EP2513827A1 - Method and device for determining a risk of graft rejection - Google Patents
Method and device for determining a risk of graft rejectionInfo
- Publication number
- EP2513827A1 EP2513827A1 EP10798295A EP10798295A EP2513827A1 EP 2513827 A1 EP2513827 A1 EP 2513827A1 EP 10798295 A EP10798295 A EP 10798295A EP 10798295 A EP10798295 A EP 10798295A EP 2513827 A1 EP2513827 A1 EP 2513827A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- recipient
- transplantation
- determining
- range
- threshold value
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
- G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
- G16H40/63—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices for local operation
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16Z—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS, NOT OTHERWISE PROVIDED FOR
- G16Z99/00—Subject matter not provided for in other main groups of this subclass
Definitions
- the invention is in the field of transplantations (or transplant) of a patient, in the field of kidney transplants.
- the invention is in the field of the management of a patient who has undergone kidney transplantation. More particularly, the invention lies in the field of estimation (or determination) of the risk of definitive rejection of a graft, including renal.
- biopsy analyzes it has been proposed to use biopsy analyzes to obtain a criterion for assessing the risk of rejection of a graft in the long term. Although such a procedure has some efficiency of determination, it remains a dangerous and expensive invasive method.
- non-invasive biomarkers collected via urine or blood
- have been proposed for the determination of the risk of rejection such as perforin, granzyme B, CD30 or specific donor antibodies.
- biomarkers require subsequent validations on large patient populations, and often appear too late to be surrogate markers (sometimes in a period of 15 to 20 months).
- Creatinine estimated at 6 and / or 12 months after transplantation is considered a marker with a good correlation with graft survival.
- critics have been issued, denouncing creatinine as a poorly predictive marker.
- An object of the present invention is to provide an early method (in the first year after the transplant) and an associated device for determining the risk of permanent rejection of a graft in the long term.
- Another object of the present invention is to provide a method for evaluating a risk of definitive rejection, this method being simple to implement and non-invasive.
- Another object of the present invention is to provide a more reliable method than the methods of determining the risk of definitive rejection proposed by the state of the art.
- the invention relates to a method for determining a risk of definitive rejection of a graft after transplantation on a recipient, characterized in that it comprises the following steps:
- a creatinine level of the recipient measured at two at least one determined moment after the transplantation, a level of proteinuria of the recipient measured at a given moment after the transplantation,
- Levels of creatinine of the graft donor at the time of collection will be understood to mean the creatinine level of the donor before removal of the graft for said transplantation.
- Such a method makes it possible to offer, after one year following the transplant (or transplantation), a score associated with the definitive rejection of the renal graft in the long term, typically eight years following the transplantation.
- the term "recipient” will be understood to mean the subject who receives the graft during a transplantation and by "donor” that from which said graft is taken.
- the invention comprises at least one of the following characteristics:
- the characteristics include two levels of creatinine in the recipient measured at two specific times after transplantation
- the step of determining the parameters comprises the determination of a Boolean parameter by comparing the creatinine level of the donor at the time of sampling with a threshold value
- the step of determining the parameters comprises the determination of a Boolean parameter by comparing the the age of the recipient with a threshold value
- step of determining the parameters comprises determining a Boolean parameter by comparing the number of previous renal transplants of the recipient with a threshold value
- the step of determining the parameters comprises the determination of a numerical parameter of each creatinine level expressed in a predetermined unit
- the step of determining the parameters comprises determining at least one numerical parameter of the proteinuria level expressed in a predetermined unit
- the step of determining the parameters comprises determining a Boolean parameter as a function of the existence or not of an acute rejection episode declared in the first year of the transplantation,
- the combination is a weighted sum
- KTFS Ki * Cr_D + K 2 * Age_R + K 3 * Ntrans + K4 * AR + K 5 * Cr_3m + K6 * V (Cr_12m) + K 7 * Gender + Ks * Pr_12m + K 9 * (Pr_12m) A 2 + Ki 0 * Gender * Pr_12m + Kn * Gender * (Pr_12m) A 2, where KTFS is the risk score,
- Cr_D is equal to 1 if the creatinine level of the donor at the time of sampling is greater than a threshold value and 0 otherwise
- Age_R is equal to 1 if the age of the recipient is greater than a threshold value and 0 in the opposite case
- Ntrans is equal to 1 if the number of previous renal transplants of the recipient is greater than a threshold value and 0 otherwise, AR is 1 if at least one acute rejection episode was reported in the first year of transplantation recipient and 0 otherwise, Cr_3m is the creatinine level of the recipient measured at a first moment after transplantation,
- Cr_12m is the creatinine level of the recipient measured at a second moment after transplantation
- Pr_12m is the rate of proteinuria of the recipient measured at a given time after transplantation
- Gender is 1 if the catcher is a man and 0 if the catcher is a woman
- Ki to Ki i are coefficients.
- the threshold value for the creatinine level of the donor is 190 ⁇ / L
- the creatine levels of the recipient are expressed in ⁇ / L
- the first and second given moments are respectively 3 months and 12 months
- the proteinuria level is expressed in g / day
- the time given for the proteinuria rate is 12 months
- Ki is chosen in a range from -1, 04 to -0.41,
- K 2 is chosen in a range from -1.10 to -0.92
- K 3 is chosen in a range from 0.89 to 1, 26,
- K 4 is chosen in a range from 0.20 to 0.33
- K 5 is selected in a range of -0.03 to 0.03,
- K ⁇ is selected in a range from 0.34 to 0.48
- K 7 is selected in a range of -0.94 -0.76,
- Kg is chosen in a range from 0.50 to 0.69
- K 9 is selected in the range of -0.08 to 0.13
- K 10 is chosen in a range from 0.38 to 0.60
- K 1 1 is chosen in a range from -0.25 to 0.15
- Ki 1 -0.0508
- the analysis of the risk score includes a step of comparing said score with a threshold value, a score greater than the threshold value meaning that the recipient is considered to be at risk of returning to dialysis,
- the invention also relates to a product / computer program containing a set of instructions specific to the implementation of the method according to the invention.
- the invention also relates to a processing system comprising a computing unit and an input interface, characterized in that it comprises means for implementing the method according to the invention.
- FIG. 1 is a schematic representation of a processing system according to a particular embodiment of the present invention
- FIG. 2 is a functional graph showing a method according to a particular embodiment of the present invention
- Figure 3 is a survival probability graph of a graft.
- a device 1 comprises a computing unit 10 capable of following computer instructions and data processing.
- a calculation unit preferably comprises a microprocessor 110 which can be of any type known from the state of the art.
- the computing unit 10 also has a storage unit 100 able to receive a computer program comprising a set of instructions specific to the implementation of the method, and to store data.
- the device 1 also comprises an input interface 12 connected to the computing unit 10 allowing a user O of the device 1 to enter data to be processed.
- Such an input interface 12 includes any element allowing input of such data to the computing unit 10 as a keyboard element optionally associated with a mouse element.
- the calculation unit furthermore comprises an output interface 14 such as a screen that allows the user to check the integrity of the data entered but also allows the computing unit 10 to be able to dialogue with the user O.
- the device 1 can be integrated in the same system as a computer or a smart mobile phone ("smartphone" in English) or any other known system of the state of the art to put in the process according to the invention.
- User O may be of any qualification and may or may not have medical qualifications.
- the data entered by the user O are sent via a network (for example the Internet) preferably in a secure manner to a remote server comprising a calculation unit capable of implementing the method according to the invention and thus to process the data received by the server.
- a remote server comprising a calculation unit capable of implementing the method according to the invention and thus to process the data received by the server.
- the server returns the result of the analysis to the user via the same network or another.
- the server stores the data and / or the result of the analysis on a means of recording.
- such a device 1 makes it possible to implement the method according to the invention, that is to say that it allows the implementation of the following steps: introducing physiological / clinical characteristics using the input interface 12 in a computing unit 10 (step 22), said features comprising:
- the creatinine level of the recipient measured at at least two moments determined after the transplantation
- analyzing said risk score to determine a risk of definitive rejection of a graft (step 25).
- the calculated score allows the determination of the risk of long-term rejection of a graft after renal transplantation for a recipient. It is based on a synthesis of a plurality of clinical risk factors.
- the method according to the invention can be implemented not only by the clinical or hospital staff but also by all the stakeholders in clinical research (pharmaceutical industry, scientists, doctors, etc.).
- the score resulting from the method of the invention is more precisely based on the weighted sum of clinical characteristics. Weights were statistically determined by using the linear predictor of the Cox model corrected by maximizing the area under the time-dependent ROC curve at 8 years after transplantation. The time studied is the delay between the transplant and the return to dialysis. 3040 patients from the observational cohort DIVAT (Computerized Data and Transplantation Ideas) were included for the estimation of this model.
- the model advantageously takes into account the characteristics include two levels of creatinine of the recipient measured at two specific times after transplantation. Indeed, it has been noticed that the taking into account of these characteristics was relevant. Specifically, the two determined times are approximately 3 months and 12 months after transplantation.
- this model established the relevance of measuring proteinuria after 12 months after transplantation. Indeed, taking into account such a characteristic was relevant.
- An important point of the model is the determination of the parameters related to the characteristics. In particular, several types of parameter determination are provided:
- the determined model is advantageously a combination of these parameters and more specifically a weighted sum.
- the score is based on a formula of the following type:
- KTFS Ki * Cr_D + K 2 * Age_R + K 3 * Ntrans + ICi * AR +
- Cr_D is equal to 1 if the creatinine level of the donor at the time of transplantation is greater than a threshold value and 0 in the opposite case
- Age_R is equal to 1 if the age of the recipient is greater than a threshold value and 0 otherwise
- Ntrans is equal to 1 if the number of previous transplants of the recipient is greater than a threshold value and 0 otherwise, 0 AR is equal to 1 if at least one definitive rejection episode was reported in the first year after the previous transplantation and 0 if not,
- Cr_3m and Cr_12m are the creatinine level of the recipient measured at at least two determined moments after transplantation
- Pr_12m is the rate of proteinuria of the recipient measured at a given time after transplantation
- Gender is 1 if the catcher is a man and 0 if the catcher is a woman
- Ki to Ki i are weighting coefficients.
- Age R 1 if the recipient's age at transplant is greater than 25 years and 0 otherwise
- Ntrans 1 if the number of previous transplants of the recipient is greater than 2 and 0 otherwise
- Pr_12m Proteinuria of the recipient measured at 1 year after the transplant in g / day A 1 if a definitive rejection episode was declared for the recipient in the first of a previous transplant and 0 otherwise
- Ki to 3 ⁇ 4i are advantageously chosen in the following ranges:
- Ki is chosen in a range from -1.04 to -0.41,
- K 2 is chosen in a range from -1.10 to -0.92,
- K 3 is chosen in a range from 0.89 to 1.26
- K 4 is chosen in a range from 0.20 to 0.33
- K 5 is selected in a range of -0.03 to 0.03,
- e is selected in a range from 0.34 to 0.48
- 0 K 7 is selected in a range of -0.94 -0.76,
- Kg is chosen in a range from 0.50 to 0.69
- K 9 is selected in the range of -0.08 to 0.13
- K 10 is chosen in a range from 0.38 to 0.60
- K 1 1 is chosen in a range from -0.25 to 0.15.
- the parameters Ki to Ki 1 have the following values:
- KTFS -0.72649 * Cr_D - l, 01017 * Age_R + 1, 07482 * Ntrans + 0.26395 * AR + 0.00114 * Cr_3m + 0.41084 * V (Cr_12m) - 0.85292 * Gender + 0, 59253 * Pr_12m + 0.02298 * (Pr_12m) A 2 + 0.48762 * Gender * Pr_12m - 0.05078 * Gender * (Pr_12m) A 2
- the determination and the combination of parameters derived from said characteristics makes it possible to offer a method for determining the risk of definitive rejection of a graft having an increased reliability compared with the state of the art.
- the use of parameters makes it possible to construct a predictive score without necessarily seeking to directly interpret the characteristics entered, as is the case in evaluation procedures. of the state of the art. It is notably this division between the clinical characteristics and their interpretation via the elaboration of parameters which allows an improved determination of the risk of definitive rejection signifying a return to dialysis.
- such a method allows the improvement of the care with a follow-up of a patient adapted to its risk of definitive rejection and it allows an optimization of the resources towards the most fragile patients.
- the method according to the invention makes it possible to shorten certain studies, in particular industrial protocols, and thus to make it possible to reduce costs and improve the benefit / risk balance for the benefit of patients.
- FIG. 3 which illustrates kidney transplant survival in the first eight years of transplantation based on the score calculated one year after transplantation
- the identification of two groups of patients according to the risk of return to dialysis is clear.
- the x-axis represents the elapsed time (in years) after transplantation and the y-axis the probability of survival of the graft expressed on a scale of 0 to 1.
- the probability of returning to dialysis before eight years of transplant is about 7%.
- This probability is of the order of 30% (high risk) in the second group (in broken lines) corresponding to a score greater than 4.04.
- the method according to the invention was tested and validated on an external sample of 343. patients.
- the method of the invention is only suitable for renal transplantation.
- the method according to the invention can advantageously be used as a criterion of determination, whether primary or secondary, in studies or research protocols. Indeed, using this method, it is possible to measure early risk of permanent rejection of a graft and allows shorter studies and therefore less risky for the patient and less expensive for the promoter of the study.
- the method according to the invention also advantageously comprises a preliminary step of measuring the creatinine of the donor at the time of sampling.
- one or more other characteristic (s) may be taken into account and therefore introduced ( s) during step (a).
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- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Medical Informatics (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Primary Health Care (AREA)
- General Health & Medical Sciences (AREA)
- Data Mining & Analysis (AREA)
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- General Business, Economics & Management (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0959043A FR2953956B1 (en) | 2009-12-16 | 2009-12-16 | METHOD AND DEVICE FOR DETERMINING A RISK OF REJECTION |
PCT/EP2010/069785 WO2011073268A1 (en) | 2009-12-16 | 2010-12-15 | Method and device for determining a risk of graft rejection |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2513827A1 true EP2513827A1 (en) | 2012-10-24 |
Family
ID=42199629
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10798295A Withdrawn EP2513827A1 (en) | 2009-12-16 | 2010-12-15 | Method and device for determining a risk of graft rejection |
Country Status (5)
Country | Link |
---|---|
US (1) | US20130006067A1 (en) |
EP (1) | EP2513827A1 (en) |
CA (1) | CA2784939A1 (en) |
FR (1) | FR2953956B1 (en) |
WO (1) | WO2011073268A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9058756B2 (en) * | 2013-03-14 | 2015-06-16 | Magnet Works, Ltd. | Modular art-post assembly and method of using the same |
EP3380968B1 (en) | 2015-11-23 | 2021-04-28 | HeartFlow, Inc. | Systems and methods for assessing organ and/or tissue transplantation by simulating one or more transplant characteristics |
US20200170580A1 (en) * | 2017-05-24 | 2020-06-04 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for assessing graft failure risk |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002095402A2 (en) * | 2001-04-18 | 2002-11-28 | Mcgill University | Individualization of therapy with hyperlipidemia agents |
US20080082358A1 (en) * | 2006-09-29 | 2008-04-03 | Cerner Innovation, Inc. | Clinical Decision Support Triggered From Another Clinical Decision Support |
-
2009
- 2009-12-16 FR FR0959043A patent/FR2953956B1/en active Active
-
2010
- 2010-12-15 US US13/516,707 patent/US20130006067A1/en not_active Abandoned
- 2010-12-15 CA CA2784939A patent/CA2784939A1/en not_active Abandoned
- 2010-12-15 WO PCT/EP2010/069785 patent/WO2011073268A1/en active Application Filing
- 2010-12-15 EP EP10798295A patent/EP2513827A1/en not_active Withdrawn
Non-Patent Citations (2)
Title |
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None * |
See also references of WO2011073268A1 * |
Also Published As
Publication number | Publication date |
---|---|
FR2953956B1 (en) | 2012-01-27 |
CA2784939A1 (en) | 2011-06-23 |
WO2011073268A1 (en) | 2011-06-23 |
FR2953956A1 (en) | 2011-06-17 |
US20130006067A1 (en) | 2013-01-03 |
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Inventor name: SOULILLOU, JEAN-PAUL Inventor name: GIRAL, MAGALI Inventor name: FOUCHER, YOHANN Inventor name: DAGUIN, PASCAL |
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Owner name: UNIVERSITE DE NANTES Owner name: CHU NANTES |
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