healthmedicinet

Forty-six of the 77 eligible patients were included in the study (Fig. 1) from Reims (?=?18), Rouen (?=?9), Hôpital Necker in Paris (?=?8), Tours (?=?4), Strasbourg (?=?3), Angers (?=?1), Rennes (?=?1), Hôpital Européen Georges Pompidou in Paris (?=?1) and Limoges (?=?1).

Patient characteristics

Clinical characteristics at the time of diagnosis of bronchiectasis are summarized
in Table 1. The mean age was 58.2 years. Twenty-four patients (52.2 %) were men. Chronic cough
and sputum (50 %) were the main symptoms leading to chest CT scan. The mean duration
of symptoms before diagnosis was 1.5 years. Most patients had undergone only one renal
transplantation (89.1 %). Autosomal dominant polycystic kidney disease (ADPKD) (32.6 %)
was the main underlying renal disease. Immunosuppressive drugs used prior to the diagnosis
of bronchiectasis are listed in Table 1. All patients received steroids and all but three of the patients received MPA (93.5 %).

Table 1. Demographic and Clinical Characteristics at the Time of Diagnosis

Few patients exhibited respiratory symptoms before renal transplantation, including
chronic cough (?=?3), dyspnea (?=?2), annual bronchitis (?=?2) and pneumonia (?=?1). No patient exhibited chronic sputum. Eighteen patients (40.9 %) were current
or former smokers and two had a diagnosis of chronic obstructive pulmonary disease.
Significant pre-existing extrarenal medical conditions were unusual, including mycobacterial
infection (?=?1) and rheumatoid arthritis (?=?1) (Table 2). No case of chronic respiratory bacterial colonization was identified.

Table 2. Pulmonary Status and Comorbidities before Renal Transplantation

CT scans

Bronchiectases were cylindrical (100 %) and usually extensive (84.8 %). Table 3 describes the characteristics of the chest CT scan. The mean total bronchiectasis
score was 7.4?±?5.5 with a significant gradient from apex to bases. Bronchiolar nodules
(41.3 %) and mucoid impactions (21.7 %) were the most common associated CT scan findings.

Table 3. CT scan features at the Time of Diagnosis

Chest X-ray prior to renal transplantation was available for 36 patients and was considered
to be normal. Chest CT scan was performed before (?=?3) or just after (?=?9) renal transplantation in 12 patients and demonstrated no signs of bronchiectasis.

Spirometry, laboratory, and microbiological data

Spirometry, laboratory and microbiological examinations were performed inconstantly
at the time of diagnosis of bronchiectasis (Table 4). For patients with available data (?=?36), mean lymphocyte count was 1295 cells/mm
³
. Hypogammaglobulinemia, defined as gammaglobulins less than 9 g/dL and/or IgG less
than 7 g/L, was observed in 15 patients (46.9 %) associated with lymphopenia in all
but one case. Mean MPA area under the concentration-time curve (AUC) evaluated in
21 patients was 42.1 mg.h/L for a mean MPA daily dose of 1.5 g/day. Spirometry was
available for 22 patients and showed an obstructive disorder in 8 cases (36.4 %).
Microbiological data were obtained in 34 cases from sputum analyses (?=?4) or fiberoptic bronchoscopy procedure (?=?30). Microorganisms were identified in 22 cases. Haemophilus influenzae was the most common pathogen. Concomitant pathogens were associated with Haemophilus influenzae in 7 patients, including Streptococcus species (?=?2), Aspergillus fumigatus (?=?2), Escherichia coli (?=?2), and Pseudomonas aeruginosa (?=?1) (data not shown).

Table 4. Laboratory, Microbiology, Spirometry Data at the time of the Diagnosis of Bronchiectasis

Initial management and outcome

MPA was stopped at the time of diagnosis of bronchiectasis in 3 patients and during
follow-up in another 8 patients. Immunoglobulin replacement therapy was initiated
in 6 patients either at the time of diagnosis (?=?3) or during follow-up (?=?3). The main symptoms reported after the diagnosis of bronchiectasis were chronic
sputum (43.5 %) and recurrent respiratory tract infections (37.0 %). None of the six
deaths (13 %) was attributable to bronchiectasis (Table 5).

Table 5. Follow-up Data

Longitudinal changes in CT scan

At least one chest CT scan was performed after the diagnosis of bronchiectasis in
28 patients (60.9 %). The last CT scan available for each patient was performed 2.6?±?2.5 years
after the diagnosis of bronchiectasis. A trend towards worsening of the total bronchiectasis
score was observed at follow-up for these 28 patients (7.7?±?6.2 vs. 10.9?±?6.7; p?=?0.07). Bronchiectasis was more extensive in 19 patients (67.9 %), while stabilization
was observed in 3 patients (10.7 %) and improvement was observed in 6 patients (21.4 %).
Bronchiolar nodules were more frequent (p?=?0.01).

Discussion

To our knowledge, this study reports the largest series of bronchiectasis diagnosed
after renal transplantation. The main finding of this study is that the clinical and
microbiological characteristics of bronchiectasis are similar to those usually described
in non-cystic fibrosis (CF) bronchiectasis 12]: (1) chronic sputum or recurrent bronchitis are the most common symptoms; (2) an
obstructive disorder is frequently associated; (3) Haemophilus influenzae is the most common micro-organism identified. However, some results need to be highlighted.
First, bronchiectasis can be diagnosed very late after renal transplantation, as illustrated
by the two previous reports in adults with a mean time to diagnosis ranging from 3
to 11.7 years 6], 7]. Second, a CT scan gradient was observed from the apex to the bases. Previous reports
have described a predominance of bronchiectasis in lower lobes in 3 patients, while
the distribution of bronchiectasis was not specified in the other 12 cases 6]–8]. Interestingly, other forms of non-CF bronchiectasis also exhibit such predominance
in the bases 13], 14]. Third, the bronchiectasis score frequently deteriorated during follow-up. As observed
in our study, some previous reports have shown that patients with non-CF bronchiectasis
had persistent or worsening symptoms on long-term follow-up 15], but very limited data are available on the course of bronchiectasis based on follow-up
CT scan score 16], 17]. Finally, the overall mortality in our series was 13 % with a median follow-up of
3 years, similar to the results of recent studies that have reported mortality rates
ranging between 16.3 % at 4 years and 29.7 % at 13 years in non-CF bronchiectasis
18]–20]. In a long-term prospective study, Loebinger et al. found that the primary cause
of death was respiratory (70.4 %), especially respiratory infection or failure 19]. In contrast, despite frequent respiratory infections, no death was related to a
respiratory cause in our series.

Prior to the study by Pijnenburg et al. in 2004, no case of bronchiectasis occurring
after renal transplantation had been reported in the literature 8]. In our study, only two patients had a diagnosis of bronchiectasis before 2004 (data
not shown). Bronchiectases were then mainly diagnosed within the ten last years, which
may be related to expanded indications of CT-scan and changes in immunosuppression
strategy. The absence of systematic chest CT scan before or just after renal transplantation
does not allow pre-existing bronchiectasis to be formally excluded. A chest CT scan
without bronchiectasis was available for only 12 patients (three before and nine after
renal transplantation). The presence of asymptomatic bronchiectasis before transplantation
in some cases therefore cannot be formally excluded. In particular, one patient had
rheumatoid arthritis and another had a history of mycobacterial infection, two potential
causes of bronchiectasis 12], 21]. Moreover, patients with ADPKD could also be at increased risk of bronchiectasis,
as recent studies have demonstrated an increased prevalence of mild-to-moderate cylindrical
bronchiectasis with bilateral lower lung predominance in ADPKD 22]–24]. ADPKD is associated with defective primary ciliary function in renal epithelial
cells. Functional abnormalities in polycystin-1 and 2, two membrane regulatory proteins
expressed in the cilia of both human airway epithelial and airway smooth muscle cells,
may result in radiological bronchiectasis due to decreased mucociliary clearance or
impaired airway injury repair 22], 24]. However, these studies present a number of limitations including the absence of
data on comorbidities associated with bronchiectasis 22] and the inclusion of transplant recipients 23]. At least, the minimal interval 0.4 year between first renal transplantation and
diagnosis of bronchiectasis, probably too short to develop bronchiectasis, argues
for undetected pre-existing bronchiectasis.

Bronchiectasis can be induced by primary or secondary immunodeficiency 12], 21], 25], 26]. Drug-induced immunosuppression following transplantation predisposes to recurrent
lung infections and increases the risk of bronchiectasis after bone marrow, heart
or lung transplantation 27]–29]. Low immunoglobulin and mannose binding protein levels after renal transplantation
are associated with infectious complications 30]. In our series, 15 patients exhibited hypogammaglobulinemia, which may contribute
to the development of bronchiectasis 7].

Three recent studies have suggested that MPA may be a causative factor of bronchiectasis
6]–8]. MPA is a relatively new immunosuppressive drug commonly used in renal transplantation
for the prevention and treatment of allograft rejection. According to the results
of these three studies, the potential involvement of MPA is based on the following
arguments: 1) some patients did not have any respiratory symptoms despite long periods
with other immunosuppressive drugs 8]; 2) an improvement of symptoms after MPA withdrawal was observed in some patients
6]; 3) some cases of bronchiectasis have been described in children who have received
renal transplantation with MPA, whereas bronchiectasis is usually very uncommon at
this age in the absence of CF or immunodeficiency 8]. In our series, five patients not treated by MPA for a first renal transplantation
developed symptomatic bronchiectasis after a second or third renal transplantation
with MPA treatment. Two mechanisms have been proposed to explain the role of MPA in
bronchiectasis. First, MPA, as a potent inosine monophosphate dehydrogenase inhibitor,
inhibits purine synthesis and severely depresses both cell-mediated and humoral immunity
by inhibiting T- and B-cell proliferation. The resulting hypogammaglobulinemia has
been shown to be more frequent and more severe in patients receiving MPA compared
to other immunosuppressive drugs 31]. Only six of the 15 patients with hypogammaglobulinemia in our study received immunoglobulin
replacement therapy. Second, MPA may directly affect bronchial epithelium by altering
mucociliary clearance 32].

Our results should be interpreted in the context of the several limitations of this
study. 1) The retrospective identification of the cases of bronchiectasis revealed
after renal transplantation is a major limitation. Even if the study design was as
rigorous possible, we can not exclude that a significant number of cases have not
been identified by the centres. 2) The retrospective design of this study does not
allow estimating the prevalence of the disease. 3) Thoracic CT scans were analysed
in all the cases by a panel of pulmonologists, and radiologist. Cases were included
in the study in presence of defined bronchiectasis. However, since HRCT scan was not
available for each patients, we cannot rule out that distal bronchiectasis should
not be visualized in some patients. 4) Observation bias may exist, even if it has
been minimized by using a standardized data collection form. In particular, information
on respiratory medical history may have been underreported. 5) The spirometry, biological
and microbiological data were very heterogeneous. Moreover, the role of potentially
pathogenic micro-organisms in the clinical course of bronchiectasis cannot be determined
in absence of repeated respiratory samplings, micro-organisms quantification and characterisation
of associated clinical status. 6) No conclusion can be drawn on the interest of MPA
withdrawal or immunoglobulin replacement therapy due to the retrospective design and
the small number of patients. Despite these limitations, we believe that our study
provides important findings on the characteristics of bronchiectasis occurring after
renal transplantation.

Finally, it should be stressed that, even after intensive investigation, one or more
causative factors are identified in only 47 % of cases of bronchiectasis 21]. It can therefore be hypothesized that multifactorial mechanisms, including underlying
diseases, immunosuppressive drugs and respiratory tract infections, could contribute
to the pathogenesis or clinical emergence of bronchiectasis after renal transplantation.
Due to the retrospective design of our study and the small number of patients, we
were not able to perform subgroup analyses in order to determine the burden of causal
variables such as ADPKD, MPA and immunoglobulin deficiency. Similar studies would
be interesting in other solid organ (liver and heart) transplantation.