Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03850756 |
| Other study ID # |
BIOTAB |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
March 4, 2019 |
| Est. completion date |
July 1, 2022 |
Study information
| Verified date |
July 2022 |
| Source |
Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Tobacco consumption is associated with the appearance of several pathologies, the best known
are Chronic Obstructive Pulmonary Disease, several types of cancer and cardiovascular
diseases. However, the association between tobacco and kidney damage is not well defined.
Some studies suggest that smoking favors progression to chronic kidney disease (CKD). CKD
does not have pharmacological treatment and the only clinical strategies useful so far are
dialysis or kidney transplantation. Therefore, knowing if tobacco is involved in this disease
is a very relevant fact, since it is a modifiable factor. Of all the risk factors associated
with the onset and progression of kidney disease is the only one that can be avoid or
eliminated. Therefore quitting smoking could help reduce the incidence of this pathology.
In this project, 3 main objectives were proposed:
1. First: to study the tobacco-CKD association in a more exhaustive way. In a population
group (patients who attend a primary care center) the renal function of smokers will be
evaluated, comparing it with that of non-smokers with similar characteristics (age, sex,
etc). In addition, the presence of certain pathologies that can affect the kidney
(diabetes mellitus, hypertension and / or frequent consumption of certain medications)
will be taken into account. To evaluate the renal functionality, the markers commonly
used in the clinic and other more novel ones will be used (urinary biomarkers of early
kidney damage).
2. Second: to assess whether smoking patients will be more likely to suffer kidney damage
in the future. This will be done by monitoring the patients mentioned above, for two
years. During this time, a group of novel markers (urinary biomarkers of predisposition
to kidney damage) that in previous studies have detected susceptibility to kidney damage
will be evaluated. It will be determined which one or more of these markers are capable
of predicting at time 0 (when the first sample of the patient is taken) the subsequent
appearance of renal damage.
3. Third: to study whether stopping smoking reduces the risk of developing CKD. It will be
evaluated whether stopping smoking reduces the susceptibility to kidney damage by using
the biomarkers mentioned above.
Description:
According to the WHO, smoking is the main cause of preventable disease and death, being a
known risk factor for the development of cancer, respiratory diseases, cardiovascular
diseases, etc. Despite the fact that the first associations between smoking and kidney
disease date back to the beginning of the last century, up to the present time, evidence has
been scarce and inconclusive in the population without risk factors associated with kidney
disease.
The increase in the worldwide prevalence of chronic kidney disease and the notable increase
in the incidence of patients reaching the final stage of the same, have alerted health
systems and have determined that nephrologists focus more on the identification of
potentially modifiable prevention factors. Chronic kidney disease has a very high social and
economic cost (almost 10% of the affected population and 3% of total health expenditure),
which requires coordinated criteria among health professionals to ensure the best levels of
quality in prevention, diagnosis and treatment. In this sense, it is recognized that the key
to preventive success is a very early diagnosis that allows intervention when the renal
functional reserve has not yet been exhausted and, therefore, the excretory function is not
yet compromised. In the clinic, one of the most used tools in the diagnosis of kidney damage
is based on the detection in the blood of products of metabolism (creatinine, urea, etc.)
that begin to accumulate once the renal excretory capacity begins to decrease. However, when
the increase in serum urea and creatinine levels is observed, more than 70% of renal function
has been lost. Thus, current trends in diagnosis seek to find sensitive markers, specific,
and easy to quantify, that detect incipient pathophysiological events produced in early
stages, when the damage is less widespread.
To evaluate in depth the association between tobacco consumption and kidney damage, as well
as the capacity to recover renal function after cessation of consumption, a longitudinal
prospective observational study is proposed. Participants will be informed of the objectives
of the project and its benefits both verbally and in writing and will have to sign an
informed consent in accordance with the Declaration of Helsinki and the WHO standards for
observational studies. Patients will be included completely anonymously and their data will
be treated confidentially according to the current data protection legislation. Patients may
withdraw freely from the study at any time.
In this study, three main objectives have been proposed:
OBJECTIVE 1: To detect subclinical renal damage in smokers through a battery of early
markers.
Previously it was carried out a pilot study with 200 patients in order to check if certain
early biomarkers of kidney damage, were able to evidence a possible early lesion not
detectable with the usual techniques. The results showed an association between tobacco and
kidney damage that needs to be confirmed with a greater number of patients. Based on these
results, a new study is considered more robust in terms of the number of patients and broader
in terms of the determined markers. It is estimated to include a total of 500 patients (125
per group). The grouping of the same will be based on whether they smoke or not and also be
taken into account if they have certain risk factors associated with the onset of kidney
damage. Therefore, they will be divided into four groups: 1-No smokers without risk factors,
2-No smokers with risk factors, 3-Smokers without risk factors, 4-Smokers with risk factors.
At the time of inclusion in the study, each patient will obtain the following information:
date of collection of the sample; general data (age, sex, drug consumption); anthropometric
measurements (body weight, height, body mass index) and analytical biochemistry (plasma
creatinine and urea). Information will also be obtained on risk factors for kidney damage
(hypertension, diabetes, cardiovascular disease or chronic pain with frequent use of NSAIDs,
including the date of diagnosis, the prescribed drugs); tobacco use, the patient will fill
out a questionnaire adapted from the WHO MONICA study, which will allow us to classify them
as a smoker, non-smoker or ex-smoker and also know the number of cigarettes / cigars consumed
per day.
After the recruitment, a urine sample will also be taken in order to analyze the presence of
biomarkers of early kidney damage. In addition, the concentration of cotinine in urine
(nicotine metabolite) will be evaluated, which will allow to know indirectly the consumption
of tobacco in smokers and the absence of tobacco in non-smokers.
OBJECTIVE 2: To study if certain predisposing markers (albumin, and others in patent phase),
already identified in previous studies, are able to detect in patients who smoke those who
are predisposed to suffer acute kidney damage.
The second strategy proposed in this project raises a new concept of intervention even
earlier, before the damage occurs. It has been developed an innovative concept:
predisposition to kidney injury. It means that different drugs and renal toxins (in
completely subtoxic doses) are capable of predisposing, or making more sensitive to
experimental animals to acute kidney damage. The relevance of this situation is that
individuals apparently unaffected by the adverse effects of a treatment, or by exposure to
toxic substances (such as tobacco) could be exposed to develop acute kidney damage.
Associated with this condition it have been identified urinary markers. Their clinical
application will allow, not only to detect this predisposition, but to stratify the patients
in a preventive and personalized way according to the individual risk of each patient as a
result of apparently innocuous pharmacological treatments, or exposure to chemical
substances.
To respond to this second objective, a follow-up of 2 years will be carried out to patients
in groups 1 and 3, that is, to non-smokers, and to smokers both without risk factors. In this
way, the information provided by the markers of kidney damage may be associated with tobacco
consumption and not with other causes. In this case, it is estimated that the total number of
participants will be 100 per group since it is possible that a percentage of patients will be
lost during the follow-up phase. At 24 months, patients will come back to the clinic and
deliver a urine sample. In these samples and in the collections in the previous objective (0
months or baseline) the predisposition markers described above will be evaluated. The levels
of biomarkers of predisposition at the beginning of the study will be related to renal
function in the medium term, evaluated by biomarkers of early damage. In addition, the usual
clinical parameters (plasma creatinine, creatinine clearance, plasma urea and proteinuria)
will be taken into account.
OBJECTIVE 3: To study whether smoking cessation reduces subclinical renal damage and / or
predisposition to acute renal damage.
With this objective, it is proposed to study whether renal parameters and markers are
restored once smoking cessation ceases. Which would mean, not only that they are a useful
tool in terms of diagnosis, but also an efficient preventive measure.
For this purpose, patients from the "Smoking Unit of the University Assistance Complex of
Salamanca (CAUSA)" will be recruited. Those patients who agree to participate in the study
will deliver a urine sample at the time of inclusion (time 0 or baseline) and also during
follow-up at 3, 6 and 12 months. In these urine samples the markers mentioned in the two
previous objectives will be determined. The data provided by the markers of both early injury
and predisposition will be useful to analyze the evolution of renal function after the
cessation of tobacco use. With this information it well be checked if smoking cessation
reduces subclinical renal damage and / or the risk of acute renal damage.
As in Objective 1, after the inclusion of the patient, the following data will be obtained:
date of collection of the sample; general data, anthropometric measurements, analytical
biochemistry, information about risk factors for kidney damage, date of the diagnosis,
prescribed drugs, questionnaire adapted from the WHO MONICA study. Other parameters will also
be obtained, such as the concentration of carbon monoxide in exhaled air (measured with a
co-oximeter) and the concentration of cotinine in the blood.
COLLECTION OF SAMPLES AND PROCESSING Each patient will be assigned a code, so its identity
will only be known by the treating physician. Urine samples will be identified under the
established code. Once collected (both those of the Primary Care Center and those of the
Smoking Unit), they will be transferred to the CAUSA Sample Bank, where they will be
centrifuged, aliquoted and stored at -80 degrees Celsius until they are determined.
ANALYSIS OF URINE SAMPLES All the analytical determinations of this study will be carried out
in the laboratories of the "Tera-gnostics of Renal and Cardiovascular Diseases" group of the
Bio-sanitary Institute of Salamanca (IBSAL). These determinations will be as follows:
proteinuria as a clinical marker of damage by Bradford colorimetric method; early markers of
kidney damage by colorimetric kits, ELISA and Western Blot; predisposition markers (in patent
phase) by Western Blot, ELISA; Tobacco use marker (cotinine in urine) by ELISA. All urinary
concentrations of markers will be corrected by urinary creatinine (colorimetric kit).
STATISTIC ANALYSIS A significance level of 0.05 will be used. The data analysis will be
performed with STATA 10 and Statistical Package for the Social Sciences (SPSS) 20.0.
Different contrasts will be applied depending on the association that is to be studied in
each case, and the type of variables, such as: normality test (Kolmogorov-Smirnov,
Shapiro-Wilk), frequency comparison (χ2), correlation test (Pearson, Spearman), comparison of
means for independent data (ANOVA and Kruskal-Wallis) and repeated measures ANOVA and
Wilcoxon test for paired data. Finally, to study simultaneously datasets with several
variables measured for each individual or parameter collected, a Multivariate Analysis will
be used, such as: regression analysis, general linear models, binary logistic regression and
correspondence analysis.
LIMITATIONS OF THE STUDY Although the study follows all the recommendations for observational
studies considered in the STROBE statement (STrengthening the Reporting of OBservational
studies in Epidemiology), there is a possibility that there are factors that have not been
considered. On the other hand, the included variables are biomarkers of early kidney damage
and predisposition to acute renal damage induced by certain renal toxins. It is possible that
there are other markers (unknown), that are not being analyzed, and that can predict the
kidney damage associated with smoking.
CONCLUSION In short, this project addresses two issues of high concern in the health field,
which are smoking and chronic kidney disease. From its conceptual basis, it raises the
possibility of finding a diagnostic tool for the early detection of chronic kidney damage
associated with tobacco consumption, with a preventive purpose in terms of the development of
the disease and in a personalized way regarding the hypersensitivity of each patient. .
Account for it with a consortium of researchers and clinicians consisting of: 1) experts in
markers of kidney damage, 2) clinicians specialized in lifestyles and cardiovascular risk, 3)
specialists in smoking.
