Clinical Trial Details
— Status: Recruiting
Administrative data
NCT number |
NCT04713774 |
Other study ID # |
Liege REBON Vasc |
Secondary ID |
|
Status |
Recruiting |
Phase |
|
First received |
|
Last updated |
|
Start date |
September 1, 2020 |
Est. completion date |
September 1, 2024 |
Study information
Verified date |
November 2023 |
Source |
University of Liege |
Contact |
Antoine Bouquegneau |
Phone |
+32473353321 |
Email |
antoine.bouquegneau[@]gmail.com |
Is FDA regulated |
No |
Health authority |
|
Study type |
Observational
|
Clinical Trial Summary
The investigators project is based on:
- Assessment of bone architecture by high resolution peripheral scanner (HRpQCT) and bone
densitometry (DEXA);
- The non-invasive detection of vascular calcifications (by abdominal CT scanner) and bone
abnormalities associated with kidney transplantation, as well as the analysis of
evolution over time;
- Longitudinal evaluation of nephrological clinical parameters (glomerular filtration
rate, number and type of rejections, immunosuppressive medications) as well as
biological and urinary parameters of mineral metabolism (parathormone, sclerostin, bone
alkaline phosphatase) depending on the type and severity of bone abnormalities;
- The evaluation of these nephrological clinical parameters and of the biological
parameters of mineral metabolism depending on the extent and evolution of vascular
calcifications but also on bone morphology;
- The study of possible relationships between bone mass and muscle mass (and functioning)
Description:
Bone and mineral abnormalities are frequent in kidney transplant patients and are associated
with a high risk of fracture, cardiovascular mortality, but also with an increase in the
frequency of hospitalisations and thus healthcare's costs. The pathophysiology of bone
disorders appearing after transplantation arises from a complex interaction between different
factors. These include both pre-transplant renal osteodystrophy lesions and bone loss
associated with the kidney transplant itself. This bone loss results from a variety of
causes. The management of these bone abnormalities is complex in daily clinical practice
because only the bone biopsy can accurately determine the type of abnormality present, and
this examination is rarely performed due to its invasive nature. The link between the
development of bone abnormalities and the presence or even the progression of vascular
calcifications remains very poorly understood. This link is however fundamental because
vascular calcifications could explain the increased risk of cardiovascular mortality in these
patients. Understanding and diagnosing bone abnormalities early, ideally in a non-invasive
manner, could help prevent bone and vascular degradation frequently found after renal
transplantation.
Despite significant improvement in recent years, mortality as well as cardiovascular
morbidity remain very high in kidney transplant patients. The reported annual risk of fatal
or non-fatal cardiovascular events is 3.5% to 5%, even after adjusting for traditional risk
factors (such as diabetes, hypertension, obesity, smoking and dyslipidemia). Certain factors
related to chronic kidney disease (CKD) or transplant appear to influence the high incidence
of cardiovascular events. These include, among others, the duration of dialysis before the
transplant, the function of the graft after transplantation, proteinuria, episodes of acute
rejection, new cases of post-transplant diabetes, the toxic effects of immunosuppressive
drugs but also the bone metabolism abnormalities observed in transplant patients.
It is therefore essential to be able to accurately assess the presence of abnormalities in
bone metabolism by non-invasive techniques and thus to determine whether or not there is a
link between them and cardiovascular morbidity and mortality. This allows appropriate
management as well as a precise assessment of the impact of new drugs on bone metabolism and
the future of transplant patients.
Currently, the clinical management of bone abnormalities includes the use of surrogate
biochemical markers such as parathyroid hormone (PTH), bone alkaline phosphatases (bPhA),
osteoprotegerin (OPG), the N-terminal propeptide of procollagen type I (P1NP), tartrate
resistant acid phosphatase type 5b (TRAP5b), C-terminal collagen type I telopeptides (CTX),
osteocalcin and sclerostin. There are conflicting data in the literature as to their
correlation with histological and histomorphometric analysis of bone biopsies. These
biomarkers tend to take a place in the diagnosis and in the follow-up of patients with
abnormalities of bone metabolism, as well as possibly in the detection of vascular
calcifications. However, the effectiveness and reliability of this biochemical approach
remain to be demonstrated.
On the other hand, imaging techniques allow us to approach the bone structure. They could
therefore also be associated with biomarkers to replace bone biopsy. Bone density by
bi-photonic x-ray absorptiometry (DEXA) is a relatively accurate and non-invasive screening
method for estimating bone mass, mainly trabecular, and which appears to help predict the
risk of fracture in kidney transplant patients. DEXA is, however, unable to assess the
microarchitecture of bone and only provides a two-dimensional assessment of bone density. The
correlation between BMD and fracture risk is, however, much less clear in patients with renal
impairment and some studies sometimes even find an absence of correlation. Currently a new
software used in DEXA, the Trabecular Bone Score (TBS), seems to help in the assessment of
bone microarchitecture. This score is most often weighted with the FRAX to give a better
value of the fracture risk. Some data currently appear in the normal population, but no
robust data are present in kidney transplant patients.
On the other hand, the peripheral high-resolution scanner (HRpQCT) provides information on
the bone micro-architecture as well as a quantitative measurement of the volumetric density
of the cortical bone, which is more impacted during renal failure, and. In this context, the
investigators goal in this study is to collect all of these biological and imaging data in
order to predict the underlying bone histomorphometry.
The analysis of bone density by DEXA will be carried out at the vertebral, hip and wrist
level as a direct result of the transplantation (first 10 days post transplant) at 3 months
and then annually for all renal transplant patients included in the study. Analysed of the
relevance of this examination for the detection of BMD and long-term fracture risk
(longitudinal study). The TBS will also be assessed by the same exam to assess its
sensitivity for the detection of fracture risk.
The high-resolution scanner will be performed on the distal part of the radius and tibia for
the evaluation of bone micro-architecture. This examination will be performed at the same
frequency as the DEXA.
Then we will evaluate prospectively (at 3 months and 12 months) with a longitudinal follow-up
the various BMD data related to the presence and evolution of vascular calcifications (see
below) detected by DEXA as well as the various blood and urinary biomarkers.
Markers such as vitamin D, Ca2 +, PTH, bPhA, OPG, P1NP, TRAP5b, CTX, osteocalcin, sclerostin,
vitamin K and the decarboxylated and dephosphorylated form of the matrix-Gla protein (MGP),
and intact fibroblast growth factor 23 (FGF23) will be evaluated in order to seek a possible
link with graft survival, the development of vascular calcifications and the risk of
fractures. Depending on the results of the DEXA performed and if a therapeutic indication is
considered in the context of fracture osteoporosis (bisphosphonates, denosumab), the patients
will be followed prospectively and their data will be collected.
A measurement of DEXA and bone microarchitecture by HRpQCT will also be carried out
bilaterally in the upper limbs in order to assess the impact of the location of the
arteriovenous fistula on bone density in view of the possible impact described in the
literature on a population of hemodialysis patients
The assessment of renal fibrosis will also be analyzed on the basis of renal biopsies
performed routinely in transplant patients at 3 months and in the event of biopsies performed
due to deterioration of renal function. The assessment of the degree of fibrosis will be
analyzed in light of the abnormalities of the phosphocalcic balance to see if a link between
the two exists.
Currently the reference technique for the detection of calcifications remains the chest
scanner with detection of CAC. This tedious and irradiating technique is however difficult to
use in current clinical practice. Calcifications of the abdominal aorta (AA) are as important
as CAC and are associated with sudden death mortality in patients with renal failure. In the
general population, the detection of calcifications by CT scan or by lateral radiography at
the AAA level (AAB profile) has shown good correlations with the level of CAC. In the general
population, the measurement of AA calcifications based on the lateral radiography images used
during DEXA also seems to demonstrate good sensitivities and specificities, when the images
obtained by DEXA are compared to the radiography of the AAB and to detection of AA
calcifications by CT scan. In a population of transplant patients, the demonstration of
calcifications via DEXA was associated with the risk of cardiovascular mortality of patients
but has never been compared to the profile blank abdomen which remains the standard
technique. In the population of kidney transplant patients, the literature has not
established a link between the detection of calcifications by these two techniques (DEXA and
abdominal scan) on the risk of cardiovascular events.
The hypothesis is that the detection and follow-up of calcifications in the aorta could only
be done with this simple and rapid test, DEXA, and that it could therefore be combined with
the measurement of BMD. We will therefore study the correlation between calcifications of the
abdominal aorta detected by abdominal CT scan and those detected by DEXA.
The first objective is to prospectively study between 40 and 50 transplant patients. We will
measure the calcifications observed by DEXA and follow them over time (first measurement
carried out 3 months after transplant, and then once a year). Correlation analyzes will be
performed to assess the sensitivity of the different techniques for the detection of
calcifications both between techniques (abdominal CT scan during the first 10 days
post-transplant and at 1 year) as well as between observers (3 observers: radiologist,
nephrologist and rheumatologist). A measurement of the difference in calcifications according
to the examinations will be evaluated to make it possible to assess the evolution of
calcifications in the same patient according to the different clinical and biological
parameters