I. Positive Luminex and negative flow cytometry in kidney transplantation: a systematic review and meta-analysis
- Please summarise this article with reflection on your practice if possible.
- What is the level of evidence provided by this study?
- What are the weakness and strength of this article?
- What is meant by the impact factor and how it is calculated?
systematic review article.
Level of evidence 1 , its` strength,All the studies included were of good quality. And its weakness, Inclusion of only a small number of studies (7 out of 1124 articles)
The article focuses on the significance of detecting low-level DSA only by Luminex along with negative FCM) on GFR, graft, patient survival, and acute rejection.
No significant difference was found between patients with PLNF and those with negative crossmatch and negative Luminex in the incidence of AR at 1 year, graft failure at 1 and 5 years, patient survival at 1 and 5 years.
The complement-fixing AB is more clinically significant than non-complement fixing AB since it is associated with ABMR and C4d staining which affects graft survival.
DSAs directed against HLA-A, HLA-B and HLA-DR are associated with earlier AMR when compared to DSA directed to HLADQ, also DSA directed against HLA C and HLA DP may have clinical significance.
Impact factor:
It is an index calculated by clarivet. It denotes the average number of citations of the articles published in a journal in the last 2 years. It is a measure of the reputation or stature of the journal with the higher the impact factor
PLNF transplantation is not frequently discussed in the published literature. Our systematic review and pooled analysis suggest that the incidence of AR, graft failure and patient mortality
is not significantly different in PLNF compared with DSA-negative transplants. However, the best desensitization strategy, if
any required, remains indeterminate. Considering the increasing kidney transplant shortage and the unremitting struggle for
timely access to transplantation, the avoidance of PLNF transplants may be unwarranted especially in patients who have
been enlisted for a long time. Multicentre collaboration and
long-term follow-up are required to better stratify the risks involved in PLNF transplantation.
Level I study with short duration.
Positive CDC xm carry high immunological risk.
less evidence for Positive Luminex negative Fcmxm.
Study shows no effect between those positive and negative Luminex in term of graft .
survival ,rejection.
Type of study ?
System. Reviews, level of evidence 1.
Advantage of study:
Level A study.
Limitations :
short duration.
Outcome not uniformly measured.
No standard cut off for MFI.
.Impact factors:
Total number. Of citation divided. By number of published. Articles.
The higher the better cited journal.
1. Please summarise this article with reflection on your practice if possible.
It was previously thought that positive preformed DSA ,is always associated with worse outcomes in comparison to DSA negative recipients . However, it has recently been appreciated that not all DSAs carry the same risk . DSAs are detected by Luminex assay with MFI as a rough measurement of their level.
a positive CDCXM is considered a high immunological risk that carries worse outcomes, while negative FCMXM is the at the lowest immunological risk with the best outcomes.
A question needs an answer was raised about the clinical significance and impact of low-level DSA detected by Luminex (positive Luminex) and negative FCMXM. (PLNF).
This systematic review of 7 retrospective studies was done to find an answer. Comparing a group of patients with (PLNF, positive luminex negative flowcytometry) with other of negative DSAs as regard acute graft rejection (AR), graft survival and patient survival .
Outcomes of the review was as follows:
Graft Function :There was no statistically significant difference in serum creatinine between the two groups in the studies conducted by Gupta et al. [3]
Variable results of Acute rejection rates during the first year postTx: some studies showed higher rates of rejection among the PLNF group others with shorter duration of follow up not exceeding 6 months showed no significant difference in rates among both groups.
Graft survival : agraft failure rates of 50% of patients among the PLNF group within a mean follow up duration of 2.8 years in crrespondance to 16.7% of negative DSAs patients. this difference seems significant, but no statistical analysis was reported. [2]
Patient survival : no reported stastically significance between PLNF and DSA-negative transplants.
As a Conclusion:
No significant evidence that low-level DSA detected by Luminex carry a significant clinical risk at least in short to medium term post Tx. Although still indicates a primed immune system, which under the right circumstances may lead to graft rejection, chronic AMR, glomerulopathy and ultimately earlier graft failure [4].
A multicentre collaboration is needed to establish an international standerdisation of the MFI cut off .
The use of C1Q assay is crucial for the actual assessment of the clinical significance of DSAs as regard complement fixation and activation rather than DSA intensity.
Reflection on practice:
Considering the shortage of kidney transplants and long waiting lists, We can accept PLNF patients for Tx especially those who have been listed for a long time. Keeping in mind that this situation would offer the patient better survival benefits than Dialysis [1]. we can proceed in Tx with frequent monitoring OF DSAs postTx and protocol Biopsy
1. What is the level of evidence provided by this study?
systematic review , level I evidence
2. What are the weakness and strength of this article?
Strength: the study design is level I , a strong design with high level of evidence
Limitations
this systematic review included a small number of studies and showing Difference in some parameters between studies:
(1) differences in a number of baseline characteristics, technical parameters and follow-up duration.
(2) Different threshold of MFI to define a ‘significant’ DSA intensity and FCXM positivity
(3) Different protocols and insuufient data of desensitization techniques, induction, maintenance and duration of mmunosuppression in between studies.
(4) variable follow-up time, and incomplete reporting of outcome data.
3. What is meant by the impact factor and how it is calculated?
An offshoot of citation analysis) which is used to sort or rank journals by their relative importance.
journals with high IF publish articles that are cited more often than journals with lower IF.
The Impact Factor is calculated by dividing the number of citations in the JCR (journal citation report) year by the total number of articles published in the two previous years.
References:
(1) Orandi BJ, Luo X, Massie AB et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med 2016; 374: 940–950
(2) Verghese PS, Smith JM, McDonald RA et al. Impaired graft survival in pedi- atric renal transplant recipients with donor-specific antibodies detected by solid-phase assays. Pediatr Transplant 2010; 14: 730–734
(3) Gupta A, Iveson V, Varagunam M et al. Pre-transplant donor-specific anti-bodies in cytotoxic negative crossmatch kidney transplants: are they rele- vant? Transplantation 2008; 85: 1200–1204
(4) 17. Patel AM, Pancoska C, Mulgaonkar S et al. Renal transplantation in patients with pre-transplant donor-specific antibodies and negative flow cytometry crossmatches. Am J Transplant 2007; 7: 2371–2377
Introduction
A positive complement-dependant cytotoxic crossmatch presents a high immunological risk, while a negative flow cytometry crossmatch is at the lower end of the risk spectrum. Yet, the presence of low-level DSA detected by Luminex alone, that is, positive Luminex and negative flow (PLNF) cytometry crossmatch lacks robust scientific exploration
In this systematic review and pooled analysis, we investigate the glomerular filtration rate, acute rejection (AR), graft survival and patient survival of PLNF transplants compared with DSA-negative transplants.
low-level DSA detected by Luminex alone does not pose significant risk at least in the short–medium term. Considering the shortage of kidney transplants and the ever-increasing waiting time, the avoidance of PLNF transplants may be unwarranted especially in patients who have been enlisted for a long time.
Indeed, evidence demonstrates that patients receiving an HLA-incompatible transplant experience a significant improvement in their survival when compared with matched patients remaining on dialysis [
positive pre-transplant complement-dependent cytotoxic crossmatch (CDCXM) is associated with high immunological risk, whereas a negative flow cytometry crossmatch (FCXM) is associated with a relatively low risk
Selection criteria
Outcome measures were determinedaprioriandincluded graft function [creatinine or glomerular filtration rate (GFR)], AR rates, graft survival and patient survival. Any study that measured and reported these outcomes in both PLNF and DSA-negative transplants were included for data extraction
Full-text analysis and data extraction were performed by two authors independent of each other. Studies in which the FCXM was not performed or not reported were excluded. Studies that included PLNF among other HLAincompatible transplants but did not provide subgroup outcomeresults were excluded. Case reports and case series including fewer than three patients were also excluded
Limitations
Our study has several inherent limitations. Although the majority of included studies are of ‘good quality’ according to the Newcastle-Ottawa quality assessment, they all suffered from significant differences in a number of baseline characteristics, technical parameters and follow-up duration. The threshold used to define a ‘significant’ DSA intensity and FCXM positivity varied across the studies. There are also several inconsistencies and under-reporting of desensitization techniques, induction, maintenance and duration of immunosuppression in between studies. The pooled analysis had to be restricted to a very small numberofstudies mainlydue tovariable follow-up time, inability to extract raw event data and incomplete reporting of outcome data.
Result
gest that the incidence of AR, graft failure and patient mortality is not significantly different in PLNF compared with DSA-negative transplants. However, the best desensitization strategy, if any required, remains indeterminate. Considering the increasing kidney transplant shortage and the unremitting struggle for timely access to transplantation, the avoidance of PLNF transplants may be unwarranted especially in patients who have been enlisted for a long time. Multicentre collaboration and long-term follow-up are required to better stratify the risks involved in PLNF transplantation.
Discussion
Our systematic review and pooled analysis consisting of seven retrospective studies did not identify significant evidence favouring DSA-negative compared with PLNF transplants in terms of AR, graft failure and patient mortality. One study reported a significantly shorter time to AR and graft failure in the PLNF transplants,
DSA should not be regarded as merely absolute cut-off values and intensities without taking into consideration their clinical significance. One can appreciate the considerable variability at which various type of DSA result in a positive FCXM at different intensities.
that Luminex detected by DSA would not have any significant influence on graft survival in patients who already had a negative Enzyme-Linked Immunosorbent Assay (ELISA) and
CDCXM, and therefore refusing a transplant based solely on Luminex measured DSAisnotwarranted. The type of DSA involved is another important factor in determining its clinical significance. In one study, patients with DSA directed to HLA-A, HLA-B and HLA-DR experienced earlier AMR compared with those with DSA directed to HLADQepitopes
The 10-year graft survival in patients with pre-transplant combined Classes I and II DSAs, both exceeding 1000 MFI, was significantly lower compared with patients with only Class I or II at the same intensities [43]. In addition, the timing of DSA detection (historical versus current) and DSA cumulative effects in case of multiple antibodies still requires investigation.
What is the level of evidence provided by this study?
Systematic Review : the level of evidence is I
The impact factor (IF) or journal impact factor(JIF) of an academic journal is a scientometric indexcalculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate’s Web of Science. As a journal-level metric, it is frequently used as a proxy for the relative importance of a journal within its field; journals with higher impact factor values are given status of being more important, or carry more prestige in their respective fields, than those with lower values. While frequently used by universities and funding bodies to decide on promotion and research proposals, it has recently come under attack for distorting good scientific practices
CalculationEdit
In any given year, the two-year journal impact factor is the ratio between the number of citations received in that year for publications in that journal that were published in the two preceding years and the total number of “citable items” published in that journal during the two preceding years
Waltman L, Traag VA (1 March 2021). “Use of the journal impact factor for assessing individual articles: Statistically flawed or not?”. F1000Research. 9: 366
1-2 groups were compared ;one included PLNF ( positive Luminex and negative FC)and the second with negative DSA regarding GFR ,acute rejection(AR) & graft and patient survival. Long time waiting list and donor shortage are the underlying cause for need for transplantation of PLNF. It was found that Tx even of sensitized patients is preferred to remaining on dialysis. Reports from several studies showed no significant difference in GFR 7 AR between the 2 groups .The current meta analysis involves cannot have final conclusion due to small number of included studies. Additionally, heterogenous criteria among included studies ;like age ,co morbidities ,HLA mismatch status, immunosuppression dosing, and their effect on AR,GFR ,patient and graft survival.
2-Level of evidence :1
3-Strength points :good quality of selected studies with clear aim with timed follow up till – end point .Weak points : remaining small number of studies after exclusion and heterogenicity of inclusion criteria as degree of HLA mismatching ,age, comorbidities.
4-Impact factor :indicates the importance of a certain journal depending on its number of citations. It is calculated in 2 years period by division of number of article citations by the number of citable articles.
Level of evidence 1A – systematic review article.
This is review focuses on the significance of detecting low level DSA only by luminex along with negative FCM) on GFR, graft, patient survival and acute rejection.
No significant difference was found between patients with PLNF and those with negative cross match and negative luminex in the incidence of AR at 1 year, graft failure at 1 and 5 years, patient survival at 1 and 5 years.
Regarding desensitization in case of PLNC, requirement and protocol is not determined till now, according to my practice the level of the DSA’s can affect the decision .
The type of DSA complement fixing AB are more clinically significant than non-complement fixing AB since it is associated with ABMR and C4d staining which affect graft survival.
MFI : different threshold for detection of DSA was set with MFI cutoff ranging from > 300 in some centers to > 1500 in others, Moreover MFI dose not correlate well with cross matching, some patients have low MFI and positive cross match, others have high MFI and negative cross match.
The specific type of HLA Ag to which DSA is formed graft survival in patients with DSA directed to both HLA class I and II is lower than when DSA is directed to either class I or II, Moreover DSAs directed against HLA-A, HLA-B and HLA-DR are associated with earlier AMR when compared to DSA directed to HLADQ, also DSA directed against HLA C and HLA DP may have clinical significance .
Strength : systematic review and the quality of included studies
limitations :
Small number of studies included in this systematic review
The cutoff used to define significant DSA and FCM
The Impact factor:
The impact factor (IF) is an index reflecting the number of citations of published articles per year in the last 2 years in a given journal, the higher the impact factor the higher is the value of the journal.
It is calculated by dividing the number of citations of published articles in that journal in that year by the total number of published citable items in the past 2 years by the same journal .
1. Please summarise this article with reflection on your practice if possible.
Summary:
This meta-analysis and systematic review of seven retrospective studies compared outcomes of DSA negative transplants with positive luminex (low-level DSA) with negative flow cytometry cross match (PLNF) with respect to acute rejection at 1 year, graft survival as well as patient survival at 1 and 5 years.
With respect to graft function, 4 studies analyzed this factor and one of them showed than DSA negative group had better graft function at 3 years but became similar to the PLNF group by 4 years. There was no significant difference between the two groups.
With respect to acute rejection, there was no difference in the 2 groups at 1 year. Although one study showed increased AMR in PLNF group and another showed AMR occurring earlier in PLNF group.
With respect to patient and graft survival at 1 and 5 years, there was no difference in the 2 groups.
So, the authors concluded that the short-term risk with PLNF transplants is not significant and it is better to undergo transplant in such a scenario rather than remaining on dialysis.
Our Practice: We have performed transplants in patients with PLNF without desensitization and with ATG induction. and regular post-transplant monitoring of DSA levels. Although the numbers are low, the results have been comparable with DSA negative patients.
2. What is the level of evidence provided by this study?
It is a systematic review and meta-analysis, Level IA evidence.
3. What are the weakness and strength of this article?
Weakness:
1) Inclusion of only a small number of studies (7 out of 1124 articles).
2) The studies included had significant differences between their characteristics and follow-up durations.
3) All the studies did not cover all the parameters.
4) The definition of DSA positivity and FCXM positivity differed in the studies.
5) The immunosuppression protocols used were not clearly defined in the studies.
6) The data reported was incomplete in the studies.
7) Publication bias could be underestimated in small number of studies using funnel plot analysis.
Strength:
1) All the studies included were of good quality.
2) No evidence of any publication bias in the studies included with respect to the funnel plot analysis.
4. What is meant by the impact factor and how it is calculated?
Impact Factor of a journal: This is a index calculated by clarivet. It denotes the average number of citations of the articles published in a journal in last 2 years. It is a measure of the reputation or stature of the journal with the higher the impact factor, the higher the stature of the journal in its field.
Systemic review including seven retrospective studies comparing outcome of positive luminex and negative flow cytometry crossmatch (PLNF) transplants with negative DSA transplants with regard to :
GFR
Graft survival
Patient survival
To see if PLNF can be safe without significant risk on transplant outcome or should we wait for more compatable donor
They identified no significant difference regarding to acute rejection,graft failure and patients mortality.
Weakness
Only 7 studies were included
DSA intensity and FCXM positivity was variable in different studies
Lemeted to articles published in English
Pooled analysis was restricted to very small numbers of studies
Strength
The majority of selected studies were of good quality
Level of evidence 3a(case control study)
Impact factor
Is the average number of times articles from journal published in the past two years have been cited in the journal
It is used to measure the importance or rank of a journal by calculating the times it’s article is cited.
●A CDCXM positive presents a high
immunological risk, while a negative FCXM is at the lower end of the risk spectrum. Yet, the presence
of low-level DSA detected by Luminex alone, that is, positive Luminex and negative flow (PLNF) cytometry crossmatch lacks robust scientific
exploration.
● conclusion of the study that the incidence of AR, graft failure and patient mortality
is not significantly different in PLNF compared with DSA-neg-
ative transplants. However, the best desensitization strategy, if
any required, remains indeterminate. Considering the increas-
ing kidney transplant shortage and the unremitting struggle for
timely access to transplantation, the avoidance of PLNF trans-
plants may be unwarranted especially in patients who have
been enlisted for a long time. Multicentre collaboration and
long-term follow-up are required to better stratify the risks in-
volved in PLNF transplantation
●level 1
systematic review
●What is meant by the impact factor and how it is calculated?
it measures the rank of a journal, the more citation of journal the much impact factor
it is calculated by dividing the number of citation of articles in the previous 2 years over the total number of article that were published in the same previous two years .
Positive Luminex and negative flow cytometry in kidney
transplantation: a systematic review and meta-analysis
Systematic review from 7 cohorts studies, level 1
Impact factor:
journal impact factor (JIF) of an academic journal is a scientometric index calculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal,
journals with higher impact factor means more important, or carry more prestige in their respective fields, than those with lower values. While frequently used by universities and funding bodies to decide on promotion and research proposals, it has recently come under attack for distorting good scientific practices.
NDT IF factor of 4.085 for 2021.
The quality of studies was evaluated using the Newcastle–Ottawa Quality Assessment
SUMAMRY:
The presence of DSA prior to transplantation associated with the poor graft survival and out come with recent improvement in the molecular immunogenetic testing the graft survival and patient outcome improved even in incompatible transplantation compared poor survival for patients on long wait list on dialysis.
In this systematic review and pooled analysis, they compare the glomerular filtration rate, acute rejection (AR), graft survival and patient survival of PLNF transplants with DSA-negative transplants. total 7 studies , five from USA , one study including pediatric population , another two studies from UK .
mean GFR was significantly better in the DSA-negative group compared with the PLNF groupat 3 years. This statistically significant difference was lost at 4 years.
incidence of AR, graft failure and patient mortality is not significantly different in PLNF compared with DSA-negative transplants. In addition, the best desensitization strategy, if any required, remains indeterminate.
Limitations:
significant variation in the baseline characteristic between the two groups
no standardization of the cutoff values of MFI quantitative assay, technical parameters and follow-up duration.
under-reporting of desensitization protocols , induction, maintenance and duration of immunosuppression in between studies.
Variable Follow up time
Incomplete data reporting regarding the outcome.
Small sample size
Presence of DSA before TX is associated with lower graft survival .But what should we do if DSA is low-level by Luminex and FG-XM is negative (PLNF). In this systemic review the authors evaluated effect of PLNF on overall graft outcome comparing with DSA-negative transplant. Seven retrospective studies containing 429 PLNF transplants were compared with 10677 DSA- negative transplants. Majority of them were not desensitized before TX .There was not any difference in acute rejection, graft failure and patient mortality between two groups. So in patients who were in waiting list for a long period it is reasonable to consider PLNF transplant.
Level of evidence for this systematic review article is 1.
Impact factor shows how much the articles in a journal are cited. More citations give higher impact factor. Impact factor of a journal is calculated by citations of a journal in two years ago divided by number of published articles in that journal during these two years.
The strength of the article was that quality of included studies were good.
The weakness of the article was:
1-for positive Luminex defined level of MFI was not considered.
2-Number of studies that fulfilled the criteria were only seven with wide variation in their method of desensitization.
3- Included studies were retrospective.
Summary of the article
Positive Luminex and negative flow cytometry in kidney transplantation: a systematic review and meta-analysis
This systematic review and pooled analysis, investigates the glomerular filtration rate,
acute rejection (AR), graft survival and patient survival of positive Luminex and negative flow (PLNF) transplants compared with DSA-negative transplants.
A positive pre-transplant complement-dependent cytotoxic crossmatch (CDCXM) is associated with high immunological risk, whereas a negative flow cytometry crossmatch (FCXM) is associated with a relatively low risk. The advent of Luminex single antigen bead technology has introduced a new tier in the continuum of HLA incompatibility. The recipients, who were previously considered HLA-compatible due to negative FCXM, can still harbor pre-existing DSAs that are detectable by Luminex alone. In this context of positive Luminex and negative flow (PLNF) cytometry, several questions remain unanswered. We do not know if these DSAs can be safely disregarded or if patients require any immunological manipulation. The primary aim of this systematic review and pooled analysis is to answer these pertinent questions and to evaluate graft function, acute rejection (AR) rates, graft survival and patient survival in PLNF compared with DSA-negative.
Current evidence suggests that low-level DSA detected by Luminex alone does not pose significant risk at least in the short–medium term. Considering the shortage of kidney transplants and the ever-increasing waiting time, the avoidance of PLNF transplants may be unwarranted
especially in patients who have been enlisted for a long time.
What is the level of evidence provided by this study?
It is a systemic review/metanalysis; its Level of evidence 1A.
What are the weakness and strength of this article?
small number of studies . under-reporting of desensitization techniques, variation in reporting of induction, maintenance and duration of immunosuppression in between studies .
Its Strength : good quality .
What is meant by the impact factor and how it is calculated?
it is a measure of frequency of citation of average article in a particular year and it measures the rank of a journal
it is calculated by dividing the number of citation of articles in the previous 2 years over the total number of article that were published in the same previous two years
It is a systemic review article with level A1
This article used GFR, acute rejection AR ,graft survival and patient survival to compare between 2 groups one with negative DSA and other with positive luminex and negative flow cytometry (PLNF ).
Graft function the difference is not significant statistically.
AR the rate of AMR is higher in PLNF than in negative DSA one year post transplant but due to variation in follow up period the difference is also not significant statistically.
Graft survival is better in negative DSA group than in PLNF and all the included studies were within confidence limits.
Patient survival no statically significant in the included studies between the 2 groups.
The strength
-included studies are assessed by Newcastle-Ottawa quality assessment.
-the studies that had been reviewed depend on the same management protocol with triple immunosuppressants for most of the patients.
-follow up the patients regarding GFR, AR,graft survival and patient survival.
Weakness
-7 articles out of 1124 reviewed in this article
-variation in FCXM and DSA cut off
-lack of discussing on desensitization protocol or if it had been done in the reviewed articles.
Impact factor indicate the strength of the article or the frequency of citations of the article, it’s calculated by dividing the number of citations in a particular year on the total number of the articles that are published in the previous 2 years.
It is a systemic review its Level of evidence 1.
The presence DSA is associated with worse outcomes in kidney transplantation compared with DSA- negative transplantation.
Kidney transplantation even with HLA incompatible graft transplant showed significant improvement in patients survival when compared with matched patients remaining on dialysis.
Positive CDC is high immunological risk, negative FCXM is associated with a relatively low risk. Patients who are FCXM negative can still have DSAs that are detectable by Luminex alone.
This review compared 7 studies which compared 2 groups of recipients one DSA-negative group and positive Luminex and negative flow cytometry (PLNF)group.
-The quality of studies was evaluated using Newcastle-Ottawa Quality Assessment.
Several studies showed no statistically significant difference in serum creatinine between the 2 groups.
The pooled analysis could not be performed due to limited reports of graft function, heterogeneous follow-up duration, and disparate measurement units.
The pooled risk of AR was not significant between PLNF and DSA-negative transplants.
Funally there were no statistically significant difference in graft and patient survival between PLNF and DSA-negative groups.
It also concluded that not any DSA detected is of clinical importance, even a relevant MFI cutoff is very heterogeneous across the centers
But the complement fixing ability and C4d deposition is of significant importance .
Streghenth of the article:
The studies included are of good quality according to Newcastle-Ottawa Quality Assessment.
Weakness points
1 The small number of articles (7) involved.
2 there is no standardized cut-off of DSA level and FXCM.
3 Different types of DSA are involved and different techniques are used.
4 heterogeneous follow-up duration
The impact factor (IF) is a measure the frequency with which the average article in a journal has been cited in a particular year.
It is used to measure the importance or rank of a journal .
The calculation by two-year period and involves dividing the number of times articles were cited by the number of articles that are citable.
In summary this article compared the kidney transplant in patients who have positive PRA by luminax and negative flow cytometry cross match (that mean they have non HLA antibodies or antibodies to minors antigen) with patients who have negative DSA
They did metanalysis for 7 articles with high selection and they found that no statistical significance between two groups in the term of patient survival,graft survival and acute rejection . Many centers they depend on MFI significance and they found less than 1000 MFI has good out come, some of them tried to do desensitization by different methods include plasmapheresis, IVIg and rituximab but also no statistical significance in the outcome. In Sudan we didn’t do transplant against positive cross match .
The article is level 1 evidence because it is meta analysis .
The weakness point is small number of articles they just 7.
The impact factor measure the strength of the journal by the number of published articles cited in particular year
Not all patients with incompatible HLA had the same risk of transplant rejection & its proved that even if patient receive incompatible kidney the outcome is better when compared to patien kept on dialysis program. After developing Luminex technology it may detect Abs can not be detected by FCXM, but the safety of these Abs is unknown when precede to transplantation with out desensitization or modifying immunosuppression. So the aim of this study is to assess the risk of AR & both graft & patient outcome in PLNF when compared to DSA negative patients.
Systemic review with meta-analysis ( level 1 evidence). Inclusion criteria include all studies assess graft function, AR rate, graft & patients outcome & using PLNF & DSA negative results.
Exclusion criteria include studies not use FCXM, studies include PLNF but not provide subgroup outcome, case report & case series include less than 3 patients.
The quality of studies evaluated by Newcastle-Ottawa Quality Assessment.
Only 7 studies included for analysis & data extraction, and just 6 of them had good quality. This systemic review did not find significant difference between DSA negative patients & PLNF regarding AR rate, graft loss & patient mortality. Just one study found a shorter time to AR & graft loss. 2 studies show that the risk of AR , AMR & graft loss is higher in PLNF transplants, but pooled analysis could not be done because they didn’t use B cell FCXM.
The inter-center variability in cut-off threshold & absolute MFI value can affect the validity of included studies. In negative FCXM, some DSA may be clinically in significant & the patient labelled as sensitized wrongly. Susal et al found that positive Luminex not have significant risk on graft outcome in patients who had negative ELISA & CDCXM, so refusing the transplant depending only on Luminex measuring DSA is not satisfying. Also it was found that the type of DSA is important, as HLA-Cw & -DP previously considered as insignificant, now it can increase risk of AR. There are 2 techniques of Luminex test differentiation in their sensitivity & specificity.
Prozone effect also present in Luminex which limit the results of studies. One of the causes of unrecognized heterogeneity of this study analysis is inter-center variability in FCXM threshold. This systemic review evidence did not didn’t support bad outcome in PLNF transplant.
Strength of the study : quality of studies evaluated by Newcastle-Ottawa Quality Assessment.
Weakness of the study:
Impact factor: it mean measuring the frequency of how many times the articles are cited in a particular year. This allow determining the rank & importance of of the journal. It can calculated by dividing the number of citation in the JCR year by the total number of articles published in the 2 previous years.
1.Abstract : Positive Luminex and negative flow( PLNF)cytometry crossmatch is still grey area in transplantation. This systematic review compares glomerular filtration rate, acute rejection, graft survival and patient survival of PLNF with DSA-negative transplants. Pooled analysis showed no big difference in the incidence of AR at 1 year, graft failure at 1 year, and patient survival at 5 year. Pool analysis of graft function was limited due to incomplete data.
Introduction : Positive CDCXM is considered to be risk while negative FCXM is low risk transplant. In the setting of PLNF, it is not clear if these DSA can be ignored without problem or they would be a need for adjusting immunosuppression.
Material & methods :
Result :
Total of 1124 articles were examined and only 7 were chose for the final analysis and data extraction based on induction criteria. Pooled data analysis was affected by inter & intra centre variability.
Graft Function :
The mean GFR was higher in the DSA-negative group compared to the PLNF. However this effect was lost at 4 years(13)
Higgin et al. showed better GFR initially in PLINE group than DSA-negative group but again this was last at 3 years(12). Other studies showed no difference in the creatinine between the tow groups(16)(17).
AR :
At 1 year post-transplant, no statistically significant difference was seen between the two groups(14). The time to rejection was shorter in the PLNF group compared to DSA-negative group(13)(17)
Graft Survival :
Shorter time to death-censored graft failure was notice in the PLNF at the mean follow up of 39.6 months(12). Verghese et al (14) reported a graft failure rate in the PLNF group around 50% and 17% in the DSA-negative group at the mean follow up of 2.8 years
Patient Survival :
Studies showed no statistically significant difference between PLNF and DSA-negative transplant (11)(12)(16)(17).
Discussion :
This study could not find any robust evidence to support superiority of of DSA negative to PLNF transplant in terms of AR, graft failure, and patient mortality. The threshold for significant DSA level was subject to variation among many transplants centres world wide. This means lack of concert evidence in this area. The DSA is important but should not be taken only as a number but its clinical relevance should be considered as well. Liorente et al (39) reported no correlation between DSA strength and the ability to activate complement. Susal et al (41) found that in the setting of negative ELISA & CDCXM, any positive DSA detected by Luminex is unlikely to be significant, and there fore patients should not be rejected on bases of DSA only. The type of DSA is also important e.g. pre-transplant with only class I or class II have better long-term survival than patients with both class I & class II (43). The Luminex results can positively false due to denturated HLA epitopes. This can lead to unnecessary exclusion of patients from transplant if this is not interpreted carefully(47). Another issue is that ; it is not clear if de-sensitisation is required in PLNF transplants. It is important to note that HLA-incompatible transplantation including positive FCXM still gives significant survival benefits (2,3). Because of donor organ shortages, prolonged waiting list time, and difficulty to access transplantation in time, refusal of PLNF is not necessary action specially for patient who have been in waiting list for long-time.
Limitations ; The majority of included studies are of good quality according to the Newcastle-Ottawa quality assessment. How ever there were few problems with this meta-analysis. These are ;
Conclusion ;
2.Meta-analysis level IA
3.Strength ; good quality studies included. Weakness ; a. Inter& intra centre variability for DSA cut-off points b. pooled analysis was limited due to insufficient data. c Number of studies were small but yet analysed by Funnel Plot
4.Impact factor ; is the strength of the article i.e. number of citations. It is calculated by ratio of cited articles to the total number articles published in the last 2 years
in 2021( updated), ndt impact factor is 3.739
– It is a systemic review withLevel of evidence 1
-DSA-positive is associated with worse overall outcomes in kidney transplantation compared with DSA- negative transplantation.
-Apoitive complement-dependent cytotoxic (CDC) crossmatch is a high immunological risk, while a negative flow cytometry crossmatch has low immunological risk.
-This is an analysis of seven retrospective studies.
-Not all HLA-incompatible kidney transplants carry the same immunological risk.
-Patients receiving HLA-incompatible transplants have significant improvement in their survival when compared with the matched patient remaining on dialysis.
-This systemic review was performed according to the preferred reporting items for systemic reviews and meta-analyses statements.
-Selection criteria: The study must report or measure graft function( creatinine or GFR), acute rejection rate, graft, and patient survival.
-The studies compare 2 groups DSA-negative group and positive Luminex and negative flow cytometry (PLNF)group.
-The quality of studies was evaluated using Newcastle-Ottawa Quality Assessment.
– Graft function: Several studies showed no statistically significant difference in serum creatinine between the 2 groups. The pooled analysis could not be performed due to limited reporting of graft function, heterogeneous follow-up duration, and disparate measurement units.
-Acute rejection: The pooled risk of AR was not significant between PLNF and DSA-negative transplants. Pooled analysis of AMR wasn’t possible due to heterogeneous follow-up duration.
-Graft and patient survival: No statistically significant difference in graft and patient survival between PLNF and DSA-negative groups.
Streghenth of the article:
-It is a systemic review with the level of evidence 1 and all studies of good quality according to Newcastle-Ottawa Quality Assessment.
Weakness points
1. The small number of articles (7) involve in this study after filtration and exclusion of other articles.
2.No standardized cut-off of DSA level and FXCM.
3. Different types of DSA are involved and different techniques are used.
4. heterogeneous follow-up duration
–The impact factor (IF) is a measure of the frequency with which the average article in a journal has been cited in a particular year. It is used to measure the importance or rank of a journal by calculating the times it, s article is cited.
-It is a calculation based on 2 years period and involves dividing the number of times articles were cited by the number of the citable articles.
Summary :
Since the discovery of DSAs ,it was found to be related to all adverse outcomes related to graft and patient survival .
With the advances in detection of the DSAs over years , it is now possible to detect even very low Titres of DSAs .
On the other hand waiting for a completely compatible donor entails staying for very long periods on dialysis which has negative impact on patient survival.
Positive CDC cross match carries the highest immunological risk , and negative flow cytometry cross match carries the lowest risk.
This systematic review compares patient and graft outcomes between DSA negative patients and those with Positive luminex negative flow cytometry cross match.
It included 7 studies , and it suggested that there is no significant difference in outcomes between the 2 groups regarding acute rejection, graft and patient survival.
It also advised that not any DSA detected is of clinical importance, even a relevant MFI cutoff is very heterogeneous across the centers
But the complement fixing ability and C4d deposition is of significant importance .
This is a meta analysis, with level of evidence I A
Strengthes include :
All studies are considered of good quality according to the Newcastle Ottawa assessment system.
Weaknesses:
Significant differences in the baseline characters , technical parameters and followup duration .
Also there was under reporting to desensitization techniques , induction therapies and maintenance IS .
The meta analysis included only small no of studies due to variability in follow up periods and underreporting of patients outcomes.
Doner specific antibodies are associated with poor outcome. Cytometry can not detect DSA at low level but Luminax can. these DSA were termed PLNF, positive luminex negative flow. This article is a systemic review and metanalysis of 7 papers .The total articles started with were 1124 but after exclusion of all weak and irrelevant papers, the final sum was 7 only .The patients with PLNF were 429 and those who were negative DSA were 10677.
after analysis , the authors did not find any statically significant difference between both groups regarding AR incidence, graft failure or survival and patient mortality. the authors stated that PLNF need not to be considered as a cause for exclusion from transplantation.
level of evidence is 1a
weakness points of the paper :
small number of papers and all are retrospectives
no unified cut off points for DSA or flow
sensitization role was not assessed
different baseline characteristics and follow up duration
strength
massive survey of data accuracy
impact factor is a measure of a journal importance through calculation of the number of times its articles have been cited in a year. it is calculated by dividing the number of articles published by the number of articles cited in 2 years preceding the year of concern
Systemic review comparing outcome of positive Luminex and negative flowcytometry crossmatch (PLNF) transplants with negative DSA transplants as regards glomerular filtration rate (GFR), graft survival and patient survival to identify whether DSAs detected by Luminex but with negative flowcytometry can be considered safe without significant risk on transplant outcome or it is better to wait for fully compatible transplant
It included seven retrospective studies and identified no significant difference between DSA negative transplant and PLNF regarding acute rejection, graft failure and patient mortality
pooled analysis of graft function wasn’t performed due to limited outcome reporting.
In the presence of negative flowcytometry crossmatch, some DSAs could be clinically irrelevant and inaccurately the patient may be considered sensitized
This systemic review doesn’t support worse outcome with PLNF transplants and that exclusion of PLNF transplant may be inappropriate especially with kidney transplant shortage and increased waiting time for transplant.
level 3a: systemic review of retrospective studies (case control studies)
limited to articles published in English
Only seven studies were included
The threshold of significance of DSA intensity and FCXM positivity was variable in different studies
The pooled analysis was restricted to very small number of studies
Funnel plot analysis is considered unreliable in exclusion of bias with small number of studies
Included studies with comparable follow up duration
The majority of selected studies were of good quality
Frequency of citation of average article in selected year
It is the ratio between number of cited articles and total number of articles published in the journal (in the two years before calculation)
Positve luminx negative flow cytometory
Summary of the article ;
This systemic review shows no significant difference in incidence of acute rejection , graft failure and patients survival in PLNF compared with DSA-negative transplant . long term follow up is required to better stratify the risks involved in PLNF transplantation .
DSA should not be regarded as merely absolute cut-off values and intensities without taking into consideration their clinical significance. Absolute DSA intensity alone does not reliably predict the actual cell-based cross match. Perhaps, the ability to fix complement is more clinically relevant. Indeed, DSA levels as low as 700 MFI were able to bind C1q beads, whereas DSA levels reaching14 500 MFI did not . DSAs that seemed to trigger C4d deposition were associated with significantly higher rates of AMR .
The type of DSA involved is another important factor in determining its clinical significance. Patients with DSA directed to HLA-A, HLA-B and HLA-DR experienced
earlier AMR compared with those with DSA directed to HLADQ epitopes . HLA-Cw DSAs are increasingly being recognized as deleterious to graft survival .
In addition, the timing of DSA detection (historical versus current) and DSA cumulative effects in case of multiple antibodies still requires investigation . In conclusion Luminex detected DSA would not have any significant influence on graft survival in patients who already had a negative Enzyme-Linked Immunosorbent Assay (ELISA) and CDCXM, and therefore refusing a transplant based solely on Luminex measured DSA is not warranted.
What is the level of evidence provided by this study ?
Level 1 A .
What are the weakness and strength of this article ?
Strength;
The majority of included articles studies are of good quality according to the Newcastle-Ottawa quality assessment .
Weakness;
Restriction to small group of studies suffered from insignificant characteristics ,technical parameter and follow up duration . Funnel plot analysis could be unreliable for investigating publication bias in this small numbers of studies . The threshold used to define a ‘significant’ DSA intensity and FCXM positivity varied across the studies. In addition to inconsistencies and under-reporting of desensitization techniques, induction, maintenance and duration of immunosuppression in between studies.
What is meant by the impact factor ? and how it is calculated ?
Impact factor is the average number of times articles from journal published in the past two year years have been cited in the journal
The impact factor of a journal is calculated by dividing the number year citations to the source items published in that journal during the previous two years .
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Summary :
Level of evidence : it is a review article of stage I evidence.
Weakness and strength :
Impact review :
Systematic review/Meta-analysis, level 1 A
thank you for your additional comments
A systematic review analysing the pooled data from retrospective studies comparing PLNF (Positive Luminex Negative Flocytometry) transplants with DSA-negative transplants regarding the glomerular filtration rate, acute rejection (AR), graft survival and patient survival.
The Pooled analysis identified there was no significant difference between PLNF (Positive Luminex Negative Flocytometry) transplants with DSA-negative transplants in the incidence of Acute rejection graft failure, patient mortality. Also, the Pooled analysis of graft function was not possible due to insufficient data.
In conclusion: According to the data analysis that low-level DSA detected by Luminex alone does not carry a significant risk at least in the short to medium term. In context of that the avoidance of PLNF transplants may be unnecessary especially with long waiting list patients. In the other side it is crucial to follow up with post-transplant DSA monitoring and protocol biopsies.
What are the weakness and strength of this article?
-strengths: The majority of included studies are of good quality according to the Newcastle-Ottawa quality assessment.
-weaknesses:
-The number of baseline characteristics, technical parameters and follow-up duration are different between studies.
-Significant DSA intensity and FCXM positivity inconsistent across the studies.
-Desensitization techniques, induction, maintenance and duration of immunosuppression not reported in some studies.
-Small number of studies mainly due to variable follow-up time
The presence of pre-formed donor-specific antibodies (DSAs) in transplant recipients is associated with significant risk of graft loss .
Apositive pre-transplant complement-dependent cytotoxic crossmatch
(CDCXM) is associated with high immunological risk,
whereas a negative flow cytometry crossmatch (FCXM) is associated
with a relatively low risk. The recipients, who were previously
considered HLA-compatible due to negative FCXM,
can still harbour pre-existing DSAs that are detectable by
Luminex alone . pool analysis done to compare between negative DSA and PLNF (positive luminex and negative flow cytometry) as regard GFR, acute rejection AR, graft and patient survival.
PLNF means Luminex detected low level of DSA. Studies did not identify significant evidence favouring DSA-negative compared with PLNF transplants in terms of AR, graft failure and patient mortality .
What is the level of evidence provided by this study?
Meta analysis level 1
What are the weakness and strength of this article? Weakness: Avery small number of studies . under-reporting of desensitization techniques, induction, maintenance and duration of immunosuppression in between studies .
Strength : good quality .
What is meant by the impact factor and how it is calculated? is a measure of the frequency with which the average article in a journal has been cited in a particular year. It is used to measure the importance or rank of a journal by calculating the times it’s articles are cited. calculated by dividing the number of citations in the JCR year by the total number of articles published in the two previous years.
Please summarise this article with reflection on your practice if possible
It is well known that the presence of preformed DSA is associated with poor graft outcome compared to DSA negative transplantation & a positive CDC crossmatching represent a high immunological risk while negative flow crossmatch poses a low immunological risk, still there are cases where DSA is positive at low level and crossmatching is negative & these cases need a scientific exploration and this was the aim of this systematic review article.
GFR, acute rejection, graft survival & patient survival of patients with positive luminex testing and negative flow crossmatching were assessed and compared to that of patients with negative DSA transplant.
This pooled analysis found that there is no significant difference in the incidence of:
Pooled analysis of graft function was not possible due to insufficient data.
These findings may be helpful to decrease waiting time for transplantation.
What is the level of evidence provided by this study?
Systematic Review : the level of evidence is I
What are the weakness and strength of this article?
Weakness of this article:
Strength of this article:
The majority of included studies were of good quality according to the Newcastle- Ottawa Quality Assessment.
What is meant by the impact factor and how it is calculated?
Is a measure of the frequency with which the average article in a journal has been cited in a particular year. It shows the importance or rank of the journal.
It’s calculation is based on a two-year period and involves dividing the number of times articles were cited by the number of articles that are citable.
This article is a systematic review with level 1 of evidence.
The strength points of this study are the search strategy and analysis methods.
One weakness of this study was the existence of inter-center variability, for example in MFI absolute level and cutoff thresholds in its included articles, and it requires inter-center collaboration to standardize practice and establish an international normalized threshold.
The pooled analysis was restricted to a very small number of studies mainly due to variable follow-up time, inability to extract raw event data and incomplete reporting of outcome data.
The impact factor is frequently used as an indicator of the importance of a journal in its field by calculating the number of times an average paper in a journal is cited within a particular year.
The presence of preformed DSA in kidney transplant recipients is associated with a high risk of graft loss.
A positive CDCXM is related to a significant risk of immunologic reactions and graft loss, whereas a negative FCXM is associated with a relatively low risk. There are many questions about the situation of negative FCXM while low levels of DSAs are detected by Luminex alone (PLNF). It is not obvious if these DSAs can be safely disregarded or if patients require any immunological manipulation.
This systematic review and pooled analysis did not identify significant evidence in favor of DSA-negative compared with PLNF transplant in terms of AR, graft survival and patient survival.
Regarding graft function with estimated GFR, there were conflicting results when the PLNF group compared to the DSA-negative group.
A higher rate of ABMR and shorter time to rejection in the PLNF group compared to the DSA-negative group was reported in some studies.
Although this pooled analysis identified a trend toward increased risk of graft failure at 1 year, it has been lost in the five-year analysis.
In these studies, cutoff thresholds for MFI were significantly different, ranged from 300 to 1500.
For interpreting the positive Luminex, some points should be taken into account:
An important issue is that DSA should not be regarded as merely absolute cut-off values and intensities without taking into consideration their clinical significance. One can be aware of the considerable variability at which various types of DSA result in a positive FCXM at different intensities.
Not only absolute DSA intensity but also its ability to fix complement are important to predict the actual cell based cross match. Some studies have demonstrated that DSAs that trigger C4d deposition are associated with a higher rate of ABMR. However, C1q assays are still largely experimental.
In the context of PLNF, some DSAs are irrelevant and wrongly labeling patients as sensitized.
On the other hand, DSAs detected by Luminex with negative ELISA and CDCXM have not any significant influence on graft survival.
The type of DSA involved is another important factor. DSAs against HLA-A, HLA-B, HLA-DR are more important in terms of graft survival. Although DSAs against HLA-Cw, HLA-DP, and HLA-DQ may have the same negative impact.
Pre-transplant combined classes I and II DSAs, with exceeding 1000 MFI, is associated with lower graft survival compared with patients with only Class I or II at the same intensities.
Potential technical limitation should be considered aside from the interlaboratory variability as well as the prozone effect as a well-known limitation associated with Luminex assays.
Denatured HLA epitopes that give rise to false-positive Luminex reactions must also be taken into account.
Therefore, refusing a transplant only based on DSAs are detected by Luminex is not warranted.
Another question is the need for desensitization in PLNF transplants. Some studies have reported that desensitization has been performed in PLNF recipients.
Kidney transplantation should always be regarded as a risk balance between remaining on the transplant list and transplantation itself. Avoidance of PLNF transplants may be unwarranted, especially in patients who have been enlisted for a long time. In this situation, careful observation via DSA monitoring and protocol biopsy is suggested.
1- Level of evidence 1
2- Summary :
The presense of preformed DSA makes the patient at high immunological risk , shortage of donor pool,m ay necessate using these kidneys, thus this systemic meta analysis aimed at investigating short and long term outcome associated with PLNF transplantation .There was no significant difference between DSA – ve and PLNF group regarding graft function (assessed by s cr and GFR) , acute rejection and patient mortality in short and longterm follow up.
Some of the included researches reveaded sigbnificant difference between DAS – ve And PLNF .
3- Limitations of this study
a- No universal cut off value for positive flowcytometry between labs .
b- DSA differ in their immunologic importance according to their intensity , their typy ( eg DSA against HLA Dr , DQ, B, A and Cw are more significant than other DSA) and their ability to activate complement
These points were not matched in the all the included studies .
c- For assessing the immunological significant of DSA detected by luminex , ELISA , CDC crossmatch should be done . This was not done in many of the included studies.
4- Strength points of this study
a- Well-designed algorythmatic selection criteria (1 st selection based on titles , then review abstracts then full text analysis).
b- All included articles are of good quality.
c- Clear target ( to include any article reporting AR ,graft function and patient outcome in DSA – ve and PLNF).
5- The impact factor (IF)
Is an index of importance of any scientific journal based on the mean number of citations of articles published by this journal in one year for two successive years.
IF is calculated every 2 years by dividing Number of citations of the journal articles divided by number of publications of the preceding 2 years .
What is the level of evidence provided by this study?
Level of evidence 1 as it is a systematic review article.
Please summarise this article with reflection on your practice if possible
This is a systematic review analyzing the significance of detecting low level DSA only by luminex in the context of negative FCM (PLNF- Positive Luminex Negative Flow) on GFR, AR, graft and patient survival.
No significant difference was found between patients with PLNF and those with negative cross match and negative luminex in the incidence of AR at 1 year, graft failure at 1 and 5 years, patient survival at 1 and 5 years, but graft function could not be assessed due to insufficient data.
Conclusion : PLNC does not offer significant risk in the short–medium term
Other studies showed an increase incidence of ABMR in patients with PLNC compared to those with negative luminex
Regarding desensitization in case of PLNC, requirement and protocol is not determined till now.
Factors affecting detection and significance of DSA
1- Intensity of DSA (MFI) : different threshold for detection of DSA was set with MFI cutoff ranging from > 300 in some centers to > 1500 in others, Moreover MFI dose not correlate well with cross matching, some patients have low MFI and positive cross match, others have high MFI and negative cross match.
2- The type of DSA which is the most important, complement fixing AB are more clinically significant than non complement fixing AB since it is associated with ABMR and C4d staining which affect badly graft survival, Moreover it is correlated well with cross matching but not with intensity of DSA, this means there may be a DSA with high intensity but is not complement fixing.
3- The specific type of HLA Ag to which DSA is formed, graft survival in patients with DSA directed to both HLA class I and II is lower than when DSA is directed to either class I or II, Moreover DSAs directed against HLA-A, HLA-B and HLA-DR are associated with earlier AMR when compared to DSA directed to HLADQ, also DSA directed against HLA C and HLA DP may have clinical significance .
4- Inter-center, inter-laboratory variability and technical errors in performing luminex and cross match techniques
5- False positive results may occur when using luminex that can be due to either technical errors or the presence of denatured HLA epitopes.
What are the weakness and strength of this article?
Strength is obtained from the type of this article which is systematic review and the quality of included studies
limitations :
⦁ Small number of studies included in this systematic review
⦁ Studies included differ significantly in baseline characteristics, technical issues and follow up duration, the cutoff used to define significant DSA and FCM
⦁ Desensitization techniques , induction and maintenance of immunosuppressive used are not reported well between studies
What is meant by the impact factor and how it is calculated?
The impact factor (IF) is an index reflecting the number of citations of published articles per year in the last 2 years in a given journal, the higher the impact factor the higher is the value of the journal
It is calculated by dividing the number of citations of published articles in that journal in that year by the total number of published citable items in the preceeding 2 years in the same journal
This systematic review with level II of evidence summarized the effect of Luminex positive but flow negative transplants with negative flow ones. although heterogeneous and some missing unattained data lead to a final evaluation of 7 studies out of 65 it highlighted the importance of Luminex itself in selected cases. drawn attention to thorough or need of deep evaluation needed to be considered in terms of selection criteria. As concluded though not robust evidenced data available it was shown that:
in terms of graft function the longer the follow-up the less the difference though it was better somehow in the first three years in favor of DSA negative cases
In terms of antibody rejection: though a non-significant difference was documented, the time to rejection was shorter in lumişnex positive cases
In terms of patient survival, results were similar
Dear Dr Ala,
Regarding the impact factor (IF), I want to add to the points mentioned by my colleagues that the impact factor is a suggestive tool of the scientific quality of the journal. Nevertheless, it has many weaknesses and misleading defects which includes (1, 2):
· Database has an English language bias, and it is dominated by American publications (as it is calculated by an American agency).
· Bias due to self-citation (some authors and journals preferentially select their own articles to raise their rank elusively).
· Review articles tend to be enormously cited and inflate the impact factor of journals.
· Lengthy articles will have many citations and give high journal impact factors.
· Journals with frequently published issues and short publication lag have a high chance of increased article citations as well as self-citation, which may cause misleading high IF.
· IF suffers from the field of science bias. The slowly changeable branches like basic science journals will be underestimated compared to rapidly evolving topics that tend to have numerous publications and citations in a short time. A clear example noted during the COVID-19 crisis; there were thousands of publications covering this topic within relatively a short time compared to fewer articles regarding other scientific fields (The IF is calculated mathematically by the number of citations irrespective of the topics studied). The exact role will explain why small research fields tend to lack journals with high IF.
· The database is not including textbooks as a source for citations.
References:
1) Seglen PO. Why the impact factor of journals should not be used for evaluating research. BMJ. 1997 Feb 15;314(7079):498-502.
2) Diamandis EP. The Journal Impact Factor is under attack – use the CAPCI factor instead. BMC Med. 2017 Jan 16;15(1):9.
Do you know any limitations of journal impact factor?
The impact factor can be influenced and biased intentionally or nonintentially by many factors.
IF used by clarivate uses last two year’s citation calcutaed as total number of citations /total number of articles
one other limitation is that it uses only citations in the web of science
compared to it:
scopus score uses last year’s citations divided by the last three years. it has limitations of includşng letters and editorials that may dilute the results
Limitations of IF:
There is a widespread misconception regarding the method of calculating impact factor.
The IF of a journal is not associated with factors like the quality of the peer review process and quality of content of the journal, but is a measure that reflects the average number of citations to articles published in journals.
Journals which publish more review articles will get the highest Ifs.
The impact factor can be calculated after completing the minimum of 3 years of publication. for that reason, journal IF cannot be calculated for new journals.
The IF applies only to journals, not to individual articles or individual scientists.
Limitations of impact factor:
Dear All, after carefully reading this manuscript, Do you consider the author’s effort to avoid heterogeneity was beneficial to the study outcome or a limiting factor that has led to including a minimum number of studies?
negative impact because of small number of studies, but avoidance of heterogenicity is essential
Level of evidence of this article
Level A1
Summary of the article
This systematic review and pooled analysis, investigated the glomerular filtration rate, acute rejection (AR), graft survival and patient survival of PLNF transplants compared with DSA-negative transplants.
Analysis identified seven retrospective studies consisting of 429 PLNF transplants and 10 677 DSA-negative transplants. Pooled analysis identified no significant difference in the incidence of AR at 1 year, graft failure at 1 year , graft failure at 5 years, patient mortality at 1 year and patient mortality at 5years. Pooled analysis of graft function was not possible due to insufficient data.
In 1969, Patel and Terasaki demonstrated for the first time that the presence of pre-formed donor-specific antibodies (DSAs) in transplant recipients is associated with significant risk of graft loss. Currently it’s appreciated that not all human leukocyte antigen (HLA)-incompatible kidney transplants carry the same immunological risk.
MATERIALS AND METHODS
Search strategy
Selection criteria
Data extraction and statistical analysis
Transplant characteristics were extracted and tabulated to generate a pooled analysis of all relevant studies.
Transplant characteristics such as:
Review Manager (RevMan), Version 5.3, Copenhagen, was used for the meta-analysis statistics . Risk ratio (RR) was calculated from the number of events in each group using the Mantel–Haenszel method and random effect model.
While performing analysis, the only included studies were those having comparable follow-up duration in order to avoid heterogeneity and minimize bias.
Forest plots were used to demonstrate the results of the meta-analysis.
Publication bias was estimated using funnel plots.
RESULTS
1.Characteristics of the studies
The search yielded a total of 1124 articles. After exclusion based on duplicates, title alone beside the abstract content, only 65 articles were selected for full text analysis. From these 65 articles only 7 articles satisfied the inclusion criteria and were included in the final content analysis and data extraction.
Two of the studies included in this meta-analysis( Willicombe et al.and Couzi et al.) did not satisfy the inclusion criteria. The study by Willicombe et al. was excluded because the B-cell FCXM was not routinely performed, while the study by Couzi et al. was excluded as the primary outcome was based on historical FCXM results and both study groups included Day 0 PLNF transplants.
In addition, Orandi et al. and Higgins et al. [10] were excluded as they investigated the same patient cohort included in Orandi et al. [11] and Higgins et al.
The seven studies that satisfied the inclusion criteria were included in the final content analysis and data:
2.Graft function
Four studies reported outcomes in terms of GFR or serum creatinine level.
3.AR
4.Graft survival
5.Patient survival
DISCUSSION
The systematic review and pooled analysis consisting of seven retrospective studies did not identify significant evidence favouring DSA-negative compared with PLNF transplants in terms of AR, graft failure and patient mortality.
One study reported a significantly shorter time to AR and graft failure in the PLNF transplants, although Kaplan–Meier analysis had included groups with positive cell-based crossmatch, without estimation of the Cox proportional hazards in each group.
The pooled analysis of AR, graft failure and patient mortality showed no overall difference between the PLNF and DSA-negative transplants. Pooled analysis of graft function was not possible due to limited outcome reporting and heterogeneous follow-up period.
The meta-analysis by Mohan et al.found that PLNF transplants were associated with nearly double the risk for AMR and higher risk for graft failure.
This meta-analysis, however, assigned significant weight to the study conducted by Willicombe et al. , which had found significantly higher incidence of AR, AMR and transplant glomerulopathy in the PLNF compared with DSA-negative transplants but did not routinely perform B-cell FCXM.
The pooled analysis identified a trend towards an increased risk of graft failure at 1 year post-transplant, this was lost in the 5 year analysis.
Looking at individual studies in this systematic review, two studies reported a significantly higher incidence of AMR in the PLNF compared with DSA-negative transplants. Due to reasons already described, the review could not perform a pooled analysis on AMR rates.
Translating the actual DSA intensities to a clinically meaningful result lacks robust scientific evidence, and the threshold at which DSA is considered ‘significant’ varies a lot among transplant centres. For instance, a pre-transplant DSA threshold of 300 mean fluoroscopic intensity (MFI) was set in a number of centres in France and the UK ,500 MFI in other centres in the UK, USA and Switzerland, a cut- off of >1500 MFI in Spain , while in the majority of centres namely in Korea, Saudi Arabia, South Africa, the Netherlands, Portugal and the USA, this figure was 1000 MFI.
Interestingly, only a minority of cited articles (6/23) provide a reason for their established thresholds:
It is yet to be determined if one should base these cut-off thresholds on merely statistical analysis, on correlation with cell-based crossmatch results or by clinical correlation. Moreover, the existence of inter-centre variability is not only limited to the cut-off threshold, but also related to the absolute MFI levels.
In one study, the implementation of a standard operating procedure reduced the inter-centre MFI variation from 62% to 25%.
The meta-analysis review showed the need for multicentre collaboration as urgently required to standardize practice and establish an international normalized threshold.
DSA should not be regarded as merely absolute cut-off val- ues and intensities without taking into consideration their clini- cal significance.
In the context of a negative FCXM, some DSAs could be clinically irrelevant and erroneously labelling patient as sensitized. Su ̈sal et al. concluded that Luminex detected by DSA would not have any significant influence on graft survival in patients who already had a negative Enzyme-Linked Immunosorbent Assay (ELISA) and CDCXM, and therefore refusing a transplant based solely on Luminex measured DSA is not warranted.
The authors did not report the number of PLNF transplants requiring desensiti- zation. One patient receiving desensitization in the PLNF group died in the early post-operative period.
Weakness and strength of the article
Strength:
Weakness :
Impact factor definition and how to be calculated
The Impact factor (IF) or journal impact factor (JIF) of an academic journal is a scientometric index calculated byClarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate’s Web of Science. As a journal-level metric, it is frequently used as a proxy for the relative importance of a journal within its field; journals with higher impact factor values are given status of being more important, or carry more prestige in their respective fields, than those with lower values.
Calculation of The Impact factor
The Impact Factor is calculated by dividing the number of citations in the JCR year by the total number of articles published in the two previous years. An Impact Factor of 1.0 means that, on average, the articles published one or two year ago have been cited one time. An Impact Factor of 2.5 means that, on average, the articles published one or two year ago have been cited two and a half times. Citing articles may be from the same journal; most citing articles are from different journals.”
Good work, but this summary needs a summary. Be more concise, please
In this systematic review and pooled analysis of seven retrospective studies, it was shown that there was no statistically significant evidence to support DSA-negative transplants as compared to PLNF transplants in terms of AR, graft failure, and patient death.
-Level of evidence 1
–this systematic review proof that transplantation of the immunological risk patient(DSA positive) is better than staying on dialysis.
strength point: the majority of included studies are of ‘good quality according to the Newcastle-Ottawa quality assessment.
weak point: A variety of baseline factors, technical parameters, and follow-up time were shown to be statistically significant. The threshold used to identify a significant DSA intensity and FCXM positivity differed from study to study.
-The impact factor (IF) is a measure of the frequency with which the average article in a journal has been cited in a particular year. It is used to measure the importance or rank of a journal by calculating the times its articles are cited.
The calculation is based on a two-year period and involves dividing the number of times articles were cited by the number of articles that are citable.
Level of evidence 1
Impact factor denote the extent of importance of journal , depends on the how many citations it has; It is a measure of the frequency with which the average article in a journal has been cited in a particular year. It is used to measure the importance or rank of a journal by calculating the times it’s articles are cited.
Calculation done on a two-year period and involves dividing the number of times articles were cited by the number of articles that are citable.
The higher IF, the higher the importance/quality of the journal.
Summary:
The study compared two groups one on negative DSA and one PLNF (positive luminex and negative flow cytometry) as regard GFR, acute rejection AR, graft and patient survival.
PLNF means Luminex detected low level of DSA.
Longtime transplant waiting list and shortage of transplant are the reasons behind transplantation of PLNF patients.
The concept of transplant sensitized patient is better than staying on dialysis, and still negative DSA can harbor it.
Several studies were done reported no significant difference in GFR, AR between both groups, but this meta-analysis includes small number of studies so, no final conclusion in that issue, also there is no uniform criteria in all patients in all studies which may be another factor affects AR, GFR, graft and patient survival like age, comorbidities, extent of HLA mismatch, and immunosuppression protocol and way of reduction of doses.
Strength points :
1- Studies included are of good quality
2- Studies included have clear target with follow up time to reach end point.
Weak points :
1- Small number of articles included after exclusion of many articles.
2- Still have variation between included studies including HLA mismatch, comorbidities, age…etc.
Excellent
This is a systemic review with level of evidence 1.
Impact Factor is used to measure the quality of articles. The impact factor of a given journal is an index calculated by Clarivate, a public American company, and represent the yearly mean number of citations of articles published in the last two years.
Weaknesses
1-Search was limited to articles published in English
2-Exclusion of many articles based on titles or abstract
3-Exclusion of case reports and case series including fewer than three patients
4-The DSA cut-off intensity varied considerably between centers and was not reported in two of the studies
5- FCXM cut-off threshold and lymphocyte sampling technique were reported in 3 out of 7
6-The majority of centers did not perform or did not report any desensitization techniques
7-Only 7 articles out of 1124 articles initially yielded by the search were reviewed
Strengths of the article
1-Quality of studies included in the review was evaluated using the Newcastle–Ottawa Quality Assessment- good quality for 6 out of 7
2-This review determined the outcomes in terms of graft function, acute rejection rates, graft survival and patient survival
3-Most patients in the included studies were maintained on the recommended triple immunosuppressive therapies, CNI, steroids and antimetabolite.
Summary of the results
–Graft function in both DSA-negative group and PLNF group showed no statistical significance.
– Acute rejection at one year post-transplant was reported by two studies. Studies reported a significantly higher antibody-mediated rejection (AMR) rate at 1 year in the PLNF compared with the DSA-negative transplant. Another study reported a significantly shorter time to AMR in the PLNF compared with DSA-negative transplants. After adjustment to variables, both studies reported no statistically significant difference in the acute rejection rates
–Graft survival outcomes at one year post-transplant were reported in four studies:
The PLNF group was associated with significantly higher risk of graft failure after controlling for age at transplant, blood transfusions and pregnancies. One study reported a shorter time to death censored graft failure in the PLNF group.
–Patient survival: Patient outcomes were reported in four studies. none reported a statistically significant difference in terms of patient survival between PLNF and DSA-negative transplants.
Excellent
1- Summary
There is no enough publications on the cross matching of low-level DSA detected by Luminex only compared to positive Luminex and negative flow (PLNF) and its implication in transplantation.
This pooled analysis showed no significant difference in the incidence of AR at 1 year , graft failure, and patient mortality both at 1 year and at 5 years for PLNF transplants compared with DSA-negative transplants
It was concluded that patients receiving an HLA-incompatible transplant had a significant higher survival rates if compared with matched patients remaining on dialysis
Regarding negative FCXM, some DSAs could be irrelevant meanwhile rendering the patient as sensitized.
Another study mentioned that DSA detected by Luminex would not have any significant effect on graft survival in patients who a had a negative ELISA and ,CDCXM, and therefore rejecting a transplant based only on Luminex measured DSA is not acceptable.
Also DSA types detected is an important factor in judging its clinical impact on the graft survival.
2-Metanalysis systematic review level 1 evidence
3-The strength
– Studies included are of good quality as evaluated by the Newcastle-Ottawa quality assessment
-A manual search of included articles was performed to identify any articles that might have been missed in the first search.
– Data extraction and analysis were performed by two authors independent authors .
– Full-text analysis was performed for those articles that potentially satisfied the inclusion criteria
-The studies with comparable follow-up duration were included to minimize bias
The weakness
-The search was limited to articles published in English language starting from 2000 and till 2016.
-7 studies only fulfilled the inclusion criteria
– the studies were retrpspective
– the included studies suffered from significant variation in multiple baseline characteristics, technical parameters and follow-up time .
– DSA cut-off intensity markedly varied between studies and wasnot mentioned in most of them , FCXM cut-off threshold and lymphocyte sampling technique were reported in only some of the studies .
– Under-mentioning of desensitization techniques and duration of immunosuppression in between studies.
-Incomplete reporting of outcome data.
4- IF is the frequency of citation of an article in a certain year
It is estimated by evaluating the journal performance within 2 years
It’s calculation is the number of times articles were cited divided by number of articles published in that journal in the 2 years preceding the calculation year
Excellent
Please summarise this article with reflection on your practice if possible.
Not all HLA incompatible kidney transplants carry the same immunological risk. Patients receiving an HLA incompatible transplant experience a significant improvement in their survival when compared with matched patients remaining on dialysis. Positive CDC is high immunological risk, negative FCXM is associated with a relatively low risk. Patients who are FCXM negative can still harbour pre existing DSA that are detectable by Luminex alone. To answer the this question about the outcome of PLNF transplant , seven retrospective studies consisting of 429 PLNF transplants and 10 677 DSA-negative transplants were systematically reviewed. Pre transplant significant DSA threshold MFI is undefined and taken as >300,>500,>1000,>1500 in various studies. MFI values across labs are not comparable. Also each DSA has an individual MFI value above which it becomes significant. DSA that tend to activate complement are associated with significantly higher rates of AMR. Luminex could be falsely positive due to denatured antigens or falsely negative due to prozone phenomenon. Whether Desentization is needed in PLNF transplants is indeterminate.
no significant difference in the incidence of AR at 1 year, graft failure at 1 and 5 years, patient mortality at 1 and 5 years.
low level DSA detected by luminex alone does not pose significant risk at least in the short-medium term.
What is the level of evidence provided by this study?
level 1
What are the weakness and strength of this article?
weakness
all the studies included had significant differences in a number of baseline characteristics, technical parameters and follow-up duration.
The threshold used to define a ‘significant’ DSA intensity and FCXM positivity
varied across the studies.
there were several inconsistencies and under reporting of desensitazion techniques, induction protocol, maintenance immunosuppression.
strength
majority of included studies are of good quality.
What is meant by the impact factor and how it is calculated?
Thomson defines impact factor as, “The journal Impact Factor is the average number of times articles from the journal published in the past two years have been cited in the JCR year. The Impact Factor is calculated by dividing the number of citations in the JCR year by the total number of articles published in the two previous years.
Only CDC cross match used to be done in our unit.