# Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients

Damien Guinault, Arnaud del Bello, Laurence Lavayssiere, Marie-Béatrice Nogier, Olivier Cointault, Nicolas Congy, Laure Esposito, Anne-Laure Hebral, Olivier Roques, Nassim Kamar, et al.

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Damien Guinault, Arnaud del Bello, Laurence Lavayssiere, Marie-Béatrice Nogier, Olivier Cointault, et al. Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients. BMC Anesthesiology, 2019, 19 (1), pp.130. 10.1186/s12871-019-0800-0. hal-03602357

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# Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients

Damien Guinault¹, Arnaud Del Bello¹, Laurence Lavayssiere¹, Marie-Béatrice Nogier¹, Olivier Cointault¹, Nicolas Congy², Laure Esposito¹, Anne-Laure Hebral¹, Olivier Roques¹, Nassim Kamar¹,³,⁴ and Stanislas Faguer¹,³,⁵*

**Abstract**

**Background:** Risk of over-immunosuppression or immunization may mitigate the overall and long-term renal outcomes of kidney transplant recipients (KTR) admitted to the ICU in the modern era but remain poorly described. Thus, there is an unmet need to better characterize the survival of KTR admitted to the ICU, but also the renal and immunological outcomes of survivors.

**Methods:** Retrospective observational study that included 200 KTR admitted between 2010 and 2016 to the ICU of a teaching hospital (median age 61 years [IQR 50.7–68]; time from transplantation 41 months [IQR 5–119]). Survival curves were compared using the Log-rank test.

**Results:** Mortality rates following admission to the ICU was low (26.5% at month-6), mainly related to early mortality (20% in-hospital), and predicted by the severity of the acute condition (SAPS2 score) but also by Epstein Barr Virus proliferation in the weeks preceding the admission to the ICU. Acute kidney injury (AKI) was highly prevalent (85.1%). Progression toward chronic kidney disease (CKD) was observed in 45.1% of survivors. 15.1% of survivors developed new anti-HLA antibodies (donor-specific antibodies 9.2% of cases) that may impact the long-term renal transplantation function.

**Conclusions:** Notwithstanding the potential biases related to the retrospective and monocentric nature of this study, our findings obtained in a large cohort of KTR suggest that survival of KTR admitted in ICU is good but in-ICU management of these patients may alter both survival and AKI to CKD transition, as well as HLA immunization. Further interventional studies, including systematic characterization of the Epstein Barr virus proliferation at the admission (i.e., a potential surrogate marker of an underlying immune paralysis and frailty) will need to address the optimal management of immunosuppressive regimen in ICU to improve survival but also renal and immunological outcomes.

**Keywords:** Renal transplantation, HLA immunization, Intensive care unit, Outcomes

**Background**

About 10% of kidney transplant recipients (KTR) experience a life-threatening disease requiring admission in an intensive care unit (ICU) [1–7]. Most admissions occur more than 6 months after the renal transplantation [3–5, 8, 9]. The main causes of admission were acute respiratory failure

(ARF) and septic shock, followed by cardiovascular complications, acute kidney injury (AKI), drug-related complications and neoplasia [4, 10].

In-hospital mortality after admission to the ICU is mostly related to the cause of admission and the number of organ failures at presentation, whereas the characteristics of the renal transplantation are not associated with the outcomes [3, 4, 6]. Whether these findings hold true in the modern era characterized by an increase of transplantations at high risk of surgical and immunological

<footnote>* Correspondence: stanislas.faguer@inserm.fr

¹Département de Néphrologie et Transplantation d'organes, Unité de Réanimation, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, 1, avenue Jean Poulhes, 31059 Toulouse, France

³Université Paul Sabatier, Toulouse III, F-31000 Toulouse, France
Full list of author information is available at the end of the article</footnote>
complications and with widespread use of prophylaxis for opportunistic infections remain to be addressed.

KTR are at higher risk of severe AKI in the ICU, com-
pared to unselected critically ill patients [3, 11], and up
to 40% of KTR will required renal replacement therapy
(RRT). AKI is now recognized as a cause of chronic kid-
ney disease (CKD), and estimated glomerular filtration
rate (eGFR) before the injury is a strong predictive factor
of progression toward CKD [12]. In old studies, the renal
outcome was poor, ranging from 20 to 30% of patients
with eGFR decline after ICU stay. KTR that develop AKI
have a relative risk of graft loss of 3.2, and up to 20% of
patients will ultimately lose their renal graft [13].

Similarly to unselected critically ill patients, renal out-
come of KTR results from the combination of the under-
lying CKD (i.e., basal eGFR), the use of nephrotoxicants in
the ICU, and episodes of ischemic, hemodynamic or septic
AKI [3, 4, 14]. In the setting of renal transplantation, im-
munological injuries may also promote the progression of
graft dysfunction observed after ICU admission. Indeed,
the withdrawal of immunosuppressive drugs and/or red
blood cells (RBC) transfusion may lead to the develop-
ment of de novo donor-specific antibodies during or after
the stay in the ICU [15, 16]. This may reduce the graft sur-
vival in ICU survivors and reduce the access to a subse-
quent transplantation in patients who lost their graft
function. To date, no study accurately assessed the im-
munological outcome in KTR admitted in ICU.

In this study, which included a large cohort of 200
KTR admitted in ICU over a 6 years period, we aimed to
identify the predictive factors for in-hospital mortality,
to characterize the predictive factors of progression from
AKI of CKD, and to assess the risk of anti-HLA
immunization, two factors associated with long-term
survival.

Patients and methods

In this retrospective single-center study, we included all
KTR admitted between January 2010 and June 2016 to
the ICU of the Department of Nephrology and Organ
Transplantation at the University Hospital of Toulouse
(France), a 10-bed tertiary care ICU backed by a 30
beds-unit of solid organ transplantation, and with 24-h-
a-day intensivist.

To be included in this study, patients met the follow-
ing criteria: (i) over 18 years of age, (ii) to have received
a renal transplantation before the admission, and (iii) an
admission to the ICU for acute conditions. Patients ad-
mitted for a close monitoring just after the renal trans-
plantation, and those with known irreversible graft
failure, were excluded from the analysis. Only the first
admission was reported.

According to the French law related to retrospective
observational studies and our Institutional Review Board

(University Hospital of Toulouse – Office of Research,  
Development and Innovation), the need for written con-  
sent was waived.

The primary objective of the study was to identify the predictive factors of death in the hospital of KTR admitted to the ICU. Secondary objectives were the characterization of the risk to develop AKI to CKD transition and to acquire HLA immunization.

Clinical characteristics

Clinical and biological data were collected from the computerized charts of the patients. The following parameters related to transplantation were collected: age at transplantation, cause of renal disease, immunosuppressive regimen, episodes of biopsy-proven antibody or T-cell-mediated rejection (ABMR and TCMR), EBV or CMV replication in blood or BK virus shedding in urine within the 6 months preceding the admission to the ICU. The parameters related to the ICU stay included age at admission, gravity scores, causes for admission, infections, organ failures, RBC transfusions, and immunosuppression management. Changes in immunosuppression were not standardized in our ICU and were left at the discretion of each physician. CKD was assessed at month 1 and 6 in survivors according to the CKD KDIGO staging [17].

Immunological tests

Assessment of anti-HLA immunization was performed according to our institutional protocol (i.e. every 12 months or after events at risk of anti-HLA immunization like RBC transfusion, acute rejection), with the Luminex® technique. A baseline value of > 500 was considered positive.

Statistical analyses

Continuous variables are reported as their median and interquartile ranges (IQR), and discontinuous variables as numbers and percentages. Univariate analyses of in-hospital mortality were performed using the Mann-Whitney or Fischer' exact tests, as appropriate. Multivariate analyses were performed using a step-by-step logistic regression model. All variables associated with in-hospital survival by univariate analysis (*p* < 0.1) were included in the multivariate analysis. Survival curves were drawn according to the Kaplan-Meier method and compared with the Log-Rank test (univariate analysis). Statistical significance was assumed at *p* < 0.05. Statistical analyses were performed using the GraphPad Prism6 (San Diego, CA, USA) and XLstat softwares (Addinsoft, Paris, France).
## Results

From January 2010 to June 2016, 286 KTR were admit-
ted at least once to our ICU, including 200 that met the
inclusion criteria (median age 61 years [IQR 50.7–68];
male to female ratio 126/74; time from transplantation
41 months [IQR 5–119]; Fig. 1). During this period 1240
patients received renal transplantation in our transplant-
ation unit, and 95 out of these 1240 (7.7%) were admitted
to the ICU. Main characteristics of the transplantation
and at the admission are summarized in Tables 1 and 2.

### Transplantation characteristics

Immunosuppressive regimen included induction therapy
in 162 patients. At admission, patients received a com-
bination of calcineurin inhibitors (81.3%; tacrolimus
74%), antimetabolites (82.3%; mycophenolic acid 79.3%),
mTOR inhibitors (19.2%) and/or steroids (92.9%). Over-
all, 123 patients received an immunosuppressive regimen
including steroids, mycophenolic acid and calcineurins
inhibitors.

Twenty-six (13%) and 34 (17%) out of the 200 patients
had presented with an ABMR and TCMR before the ad-
mission in the ICU (12 (6%) developed both ABMR and

TCMR). When available within the 6 months preceding
the admission to the ICU, CMV and EBV replication in
the blood were observed in 16/142 patients (11.3%), 39/
127 (30.7%), respectively.

### Characteristics in the ICU

At admission, median SOFA gravity score was 6 [IQR 4–8].
Main causes of admission were ARF (27.5%), septic shock
(26.5%), post-operative period (peritonitis, hemorrhage,
23%), acute neurological disorder (6%), AKI requiring RRT
(5%) or cardiac arrest (1%).

Altogether, 114/200 admissions (57%) were related to
an infection (lungs (28.5%), urine (13%), gut (12%) or
other (3.5%)). Pyogenes-related infections were diag-
nosed in 101 patients, whereas aspergillosis, candidemia,
pneumocystosis and CMV infections were identified in
8, 8, 7 and 5 patients, respectively. Multiple infections
were identified in 29 patients (14.5%).

Median time of hospitalization in the ICU was 5 days
[IQR 2–10]. Among the 200 individuals, 107 (53.5%) re-
quired mechanical ventilation, and 97 (48.5%) required
vasopressive drugs. One hundred and seventy-one pa-
tients (85.5%) developed AKI, including 113 (56.5%) with

<figure><img src="image_3.png" /><figcaption>**Fig. 1** Flowchart of the study</figcaption></figure>
<table><caption>**Table 1** Characteristics of the 200 kidney transplant recipients before admission in ICU</caption><thead><tr><th>Characteristics</th><th>Total<br>N = 200</th><th>Survivors<br>N = 160</th><th>In-hospital death<br>N = 40</th><th>p</th></tr></thead><tbody><tr><td>Age (n, %)</td><td>61 [51–68]</td><td>60 [49–66]</td><td>65 [58–70]</td><td>0.07</td></tr><tr><td>Male gender (n, %)</td><td>126 (63)</td><td>97 (60.6)</td><td>29 (72.5)</td><td>0.20</td></tr><tr><td>Comorbidities (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>71 (35.5)</td><td>56 (35)</td><td>15 (37.5)</td><td>0.81</td></tr><tr><td>Heart disease (left ventricular systolic function &lt; 45%)</td><td>97 (48.5)</td><td>73 (45.5)</td><td>24 (60)</td><td>0.11</td></tr><tr><td>Peripheral arterial disease</td><td>23 (11.5)</td><td>60 (37.5)</td><td>24 (60)</td><td>0.01</td></tr><tr><td>Solid cancer</td><td>11 (5.5)</td><td>6 (3.8)</td><td>5 (12.5)</td><td>0.05</td></tr><tr><td>Active hematological malignancy</td><td>9 (4.5)</td><td>6 (3.8)</td><td>3 (7.5)</td><td>1.00</td></tr><tr><td>Transplantation characteristics (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Deceased donor</td><td>15 (7.5)</td><td>14 (8.7)</td><td>1 (2.5)</td><td>0.31</td></tr><tr><td>First kidney transplantation</td><td>166 (83)</td><td>136 (85)</td><td>30 (75)</td><td>0.20</td></tr><tr><td>Induction</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>30 (15)</td><td>23 (14.4)</td><td>7 (17.5)</td><td>0.62</td></tr><tr><td>Polyclonal antibodies</td><td>90 (45)</td><td>74 (46.3)</td><td>16 (40)</td><td>0.58</td></tr><tr><td>IL2R blocking agents</td><td>72 (36)</td><td>57 (35.6)</td><td>15 (37.5)</td><td>0.85</td></tr><tr><td>Immunosuppressive regimen</td><td></td><td></td><td></td><td></td></tr><tr><td>Steroids</td><td>184 (92)</td><td>148 (92.5)</td><td>36 (90)</td><td>1.00</td></tr><tr><td>CNI</td><td>161 (80.5)</td><td>131 (81.8)</td><td>30 (75)</td><td>0.49</td></tr><tr><td>Tacrolimus</td><td>123 (61.5)</td><td>104 (65)</td><td>19 (4.8)</td><td>0.97</td></tr><tr><td>Antimetabolites</td><td>163 (81.5)</td><td>137 (85.6)</td><td>26 (65)</td><td>0.008</td></tr><tr><td>MMF</td><td></td><td></td><td></td><td></td></tr><tr><td>mTOR inhibitors</td><td>36 (18)</td><td>29 (18.1)</td><td>7 (17.5)</td><td>1.00</td></tr><tr><td>Belatacept</td><td>8 (4)</td><td>6 (3.8)</td><td>2 (5)</td><td>0.65</td></tr><tr><td>CNI, MPA, Steroids association</td><td>xx</td><td>xx</td><td>xx</td><td></td></tr><tr><td>History of acute rejection</td><td></td><td></td><td></td><td></td></tr><tr><td>Antibody mediated rejection</td><td>26 (13)</td><td>19 (11.8)</td><td>7 (17.5)</td><td>0.43</td></tr><tr><td>T-cell mediated rejection</td><td>34 (17)</td><td>28 (17.5)</td><td>6 (15)</td><td>0.82</td></tr><tr><td>Viral status before the admission <sup>#</sup> (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Blood <i>Cytomegalovirus</i> detection (n = 142)</td><td>16 (11.3)</td><td>9/107 (8.4)</td><td>7/35 (20)</td><td>0.07</td></tr><tr><td>Blood <i>Epstein-Barr virus</i> detection (n = 127)</td><td>39 (30.7)</td><td>24/96 (25)</td><td>15/31 (48)</td><td>0.02</td></tr><tr><td>Urine BK virus shedding (n = 115)</td><td>28 (24.3)</td><td>18/90 (20)</td><td>10/25 (40)</td><td>0.04</td></tr><tr><td>Immunological status before the admission in ICU (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Anti-HLA immunization (n = 188)</td><td>71 (38)</td><td>59/152 (38)</td><td>12/36 (33)</td><td>0.57</td></tr><tr><td>Donor-specific antibodies</td><td>23 (12.2)</td><td>19 (12.5)</td><td>4 (11.1)</td><td>1.00</td></tr></tbody></table>

Abbreviations: IL-2R, interleukin-2-receptor; CNI, calcineurin inhibitors; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; ICU, intensive care unit

KDIGO stage 3 AKI and 103 (51.5%) that required RRT. One hundred and forty-two out of the 200 patients (71%) benefitted from RBC transfusion.

## Management of immunosuppression in the ICU

At the admission, median residual concentration of tacrolimus and ciclosporine-A were 6.6 ng/mL [IQR 4.6–11.2] and 127 ng/mL [IQR 77–223], respectively. Prednisolone was switched to hydrocortisone (150 to 300 mg/day) in 42

patients, including 35 with septic shock. Calcineurin inhibitors were withdrawal in 40 patients (20%) and concentration targets were reduced in the others (tacrolimus residual 5–8 ng/mL; cyclosporine-A residual (70–220 ng/mL). Antimetabolites were stopped in 61/163 patients (37.4%), including 19 with sepsis. In 48 out of these 61 patients, the dose of steroids was increased. Overall, the immunosuppressive regimen was modified in 155 patients (77.5%).
<table><caption>**Table 2** Characteristics of the 200 kidney-transplant recipients at the admission in ICU and during ICU stay</caption><thead><tr><th>Characteristics</th><th>Total<br>N = 200</th><th>Survivors<br>N = 160</th><th>In-hospital death<br>N = 40</th><th>p</th></tr></thead><tbody><tr><td>Time since kidney transplantation (months)</td><td>40 [5–119]</td><td>37 [4–118]</td><td>54 [12–122]</td><td>0.14</td></tr><tr><td>Causes of admission (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Acute respiratory failure</td><td>55 (27.5)</td><td>42 (26.3)</td><td>13 (32.5)</td><td>0.43</td></tr><tr><td>Septic shock</td><td>53 (26.5)</td><td>42 (26.3)</td><td>11 (27.5)</td><td>0.84</td></tr><tr><td>Unplanned surgery</td><td>46 (23)</td><td>40 (25)</td><td>6 (15)</td><td>0.21</td></tr><tr><td>Cardiogenic shock</td><td>18 (9)</td><td>12 (7.5)</td><td>6 (15)</td><td>0.21</td></tr><tr><td>Acute neurological condition</td><td>12 (6)</td><td>9 (5.6)</td><td>3 (7.5)</td><td>0.71</td></tr><tr><td>Acute kidney injury</td><td>10 (5)</td><td>10 (6.3)</td><td>0 (0)</td><td>0.22</td></tr><tr><td>Others</td><td>6 (3)</td><td>5 (3.1)</td><td>1 (2.5)</td><td>1.00</td></tr><tr><td>Sepsis at the admission (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>114 (57)</td><td>89 (55.6)</td><td>25 (63)</td><td>0.48</td></tr><tr><td>Lung</td><td>57 (50)</td><td>47 (52.9)</td><td>10 (40)</td><td>0.70</td></tr><tr><td>Urinary</td><td>26 (22.8)</td><td>23 (25.8)</td><td>3 (7.5)</td><td>0.30</td></tr><tr><td>Peritonitis</td><td>24 (21)</td><td>14 (15.7)</td><td>10 (25)</td><td>0.01</td></tr><tr><td>Others</td><td>7 (6.1)</td><td>5 (5.1)</td><td>2 (1.4)</td><td>0.64</td></tr><tr><td>Organ failures (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>SOFA score</td><td>6 [4–8]</td><td>6 [4–8]</td><td>8 [7–10]</td><td>&lt; 0.001</td></tr><tr><td>SAPS2 score</td><td>50 [39–63]</td><td>48 [37–59]</td><td>67 [57–77]</td><td>&lt; 0.001</td></tr><tr><td>Acute kidney injury (KDIGO)</td><td></td><td></td><td></td><td></td></tr><tr><td>stage 1</td><td>49 (24.5)</td><td>42 (26.3)</td><td>7 (17.5)</td><td></td></tr><tr><td>stage 2</td><td>8 (4)</td><td>6 (3.8)</td><td>2 (5)</td><td></td></tr><tr><td>stage 3</td><td>113 (56.5)</td><td>86 (53.8)</td><td>27 (67.5)</td><td>0.008</td></tr><tr><td>Renal replacement therapy</td><td>103 (51.5)</td><td>76 (47.5)</td><td>27 (67.5)</td><td>0.03</td></tr><tr><td>Mechanical ventilation</td><td>107 (53.5)</td><td>78 (48.8)</td><td>29 (72.5)</td><td>0.008</td></tr><tr><td>Vasopressive drugs</td><td>97 (48.5)</td><td>68 (42.5)</td><td>29 (72.5)</td><td>0.001</td></tr><tr><td>Normalized prothrombin time &lt; 50%</td><td>11 (5.5)</td><td>5 (3.1)</td><td>6 (15)</td><td>0.01</td></tr><tr><td>RBC transfusion</td><td>142 (71)</td><td>109 (68.1)</td><td>33 (82.5)</td><td>0.08</td></tr><tr><td>Immunosuppressive regimen (n, %)</td><td></td><td></td><td></td><td></td></tr><tr><td>No change</td><td>45 (22.5)</td><td>45 (28.1)</td><td>0 (0)</td><td>0.02</td></tr><tr><td>Increased dose of steroids</td><td>136 (68)</td><td>100 (62.5)</td><td>36 (90)</td><td>0.2</td></tr><tr><td>Withdrawal of CNI</td><td>40 (20)</td><td>25 (15.6)</td><td>15 (37.5)</td><td>0.004</td></tr><tr><td>Withdrawal of antimetabolites</td><td>61 (30)</td><td>48 (30)</td><td>13 (32.5)</td><td>0.85</td></tr></tbody></table>

## Predictive factors of in-hospital mortality

Of the 200 patients, 25 (12.5%), 40 (20%) and 45 (22.5%) died in the ICU, the hospital, or before day-90, respectively. After a median follow-up of 19 months [IQR 3–45], median survival was not reached and survival at month 80 was estimated at 60% (Fig. 2). Main causes of death in the ICU were sepsis in 16 patients, cardiogenic shock in 4, cerebrovascular stroke in 2, cancers in 2, and fulminant hepatitis in 1.

By univariate analysis, predictive factors of in-hospital death were the following (Tables 1 and 2): history of peripheral arterial disease, immunosuppressive regimen

without antimetabolites at admission, high gravity scores at day 1, organ failure (mechanical ventilation; vasopressive drugs; RRT; normalized prothrombin time < 50% at admission), and withdrawal of CNI in the ICU. In patients with available data, a history of positive EBV viremia or BK viruria was also predictive of death in hospital.

By multivariate analysis, SAPS2 score (OR 1.06, IC<sub>95%</sub> [1.03–1.08], *p* < 0.0001) and CNI withdrawal in ICU (OR 2.65, IC<sub>95%</sub> [1.11–6.32], *p* = 0.027) were the only predictive factors of death during the hospital stay. When the analysis was conducted in the sub-group of patients with
<figure><img src="image_4.png" /></figure>

available virology data (n = 127), the two factors that in-
dependently predicted the risk of death in hospital were
the gravity SAPS2 score at admission (OR 1.07, IC95%
[1.03–1.11], *p* = 0.001) and a positive EBV viremia in the
6 months preceding the admission (OR 4.35, IC95%
[1.52–12.5], *p* = 0.006).

Renal graft outcome

As a secondary objective, we characterized the risk to
develop AKI to CKD transition. Graft survival is shown
in Fig. 3a. Median graft survival was 10 months. To bet-
ter characterize the renal outcome and progression from
AKI toward CKD in KTR admitted to the ICU, we stud-
ied the sub-group of patients with stable renal function
at admission (i.e. admitted more than 1 month after the
renal transplantation) and still alive 6 months after the
admission to the ICU. In these 113 patients, median
eGFR at month 6 was 35 mL/min/1.73 m² [IQR 11–55],
compared to 44 mL/min/1.73m² [IQR 27–61] before

hospitalization in the ICU (p = 0.002). A progression of
at least one stage in the CKD KDIGO classification was
observed in 34 (30.1%) and 51 (45.1%) patients at 1 and
6 months, respectively (Fig. 3b). Staging of the CKD be-
fore the admission (stage 4–5, 58% vs. stage 1–3 28.1%,
p = 0.006) and the severity of AKI (stage 3 55.4% vs.
stage 0–2 34.2%, p = 0.04) were significantly associated
with a progression of the CKD stage at month 6.

Immunological outcomes

Among the 119 patients with anti-HLA immuno-
logical status available before and 6 months after the
admission to the ICU, 18 (15.1%) developed anti-HLA
antibodies after the ICU stay, including 11 with
donor-specific antibodies (DSA; 9.2%). Among these
18 patients, 6 had no detectable anti-HLA antibodies
before admission, 7 had anti-HLA antibodies, and 5
had DSA. Two patients had an active ABMR, and
two others stopped immunosuppressive drugs before
admission. During the stay in ICU, 13 patients re-
ceived RBC transfusions, and 4 needed transplant re-
moval (urinoma, renal vein thrombosis, graft
intolerance syndrome or emphysematous pyeloneph-
ritis). Two additional patients benefitted from trans-
plant removal in the next 6 months. Patients that did
not acquire HLA immunization during ICU had a
significantly poorer renal prognosis (62 vs. 90% func-
tional graft at 12 months; p = 0.06).

Discussion

In this study, we reported the predictive factors of in-
hospital mortality in a large cohort of 200 KTR ad-
mitted to the ICU. Risk of transition from AKI to
CKD, and anti-HLA immunization, were also re-
ported. Notwithstanding the monocentric status of
this study and the inherent biases of ICU admission
and management, our ICU is the referral center for
KTR requiring admission to the ICU (except for
neurological and cardiac surgery) in a large region in
the south-west of France (~2.3 million inhabitants).
Thus, the studied cohort accurately described the
causes of KTR admission to the ICU, characteristics
at presentation, and specific outcomes.

Over the study period, the estimated incidence of ICU
admission (7.7%) was closed to the one reported in re-
cent studies (4.5 to 10.2%) [2–5, 7]. Median time from
renal transplantation to ICU admission was longer (41
months vs. 4.4 to 25.2 months [1–5, 7–9, 18]) except in
one study [19]. The mortality rate was not influenced by
the timing of ICU admission, thus confirming survival in
the ICU is not associated to the characteristics of the
transplantation [2, 5, 20, 21].

Our series confirms that ARF and sepsis are the main
causes of ICU admission in KTR [1, 3–6, 9, 18, 20, 21].
<figure><img src="image_5.png" /></figure>

Lung infection was the main cause of ARF with acute pulmonary edema ranking second, pointing to the high risk of sodium overload in KTR (steroids, underlying CKD or heart disease). Multiple causes of ARF were identified in 11% of patients, confirming that management of KTR should follow a dedicated workup (transplantation history, immunosuppressive regimens, underlying chronic disorders) [10, 22]. Here, 14.5% of the individuals admitted to the ICU for infection had at least two concomitant infections.

Contrasting to older studies [5, 6, 21], the mortality rate in our study (i.e., 20% in the hospital and 26.5% 6 months after the ICU stay) was lower than in unselected critically ill patients [23]. Of note, severity scores at the admission predicted mortality in hospital between 15 and 50% [24, 25]. This mortality rate, close to the one observed in two recent French studies, suggests that usual gravity scores may be undermined in KTR. Management of KTR in ICUs specialized in the field of transplantation and immunocompromised patients may also improves the outcome of these patients [3, 4]. Prognosis of solid organ transplant recipients with sepsis may be better than expected in unselected critically ill patients after adjustments on gravity scores, causes of admission, and number of organ failures [26]. Immunosuppressive drugs with reduction of the risk of hyper-inflammation state and subsequent refractory acute respiratory distress syndrome or shock may account for this discrepancy.

Interestingly, we showed for the first time that EBV replication in the months preceding the admission of KTR to the ICU was associated with a poorer outcome. EBV replication per se is not associated with a poorer outcome in unselected KTR [27]. However, chronic EBV replication may be the trigger or the consequence of T-cell exhaustion, an acquired immune paralysis observed in patients with chronic exposure to viral or cancer

antigens [28], associated with an increased risk of mortality or nosocomial infections in patient admitted in ICU for sepsis, burns or traumas [29]. Chronic EBV replication may thus be a surrogate marker of frailty associated with a higher risk of mortality in ICU. Further studies are warranted to confirm that EBV status at the time of admission in ICU may help to identify patients at high risk of death.

In our cohort, AKI was highly prevalent (81.5%) and 51.5% of patients required RRT, contrasting with unselected critically ill patients (19 to 57% and 4.5 to 13.5%, respectively) [30, 31]. In addition to known risk factors for the development of AKI in the ICU, the use of calcineurin inhibitors, the previous episodes of AKI and the underlying CKD, all increased the risk of AKI in KTR with acute condition [13, 14, 32, 33]. Moreover, we showed that progression of CKD after admission to the ICU is highly prevalent (30% at 1 month and 45% at 6 months in our series, compared to 12–20% at 3 months in older studies [3, 4, 11] and was well predicted by the basal CKD stage and the severity of the AKI. The high incidence of transition toward CKD in KTR, which continues beyond month 3, also points to additional and persistent renal injuries specifically encountered in this population. Whether specific management in ICU regarding the immunosuppressive regimen [10], prophylaxis of cytomegalovirus proliferation [34], and RBC transfusion policies [15] may help to overcome the risk to develop anti-HLA antibodies after admission to the ICU (15.1% of survivors in our series) in solid organ transplantation recipients need to be tested in prospective trials, because our retrospective study cannot lead to specific recommendations.

Several limitations may be underlined. First, the retrospective design of the study prevented the assessment of EBV viremia in all the KTR admitted to the ICU during
the inclusion period. Nonetheless, this parameter was
available in a significant number of patients (n = 127).
Second, management of immunosuppressive regimen
may vary during the ICU stay according to the patient
status. Here, we discriminate patients according the
maintain or the withdrawal of immunosuppressive drugs
but how long patients had reduced immunosuppressive
regimen was unknown in most patients. This limitation
may also have modulated the risk of HLA immunization.
Last, we reported here a large cohort of KTR admitted
to the ICU in order to describe the different clinical sce-
narios that can lead to ICU admission in these patients.
However, the various causes of admission introduced
heterogeneity in term of both mortality and risk of
immunization that need to be taken in account. It also
prevents to draw firm conclusions about the optimal im-
munosuppressive management.

In summary, we showed that survival of KTR follow-
ing admission to the ICU is predicted by the severity of
the acute condition but also by viral replication (i.e., the
underlying immune defense status). ICU admission is as-
sociated with a very high risk of AKI and progression to-
ward CKD, as well as a significant risk of HLA
immunization.

Abbreviations

ABMR: Antibodies-Mediated Rejection; AKI: Acute Kidney Injury; CKD: Chronic Kidney Disease; CMV: Cytomegalovirus; CNI : Calcineurin Inhibitors;
DSA: Donor-Specific Antibodies; EBV: Epstein Barr Virus; GFR: Glomerular Filtration Rate; HLA: Human Leukocytes Antigens; ICU: Intensive Care Unit;
KTR: Kidney Transplant Recipients; RBC: Red Blood Cells; RRT: Renal Replacement Therapy; TCMR: T-Cells Mediated Rejection

Acknowledgments

None

Authors’ contributions

SF and DG designed the study; SF, DG and NKD analyzed the patient data; SF, NK and DG wrote the manuscript; SF, LL, MBN, OC, NK, ADB, DG, ALH, OR and LE followed patients; NC preformed immunological analyses. All authors read and approved the final manuscript.

Funding

None

Availability of data and materials

The datasets used and/or analyzed during the current study are available
from the corresponding author on reasonable request.

Ethics approval and consent to participate

This retrospective observational study was conducted according to our
Institutional Review Board instructions (University Hospital of Toulouse –
Office of Research, Development and Innovation).

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Author details

¹Département de Néphrologie et Transplantation d'organes, Unité de Réanimation, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, 1, avenue Jean Poulhes, 31059 Toulouse, France. ²Laboratoire

d'Immunologie, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, F-31000 Toulouse, France. ³Université Paul Sabatier, Toulouse III, F-31000 Toulouse, France. ⁴Institut National de la Santé et de la Recherche Médicale, U1043, IFR-BMT, CHU Purpan, Toulouse, France. ⁵Institut National de la Santé et de la Recherche Médicale, Institut des Maladies Métaboliques et Cardiovasculaires, U1048 (Renal Fibrosis lab), and French Intensive care Renal Network (F.I.R.N), Toulouse, France.

Received: 25 January 2019 Accepted: 5 July 2019

Published online: 17 July 2019

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