BACKGROUNDLack of adherence to immunosuppressive drugs is a risk factor for development of de novo donor-specific antibodies (dnDSA) and can contribute to antibody-mediated rejection and graft loss. ...Moreover, nonadherence is the main determinant of immunosuppressive drug level variability. High intrapatient variability of tacrolimus relates to a worse outcome in transplant recipients through unknown mechanisms. We hypothesized that a high within-patient variability of tacrolimus could increase the rate of dnDSA development and contribute to further death-censored graft loss (DCGL).
METHODSWe included 310 adult renal transplants receiving twice-daily tacrolimus throughout their first posttransplant year, with (1) at least 3 blood trough levels available to calculate coefficient of variation (CV) from month 4 to 12, (2) graft survival longer than 1 year, and (3) absence of pretransplant DSA. The dnDSA were analyzed in sera at 1, 3, and 5 years and around 6 month before the last follow-up visit or graft loss by single-antigen beads.
RESULTSDuring the follow-up, 53 patients lost their graft excluding death. A total of 116 patients (37.4%) had a CV greater than 30% and 39 (12.6%) developed dnDSA. Coefficient of variation greater than 30% (hazards ratio, 2.613; 95% confidence interval, 1.361-5.016; P = 0.004) independently related to DCGL. Acute rejection, re-transplant and CV greater than 30% (hazards ratio, 2.925; 95% confidence interval, 1.473-5.807; P = 0.002) were the only variables related to dnDSA development by Cox regression analysis.
CONCLUSIONSTacrolimus level variability is a strong risk factor for dnDSA development and DCGL. Variability must be added to the current monitoring of kidney transplant recipients due to its relationship with adherence and to graft outcome.
Secretory phospholipase A2 receptor (PLA2R) is the target antigen of the auto-antibodies produced in most (∼ 70%) patients with primary membranous nephropathy (pMN). The applicability of anti-PLA2R1 ...antibody monitoring for the prediction of MN recurrence in kidney transplant recipients still is a matter of debate.
We sought to characterize the presence and concentration of anti-PLA2R antibodies by enzyme-linked immunosorbent assay (ELISA) in a cohort of 21 patients with pMN before and after transplantation to evaluate whether anti-PLA2R concentrations could predict pMN recurrence.
The presence of pMN recurrence was significantly correlated with the existence of a positive ELISA assay at graft biopsy or with high level of anti-PLA2R1 activity before transplantation (P = 0.03). In the receiver operating characteristic analysis, anti-PLA2R levels (cut-off of 45 U/mL) during the pretransplantation period accurately predicted pMN recurrence, with a sensitivity of 85.3%, specificity of 85.1%, negative predictive value of 92%, and an area under the curve of 90.8%. This finding supports the hypothesis that anti-PLA2R cause pMN recurrence in humans and indicates the need to prove in an experimental model. Furthermore, 6 of 7 patients with recurrence were carriers of HLA DQA1* 05:01/05 and DQB1* 02:01, confirming these DQ alleles as those associated with higher anti-PLA2R levels.
This study is the first to demonstrate pretransplantation circulating anti-PLA2R antibodies in a cohort of renal transplant recipients who prospectively developed recurrent disease. Currently, anti-PLA2R levels measured by ELISA may be a rational tool to establish the risk of MN recurrence in renal allograft recipients.
(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both ...acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant
c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant
c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.
In patients with chronic kidney disease (CKD), the main cause of morbidity and mortality is cardiovascular disease (CVD). Both coronary artery calcium scoring by computed tomography (CT) and optical ...coherence tomography (OCT) are used to identify patients at increased risk for ischemic heart disease, thereby indicating a higher cardiovascular risk profile. Our study aimed to investigate the utility of these techniques in the CKD population. In patients with CKD, OCT was used to measure the choroidal thickness (CHT) and the thickness of the peripapillary retinal nerve fiber layer (pRNFL). A total of 127 patients were included, including 70 men (55%) with an estimated glomerular filtration rate (eGFR) of 39 ± 30 mL/min/1.73 m
. Lower pRNFL thickness was found to be related to high-sensitivity troponin I (r = -0.362,
< 0.001) and total coronary calcification (r = -0.194,
= 0.032). In a multivariate analysis, pRNFL measurements remained associated with age (β = -0.189; -0.739--0.027;
= 0.035) and high-sensitivity troponin I (β = -0.301; -0.259--0.071;
< 0.001). Severe coronary calcification (Agatston score ≥ 400 HU) was related to a worse eGFR (
= 0.008), a higher grade of CKD (
= 0.036), and a thinner pRNFL (
= 0.011). The ROC curve confirmed that the pRNFL measurement could determine the patients with an Agatston score of ≥400 HU (AUC 0.638; 95% CI 0.525-0.750;
= 0.015). Our study concludes that measurement of pRNFL thickness using OCT is related to the markers associated with ischemic heart disease, such as coronary calcification and high-sensitivity troponin I, in the CKD population.
Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for ...pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.
Patients with end-stage renal disease have very high mortality. In individuals on hemodialysis, cardiovascular deaths account for ~50% of all deaths in this population, mostly due to arrhythmia. To ...determine the causes of these arrhythmic deaths is essential in order to adopt preventive strategies. The main objective of this study was to investigate whether, the presence of QTc interval alterations, from electrolyte abnormalities or presence of rare genetic variants, could have a relationship with sudden arrhythmogenic deaths in end-stage renal disease patients.
We recorded the pre- and post-dialysis QTc interval in 111 patients undergoing hemodialysis. In 47 of them, we analyzed 24 SCD-related genes including the most prevalent genes associated with long QT syndrome using a custom resequencing panel.
We found a positive although not significant association between the presence of long QTc and mortality in a subset of end-stage renal disease patients. In addition, in five patients with long QTc only after dialysis (21.7%) we detected rare potentially pathogenic genetic variants. Three out of these five carriers subsequently died suddenly.
Genetic background may be determinant in the risk of sudden cardiac death in these patients. We recommend evaluating the QTc interval before and after hemodialysis, and performing a genetic analysis of individuals with long QTc after hemodialysis.
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of myeloid regulatory cells that were originally described in cancer. Several studies in animal models point to MDSC as ...important players in the induction of allograft tolerance due to their immune modulatory function. Most of the published studies have been performed in animal models, and the data addressing MDSCs in human organ transplantation are scarce. We evaluated the phenotype and function of different MDSCs subsets in 38 kidney transplant recipients (KTRs) at different time points. Our data indicate that monocytic MDSCs (Mo-MDSC) increase in KTR at 6 and 12 months posttransplantation. On the contrary, the percentages of polymorphonuclear MDSC (PMN-MDSC) and early-stage MDSC (e-MDSC) are not significantly increased. We evaluated the immunosuppressive activity of Mo-MDSC in KTR and confirmed their ability to increase regulatory T cells (Treg)
. Interestingly, when we compared the ability of Mo-MDSC to suppress T cell proliferation, we observed that tacrolimus, but not rapamycin-treated KTR, was able to inhibit CD4
T cell proliferation
. This indicates that, although mTOR inhibitors are widely regarded as supportive of regulatory responses, rapamycin may impair Mo-MDSC function, and suggests that the choice of immunosuppressive therapy may determine the tolerogenic pathway and participating immune cells that promote organ transplant acceptance in KTR.
Antibody-mediated rejection (AbMR) is one of the leading causes of graft loss in kidney transplantation and B cells play an important role in the development of it. A B-cell activating factor (BAFF) ...is a cytokine involved in B cell ontogeny. Here, we analyzed whether B cell maturation and the effect of B cell soluble factors, such as BAFF could be involved in AbMR. Serum BAFF levels and B and T cell subpopulations were analyzed 109 kidney transplant patients before transplantation and at 6 and 12 months after kidney transplantation. Pretransplant serum BAFF levels as well as memory B cell subpopulations were significantly higher in those patients who suffered clinical AbMR during the first 12 months after kidney transplantation. Similar results were observed in the prospective analysis of patients with subclinical antibody-mediated rejection detected in the surveillance biopsy performed at 12 months after kidney transplantation. A multivariate analysis confirmed the independent role of BAFF in the development of AbMR, irrespective of other classical variables. Pretransplant serum BAFF levels could be an important non-invasive biomarker for the prediction of the development of AbMR and posttransplant increased serum BAFF levels contribute to AbMR.
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