Antiphospholipid antibodies and renal transplant: A systematic review and meta-analysis
Introduction
The presence and persistence of antiphospholipid antibodies (aPL) detected via immune or clotting assays in association with vascular occlusions in either arterial or venous districts characterises the antiphospholipid syndrome (APS): in isolation it is defined primary APS, in association to other autoimmune disease including systemic lupus erythematosus it is defined as secondary [1]. While renal artery stenosis and thrombosis, renal infarction, renal vein thrombosis and chronic nephropathy are recognised features of kidney involvement in the APS [2], the role of aPL in kidney transplantation is less clear given the varying types of studies performed, the different aPL measured and the different endpoints employed [3]. We performed this systematic review to evaluate the outcome of renal allograft post kidney transplantation in recipients positive for aPL pre and/or post allograft; in particular the systematic review will try to answer two major questions: whether aPL influence the outcome of the renal allograft and whether anticoagulation affects allograft survival.
Section snippets
Search strategy and selection criteria
A systematic review according to the PRISMA guidelines [4] was carried out by searching the electronic databases MEDLINE and EMBASE from January 1985 to March 2018; for the search strategy, we used the terms [‘renal ‘OR ‘kidney transplant ’] and [‘anticardiolipin’ OR ‘anti-beta 2-glycoprotein-I’ OR ‘antiphospholipid syndrome,’ OR ‘lupus anticoagulant’ OR ‘lupus inhibitor’]. The same terms were used screen two data bases for grey literature, Open Grey and OAIster. The first search yielded 392
Number and quality of the studies
After completion of the screening and exclusion process (Fig. 1) we identified 22 cohort studies exploring the relationship between aPL and renal transplant [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31] (Table 1). A score of ≥7 on the NOQAS arbitrarily defined a good study and only two studies had low score at 4; the inter-rater reliability agreement of the two investigators (MM and PRJA) for NOQAS was
Allograft thrombosis
The diagnosis of allograft thrombosis was consistently biopsy proven [11], [14], [15], [23], [25], [26], [27], [28], [29], [30], [31] and occasionally supported by renal ultrasound or radionuclide scanning before biopsy [18].
Non allograft thrombosis
Two specific studies defined non allograft thrombosis as de novo coronary artery disease, cerebrovascular disease, peripheral vascular disease post renal allograft transplant [17], [22].
Allograft loss from all causes
The definition of allograft loss varied amongst studies: one study defined it as
Allograft thrombosis
Nine articles evaluated the relationship between different aPL and allograft thrombosis. They comprised 2106 aPL−ve and 1019 aPL+ve recipients for the effect size of this outcome [11,14,15,23,26,28–31]; the pooled prevalence of allograft thrombosis was significantly greater in aPL+ve than negative recipients (10.4% vs 1.7%) with wide heterogeneity (I2 = 89.5%, p < 0.0001) (Fig. 2(A)). Subgroup analysis after removal of three studies dealing with primary APS [10,13,30] still yielded a
Discussion
To gather a meaningful picture of the relation between aPL and renal allograft the studies included in the systematic review were grouped according to outcomes that for their nature dealt with the loss of the grafted kidney however defined: thrombosis, allograft loss proper, allograft rejection, allograft malfunction and duration with some information on vascular occlusion other than graft thrombosis.
Amongst the outcomes, the meta-analysis shows that aPL strongly associated with allograft
Conclusion
There is a strong link between aPL and different renal allograft outcomes including intra and extra-renal thrombosis, allograft loss proper and allograft duration but not with allograft rejection. AVK anticoagulants are effective in preventing allograft thrombosis though this could be offset by an increased risk of bleeding in the perioperative period. The limited numbers of papers reporting data on LA and the expression of data as percentage of recipients positive for aPL rather than aPL
References (47)
Antiphospholipid syndrome
Thromb Res
(2017)- et al.
Kidney allograft: a target for systemic disease
Presse Med
(2012) - et al.
Misleading funnel plot for detection of bias in meta-analysis
Clin Epidemiol
(2000) - et al.
Prospective study on autoantibodies against apolipoprotein H (beta2GPI) in several clinical parameters from patients with terminal renal failure and functioning renal transplants
Transplant Proc
(2009) - et al.
Antiphospholipid antibody syndrome and posttransplant renal thrombosis
Transplant Proc
(1999) - et al.
Anticardiolipin antibodies after kidney transplantation in patients without connective tissue disease
Transplant Proc
(1999) - et al.
Antiphospholipid antibodies as a risk factor for atherosclerotic events in renal transplant recipients
Kidney Int
(2003) - et al.
Severe vascular lesions and poor functional outcome in kidney transplant recipients with lupus anticoagulant antibodies
Am J Transplant
(2010) - et al.
Antiphospholipid antibodies in renal allograft recipients
Transplant Proc
(2013) - et al.
Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry
Am J Med
(1996)
β2-glycoprotein I, lipopolysaccharide and endothelial TLR4: three players in the two hit theory for anti-phospholipid-mediated thrombosis
J Autoimmun
Acute and chronic allograft dysfunction in kidney transplant recipients
Med Clin North Am
Memory B cells producing somatically mutated antiphospholipid antibodies are present in healthy individuals
Blood
Renal involvement in primary antiphospholipid syndrome
J Nephrol
PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation
BMJ
Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events
Stat Med
The case of the misleading funnel plot
Br Med J
Prevalence and clinical significance of antiphospholipid antibodies in renal transplant recipients
Transplant Proc
Risk of early renal allograft failure is increased for patients with antiphospholipid antibodies
Transplant Int
Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: a multicenter study
Transplantation
Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis
Transplantation
Antiphospholipid antibodies and renal transplantation: a risk assessment
Lupus
Cited by (10)
Incidence of Kidney Replacement Therapy and Subsequent Outcomes Among Patients With Systemic Lupus Erythematosus: Findings From the ERA Registry
2022, American Journal of Kidney DiseasesCitation Excerpt :The median follow-up of patients in the present study was 4.4 years, which may not allow for the development of specific complications that are unique to patients with SLE. A variety of factors may contribute to adverse outcomes in SLE patients, such as history of aggressive immunosuppressive treatment and presence of antiphospholipid antibodies potentiating the risk of vascular access failure and thrombotic complications, including allograft thrombosis.25,26 Delayed waitlisting for kidney transplant and prolonged time to transplant (as shown in our study), likely due to persistent disease activity or complications arising from the disease itself,27 result in a lower overall rate of transplant, including preemptive kidney transplant.
Antiphospholipid Syndrome Nephropathy and Other Thrombotic Microangiopathies Among Patients With Systemic Lupus Erythematosus
2019, Advances in Chronic Kidney DiseaseCitation Excerpt :Late lesions display fibrointimal hyperplasia with luminal obliteration and organized thrombi with recanalization in small caliber arteries (Fig 3), focal cortical atrophy, and tubular thyroidization.3,9 Graft thrombosis is the main risk for patients with APS after a renal transplant.22,23 A recent meta-analysis of 22 cohort studies found a higher prevalence of thrombosis (10.4% vs 1.7%) and TMA (10.2% vs 0%) in renal allograft in patients with the presence of antiphospholipid antibodies compared to none.23
Lupus Nephritis and Kidney Transplantation: Where Are We Today?
2019, Advances in Chronic Kidney DiseaseCitation Excerpt :The presence of aPL antibodies is associated with early graft thrombosis and graft failure.31-33 In a systematic review of 22 cohort studies (6 of them included SLE patients), Ames and colleagues34 reported that the pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL positive recipients, but the pooled prevalence of allograft malfunction and rejection was similar between aPL negative and aPL positive recipients. Ames and colleagues also found that oral antivitamin K anticoagulants effectively prevented allograft thrombosis in aPL recipients, though this must be weighed against the risk of increased risk of bleeding during the perioperative period.
The impact of antiphospholipid antibodies/antiphospholipid syndrome on systemic lupus erythematosus
2024, Rheumatology (United Kingdom)Antiphospholipid Syndrome in Renal Allograft Recipients—A Long-Term Multicenter Analysis
2023, Journal of Clinical Medicine
Conflict of interest: None of the authors have any conflict of interest to declare.