# Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

Dominique Bertrand, Julien Dehay, Julien Ott, Rebecca Sberro, Charlotte Brunelle, Nassim Kamar, Charlotte Colosio, Valérie Châtelet, Laetitia Albano, Sophie Girerd, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Dominique Bertrand, Julien Dehay, Julien Ott, Rebecca Sberro, Charlotte Brunelle, et al. Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study. Transplant International, 2017, 30 (3), pp.256-265. 10.1111/tri.12923. inserm-02454047

HAL Id: inserm-02454047

https://inserm.hal.science/inserm-02454047

Submitted on 27 May 2024

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# Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

Dominique Bertrand, Julien Dehay, Julien Ott, Rebecca Sberro, Charlotte Brunelle, Nassim Kamar, Charlotte Colosio, Valérie Châtelet, Laetitia Albano, Sophie Girerd, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Dominique Bertrand, Julien Dehay, Julien Ott, Rebecca Sberro, Charlotte Brunelle, et al. Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study. Transplant International, 2017, 30 (3), pp.256-265. 10.1111/tri.12923. inserm-02454047

HAL Id: inserm-02454047

https://inserm.hal.science/inserm-02454047v1

Submitted on 27 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
ORIGINAL ARTICLE

# Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

Dominique Bertrand¹, Julien Dehay¹, Julien Ott², Rebecca Sberro³, Charlotte Brunelle⁴, Nassim Kamar⁵,
Charlotte Colosio⁶, Valérie Chatelet⁷, Laetitia Albano⁸, Sophie Girerd⁹, Vincent Audard¹⁰,
Christelle Barbet¹¹, Jacques Dantal¹², Didier Ducloux¹³, Antoine Durrbach¹⁴, Valérie Garrigue¹⁵,
Marc Hazzan¹⁶, Anne-Elisabeth Heng¹⁷, Christophe Mariat¹⁸, Pierre Merville¹⁹, Jean-Philippe Rerolle²⁰,
Bruno Moulin² & Dominique Guerrot¹

1 Nephrology Dialysis Transplantation,
Centre Hospitalier Universitaire de Rouen,
Rouen, Haute-Normandie, France

2 Department of Nephrology and Renal
Transplantation, Hopitaux Universitaires de
Strasbourg, Strasbourg, Alsace, France

3 Service de Transplantation et Unité de
soins intensifs, Hôpital Necker, Paris, France

4 Nephrology and Transplantation, CHU
Grenoble, Grenoble, France

5 Department of Nephrology and Organ
Transplantation Toulouse, CHU Rangueil,
Haute Garonne, France

6 Nephrology Dialysis Transplantation, CHU
Reims, Reims, France

7 Nephrology Dialysis Transplantation, CHU
Caen, Caen, France

8 Nephrology-Dialysis-Transplantation, Nice
University Hospital, Nice, PACA, France

9 Nephrology Dialysis Transplantation, CHU
Nancy, Nancy, France

10 Hôpital Henri Mondor Creteil, Île-de-
France, France

11 Nephrology Dialysis Transplantation,
CHU Tours, Tours, France

12 Nephrology Dialysis Transplantation,
Centre Hospitalier Universitaire, Nantes,
France

13 Department of Nephrology, CHU
Besançon, Besançon, France

14 Nephrology and Transplantation,
Hôpital Bicêtre, Paris, France

15 Nephrology Transplantation, CHU
Montpellier, Montpellier, France

16 Service de Néphrologie, CHRU Lille,
Lille, France

17 Service de Néphrologie, Hôpital Gabriel
Montpied, CHU Clermont-Ferrand,
Clermont-Ferrand, France

18 Nephrology Dialysis Transplantation,
CHU Saint Etienne, Saint Etienne, France

19 Transplantation Rénale, CHU Bordeaux,
Bordeaux, France

20 Nephrology Transplantation, CHU
Limoges, Limoges, France

SUMMARY

Kidney transplantation is one of the therapeutic options for end-stage renal disease (ESRD) in systemic sclerosis (SS). Current evidence demonstrates poorer patient and graft survival after transplantation in SS than in other primary kidney diseases. All the patients presenting ESRD associated with SS who had received a kidney allograft between 1987 and 2013 were systematically included from 20 French kidney transplantation centres. Thirty-four patients received 36 kidney transplants during the study period. Initial kidney disease was scleroderma renal crisis in 76.4%. Extrarenal involvement of SS was generally stable, except cardiac and gastrointestinal involvements, which worsened after kidney transplantation in 45% and 26% of cases, respectively. Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post-transplant, respectively. Pulmonary involvement of SS was an independent risk factor of death after transplantation. Death-censored graft survival was 97.2% after 1 and 3 years, and 92.8% after 5 years. Recurrence of scleroderma renal crisis was diagnosed in three cases. In our study, patient and graft survivals after kidney transplantation can be considered as excellent. On this basis, we propose that in the absence of extrarenal contraindication, SS patients presenting with ESRD should be considered for kidney transplantation.

Transplant International 2017; 30: 256-265

Key words

graft and patient survival, kidney transplantation, systemic sclerosis

Received: 23 August 2016; Revision requested: 30 September 2016; Accepted: 12 December 2016

Correspondence

Dominique Bertrand MD, Nephrology Department, Rouen University Hospital, 1 rue de Germont,
76031 Rouen, France.

Tel.: +33 2 32 88 90 02;

fax: +33 2 32 88 91 15;

e-mail: dominique.bertrand@chu-rouen.fr
ORIGINAL ARTICLE

# Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

Dominique Bertrand<fnref n="1" />, Julien Dehay<fnref n="1" />, Julien Ott<fnref n="2" />, Rebecca Sberro<fnref n="3" />, Charlotte Brunelle<fnref n="4" />, Nassim Kamar<fnref n="5" />,
Charlotte Colosio<fnref n="6" />, Valérie Chatelet<fnref n="7" />, Laetitia Albano<fnref n="8" />, Sophie Girerd<fnref n="9" />, Vincent Audard<fnref n="10" />,
Christelle Barbet<fnref n="11" />, Jacques Dantal<fnref n="12" />, Didier Ducloux<fnref n="13" />, Antoine Durrbach<fnref n="14" />, Valérie Garrigue<fnref n="15" />,
Marc Hazzan<fnref n="16" />, Anne-Elisabeth Heng<fnref n="17" />, Christophe Mariat<fnref n="18" />, Pierre Merville<fnref n="19" />, Jean-Philippe Rerolle<fnref n="20" />,
Bruno Moulin<fnref n="2" /> & Dominique Guerrot<fnref n="1" />

SUMMARY

Kidney transplantation is one of the therapeutic options for end-stage renal disease (ESRD) in systemic sclerosis (SS). Current evidence demonstrates poorer patient and graft survival after transplantation in SS than in other primary kidney diseases. All the patients presenting ESRD associated with SS who had received a kidney allograft between 1987 and 2013 were systematically included from 20 French kidney transplantation centres. Thirty-four patients received 36 kidney transplants during the study period. Initial kidney disease was scleroderma renal crisis in 76.4%. Extrarenal involvement of SS was generally stable, except cardiac and gastrointestinal involvements, which worsened after kidney transplantation in 45% and 26% of cases, respectively. Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post-transplant, respectively. Pulmonary involvement of SS was an independent risk factor of death after transplantation. Death-censored graft survival was 97.2% after 1 and 3 years, and 92.8% after 5 years. Recurrence of scleroderma renal crisis was diagnosed in three cases. In our study, patient and graft survivals after kidney transplantation can be considered as excellent. On this basis, we propose that in the absence of extrarenal contraindication, SS patients presenting with ESRD should be considered for kidney transplantation.

Transplant International 2017; 30: 256-265

Key words

graft and patient survival, kidney transplantation, systemic sclerosis

Received: 23 August 2016; Revision requested: 30 September 2016; Accepted: 12 December 2016

Correspondence

Dominique Bertrand MD, Nephrology Department, Rouen University Hospital, 1 rue de Germont,
76031 Rouen, France.

Tel.: +33 2 32 88 90 02;

fax: +33 2 32 88 91 15;

e-mail: dominique.bertrand@chu-rouen.fr

<footnote n="1">1 Nephrology Dialysis Transplantation,
Centre Hospitalier Universitaire de Rouen,
Rouen, Haute-Normandie, France</footnote>

<footnote n="2">2 Department of Nephrology and Renal
Transplantation, Hopitaux Universitaires de
Strasbourg, Strasbourg, Alsace, France</footnote>

<footnote n="3">3 Service de Transplantation et Unité de
soins intensifs, Hôpital Necker, Paris, France</footnote>

<footnote n="4">4 Nephrology and Transplantation, CHU
Grenoble, Grenoble, France</footnote>

<footnote n="5">5 Department of Nephrology and Organ
Transplantation Toulouse, CHU Rangueil,
Haute Garonne, France</footnote>

<footnote n="6">6 Nephrology Dialysis Transplantation, CHU
Reims, Reims, France</footnote>

<footnote n="7">7 Nephrology Dialysis Transplantation, CHU
Caen, Caen, France</footnote>

<footnote n="8">8 Nephrology-Dialysis-Transplantation, Nice
University Hospital, Nice, PACA, France</footnote>

<footnote n="9">9 Nephrology Dialysis Transplantation, CHU
Nancy, Nancy, France</footnote>

<footnote n="10">10 Hopital Henri Mondor Creteil, Île-de-
France, France</footnote>

<footnote n="11">11 Nephrology Dialysis Transplantation,
CHU Tours, Tours, France</footnote>

<footnote n="12">12 Nephrology Dialysis Transplantation,
Centre Hospitalier Universitaire, Nantes,
France</footnote>

<footnote n="13">13 Department of Nephrology, CHU
Besançon, Besançon, France</footnote>

<footnote n="14">14 Nephrology and Transplantation,
Hôpital Bicêtre, Paris, France</footnote>

<footnote n="15">15 Nephrology Transplantation, CHU
Montpellier, Montpellier, France</footnote>

<footnote n="16">16 Service de Néphrologie, CHRU Lille,
Lille, France</footnote>

<footnote n="17">17 Service de Néphrologie, Hôpital Gabriel
Montpied, CHU Clermont-Ferrand,
Clermont-Ferrand, France</footnote>

<footnote n="18">18 Nephrology Dialysis Transplantation,
CHU Saint Etienne, Saint Etienne, France</footnote>

<footnote n="19">19 Transplantation Rénale, CHU Bordeaux,
Bordeaux, France</footnote>

<footnote n="20">20 Nephrology Transplantation, CHU
Limoges, Limoges, France</footnote>
Introduction

Systemic sclerosis (SS) is a connective tissue disorder
involving multiple organs and characterized by excessive
collagen deposition, autoimmunity, vascular hyperreac-
tivity and obliterative microvascular phenomena [1].
Vascular injury manifests as Raynaud's phenomenon
(RP), digital ischaemia, pulmonary arterial hypertension
and scleroderma renal crisis (SRC) [2]. Renal involve-
ment in SS most frequently presents as rapidly progres-
sive renal failure with malignant hypertension and
oliguria, known as SRC. SRC is associated with limited
skin involvement in 1% SS patients, and with diffuse skin
involvement in 5% cases. The introduction of angioten-
sin-converting enzyme (ACE) inhibitors has tempered
the poor renal and overall prognosis associated with SRC,
and often leads to reversal of the syndrome [3–5]. How-
ever, up to 50% of patients still require long-term dialy-
sis, and in this situation, kidney transplantation may be a
valuable therapeutic option [6]. Nevertheless, data avail-
able show poorer patient and graft survival than in other
primary renal diseases [7]. Here, we report an observa-
tional study on 34 patients with SS who underwent renal
transplantation. We report patient and graft outcomes,
and, for the first time, evolution of extrarenal involve-
ment after transplantation.

Materials and methods

This retrospective multicentre nationwide study was
performed in all the 20 kidney transplantation centres
in France. A questionnaire was sent to each depart-
ment in order to ensure a systematic data collection
for every patient with systemic sclerosis having
received a kidney transplant between 1987 and 2013.
The number of patients with SS transplanted during
this period was confirmed with the national database
of kidney transplantation Cristal. Diagnosis of SS was
performed in each centre according to the diagnostic
criteria used in the concerned period. During the
inclusion period, from 1987 to 2013, four classification
criteria were successively used [8–11]. Scleroderma
renal crisis (SRC) was defined by a severe arterial
hypertension associated with microangiopathic haemo-
lytic anaemia, thrombocytopenia and accelerated olig-
uric renal failure, confirmed or not by a renal biopsy,
according the diagnostic criteria reported by Steen in
2003 [12,13].

The medical charts and demographics were recorded,
including age, gender, weight, comorbidities, type of
dialysis before transplantation, cause of the renal

disease, kidney histology, history of scleroderma, HLA
immunization and date of transplantation. Data regard-
ing the renal transplantation and outcomes were col-
lected, including patient and graft survival, evolution of
scleroderma after transplantation, immunosuppressive
therapy, acute rejection episodes, causes of graft loss
and patient death.

Extrarenal involvement of systemic sclerosis was
defined as following:

1 Cardiac involvement: presence or history of myocardopathy and/or pericarditis

2 Pulmonary involvement: presence or history of inter-
stitial and/or pulmonary fibrosis and/or pulmonary
artery hypertension

3 Gastrointestinal involvement: presence or history of reflux, oesophagitis, gastritis, pancreatitis, oesophageal sclerosis or dysmotility syndrome.

4 Rheumatologic involvement: presence or history of polyarthritis or tendonitis

5 Cutaneous involvement: presence or history of cutaneous sclerosis and/or Raynaud phenomenon and/or digital ischaemia.

Clinical records were specifically reviewed for the
evolution of lesions related to SS after kidney transplan-
tation. Worsening, improvement or stability of extrare-
nal involvement was considered on the basis of the
available data from each centre.

Quantitative data were presented as mean (SD) or
median (range) when data were not normally dis-
tributed. Qualitative data were presented as percent-
ages. Survival data were assessed by Kaplan-Meier
analysis. Cox regression analysis was used to evaluate
potential risk factors for patient survival. All factors
with *P* < 0.1 in the univariate analysis were included
in the multivariate model. A *P* value <0.05 was consid-
ered statistically significant. All analyses were per-
formed using STATVIEW version 5.0 (SAS Institute, Cary,
NC, USA).

Results

Thirty-four patients (36 kidney transplantations) were included. Two kidney allografts came from living donors. The patients' characteristics at the time of transplantation are described in Table 1. Characteristics of extrarenal involvement are summarized in Table 2. Cardiac involvement was associated in 11 of 34 patients (32.3%), whereas pulmonary involvement was present in 13 of 34 recipients (38.2%). Gastrointestinal and rheumatic involvement was associated, respectively, in 53% and 20.6% cases. All the patients demonstrated
Introduction

Systemic sclerosis (SS) is a connective tissue disorder
involving multiple organs and characterized by excessive
collagen deposition, autoimmunity, vascular hyperreac-
tivity and obliterative microvascular phenomena [1].
Vascular injury manifests as Raynaud's phenomenon
(RP), digital ischaemia, pulmonary arterial hypertension
and scleroderma renal crisis (SRC) [2]. Renal involve-
ment in SS most frequently presents as rapidly progres-
sive renal failure with malignant hypertension and
oliguria, known as SRC. SRC is associated with limited
skin involvement in 1% SS patients, and with diffuse skin
involvement in 5% cases. The introduction of angioten-
sin-converting enzyme (ACE) inhibitors has tempered
the poor renal and overall prognosis associated with SRC,
and often leads to reversal of the syndrome [3-5]. How-
ever, up to 50% of patients still require long-term dialy-
sis, and in this situation, kidney transplantation may be a
valuable therapeutic option [6]. Nevertheless, data avail-
able show poorer patient and graft survival than in other
primary renal diseases [7]. Here, we report an observa-
tional study on 34 patients with SS who underwent renal
transplantation. We report patient and graft outcomes,
and, for the first time, evolution of extrarenal involve-
ment after transplantation.

Materials and methods

This retrospective multicentre nationwide study was
performed in all the 20 kidney transplantation centres
in France. A questionnaire was sent to each depart-
ment in order to ensure a systematic data collection
for every patient with systemic sclerosis having
received a kidney transplant between 1987 and 2013.
The number of patients with SS transplanted during
this period was confirmed with the national database
of kidney transplantation Cristal. Diagnosis of SS was
performed in each centre according to the diagnostic
criteria used in the concerned period. During the
inclusion period, from 1987 to 2013, four classification
criteria were successively used [8–11]. Scleroderma
renal crisis (SRC) was defined by a severe arterial
hypertension associated with microangiopathic haemo-
lytic anaemia, thrombocytopenia and accelerated olig-
uric renal failure, confirmed or not by a renal biopsy,
according the diagnostic criteria reported by Steen in
2003 [12,13].

The medical charts and demographics were recorded,
including age, gender, weight, comorbidities, type of
dialysis before transplantation, cause of the renal

disease, kidney histology, history of scleroderma, HLA
immunization and date of transplantation. Data regard-
ing the renal transplantation and outcomes were col-
lected, including patient and graft survival, evolution of
scleroderma after transplantation, immunosuppressive
therapy, acute rejection episodes, causes of graft loss
and patient death.

Extrarenal involvement of systemic sclerosis was
defined as following:

1 Cardiac involvement: presence or history of myocardopathy and/or pericarditis

2 Pulmonary involvement: presence or history of inter-
stitial and/or pulmonary fibrosis and/or pulmonary
artery hypertension

3 Gastrointestinal involvement: presence or history of reflux, oesophagitis, gastritis, pancreatitis, oesophageal sclerosis or dysmotility syndrome.

4 Rheumatologic involvement: presence or history of polyarthritis or tendonitis

5 Cutaneous involvement: presence or history of cutaneous sclerosis and/or Raynaud phenomenon and/or digital ischaemia.

Clinical records were specifically reviewed for the
evolution of lesions related to SS after kidney transplan-
tation. Worsening, improvement or stability of extrare-
nal involvement was considered on the basis of the
available data from each centre.

Quantitative data were presented as mean (SD) or
median (range) when data were not normally dis-
tributed. Qualitative data were presented as percent-
ages. Survival data were assessed by Kaplan-Meier
analysis. Cox regression analysis was used to evaluate
potential risk factors for patient survival. All factors
with *P* < 0.1 in the univariate analysis were included
in the multivariate model. A *P* value <0.05 was consid-
ered statistically significant. All analyses were per-
formed using STATVIEW version 5.0 (SAS Institute, Cary,
NC, USA).

Results

Thirty-four patients (36 kidney transplantations) were included. Two kidney allografts came from living donors. The patients' characteristics at the time of transplantation are described in Table 1. Characteristics of extrarenal involvement are summarized in Table 2. Cardiac involvement was associated in 11 of 34 patients (32.3%), whereas pulmonary involvement was present in 13 of 34 recipients (38.2%). Gastrointestinal and rheumatic involvement was associated, respectively, in 53% and 20.6% cases. All the patients demonstrated
cutaneous involvement. There were no specific con-
traindications to transplantation regarding disease activ-
ity, serological markers or active extrarenal
manifestations of SS. Nevertheless, in the case of too
advanced cardiac or pulmonary involvement, kidney
transplantation was not considered, but these criteria
varied between centres.

The initial renal disease was scleroderma renal crisis in 76.4% (26/34) patients (Table 1). A biopsy was carried out in 18 of 34 patients. It showed evidence of scleroderma renal crisis in 13 of 18 patients. Three patients developed a biopsy-proven MPO ANCA vasculitis (8.8%). The two remaining biopsies showed chronic vascular changes with fibrosis and tubular atrophy. Systemic sclerosis and kidney disease were simultaneously diagnosed in 16 patients, and in 62% (10/16) with a diagnosis of SRC. Renal failure appeared after a mean period of time of 24 months (0–283) after systemic sclerosis had been diagnosed. At the time of renal diagnosis, 15 of 34 patients (44.1%) required dialysis immediately. Twenty-eight patients of 34 underwent haemodialysis (82%), while six (18%) were on peritoneal dialysis. In three of 34 patients, dialysis was transiently withdrawn because of a spontaneous recovery of renal function, but all the patients were on dialysis supportive treatment at the time of transplantation.

Kidney transplantation was performed 45 months (5–153) after the initiation of dialysis, and 25 months (3–141) after registration on the waiting list (Table 1). It was the first transplantation in 34 of 36 cases. Only one of 36 grafts (2.7%) had a primary nonfunction. Five (13.9%) presented a delayed graft function, and five (13.9%) presented an early episode of rejection. No patient died immediately after surgery. Induction of immunosuppressive therapy included antilymphocyte serum in 17 of 36 grafts (47.2%), anti-IL-2 receptor antibodies in 14 (38.9%), calcineurin inhibitors in 33 (91.7%) and mycophenolate mofetil in 28 (77.8%). Induction also included steroids in 32 of 36 (88.9%) cases, and high dose (60 mg prednisolone to 500 mg methylprednisolone) was given in 27 cases (84%). Steroids were stopped in 11 of 30 cases (36.7%), after an average period of time of 6.4 months (1.0–12.5). Immunosuppressive therapy is summarized in Table 3.

Renin–angiotensin–aldosterone system blockers were largely prescribed (27/36, 75%), introduced after a mean period of time of 10.1 months after kidney transplantation.

We observed seven graft losses after a mean
82.2 months (1.5–167). Four were secondary to chronic

<table><caption>**Table 1.** Characteristics of patients at transplantation.</caption>
  <tbody>
    <tr>
      <td>Variable</td>
      <td></td>
    </tr>
    <tr>
      <td>Age (year)</td>
      <td>52.9 (27.7–75.5)</td>
    </tr>
    <tr>
      <td>Sex ratio M/F</td>
      <td>11/23</td>
    </tr>
    <tr>
      <td>BMI (kg/m<sup>2</sup>)</td>
      <td>21.5 (13.0–27.8)</td>
    </tr>
    <tr>
      <td>Diabetes – n (%)</td>
      <td>1 (2.8)</td>
    </tr>
    <tr>
      <td>Hypertension – n (%)</td>
      <td>23 (63.9)</td>
    </tr>
    <tr>
      <td>Active smoking – n (%)</td>
      <td>12 (33.3)</td>
    </tr>
    <tr>
      <td>Coronary artery disease – n (%)</td>
      <td>0 (0)</td>
    </tr>
    <tr>
      <td>Initial renal disease</td>
      <td></td>
    </tr>
    <tr>
      <td>Scleroderma renal crisis – n (%)</td>
      <td>26 (76.5)</td>
    </tr>
    <tr>
      <td>ANCA vasculitis – n (%)</td>
      <td>3 (8.8)</td>
    </tr>
    <tr>
      <td>Other – n (%)</td>
      <td>5 (14.7)</td>
    </tr>
    <tr>
      <td>Extrarenal involvement of scleroderma before transplantation</td>
      <td></td>
    </tr>
    <tr>
      <td>Pulmonary – n (%)</td>
      <td>13 (38.2)</td>
    </tr>
    <tr>
      <td>Cutaneous – n (%)</td>
      <td>34 (100)</td>
    </tr>
    <tr>
      <td>Cardiac – n (%)</td>
      <td>11 (32.4)</td>
    </tr>
    <tr>
      <td>Rheumatologic – n (%)</td>
      <td>7 (20.6)</td>
    </tr>
    <tr>
      <td>Digestive – n (%)</td>
      <td>19 (55.8)</td>
    </tr>
    <tr>
      <td>Time frame</td>
      <td></td>
    </tr>
    <tr>
      <td>Between RRT and registration on waiting list (months)</td>
      <td>25 (3–141)</td>
    </tr>
    <tr>
      <td>Between RRT and RTx (months)</td>
      <td>45 (5–153)</td>
    </tr>
  </tbody>
</table>

RRT, renal replacement therapy; RTx, renal transplantation.

antibody-mediated rejection (positive for donor-specific antibody), one to scleroderma renal crisis recurrence, one to a tumour of the graft (renal cell carcinoma) and one was due to an infectious disease (urinary septic shock). Death-censored graft survival was 97.2% after 1 and 3 years and 92.8% after 5 years (Fig. 1).

Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post-transplant, respectively. One patient died due to extrarenal involvement of systemic sclerosis, two to infectious diseases, three to cardiovascular disease and one to cancer. Death occurred after an average of 61.7 months (16.5–150.7 months) (Fig. 2).

Three cases of scleroderma renal crisis recurrence were suspected clinically, ascertained by a renal graft biopsy: the first biopsy showed typical lesions of thrombotic microangiopathy, and the two others showed fibroproliferative endarteritis with ischaemic glomeruli and interstitial fibrosis. They occurred, respectively, 1, 4 and 57 months after transplantation. The characteristics of patients with disease recurrence are presented in Table 4. In the 26 patients with SRC as initial renal disease, 14 (54%) experienced a renal graft biopsy during their follow-up, after a mean of 16 months. Three biopsies demonstrated the three suspected recurrence of SRC. In the 11 other kidney biopsies performed, no vascular change
cutaneous involvement. There were no specific con-
traindications to transplantation regarding disease activ-
ity, serological markers or active extrarenal
manifestations of SS. Nevertheless, in the case of too
advanced cardiac or pulmonary involvement, kidney
transplantation was not considered, but these criteria
varied between centres.

The initial renal disease was scleroderma renal crisis in 76.4% (26/34) patients (Table 1). A biopsy was carried out in 18 of 34 patients. It showed evidence of scleroderma renal crisis in 13 of 18 patients. Three patients developed a biopsy-proven MPO ANCA vasculitis (8.8%). The two remaining biopsies showed chronic vascular changes with fibrosis and tubular atrophy. Systemic sclerosis and kidney disease were simultaneously diagnosed in 16 patients, and in 62% (10/16) with a diagnosis of SRC. Renal failure appeared after a mean period of time of 24 months (0–283) after systemic sclerosis had been diagnosed. At the time of renal diagnosis, 15 of 34 patients (44.1%) required dialysis immediately. Twenty-eight patients of 34 underwent haemodialysis (82%), while six (18%) were on peritoneal dialysis. In three of 34 patients, dialysis was transiently withdrawn because of a spontaneous recovery of renal function, but all the patients were on dialysis supportive treatment at the time of transplantation.

Kidney transplantation was performed 45 months (5–153) after the initiation of dialysis, and 25 months (3–141) after registration on the waiting list (Table 1). It was the first transplantation in 34 of 36 cases. Only one of 36 grafts (2.7%) had a primary nonfunction. Five (13.9%) presented a delayed graft function, and five (13.9%) presented an early episode of rejection. No patient died immediately after surgery. Induction of immunosuppressive therapy included antilymphocyte serum in 17 of 36 grafts (47.2%), anti-IL-2 receptor antibodies in 14 (38.9%), calcineurin inhibitors in 33 (91.7%) and mycophenolate mofetil in 28 (77.8%). Induction also included steroids in 32 of 36 (88.9%) cases, and high dose (60 mg prednisolone to 500 mg methylprednisolone) was given in 27 cases (84%). Steroids were stopped in 11 of 30 cases (36.7%), after an average period of time of 6.4 months (1.0–12.5). Immunosuppressive therapy is summarized in Table 3.

Renin–angiotensin–aldosterone system blockers were largely prescribed (27/36, 75%), introduced after a mean period of time of 10.1 months after kidney transplantation.

We observed seven graft losses after a mean
82.2 months (1.5–167). Four were secondary to chronic

<table><caption>**Table 1.** Characteristics of patients at transplantation.</caption>
  <tbody>
    <tr>
      <td>Variable</td>
      <td></td>
    </tr>
    <tr>
      <td>Age (year)</td>
      <td>52.9 (27.7–75.5)</td>
    </tr>
    <tr>
      <td>Sex ratio M/F</td>
      <td>11/23</td>
    </tr>
    <tr>
      <td>BMI (kg/m<sup>2</sup>)</td>
      <td>21.5 (13.0–27.8)</td>
    </tr>
    <tr>
      <td>Diabetes – n (%)</td>
      <td>1 (2.8)</td>
    </tr>
    <tr>
      <td>Hypertension – n (%)</td>
      <td>23 (63.9)</td>
    </tr>
    <tr>
      <td>Active smoking – n (%)</td>
      <td>12 (33.3)</td>
    </tr>
    <tr>
      <td>Coronary artery disease – n (%)</td>
      <td>0 (0)</td>
    </tr>
    <tr>
      <td>Initial renal disease</td>
      <td></td>
    </tr>
    <tr>
      <td>Scleroderma renal crisis – n (%)</td>
      <td>26 (76.5)</td>
    </tr>
    <tr>
      <td>ANCA vasculitis – n (%)</td>
      <td>3 (8.8)</td>
    </tr>
    <tr>
      <td>Other – n (%)</td>
      <td>5 (14.7)</td>
    </tr>
    <tr>
      <td>Extrarenal involvement of<br/>scleroderma before transplantation</td>
      <td></td>
    </tr>
    <tr>
      <td>Pulmonary – n (%)</td>
      <td>13 (38.2)</td>
    </tr>
    <tr>
      <td>Cutaneous – n (%)</td>
      <td>34 (100)</td>
    </tr>
    <tr>
      <td>Cardiac – n (%)</td>
      <td>11 (32.4)</td>
    </tr>
    <tr>
      <td>Rheumatologic – n (%)</td>
      <td>7 (20.6)</td>
    </tr>
    <tr>
      <td>Digestive – n (%)</td>
      <td>19 (55.8)</td>
    </tr>
    <tr>
      <td>Time frame</td>
      <td></td>
    </tr>
    <tr>
      <td>Between RRT and registration<br/>on waiting list (months)</td>
      <td>25 (3–141)</td>
    </tr>
    <tr>
      <td>Between RRT and RTx (months)</td>
      <td>45 (5–153)</td>
    </tr>
  </tbody>
</table>

RRT, renal replacement therapy; RTx, renal transplantation.

antibody-mediated rejection (positive for donor-specific antibody), one to scleroderma renal crisis recurrence, one to a tumour of the graft (renal cell carcinoma) and one was due to an infectious disease (urinary septic shock). Death-censored graft survival was 97.2% after 1 and 3 years and 92.8% after 5 years (Fig. 1).

Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post-transplant, respectively. One patient died due to extrarenal involvement of systemic sclerosis, two to infectious diseases, three to cardiovascular disease and one to cancer. Death occurred after an average of 61.7 months (16.5–150.7 months) (Fig. 2).

Three cases of scleroderma renal crisis recurrence were suspected clinically, ascertained by a renal graft biopsy: the first biopsy showed typical lesions of thrombotic microangiopathy, and the two others showed fibroproliferative endarteritis with ischaemic glomeruli and interstitial fibrosis. They occurred, respectively, 1, 4 and 57 months after transplantation. The characteristics of patients with disease recurrence are presented in Table 4. In the 26 patients with SRC as initial renal disease, 14 (54%) experienced a renal graft biopsy during their follow-up, after a mean of 16 months. Three biopsies demonstrated the three suspected recurrence of SRC. In the 11 other kidney biopsies performed, no vascular change
<table><caption>**Table 2.** Characteristics of extrarenal involvements and evolution after kidney transplantation.</caption><thead><tr><th rowspan="2">Patient</th><th rowspan="2">SRC</th><th colspan="2">Heart</th><th colspan="2">Lung</th><th colspan="2">Digestive tract</th><th colspan="2">Joint and muscular</th><th colspan="2">Skin</th><th rowspan="2">Follow-up after KT (months)</th></tr><tr><th>Type</th><th>After KT</th><th>Type</th><th>After KT</th><th>Type</th><th>After KT</th><th>Type</th><th>After KT</th><th>Yes</th><th>After KT</th><th>Yes</th></tr></thead><tbody><tr><td>1</td><td>No</td><td>Pericarditis</td><td>Improve (NR)</td><td>ILD</td><td>Stable</td><td>Reflux/gastritis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>57</td></tr><tr><td>2</td><td>Yes</td><td>Constrictive pericarditis</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>62.8</td></tr><tr><td>3</td><td>Yes</td><td>Pericarditis</td><td>Stable</td><td>PAH</td><td>Stable</td><td>Reflux/gastritis</td><td>Worsening</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>150.8</td></tr><tr><td>4</td><td>Yes</td><td>Myocardiopathy</td><td>Worsening</td><td>PAH</td><td>Stable</td><td>Reflux/ Reflux/ Reflux/oesophageal sclerosis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>50.6</td></tr><tr><td>5</td><td>Yes</td><td></td><td></td><td></td><td>Worsening</td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>10.2</td></tr><tr><td>6</td><td>Yes</td><td>Myocardiopathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>0.9</td></tr><tr><td>7</td><td>Yes</td><td>Pericarditis</td><td>Improve (NR)</td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>77.8</td></tr><tr><td>8</td><td>No</td><td>Pericarditis/ myocardipathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Worsening</td><td>Worsening</td><td>63.1</td></tr><tr><td>9</td><td>Yes</td><td>Pericarditis</td><td>Worsening (tamponade)</td><td>ILD</td><td>Stable</td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>30.2</td></tr><tr><td>10</td><td>Yes</td><td>Pericarditis</td><td>Improve (NR)</td><td>ILD + PAH Pleurisy</td><td>Improve Improve (NR)</td><td>Gastritis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>17.8</td></tr><tr><td>11</td><td>Yes</td><td>Myocardiopathy</td><td>Stable</td><td>ILD</td><td>Stable</td><td>Pancreatitis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>60.1</td></tr><tr><td>12</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td>Reflux</td><td>Worsening</td><td>Stable</td><td>Yes</td><td>Improve</td><td>Improve</td><td>19.4</td></tr><tr><td>13</td><td>No</td><td></td><td></td><td>ILD</td><td>Stable</td><td>Oesophagitis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>68</td></tr><tr><td>14</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td>Dysmotility Syndrome</td><td>Improve</td><td>Polyarthralgia</td><td>Yes</td><td>Stable</td><td>Stable</td><td>60.3</td></tr><tr><td>15</td><td>No</td><td></td><td></td><td>ILD</td><td>Improve</td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>56.6</td></tr><tr><td>16</td><td>Yes</td><td></td><td></td><td>PAH</td><td>Stable</td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>60.9</td></tr><tr><td>17</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td>Reflux/oesophagitis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Stable</td><td>Stable</td><td>18.3</td></tr><tr><td>18</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>76.3</td></tr><tr><td>19</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>10.6</td></tr><tr><td>20</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>14.8</td></tr><tr><td>21</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>160.6</td></tr><tr><td>22</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>21.2</td></tr><tr><td>23</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>30.4</td></tr><tr><td>24</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>96.3</td></tr><tr><td>25</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>166.5</td></tr><tr><td>26</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>96</td></tr><tr><td>27</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>71.9</td></tr><tr><td>28</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Worsening</td><td>Worsening</td><td>16.5</td></tr><tr><td>29</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>104.7</td></tr><tr><td>30</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Worsening</td><td>Worsening</td><td>50.5</td></tr><tr><td>31</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Worsening</td><td>Worsening</td><td>96.6</td></tr><tr><td>32</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Worsening</td><td>Worsening</td><td>69</td></tr><tr><td>33</td><td>Yes</td><td>Pericarditis/ myocardipathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td>Yes</td><td>Stable</td><td>Stable</td><td>167.4</td></tr><tr><td>34</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total (%)</td><td>26/34</td><td>11/34</td><td>13/34</td><td>19/34</td><td>19/34</td><td>Reflux/oesophagitis</td><td>Stable</td><td>Tendonitis</td><td>7/34</td><td>34/34</td><td>Stable</td><td>118.8</td></tr><tr><td></td><td>76.40%</td><td>32.40%</td><td>38.20%</td><td>55.80%</td><td>20.60%</td><td>Reflux/oesophagitis</td><td>Worsening</td><td></td><td></td><td>100%</td><td></td><td></td></tr></tbody></table>

PAH, pulmonary artery hypertension; ILD, interstitial lung disease; SRC, scleroderma renal crisis; NR, no recurrence; KT, kidney transplantation.
<table><caption>**Table 2.** Characteristics of extrarenal involvements and evolution after kidney transplantation.</caption><thead><tr><th rowspan="2">Patient</th><th rowspan="2">SRC</th><th colspan="2">Heart</th><th colspan="2">Lung</th><th colspan="2">Digestive tract</th><th colspan="2">Joint and muscular</th><th colspan="2">Skin</th><th rowspan="2">Follow-up after KT (months)</th></tr><tr><th>Type</th><th>Type</th><th>Type</th><th>Type</th><th>Type</th><th>Type</th><th>Type</th><th>Type</th><th>After KT</th><th>After KT</th><th>After KT</th></tr></thead><tbody><tr><td>1</td><td>No</td><td>Pericarditis</td><td>Improve (NR)</td><td>ILD</td><td>Stable</td><td>Reflux/gastritis</td><td>Stable</td><td>Stable</td><td>Yes</td><td>Yes</td><td>Stable</td><td>57</td></tr><tr><td>2</td><td>Yes</td><td>Constrictive pericarditis</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>62.8</td></tr><tr><td>3</td><td>Yes</td><td>Pericarditis</td><td>Stable</td><td>PAH</td><td>Stable</td><td>Reflux/gastritis</td><td>Worsening</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Stable</td><td>150.8</td></tr><tr><td>4</td><td>Yes</td><td>Myocardiopathy</td><td>Worsening</td><td>PAH</td><td>Stable</td><td>Reflux/ Reflux/ Reflux/oesophageal sclerosis</td><td>Stable</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Stable</td><td>50.6</td></tr><tr><td>5</td><td>Yes</td><td></td><td></td><td></td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>10.2</td></tr><tr><td>6</td><td>Yes</td><td>Myocardiopathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>7</td><td>Yes</td><td>Pericarditis</td><td>Improve (NR)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>8</td><td>No</td><td>Pericarditis/ myocardiopathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>9</td><td>Yes</td><td>Pericarditis</td><td>Worsening (tamponade)</td><td>ILD</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>10</td><td>Yes</td><td>Pericarditis</td><td>Improve (NR)</td><td>ILD + PAH Pleurisy</td><td>Improve Improve (NR)</td><td>Gastritis</td><td>Stable</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Stable</td><td>17.8</td></tr><tr><td>11</td><td>Yes</td><td>Myocardiopathy</td><td>Stable</td><td>ILD</td><td>Stable</td><td>Pancreatitis</td><td>Stable</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Stable</td><td>60.1</td></tr><tr><td>12</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td>Reflux Oesophagitis</td><td>Worsening</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Improve</td><td>19.4</td></tr><tr><td>13</td><td>No</td><td></td><td></td><td>ILD</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>68</td></tr><tr><td>14</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>60.3</td></tr><tr><td>15</td><td>No</td><td></td><td></td><td>ILD</td><td>Improve</td><td>Dysmotility Syndrome</td><td>Stable</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Stable</td><td>56.6</td></tr><tr><td>16</td><td>Yes</td><td></td><td></td><td>PAH</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>60.9</td></tr><tr><td>17</td><td>Yes</td><td></td><td></td><td>ILD</td><td>Stable</td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>18.3</td></tr><tr><td>18</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>76.3</td></tr><tr><td>19</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>10.6</td></tr><tr><td>20</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>14.8</td></tr><tr><td>21</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>160.6</td></tr><tr><td>22</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>21.2</td></tr><tr><td>23</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>30.4</td></tr><tr><td>24</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>96.3</td></tr><tr><td>25</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>166.5</td></tr><tr><td>26</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>96</td></tr><tr><td>27</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>71.9</td></tr><tr><td>28</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Worsening</td><td>16.5</td></tr><tr><td>29</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Stable</td><td>104.7</td></tr><tr><td>30</td><td>No</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Worsening</td><td>50.5</td></tr><tr><td>31</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Worsening</td><td>96.6</td></tr><tr><td>32</td><td>Yes</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Worsening</td><td>69</td></tr><tr><td>33</td><td>Yes</td><td>Pericarditis/ myocardiopathy</td><td>Worsening</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Worsening</td><td>167.4</td></tr><tr><td>34</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total (%)</td><td>26/34</td><td>11/34</td><td>13/34</td><td>13/34</td><td>19/34</td><td>Reflux/oesophagitis</td><td>Stable</td><td>7/34</td><td>34/34</td><td>Yes</td><td>Stable</td><td>118.8</td></tr><tr><td></td><td>76.40%</td><td>32.40%</td><td>38.20%</td><td>55.80%</td><td>55.80%</td><td>Reflux/oesophagitis</td><td>Worsening</td><td>20.60%</td><td>100%</td><td></td><td></td><td></td></tr></tbody></table>

PAH, pulmonary artery hypertension; ILD, interstitial lung disease; SRC, scleroderma renal crisis; NR, no recurrence; KT, kidney transplantation.
(fibroproliferative endarteritis or thrombotic microangiopathy) matching with a renal involvement of SS was observed.

The evolution of extrarenal involvement is depicted in Table 2. No patient developed new extrarenal manifestation after kidney transplantation. After a mean follow-up of 65.7 months (0.9–167.4 months), cutaneous, pulmonary, cardiac, rheumatic and digestive involvements remained stable or improved in 85.3%, 92.3%, 54.5%, 85.7% and 72.2% cases, respectively. Five of 11 patients showed cardiac worsening, and five of 18 showed digestive worsening.

To determine the risk factors for patient death after kidney transplantation, we performed a Cox regression analysis. Univariate and multivariate analyses revealed that the presence of pulmonary involvement associated with SS [HR = 10.5, 95% CI (1.1–96.7); P = 0.03] was an independent risk factor (Table 5).

Discussion

The first kidney transplantation performed in a patient with systemic sclerosis was reported by Richardson [14]. At that time, kidney transplantation was considered safe for patients whose primary organ involvement by scleroderma was renal, and whose other lesions were relatively stable. Many years later, Gibney et al. [6] confirmed that kidney transplantation improved patient survival. They studied 258 ESRD patients with a diagnosis of SS, of whom 142 were transplanted, while the other patients remained

<table><caption>**Table 3.** Immunosuppressive therapy after kidney transplantation.</caption><thead><tr><th></th><th>%</th></tr></thead><tbody><tr><td colspan="2"><strong>Induction immunosuppressive therapy</strong></td></tr><tr><td>Induction</td><td>86.1</td></tr><tr><td>Antilymphocyte serum (%)</td><td>47.2</td></tr><tr><td>Anti-IL-2 receptor (%)</td><td>38.9</td></tr><tr><td>Steroids (%)</td><td>88.9</td></tr><tr><td>Steroid pulse (%)</td><td>84.0</td></tr><tr><td colspan="2"><strong>Maintenance immunosuppressive therapy</strong></td></tr><tr><td>Steroids (%)</td><td>83.3</td></tr><tr><td>Steroid weaning (%)</td><td>30.5</td></tr><tr><td>CNI (%)</td><td>91.7</td></tr><tr><td>Ciclosporin</td><td>30.7</td></tr><tr><td>Tacrolimus</td><td>61.0</td></tr><tr><td>Antimetabolites (%)</td><td>91.7</td></tr><tr><td>MMF</td><td>77.8</td></tr><tr><td>Azathioprine</td><td>13.9</td></tr><tr><td>Sirolimus (%)</td><td>5.5</td></tr></tbody></table>

on the waiting list [United Network for Organ Sharing (UNOS) registry from 1985 to 2002]. Patient survival with a transplant was, respectively, 90.1% and 79.5% after 1 and 3 years, significantly higher compared with SS patients on the waiting list (81.1% and 54.6%, respectively). Unfortunately, the authors did not provide information regarding the severity of the systemic disease, and whether SS was the cause of ESRD was unknown. Based on the current literature, it is therefore difficult to know which ESRD patients with systemic sclerosis would most probably benefit from kidney transplantation, and whether specific extrarenal involvements should be a contraindication to kidney transplantation.

As reported in the literature, survival in patients with ESRD SS is dramatically poor [12,15–17]. According to the French ESRD patients’ database (REIN registry: Réseau épidémiologie et information en néphrologie), 98 patients with SS were dialysed between 2001 and 2013, of which 81% had ESRD secondary to a scleroderma renal crisis. In this French cohort, patient survival was, respectively, 75%, 55% and 32% after 1, 3 and 5 years. Pham et al. [18] reported a patient survival of, respectively, 89.8%, 81.1%, 72.7% and 53.7% at 1, 3, 5 and 10 years post-transplant in 260 kidney allograft recipients from UNOS registry, whose transplantation was performed between 1987 and 2004. Bleyer et al. [7] analysed the relationship between the underlying renal disease and renal transplantation outcomes in 23 838 living and 67 183 deceased donor renal transplantations from the UNOS registry between 1987 and 1996, and found that outcomes (patient and graft survival) in patients with SS were reduced, compared to the patients transplanted because of another renal disease. In comparison, in our study, the patient survival was excellent after transplantation. The absence of a control group including patients with SS remaining on the waiting list is an important limit. We therefore cannot ascertain which patients with SS may most probably benefit from kidney transplantation. However, these meaningful data could help clinicians to better define the ideal recipient for transplantation. In addition, a potential selection bias is that our population might have undergone a more selective screening before registration on the waiting list. Nevertheless, the severity of SS was confirmed by extrarenal involvement of SS.

Non-death-censored graft survival in our study was, respectively, 97.2%, 87.8% and 76.6% after 1, 3 and 5 years, superior to the survival reported by Gibney et al. [6], respectively, 68.0% and 60.3% after 1 and 3 years post-transplant (UNOS registry from 1985 to
(fibroproliferative endarteritis or thrombotic microangiopathy) matching with a renal involvement of SS was observed.

The evolution of extrarenal involvement is depicted in Table 2. No patient developed new extrarenal manifestation after kidney transplantation. After a mean follow-up of 65.7 months (0.9–167.4 months), cutaneous, pulmonary, cardiac, rheumatic and digestive involvements remained stable or improved in 85.3%, 92.3%, 54.5%, 85.7% and 72.2% cases, respectively. Five of 11 patients showed cardiac worsening, and five of 18 showed digestive worsening.

To determine the risk factors for patient death after kidney transplantation, we performed a Cox regression analysis. Univariate and multivariate analyses revealed that the presence of pulmonary involvement associated with SS [HR = 10.5, 95% CI (1.1–96.7); P = 0.03] was an independent risk factor (Table 5).

Discussion

The first kidney transplantation performed in a patient with systemic sclerosis was reported by Richardson [14]. At that time, kidney transplantation was considered safe for patients whose primary organ involvement by scleroderma was renal, and whose other lesions were relatively stable. Many years later, Gibney et al. [6] confirmed that kidney transplantation improved patient survival. They studied 258 ESRD patients with a diagnosis of SS, of whom 142 were transplanted, while the other patients remained

<table><caption>**Table 3.** Immunosuppressive therapy after kidney transplantation.</caption><thead><tr><th></th><th>%</th></tr></thead><tbody><tr><td colspan="2"><strong>Induction immunosuppressive therapy</strong></td></tr><tr><td>Induction</td><td>86.1</td></tr><tr><td>Antilymphocyte serum (%)</td><td>47.2</td></tr><tr><td>Anti-IL-2 receptor (%)</td><td>38.9</td></tr><tr><td>Steroids (%)</td><td>88.9</td></tr><tr><td>Steroid pulse (%)</td><td>84.0</td></tr><tr><td colspan="2"><strong>Maintenance immunosuppressive therapy</strong></td></tr><tr><td>Steroids (%)</td><td>83.3</td></tr><tr><td>Steroid weaning (%)</td><td>30.5</td></tr><tr><td>CNI (%)</td><td>91.7</td></tr><tr><td>Ciclosporin</td><td>30.7</td></tr><tr><td>Tacrolimus</td><td>61.0</td></tr><tr><td>Antimetabolites (%)</td><td>91.7</td></tr><tr><td>MMF</td><td>77.8</td></tr><tr><td>Azathioprine</td><td>13.9</td></tr><tr><td>Sirolimus (%)</td><td>5.5</td></tr></tbody></table>

on the waiting list [United Network for Organ Sharing (UNOS) registry from 1985 to 2002]. Patient survival with a transplant was, respectively, 90.1% and 79.5% after 1 and 3 years, significantly higher compared with SS patients on the waiting list (81.1% and 54.6%, respectively). Unfortunately, the authors did not provide information regarding the severity of the systemic disease, and whether SS was the cause of ESRD was unknown. Based on the current literature, it is therefore difficult to know which ESRD patients with systemic sclerosis would most probably benefit from kidney transplantation, and whether specific extrarenal involvements should be a contraindication to kidney transplantation.

As reported in the literature, survival in patients with ESRD SS is dramatically poor [12,15–17]. According to the French ESRD patients’ database (REIN registry: Réseau épidémiologie et information en néphrologie), 98 patients with SS were dialysed between 2001 and 2013, of which 81% had ESRD secondary to a scleroderma renal crisis. In this French cohort, patient survival was, respectively, 75%, 55% and 32% after 1, 3 and 5 years. Pham et al. [18] reported a patient survival of, respectively, 89.8%, 81.1%, 72.7% and 53.7% at 1, 3, 5 and 10 years post-transplant in 260 kidney allograft recipients from UNOS registry, whose transplantation was performed between 1987 and 2004. Bleyer et al. [7] analysed the relationship between the underlying renal disease and renal transplantation outcomes in 23 838 living and 67 183 deceased donor renal transplantations from the UNOS registry between 1987 and 1996, and found that outcomes (patient and graft survival) in patients with SS were reduced, compared to the patients transplanted because of another renal disease. In comparison, in our study, the patient survival was excellent after transplantation. The absence of a control group including patients with SS remaining on the waiting list is an important limit. We therefore cannot ascertain which patients with SS may most probably benefit from kidney transplantation. However, these meaningful data could help clinicians to better define the ideal recipient for transplantation. In addition, a potential selection bias is that our population might have undergone a more selective screening before registration on the waiting list. Nevertheless, the severity of SS was confirmed by extrarenal involvement of SS.

Non-death-censored graft survival in our study was, respectively, 97.2%, 87.8% and 76.6% after 1, 3 and 5 years, superior to the survival reported by Gibney et al. [6], respectively, 68.0% and 60.3% after 1 and 3 years post-transplant (UNOS registry from 1985 to
<figure><img src="image_3.png" /><figcaption>**Figure 1** Death-censored graft survival. Death-censored graft survival was 97.2% after 1 and 3 years and 92.8% after 5 years post-transplant.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Figure 2** Patient survival. Patient survival was 100%, 93.8% and 82.5% at 1, 3, and 5 years post-transplant, respectively.</figcaption></figure>

2002). In this study, early graft loss was common, occurred more often within 90 days of transplantation and was related to death with functioning graft in the majority of cases. Moreover, the results reported on the causes, and the frequency of early graft loss, suggest that patients with SS are particularly susceptible to early

death, acute rejection and thrombosis. In our study, there was no early death with a functioning graft, and primary nonfunction due to a possible recurrence of SRC was reported in only one recipient. Pham *et al.* [18] reported a graft survival (non-death-censored) at 1, 3, 5 and 10 years post-transplant, respectively, of 78.7%,
<figure><img src="image_3.png" /><figcaption>**Figure 1** Death-censored graft survival. Death-censored graft survival was 97.2% after 1 and 3 years and 92.8% after 5 years post-transplant.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Figure 2** Patient survival. Patient survival was 100%, 93.8% and 82.5% at 1, 3, and 5 years post-transplant, respectively.</figcaption></figure>

2002). In this study, early graft loss was common, occurred more often within 90 days of transplantation and was related to death with functioning graft in the majority of cases. Moreover, the results reported on the causes, and the frequency of early graft loss, suggest that patients with SS are particularly susceptible to early

death, acute rejection and thrombosis. In our study, there was no early death with a functioning graft, and primary nonfunction due to a possible recurrence of SRC was reported in only one recipient. Pham *et al.* [18] reported a graft survival (non-death-censored) at 1, 3, 5 and 10 years post-transplant, respectively, of 78.7%,
<table><caption>**Table 4.** Characteristics of patients with a scleroderma renal crisis recurrence.</caption><thead><tr><th></th><th>Patient 1</th><th>Patient 2</th><th>Patient 3</th></tr></thead><tbody><tr><td>Gender</td><td>F</td><td>F</td><td>F</td></tr><tr><td>Age</td><td>56</td><td>47</td><td>34</td></tr><tr><td>Initial renal disease</td><td>SRC</td><td>SRC</td><td>SRC</td></tr><tr><td>Biopsy</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Graft loss</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Year of transplantation</td><td>1989</td><td>1997</td><td>2013</td></tr><tr><td>Time frame</td><td></td><td></td><td></td></tr><tr><td>Between start of renal disease and RRT</td><td>2.0 months</td><td>0.3 month</td><td>1.2 month</td></tr><tr><td>Between RRT and Tx</td><td>10 months</td><td>24 months</td><td>33 months</td></tr><tr><td>Between Tx and recurrence</td><td>1 month</td><td>57 months</td><td>4 months</td></tr><tr><td>Immunosuppressive therapy</td><td></td><td></td><td></td></tr><tr><td>CNI</td><td>Ciclosporin</td><td>Ciclosporin</td><td>Tacrolimus</td></tr><tr><td>Steroids</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>ACEi</td><td>Yes</td><td>Yes</td><td>Yes</td></tr></tbody></table>

F, female; RRT, renal replacement therapy; RTx, renal transplantation; CNI, calcineurin inhibitors; ACEi, Angiotensin-converting enzyme inhibitors.

<table><caption>**Table 5.** Risk factors for patient death after transplantation. Cox analysis</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Univariate analysis<br>P value</th><th colspan="3">Multivariate analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P value</th></tr></thead><tbody><tr><td>Sex (M/F)</td><td>0.9</td><td></td><td></td><td></td></tr><tr><td>Patient age</td><td>0.65</td><td></td><td></td><td></td></tr><tr><td>SRC (initial renal disease)</td><td>0.58</td><td></td><td></td><td></td></tr><tr><td>Time frame between RRT and KT</td><td>0.53</td><td></td><td></td><td></td></tr><tr><td>Immunization (anti-HLA antibody positivity)</td><td>0.96</td><td></td><td></td><td></td></tr><tr><td>Use of antilymphocyte serum</td><td>0.29</td><td></td><td></td><td></td></tr><tr><td>Use of tacrolimus</td><td>0.69</td><td></td><td></td><td></td></tr><tr><td>Use of ciclosporin</td><td>0.57</td><td></td><td></td><td></td></tr><tr><td>Steroids weaning</td><td>0.68</td><td></td><td></td><td></td></tr><tr><td>Acute rejection in the first year after transplantation</td><td>0.66</td><td></td><td></td><td></td></tr><tr><td>Cardiac involvement</td><td>0.54</td><td></td><td></td><td></td></tr><tr><td>Pulmonary involvement</td><td><strong>0.03</strong></td><td><strong>10.5</strong></td><td><strong>1.1–96.7</strong></td><td><strong>0.03</strong></td></tr><tr><td>Gastrointestinal involvement</td><td>0.9</td><td></td><td></td><td></td></tr><tr><td>Rheumatic involvement</td><td>0.9</td><td></td><td></td><td></td></tr></tbody></table>

SRC, sclerodermic renal crisis; RRT, renal replacement therapy; KT, kidney transplantation. Bold values: independent risk factor for death.

68.6%, 56.7% and 26.7% (UNOS registry from 1987 to 2004), which was far below the results we report. According to Bleyer *et al.* [7], graft survival in patients with SS was largely below that found in other kidney diseases (79.5% and 71.8% after 1 and 3 years post-transplant). Both European and US reports have demonstrated poorer graft survival than in other primary renal diseases [7,19]. In our study, death-censored graft survival was excellent and comparable to those of the global French cohort of kidney transplantations performed between 1993 and 2010, respectively, at 91.2% after 1 year, and 79.7% after 5 years (Agence de

Biomédecine, annual report). An important point to underline is that our data are collected from a more recent period (1987–2012) than the data reported in the previous literature, which could partly explain the better results in our population. Indeed, the more efficient immunosuppressive therapy for rejection, but also for systemic sclerosis, and the better selection of the kidney transplant recipients during this period probably improved graft survival.

Our work is limited by the number of patients transplanted during the study period. Nevertheless, it provides relevant information, especially about extrarenal
<table><caption>**Table 4.** Characteristics of patients with a scleroderma renal crisis recurrence.</caption><thead><tr><th></th><th>Patient 1</th><th>Patient 2</th><th>Patient 3</th></tr></thead><tbody><tr><td>Gender</td><td>F</td><td>F</td><td>F</td></tr><tr><td>Age</td><td>56</td><td>47</td><td>34</td></tr><tr><td>Initial renal disease</td><td>SRC</td><td>SRC</td><td>SRC</td></tr><tr><td>Biopsy</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Graft loss</td><td>Yes</td><td>No</td><td>No</td></tr><tr><td>Year of transplantation</td><td>1989</td><td>1997</td><td>2013</td></tr><tr><td>Time frame</td><td></td><td></td><td></td></tr><tr><td>Between start of renal disease and RRT</td><td>2.0 months</td><td>0.3 month</td><td>1.2 month</td></tr><tr><td>Between RRT and Tx</td><td>10 months</td><td>24 months</td><td>33 months</td></tr><tr><td>Between Tx and recurrence</td><td>1 month</td><td>57 months</td><td>4 months</td></tr><tr><td>Immunosuppressive therapy</td><td></td><td></td><td></td></tr><tr><td>CNI</td><td>Ciclosporin</td><td>Ciclosporin</td><td>Tacrolimus</td></tr><tr><td>Steroids</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>ACEi</td><td>Yes</td><td>Yes</td><td>Yes</td></tr></tbody></table>

F, female; RRT, renal replacement therapy; RTx, renal transplantation; CNI, calcineurin inhibitors; ACEi, Angiotensin-converting enzyme inhibitors.

<table><caption>**Table 5.** Risk factors for patient death after transplantation. Cox analysis</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Univariate analysis<br>P value</th><th colspan="3">Multivariate analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P value</th></tr></thead><tbody><tr><td>Sex (M/F)</td><td>0.9</td><td></td><td></td><td></td></tr><tr><td>Patient age</td><td>0.65</td><td></td><td></td><td></td></tr><tr><td>SRC (initial renal disease)</td><td>0.58</td><td></td><td></td><td></td></tr><tr><td>Time frame between RRT and KT</td><td>0.53</td><td></td><td></td><td></td></tr><tr><td>Immunization (anti-HLA antibody positivity)</td><td>0.96</td><td></td><td></td><td></td></tr><tr><td>Use of antilymphocyte serum</td><td>0.29</td><td></td><td></td><td></td></tr><tr><td>Use of tacrolimus</td><td>0.69</td><td></td><td></td><td></td></tr><tr><td>Use of ciclosporin</td><td>0.57</td><td></td><td></td><td></td></tr><tr><td>Steroids weaning</td><td>0.68</td><td></td><td></td><td></td></tr><tr><td>Acute rejection in the first year after transplantation</td><td>0.66</td><td></td><td></td><td></td></tr><tr><td>Cardiac involvement</td><td>0.54</td><td></td><td></td><td></td></tr><tr><td>Pulmonary involvement</td><td><strong>0.03</strong></td><td><strong>10.5</strong></td><td><strong>1.1–96.7</strong></td><td><strong>0.03</strong></td></tr><tr><td>Gastrointestinal involvement</td><td>0.9</td><td></td><td></td><td></td></tr><tr><td>Rheumatic involvement</td><td>0.9</td><td></td><td></td><td></td></tr></tbody></table>

SRC, sclerodermic renal crisis; RRT, renal replacement therapy; KT, kidney transplantation. Bold values: independent risk factor for death.

68.6%, 56.7% and 26.7% (UNOS registry from 1987 to 2004), which was far below the results we report. According to Bleyer *et al.* [7], graft survival in patients with SS was largely below that found in other kidney diseases (79.5% and 71.8% after 1 and 3 years post-transplant). Both European and US reports have demonstrated poorer graft survival than in other primary renal diseases [7,19]. In our study, death-censored graft survival was excellent and comparable to those of the global French cohort of kidney transplantations performed between 1993 and 2010, respectively, at 91.2% after 1 year, and 79.7% after 5 years (Agence de

Biomédecine, annual report). An important point to underline is that our data are collected from a more recent period (1987–2012) than the data reported in the previous literature, which could partly explain the better results in our population. Indeed, the more efficient immunosuppressive therapy for rejection, but also for systemic sclerosis, and the better selection of the kidney transplant recipients during this period probably improved graft survival.

Our work is limited by the number of patients transplanted during the study period. Nevertheless, it provides relevant information, especially about extrarenal
involvement in patients with SS and evolution after kid-
ney transplantation. Gibney *et al*. [6] reported the evo-
lution of skin lesions in four patients with SS having
received a kidney allograft, who presented a subsequent
improvement of Rodnan score. It would have been
interesting to compare the disease activity before and
after kidney transplantation. Unfortunately due to the
retrospective multicentre design of this study, standard-
ized clinical and biological data at baseline were not
available. Nevertheless, the present study reports, for the
first time, broader data on extrarenal involvement at
time and after transplantation. Although this systemic
disease is generally stable or improved, these results also
highlight the fact that special attention should be paid
to cardiac and gastrointestinal involvement, which may
worsen after transplantation. On this basis, we consider
that a close monitoring of extrarenal involvement is
necessary before and after kidney transplantation, but
suggest that kidney transplantation could be a highly
valuable option in systemic sclerosis patients with stable
extrarenal involvement. The multicentre nature of our
study enhances this conclusion. Furthermore, pul-
monary involvement of SS was found to be an indepen-
dent risk factor of death after kidney transplantation in
our study. Pulmonary disease in patients with SS can be
classified into two main groups: (i) primary pulmonary
disease (i.e. lung parenchyma involvement and pul-
monary hypertension) and (ii) secondary pulmonary
disease (i.e. airway illness due to bronco-aspiration that
is secondary to gastro-oesophageal reflux, toxicity due
to medications, and infections, among others) [20–22].
The presence of parenchymal lung disease (HR = 2.9,
*P* = 0.023), pulmonary hypertension (HR = 4.78,
*P* = 0.002) and renal disease (HR = 2.78, *P* = 0.016) is
associated with increased mortality in patients with SS
[23] in the nontransplant setting. The presence of ILD
or PH is responsible for 60% of the mortality in these
patients [23]. According to our findings, in the trans-
plant setting, pulmonary involvement seems to have the
same impact on mortality. Therefore, special caution
should be paid before kidney transplantation to find
and explore any parenchymal lung disease and pul-
monary hypertension. This could constitute a con-
traindication for kidney transplantation.

In our study, there were three cases of suspected
recurrence of SRC (3/36 kidney transplantation, 8.3%)
between 1 and 57 months post-transplant. One recur-
rence caused graft loss. At time of recurrence, all three
patients were under CNI, steroids and ACE inhibitors.
Furthermore, there were no subclinical vascular changes
in the other follow-up biopsies performed in this study.

In the literature, six cases are reported and the inci-
dence of recurrence of SRC causing graft loss based on
UNOS database was very low, estimated to be 1.9% (5/
260 kidney transplantations performed) [18]. It is possi-
ble that published case series may over-report the recur-
rence rate, because of a bias in publications of more
difficult cases, with worse outcomes, while UNOS may
under-report the actual recurrence rate. One of the
most important facts concerning the recurrence of SRC
is the potential differential diagnosis (acute or chronic
antibody-mediated rejection and CNI toxicity [24]). It
is therefore challenging to ascertain the final diagnosis,
especially in retrospective studies. In the nontransplant
setting, the suggested predictors for SRC are quite well
defined [12,25–27]. In the transplant setting, progres-
sion of diffuse skin thickening, new onset anaemia and
cardiac complications may be predictive for SRC occur-
rence [18]. These points also have to be considered with
caution because of important bias in previous publica-
tions and the very low number of cases. The literature
review and the UNOS data suggest that most recur-
rences occur within a few months, usually before the
end of the second year post-transplantation. A close
monitoring for evidence of recurrence within the first
2 years after transplantation is therefore warranted.
Nevertheless, our study shows that nephrologists also
must be cautious for a recurrence of SRC after this per-
iod of time (57 months after transplantation for one
patient in our cohort). The detection of RNA poly-
merase III might be a useful tool to screen patients with
higher risk for SRC recurrence [28,29].

The immunosuppressive regimen used in kidney
transplantation may have an important role in the
improvement of the systemic manifestations of the dis-
ease. There is no consensus in this specific setting. In
1991, Ruiz *et al.* [24] suggested cyclosporine be avoided
in systemic sclerosis after kidney transplantation, mainly
to reduce superimposed vascular toxicity, as endothelial
lesions are suspected to participate to the pathophysiol-
ogy of the disease. In our study, a large majority
(91.7%) of the kidney transplant recipients were treated
with CNI (22 patients with tacrolimus and 11 with
ciclosporin), without serious adverse events. We there-
fore believe that the use of CNI in SS transplanted
patients should be considered as generally safe. The
same conclusion could be drawn with corticosteroids:
88.9% of the cohort received high-dose corticosteroids
as an induction before kidney transplantation, followed
by low-dose corticosteroids, which were continued in
63.3% of patients. Steroid therapy is a classical risk fac-
tor of SRC in systemic sclerosis, but whether the use of
involvement in patients with SS and evolution after kid-
ney transplantation. Gibney *et al*. [6] reported the evo-
lution of skin lesions in four patients with SS having
received a kidney allograft, who presented a subsequent
improvement of Rodnan score. It would have been
interesting to compare the disease activity before and
after kidney transplantation. Unfortunately due to the
retrospective multicentre design of this study, standard-
ized clinical and biological data at baseline were not
available. Nevertheless, the present study reports, for the
first time, broader data on extrarenal involvement at
time and after transplantation. Although this systemic
disease is generally stable or improved, these results also
highlight the fact that special attention should be paid
to cardiac and gastrointestinal involvement, which may
worsen after transplantation. On this basis, we consider
that a close monitoring of extrarenal involvement is
necessary before and after kidney transplantation, but
suggest that kidney transplantation could be a highly
valuable option in systemic sclerosis patients with stable
extrarenal involvement. The multicentre nature of our
study enhances this conclusion. Furthermore, pul-
monary involvement of SS was found to be an indepen-
dent risk factor of death after kidney transplantation in
our study. Pulmonary disease in patients with SS can be
classified into two main groups: (i) primary pulmonary
disease (i.e. lung parenchyma involvement and pul-
monary hypertension) and (ii) secondary pulmonary
disease (i.e. airway illness due to bronco-aspiration that
is secondary to gastro-oesophageal reflux, toxicity due
to medications, and infections, among others) [20–22].
The presence of parenchymal lung disease (HR = 2.9,
*P* = 0.023), pulmonary hypertension (HR = 4.78,
*P* = 0.002) and renal disease (HR = 2.78, *P* = 0.016) is
associated with increased mortality in patients with SS
[23] in the nontransplant setting. The presence of ILD
or PH is responsible for 60% of the mortality in these
patients [23]. According to our findings, in the trans-
plant setting, pulmonary involvement seems to have the
same impact on mortality. Therefore, special caution
should be paid before kidney transplantation to find
and explore any parenchymal lung disease and pul-
monary hypertension. This could constitute a con-
traindication for kidney transplantation.

In our study, there were three cases of suspected
recurrence of SRC (3/36 kidney transplantation, 8.3%)
between 1 and 57 months post-transplant. One recur-
rence caused graft loss. At time of recurrence, all three
patients were under CNI, steroids and ACE inhibitors.
Furthermore, there were no subclinical vascular changes
in the other follow-up biopsies performed in this study.

In the literature, six cases are reported and the inci-
dence of recurrence of SRC causing graft loss based on
UNOS database was very low, estimated to be 1.9% (5/
260 kidney transplantations performed) [18]. It is possi-
ble that published case series may over-report the recur-
rence rate, because of a bias in publications of more
difficult cases, with worse outcomes, while UNOS may
under-report the actual recurrence rate. One of the
most important facts concerning the recurrence of SRC
is the potential differential diagnosis (acute or chronic
antibody-mediated rejection and CNI toxicity [24]). It
is therefore challenging to ascertain the final diagnosis,
especially in retrospective studies. In the nontransplant
setting, the suggested predictors for SRC are quite well
defined [12,25–27]. In the transplant setting, progres-
sion of diffuse skin thickening, new onset anaemia and
cardiac complications may be predictive for SRC occur-
rence [18]. These points also have to be considered with
caution because of important bias in previous publica-
tions and the very low number of cases. The literature
review and the UNOS data suggest that most recur-
rences occur within a few months, usually before the
end of the second year post-transplantation. A close
monitoring for evidence of recurrence within the first
2 years after transplantation is therefore warranted.
Nevertheless, our study shows that nephrologists also
must be cautious for a recurrence of SRC after this per-
iod of time (57 months after transplantation for one
patient in our cohort). The detection of RNA poly-
merase III might be a useful tool to screen patients with
higher risk for SRC recurrence [28,29].

The immunosuppressive regimen used in kidney
transplantation may have an important role in the
improvement of the systemic manifestations of the dis-
ease. There is no consensus in this specific setting. In
1991, Ruiz *et al.* [24] suggested cyclosporine be avoided
in systemic sclerosis after kidney transplantation, mainly
to reduce superimposed vascular toxicity, as endothelial
lesions are suspected to participate to the pathophysiol-
ogy of the disease. In our study, a large majority
(91.7%) of the kidney transplant recipients were treated
with CNI (22 patients with tacrolimus and 11 with
ciclosporin), without serious adverse events. We there-
fore believe that the use of CNI in SS transplanted
patients should be considered as generally safe. The
same conclusion could be drawn with corticosteroids:
88.9% of the cohort received high-dose corticosteroids
as an induction before kidney transplantation, followed
by low-dose corticosteroids, which were continued in
63.3% of patients. Steroid therapy is a classical risk fac-
tor of SRC in systemic sclerosis, but whether the use of
high-dose steroids may precipitate SRC in renal trans-
plant recipients is currently debated. Although no gen-
eral recommendation can be made, steroids appear as a
reasonable immunosuppressive option in this context.
Due to the relatively limited number of patients, the
present study cannot conclude on the best immunosup-
pressive regimen to use in this setting. The most fre-
quent combination was the use of an induction therapy
including antilymphocyte serum or anti-IL-2 receptor,
and a maintenance immunosuppressive therapy with
tacrolimus, mycophenolate mofetil and steroids. Ster-
oids were weaned in a large number of cases. Impor-
tantly, outcomes with this standard combination were
clearly acceptable, with a rejection rate at 1 year of
13.8% (5/36) and a SRC recurrence rate of 8.3%. We
speculate that using an immunosuppressive combina-
tion therapy with reduced vascular toxicity, including
mTOR inhibitors or belatacept rather than CNI, could
be beneficial in SS, but neither the present study nor
previous literature has specifically addressed this issue.

In a series of chronic dialysis-dependent patients, Siva
et al. [30] reported that a recovery of renal function
occurred in 10% (n = 13) scleroderma patients, as com-
pared to 1% (n = 437) ESRD patients with other causes
of kidney disease (P < 0.001). Recovery was most likely in
the first 12–18 months following dialysis initiation. On
this basis, several authors have recommended to wait at
least 2 years after beginning dialysis, before enrolling
patients on the waiting list. In our study, 76% of the
patients were on the waiting list before the 2-year limit,
and none of these patients recovered renal function before
kidney transplantation. Altogether, the time between dial-
ysis initiation and transplantation was 45 months. We
believe that postponing the enrolment on the waiting list
after 6 months of dialysis for a reason unsupported by
clear current evidence can increase both the time of dialy-
sis and the overall risk of mortality in this setting.

In summary, our observational study provides valu-
able information about kidney transplantation in
patients with systemic sclerosis and shows that out-
comes may potentially be better than previously
thought. This study provides original information on
the presence and evolution of extrarenal involvement
and immunosuppressive strategy in transplanted SS
patients. Pulmonary involvement was an independent
risk factor of death after transplantation, and a rigorous
exploration should be performed before listing patient
for transplantation. Special care should be taken regard-
ing the presence and the evolution of cardiac and gas-
trointestinal disease in this setting. Further studies
including larger cohorts would be useful to better define
the ideal recipient for kidney transplantation in systemic
sclerosis.

Funding

The authors have declared no funding.

Conflict of interest

The authors have declared no conflicts of interest.

Acknowledgements

DB: performed research, collected data, analyzed data, and wrote the paper. JD: collected the data, performed research, and contributed to the writing. BM, DG: contributed to the revision and approval of the paper. All the others authors: collected data and contributed to the approval of the paper. We gratefully acknowledge all the French kidney transplant departments. We would like to thank Cécile Couchoud for providing the data of patients with ESRD SS from REIN registry.

REFERENCES

1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. *N Engl J Med* 2009; **360**: 1989.

2. Steen VD. The many faces of scleroderma. *Rheum Dis Clin North Am* 2008; **34**: 1.

3. Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. *Ann Intern Med* 1990; **113**: 352.

4. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. *Ann Intern Med* 2000; **133**: 600.

5. Shor R, Halabe A. New trends in the treatment of scleroderma renal crisis. *Nephron* 2002; **92**: 716.

6. Gibney EM, Parikh CR, Jani A, Fischer MJ, Collier D, Wiseman AC. Kidney transplantation for systemic sclerosis improves survival and may modulate disease activity. *Am J Transplant* 2004; **4**: 2027.

7. Bleyer AJ, Donaldson LA, McIntosh M, Adams PL. Relationship between underlying renal disease and renal transplantation outcome. *Am J Kidney Dis* 2001; **37**: 1152.

8. Masi AT. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). *Arthritis Rheum* 1980; **23**: 581.
high-dose steroids may precipitate SRC in renal trans-
plant recipients is currently debated. Although no gen-
eral recommendation can be made, steroids appear as a
reasonable immunosuppressive option in this context.
Due to the relatively limited number of patients, the
present study cannot conclude on the best immunosup-
pressive regimen to use in this setting. The most fre-
quent combination was the use of an induction therapy
including antilymphocyte serum or anti-IL-2 receptor,
and a maintenance immunosuppressive therapy with
tacrolimus, mycophenolate mofetil and steroids. Ster-
oids were weaned in a large number of cases. Impor-
tantly, outcomes with this standard combination were
clearly acceptable, with a rejection rate at 1 year of
13.8% (5/36) and a SRC recurrence rate of 8.3%. We
speculate that using an immunosuppressive combina-
tion therapy with reduced vascular toxicity, including
mTOR inhibitors or belatacept rather than CNI, could
be beneficial in SS, but neither the present study nor
previous literature has specifically addressed this issue.

In a series of chronic dialysis-dependent patients, Siva
et al. [30] reported that a recovery of renal function
occurred in 10% (n = 13) scleroderma patients, as com-
pared to 1% (n = 437) ESRD patients with other causes
of kidney disease (P < 0.001). Recovery was most likely in
the first 12–18 months following dialysis initiation. On
this basis, several authors have recommended to wait at
least 2 years after beginning dialysis, before enrolling
patients on the waiting list. In our study, 76% of the
patients were on the waiting list before the 2-year limit,
and none of these patients recovered renal function before
kidney transplantation. Altogether, the time between dial-
ysis initiation and transplantation was 45 months. We
believe that postponing the enrolment on the waiting list
after 6 months of dialysis for a reason unsupported by
clear current evidence can increase both the time of dialy-
sis and the overall risk of mortality in this setting.

In summary, our observational study provides valu-
able information about kidney transplantation in
patients with systemic sclerosis and shows that out-
comes may potentially be better than previously
thought. This study provides original information on
the presence and evolution of extrarenal involvement
and immunosuppressive strategy in transplanted SS
patients. Pulmonary involvement was an independent
risk factor of death after transplantation, and a rigorous
exploration should be performed before listing patient
for transplantation. Special care should be taken regard-
ing the presence and the evolution of cardiac and gas-
trointestinal disease in this setting. Further studies
including larger cohorts would be useful to better define
the ideal recipient for kidney transplantation in systemic
sclerosis.

Funding

The authors have declared no funding.

Conflict of interest

The authors have declared no conflicts of interest.

Acknowledgements

DB: performed research, collected data, analyzed data, and wrote the paper. JD: collected the data, performed research, and contributed to the writing. BM, DG: contributed to the revision and approval of the paper. All the others authors: collected data and contributed to the approval of the paper. We gratefully acknowledge all the French kidney transplant departments. We would like to thank Cécile Couchoud for providing the data of patients with ESRD SS from REIN registry.

REFERENCES

1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. *N Engl J Med* 2009; **360**: 1989.

2. Steen VD. The many faces of scleroderma. *Rheum Dis Clin North Am* 2008; **34**: 1.

3. Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. *Ann Intern Med* 1990; **113**: 352.

4. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. *Ann Intern Med* 2000; **133**: 600.

5. Shor R, Halabe A. New trends in the treatment of scleroderma renal crisis. *Nephron* 2002; **92**: 716.

6. Gibney EM, Parikh CR, Jani A, Fischer MJ, Collier D, Wiseman AC. Kidney transplantation for systemic sclerosis improves survival and may modulate disease activity. *Am J Transplant* 2004; **4**: 2027.

7. Bleyer AJ, Donaldson LA, McIntosh M, Adams PL. Relationship between underlying renal disease and renal transplantation outcome. *Am J Kidney Dis* 2001; **37**: 1152.

8. Masi AT. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). *Arthritis Rheum* 1980; **23**: 581.
9. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis). Classification, subsets, and pathogenesis. *J Rheumatol* 1988; **15**: 202.

10. LeRoy EC, Medsger T. Criteria for the classification of early systemic sclerosis. *J Rheumatol* 2001; **28**: 1573.

11. Hudson M, Taillefer S, Steele R, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. *Clin Exp Rheumatol* 2007; **25**: 754.

12. Steen VD. Scleroderma renal crisis. *Rheum Dis Clin North Am* 2003; **29**: 315.

13. Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. *Clin Exp Rheumatol* 2003; **21**(3 Suppl. 29): S29.

14. Richardson JA. Hemodialysis and kidney transplantation for renal failure from scleroderma. *Arthritis Rheum* 1973; **16**: 265.

15. Walker JG, Ahern MJ, Smith MD, et al. Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment. *Intern Med J* 2003; **33**: 216.

16. Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. *QJM* 2007; **100**: 485.

17. Guillevin L, Berezne A, Seror R, et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and

427 controls. *Rheumatology* (Oxford) 2012; **51**: 460.

18. Pham PT, Pham PC, Danovitch GM, et al. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. *Am J Transplant* 2005; **5**: 2565.

19. Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders. *Q J Med* 1990; **74**: 63.

20. Morales-Cárdenas A, Pérez-Madrid C, Arias L, et al. Pulmonary involvement in systemic sclerosis. *Autoimmun Rev* 2016; **15**: 1094.

21. Desbois AC, Cacoub P. Systemic sclerosis: an update in 2016. *Autoimmun Rev* 2016; **15**: 417.

22. Hant FN, Herpel LB, Silver RM. Pulmonary manifestations of scleroderma and mixed connective tissue disease. *Clin Chest Med* 2010; **31**: 433.

23. Bauer PR, Schiavo DN, Osborn TG, et al. Influence of interstitial lung disease on outcome in systemic sclerosis: a population-based historical cohort study. *Chest* 2013; **144**: 571.

24. Ruiz JC, Val F, de Francisco AL, et al. Progressive systemic sclerosis and renal transplantation: a contraindication to ciclosporin. *Nephron* 1991; **59**: 330.

25. Steen VD, Medsger TA Jr, Osial TA Jr, Ziegler GL, Shapiro AP, Rodnan GP. Factors predicting development of renal involvement in progressive systemic sclerosis. *Am J Med* 1984; **76**: 779.

26. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. *Arthritis Rheum* 1998; **41**: 1613.

27. Lee AT, Burnet S. Corticosteroid-induced scleroderma renal crisis. *Med J Aust* 2002; **177**: 459.

28. Emilie S, Goulvestre C, Bérezné A, Pagnoux C, Guillevin L, Mouthon L. Anti-RNA polymerase III antibodies are associated with scleroderma renal crisis in a French cohort. *Scand J Rheumatol* 2011; **40**: 404.

29. Hesselstrand R, Scheja A, Wuttge DM. Scleroderma renal crisis in a Swedish systemic sclerosis cohort: survival, renal outcome, and RNA polymerase III antibodies as a risk factor. *Scand J Rheumatol* 2012; **41**: 39.

30. Siva B, McDonald SP, Hawley CM, et al. End-stage kidney disease due to scleroderma – outcomes in 127 consecutive ANZDATA registry cases. *Nephrol Dial Transplant* 2011; **26**: 3165.
9. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis). Classification, subsets, and pathogenesis. *J Rheumatol* 1988; **15**: 202.

10. LeRoy EC, Medsger T. Criteria for the classification of early systemic sclerosis. *J Rheumatol* 2001; **28**: 1573.

11. Hudson M, Taillefer S, Steele R, et al. Improving the sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis. *Clin Exp Rheumatol* 2007; **25**: 754.

12. Steen VD. Scleroderma renal crisis. *Rheum Dis Clin North Am* 2003; **29**: 315.

13. Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. *Clin Exp Rheumatol* 2003; **21**(3 Suppl. 29): S29.

14. Richardson JA. Hemodialysis and kidney transplantation for renal failure from scleroderma. *Arthritis Rheum* 1973; **16**: 265.

15. Walker JG, Ahern MJ, Smith MD, et al. Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment. *Intern Med J* 2003; **33**: 216.

16. Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. *QJM* 2007; **100**: 485.

17. Guillevin L, Berezne A, Seror R, et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and

427 controls. *Rheumatology* (Oxford) 2012; **51**: 460.

18. Pham PT, Pham PC, Danovitch GM, et al. Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature. *Am J Transplant* 2005; **5**: 2565.

19. Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders. *Q J Med* 1990; **74**: 63.

20. Morales-Cárdenas A, Pérez-Madrid C, Arias L, et al. Pulmonary involvement in systemic sclerosis. *Autoimmun Rev* 2016; **15**: 1094.

21. Desbois AC, Cacoub P. Systemic sclerosis: an update in 2016. *Autoimmun Rev* 2016; **15**: 417.

22. Hant FN, Herpel LB, Silver RM. Pulmonary manifestations of scleroderma and mixed connective tissue disease. *Clin Chest Med* 2010; **31**: 433.

23. Bauer PR, Schiavo DN, Osborn TG, et al. Influence of interstitial lung disease on outcome in systemic sclerosis: a population-based historical cohort study. *Chest* 2013; **144**: 571.

24. Ruiz JC, Val F, de Francisco AL, et al. Progressive systemic sclerosis and renal transplantation: a contraindication to ciclosporin. *Nephron* 1991; **59**: 330.

25. Steen VD, Medsger TA Jr, Osial TA Jr, Ziegler GL, Shapiro AP, Rodnan GP. Factors predicting development of renal involvement in progressive systemic sclerosis. *Am J Med* 1984; **76**: 779.

26. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. *Arthritis Rheum* 1998; **41**: 1613.

27. Lee AT, Burnet S. Corticosteroid-induced scleroderma renal crisis. *Med J Aust* 2002; **177**: 459.

28. Emilie S, Goulvestre C, Bérezné A, Pagnoux C, Guillevin L, Mouthon L. Anti-RNA polymerase III antibodies are associated with scleroderma renal crisis in a French cohort. *Scand J Rheumatol* 2011; **40**: 404.

29. Hesselstrand R, Scheja A, Wuttge DM. Scleroderma renal crisis in a Swedish systemic sclerosis cohort: survival, renal outcome, and RNA polymerase III antibodies as a risk factor. *Scand J Rheumatol* 2012; **41**: 39.

30. Siva B, McDonald SP, Hawley CM, et al. End-stage kidney disease due to scleroderma – outcomes in 127 consecutive ANZDATA registry cases. *Nephrol Dial Transplant* 2011; **26**: 3165.