a mediation analysis would seem preferable to me.

3. The visual quality of the Kaplan Meier curves is poor. I would also appreciate the addition of numbers at risk in view.

4. I do not completely understand how the number in table 3 add up for dialysis type. If 31.1% of the patient without DGF were on PD, how kan 75.6% of the patients be on HD? This sum is 106.7%.

5. I would leave out the serum creatinine determinations in table 2 and 8. This does not add much next to the eGFR.

6. The text contains a large number of textual errors and needs editing, preferably by a native speaker.

Reviewer #3: This is a retrospective observational study that offers an interesting perspective on a topic that has not been well studied, and may have implications for the perioperative management of kidney transplant patients.

Study design: it is unclear why the authors have chosen MAP 80 as their cut off and, although they correctly assert in the introduction that there is no consensus, it would have been useful to understand their rationale. In the perioperative literature, must studies target MAP 70-90 as a trade off between ensuring adequate renal blood flow, and minimising the vasoconstrictive effects of the agents used to raise the blood pressure intra-operatively. It is likely that were there to be an association between hypotension and graft outcome, this would be as a result of the management in the perioperative period. It would have been useful, therefore, to include data and analysis of the BP immediately before, during and after the surgery to understand if this altered outcome in any way.

Also, what else changed during the period being studied? How was the recipient managed and what factors were taken into consideration? In particular, did the patient's pre-existing blood pressure alter the MAP target perioperatively?

Results: Table 1 - the number of hypertensive patients in line 3 (900) does not match the number in the study design (935). In light of the lack of discussion around MAP targets, inevitably I am left wondering what the results of the study would have been had the MAP cut off been different.

Discussion: the authors have not paid enough attention to a discussion around the effect of the recipient's chronic blood pressure on their management perioperatively, and in particular how the blood pressure and other variables of cardiac output were managed. We know that flow is particularly important in the denervated transplanted kidney - how was this monitored and managed? Could the intra-operative management of the hypotensive patients explain the poorer outcomes?

Overall, this paper raises some pertinent questions; however, the study design at present limits its relevance to clinical practice given the fact that data around the perioperative management of the patients has not been studied.

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Reviewer #1: Yes: Marc J Clancy

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2021 Apr 5;16(4):e0249552. doi: 10.1371/journal.pone.0249552.r002

Author response to Decision Letter 0

22 Jan 2021

Academic editor

Response. We thank the Academic Editor for his consideration of our paper. According to Academic Editor and reviewers' suggestion, we performed an in-depth revision reconsidering our manuscript with a clear focus on its primary aim (the role of pre-existing chronic hypotension in DGF occurrence and its possible effects on long-term outcomes); additionally, we expanded and rewrote methods, results, and discussion including all findings of available perioperative data and blood pressure management. At least, as suggested, the English language has been evaluated by a native English speaker. We hope that all reviewers' questions are now adequately addressed, and the new version of the manuscript will be suitable for publication in Plos One.

Some further specific points:

The manuscript appropriately ends on highlighting the danger inherent in allocating older donor kidneys to the hypotensive group.

Table s 2 and 8 would be better presented as graphs

Table 5: several P values appear nonsensical

Response: We appreciate all Rev#1 comments that allow us to improve our paper's quality. According to his suggestions, we have evaluated all our manuscript, also including the available perioperative data. We have consequently rewritten the introduction, methods, results, and discussion focusing on the importance of perioperative management and commenting on the study results by Gingell-Littlejohn et al. (now Ref#11) in introduction and discussion.

In the discussion, we have also included an entire section about the need for a rational perioperative approach to minimize hypotension and its potential detrimental role for transplant outcome, stressing the importance of goal-direct therapies (Page 16-17, Line 292-300).

According to Rev#2 comments, we also implemented our model eliminating the propensity score and modifying the multivariate analysis, even including the length of time spent on dialysis, which is significant in both univariate and multivariate analysis (Table 2); in our opinion, the addition of this substantial variable (for which the thank Rev#1) stress the importance and the generalizability of our results.

As requested, Tables 2 and 8 were presented as graphs (now Figure 2 and 5), and Table 5 (now Table 4) was rewritten, including appropriate statistical analysis.

As also appropriately suggested, we stated in the last part of the discussion that allocation and institutional policies should carefully consider patients with pre-existing chronic hypotension, primarily when expanded-criteria donors are used, focusing on maximizing patient outcomes with a corresponding implementation of system resources (Page 17, Line 312-314).

Response: We appreciate Rev#2 considerations because they allow us to refine our analysis. As reported in the Academic editor and Rev#1 response, we modified the introduction (and the whole manuscript), primarily focusing on our study's aim (the role of pre-existing chronic hypotension in DGF occurrence and its possible effects on long-term outcomes) and after that discussing all the implications of our findings.

Response: As reported in Rev#1 comment, we implemented our model eliminating the propensity score and modifying the multivariate analysis, also including, for example, the length of time spent on dialysis, which is significant in univariate and multivariate analysis; in our opinion, the implementation of our research stresses the importance and the generalizability of our results.

3. The visual quality of the Kaplan Meier curves is poor. I would also appreciate the addition of numbers at risk in view.

Response: We modified Figures 1, 4, and 6 according to the requested resolution format, adding the numbers at risk.

4. I do not completely understand how the number in table 3 add up for dialysis type. If 31.1% of the patient without DGF were on PD, how kan 75.6% of the patients be on HD? This sum is 106.7%.

Response: We apologize for this error. As expressed in all comments, we performed an in-depth revaluation of all results, correcting and revisioning all data. In the updated version, table 2 now reported the correct percentages.

5. I would leave out the serum creatinine determinations in table 2 and 8. This does not add much next to the eGFR.

Response: Serum creatinine determinations have been eliminated; as suggested by Rev#1, Tables 2 and 8 are now expressed as graphs (Figures 2 and 5, respectively).

6. The text contains a large number of textual errors and needs editing, preferably by a native speaker.

Response: As also requested by Academic Editor, the manuscript language has been reviewed by a native English speaker.

Study design: it is unclear why the authors have chosen MAP 80 as their cut off and, although they correctly assert in the introduction that there is no consensus, it would have been useful to understand their rationale. In the perioperative Literature, must studies target MAP 70-90 as a trade off between ensuring adequate renal blood flow, and minimising the vasoconstrictive effects of the agents used to raise the blood pressure intra-operatively. It is likely that were there to be an association between hypotension and graft outcome, this would be as a result of the management in the perioperative period. It would have been useful, therefore, to include data and analysis of the BP immediately before, during and after the surgery to understand if this altered outcome in any way.

Response: We thank Rev#3 for his/her comment. As expressed above, we have evaluated all our paper, including the available perioperative data and rewriting introduction, methods, results, and discussion focusing on the importance of perioperative management. Briefly, as stated in methods, all our patients were similarly managed with a target MBP of 80 mmHg maintained with crystalloids and the association of dopamine in case of persistent sub-target values, and we found a significant correlation between pre-existing and intraoperative hypotension; at the same time, we are aware that the cut-off for hypotension is a matter of debate: however, based on previous experience in literature and the prior demonstration of a correlation between PNF and a pre-transplant MBP<80 mmHg in Webber et al. (Ref#4), we decided to maintain this threshold (as now better expressed in both introduction and methods). The new implementation of multivariate analysis with the demonstration of a higher correlation between pre-existing hypotension and DGF suggests, in our opinion, the importance of the analyzed variable and the need for a consistent and rational perioperative approach to minimize its effect on transplant outcome.

All these considerations are now included in the manuscript, focusing on goal-direct therapies' importance (Page 16-17, Line 292-300).

Response: As for Rev#2, we apologize for this error. As expressed in all comments, we performed an in-depth revaluation of all results, correcting and revisioning all data. Table 1 now included the correct numbers and percentages.

Response: As mentioned above, we now stated in methods that all our patients were similarly managed with a target MBP of 80 mmHg maintained with crystalloids infusions and dopamine association in case of persistent sub-target values. The analysis of available intraoperative data (before, during – at reperfusion – and after the surgery) identifies a close correlation between "historical" and intraoperative hypotension and an increased administered volume (>3000 mL) in hypotensive patients. We agree with Rev#3 that the number of perioperative data is a limitation of our study (as for most of the available Literature papers about this topic); however, the implementation of multivariate analysis with the demonstration of a higher correlation between pre-existing hypotension and DGF suggest, in our opinion, the importance of the analyzed variable and the need of a consistent and rational perioperative approach to minimize its effect on transplant outcome.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file.^{(27KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0249552.r003

Decision Letter 1

Frank JMF Dor

11 Feb 2021

PONE-D-20-31022R1

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

PLOS ONE

Dear Dr. Biancone,

==============================

ACADEMIC EDITOR:

Many thanks for making the revisions as per the reviewers' recommendations. They certainly have improved the quality of the MS, but the reviewers still have a few outstanding points that need to be addressed, as i think they are important. They are specified in the comments below. I would encourage you to thoroughly go through them and make the appropriate revisions. I think the MS should be acceptable for publication after that, but will depend on the quality of the revisions and will undergo thorough re-review especially in the light of the outstanding concerns.

==============================

Please submit your revised manuscript by Mar 28 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Frank JMF Dor, M.D., Ph.D., FEBS, FRCS

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Reviewer #1: The authors appear to have carefully considered the extensive review comments. the revised version is much clearer and of value to the journal's readership in highlighting the important consequences of recipient hypotension for kidney transplantation. the manuscript highlights the importance of considering this factor in both policy decisions around allocation and actual management of individual patients. the manuscript makes appropriate suggestions regarding further studies in the area in line with initial reviews.

Reviewer #2: After the thorough revision the paper is much more focused and has clearly improved. The writing is also clearly improved . I do have one question about the multivariate analysis as shown in table 5. The authors state that the included the significant predictors for DGF as shown in table 2. However the highly significant predictors type of dialysis and donor hypertension are left out. I believe this is not explained in the manuscript. Especially type of dialysis seams an important determinant to ad in this analysis.

Reviewer #3: Thank you for your revisions and I acknowledge the significant amount of work that the authors have put into the manuscript. However, I have two significant concerns:

1. There remain some significant English grammatical and spelling errors particularly in the introduction, methods and discussion. These would need to be resolved prior to the publication;

2. My previous comments regarding the management in the perioperative period. Having looked at the supplementary data provided, this is insufficient to provide analysis: data are only provided for 89 of the 1127 receipients and it is difficult to draw any meaningful conclusions from the data presented. The outstanding issue of how those patients with pre-existing hypotension were managed in the perioperative still needs to be resolved.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Dr Marc Wittenberg BSc(Hons), MBChB, FRCA

PLoS One. 2021 Apr 5;16(4):e0249552. doi: 10.1371/journal.pone.0249552.r004

Author response to Decision Letter 1

11 Mar 2021

Academic editor

Many thanks for making the revisions as per the reviewers’ recommendations. They certainly have improved the quality of the MS, but the reviewers still have a few outstanding points that need to be addressed, as i think they are important. They are specified in the comments below. I would encourage you to thoroughly go through them and make the appropriate revisions. I think the MS should be acceptable for publication after that, but will depend on the quality of the revisions and will undergo thorough re-review especially in the light of the outstanding concerns.

Response. We thank the Academic Editor for his comments. According to reviewers’ suggestion, we re-checked patients schedule for perioperative data (which are now available in 917/1127); as reported below, we found a high concordance between “historical” hypotension and an MBP<80 mmHg immediately before, during (at reperfusion), or after the surgery (K=0.616); however, pre-existing hypotension showed a better association with DGF. As now better expressed in results and discussion sections, our findings suggest that, besides being only related to intraoperative hypotension, chronic pre-existing blood pressure status may better describe a high-risk profile of KTs who may develop DGF.

As also indicated by Rev#2, we implemented the multivariate analysis including dialysis type and donor hypertension and confirming that patients in the hypotensive group had the higher risk of experiencing DGF (OR, 5.4; 95% confidence interval [CI], 2.8 to 10.6). As also suggested, the English language has been extensively evaluated.

Reviewer #1: The authors appear to have carefully considered the extensive review comments. the revised version is much clearer and of value to the journal’s readership in highlighting the important consequences of recipient hypotension for kidney transplantation. the manuscript highlights the importance of considering this factor in both policy decisions around allocation and actual management of individual patients. the manuscript makes appropriate suggestions regarding further studies in the area in line with initial reviews.

Response: We appreciate Rev#1 consideration for our paper.

Response: We agree with Rev#2 comments, and, according to his/her suggestions, we implemented the multivariate analysis, including dialysis type and donor hypertension. This final elaboration confirms that patients in the hypotensive group had the higher risk of experiencing DGF (OR, 5.4; 95% confidence interval [CI], 2.8 to 10.6).

Reviewer #3: Thank you for your revisions and I acknowledge the significant amount of work that the authors have put into the manuscript. However, I have two significant concerns:

1. There remain some significant English grammatical and spelling errors particularly in the introduction, methods and discussion. These would need to be resolved prior to the publication;

Response: We thank Rev#3 for his comments. According to his suggestions:

1- The English language has been further extensively evaluated

2- We re-checked patients schedule for perioperative data (which are now available in 917/1127); as reported, we found a concordance between “historical” hypotension and an MBP<80 mmHg immediately before, during (at reperfusion), or after the surgery (K=0.616); however, pre-existing hypotension showed a better association with DGF [OR for perioperative hypotension 2.8 (1.9-4.1) vs. 5.4 (2.8-10.6)]. As now better expressed in results and discussion sections, our findings suggest that, besides being only related to intraoperative hypotension, chronic pre-existing blood pressure status may better describe a high-risk profile of KTs who may develop DGF. We then stressed in the discussion section the need for a rational peri- and postoperative fluid management to maintain adequate kidney perfusion without a maximization of cardiac filling, considering that a goal-directed therapy may represent the optimal approach in this setting.

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PLoS One. doi: 10.1371/journal.pone.0249552.r005

Decision Letter 2

Frank JMF Dor

22 Mar 2021

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

PONE-D-20-31022R2

Dear Dr. Biancone,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewer #2: All comments have been addressed

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PLoS One. doi: 10.1371/journal.pone.0249552.r006

Acceptance letter

Frank JMF Dor

25 Mar 2021

PONE-D-20-31022R2

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

Dear Dr. Biancone:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. The raw data elaborated in this study are included in supporting information [(sheet 1: Overall population; sheet 2: Perioperative MBP] (last access date 03/10/2021).

(XLSX)

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Data Availability Statement

All relevant data are within the manuscript and its Supporting information files.

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PERMALINK

Recipient pre-existing chronic hypotension is associated with delayed graft function and inferior graft survival in kidney transplantation from elderly donors

Caterina Dolla

Alberto Mella

Giacinta Vigilante

Fabrizio Fop

Anna Allesina

Roberto Presta

Aldo Verri

Paolo Gontero

Fabio Gobbi

Roberto Balagna

Roberta Giraudi

Luigi Biancone

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Materials and methods

Study design

Immunosuppressive regimen and perioperative management

Statistical analysis

Results

Characteristics of the studied population and the role of DGF

Table 1. Clinical and demographic characteristics of the studied population.

Fig 1. Graft and patient survival by DGF in the studied population.

Fig 2. Renal function in studied population according to DGF occurrence.

Table 2. Factors associated with DGF (univariate analysis).

Association between pre-existing hypotension and DGF

Fig 3. DGF incidence in the hypotensive, normotensive, and hypertensive group.

Table 3. DGF incidence according to pre-existing blood pressure status.

Table 4. Characteristics of the studied population according to pre-existing blood pressure status.

Table 5. Factors associated with DGF (multivariate analysis).

Hypotension-related DGF may influence death-censored graft survival in KT from elderly donors

Fig 4. Graft and patient survival by pre-existing blood pressure status in the studied population.

Fig 5. Renal function in studied population according to pre-existing blood pressure status.

Fig 6. Death-censored graft survival by pre-existing blood pressure status and stratified by donor age.

Table 6. Multivariate Cox regression analysis.

Pre-existing hypotension is both associated with DGF in paired kidneys and with perioperative hypotension

Discussion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Frank JMF Dor

Roles

Author response to Decision Letter 0

Decision Letter 1

Frank JMF Dor

Roles

Author response to Decision Letter 1

Decision Letter 2

Frank JMF Dor

Roles

Acceptance letter

Frank JMF Dor

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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