Graft microvasculature is a major target of donor‐specific antibodies (DSA) and endothelial damage is direct evidence of antibody‐mediated rejection (ABMR). Using immunohistochemistry, we analyzed ...the expression of three microvascular endothelial activation markers (fascin, vimentin, and hsp47), suggestive of endothelial‐to‐mesenchymal transition (EndMT) in 351 graft biopsies from 248 kidney recipients, with concomitant screening of circulating antihuman leukocyte antigen (HLA) DSA at the time of the biopsy. The factors associated with EndMT marker expression were DSA and the presence of microvascular inflammation (MI). EndMT expressing grafts had significantly more allograft loss compared to EndMT negative grafts (P < .0001). The expression of EndMT markers positively correlated with anti‐HLA DSA class II mean fluorescence intensity (MFI) levels and especially identified DQ and DR antibodies as being more closely associated with microvascular injury. Moreover, only DSA linked to positive EndMT score affected allograft survival, regardless of DSA MFI levels or presence of C4d deposition. Thus, EndMT markers could represent a clinically relevant tool for early identification of ongoing endothelial injury, harmful DSA, and patients at high risk for allograft failure.
Fascin, vimentin, and hsp47 endothelial expression in patients with donor‐specific antibodies is a sensitive marker for early diagnosis of antibody‐mediated rejection and impacts kidney graft outcome.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as ...the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 -37.7, -1.1, P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early posttransplant steroid withdrawal may increase the risk of acute rejection and the occurrence of subclinical acute rejection (SCAR). We assessed the feasibility and safety of early steroid ...withdrawal in low-risk patients receiving cyclosporine A (CsA) and the impact of optimization of mycophenolic acid exposure on steroid withdrawal success.
De novo, low-immunological risk kidney recipients received an anti-interleukin-2-receptor-α antibody induction, a short course of 7 days of corticosteroids, and CsA with 2-hr postdose concentration monitoring. They were randomized to adjusted dose (AD) of mycophenolate mofetil (MMF) using therapeutic drug monitoring (TDM) or a fixed-dose (FD) regimen. MMF 3 g was initiated posttransplant and then adjusted starting at week 2 to a 0 to 12 hr area under the concentration time curve of 40 mg · h/L versus 2 g daily, respectively. The primary endpoint was a composite of the proportion of patients experiencing biopsy-proven acute rejection (BPAR) and those with SCAR identified on the 3-month protocol biopsy.
Among 247 analyzed patients, only 22 in the AD group and 17 in the FD group experienced BPAR or SCAR (P=0.46). The rate of SCAR was low: 4% (AD) and 2.5% (FD). No between-group difference in the incidence of BPAR was observed. TDM yielded MMF doses ranging from 1 to 4 g/d and significantly reduced interpatient variability at weeks 26 and 52 in the AD group.
In low-immunological risk kidney recipients, MMF combined with CsA allows early corticosteroid discontinuation with good tolerability. In this group of patients, TDM of MMF does not improve clinical outcome.
Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of ...antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.
Background
Severe onychomycosis treatment in kidney transplant recipients (KTR) is challenging because of drug interactions and adverse events. Tacrolimus remains the antirejection treatment (ART) of ...choice in kidney transplantation but tolerance with systemic terbinafine for the management of severe onychomycosis has not been studied.
Objective
This study illustrates severe onychomycosis management in a kidney transplantation setting and investigates systemic terbinafine tolerance profile in KTR.
Patients/Methods
We retrospective analysed clinical data of KTR with a confirmed diagnosis of severe onychomycosis.
Results
We retrieved a total of 29 KTR with severe onychomycosis needing an oral treatment to manage onychomycosis. In 55.1% (16/29) KTR, altered renal biological parameters or lack of guidelines to manage severe onychomycosis were the main reasons to deterring clinicians from prescribing oral treatments. 13 patients received an oral terbinafine treatment (9, 3 and 1 with a tacrolimus, cyclosporine and everolimus‐based ART, respectively). Clinical and biological follow‐up did not reveal severe drug interactions. ART blood levels showed significant variations in 2 patients without clinical consequences in renal graft. Two patients reported mild adverse events but after only one dose of terbinafine. Using an open‐source image analysis program, clinical evolution of onychomycosis could be retrospectively quantified and followed up.
Conclusions
The results presented here suggest that oral terbinafine can be proposed to treat severe onychomycosis with an acceptable tolerance profile in KTR with different ART such as tacrolimus and highlight the need of multicentric studies to establish guidelines for onychomycosis treatment in KTR.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Background
This national multicentre retrospective cohort study aimed to assess the long-term outcomes of dual kidney transplantation (DKT) and compare them with those obtained from single ...kidney transplantation (SKT).
Methods
Our first analysis concerned all first transplants performed between May 2002 and December 2014, from marginal donors, defined as brain death donors older than 65 years, with an estimated glomerular filtration rate (eGFR) lower than 90 mL/min/1.73 m2. The second analysis was restricted to transplants adequately allocated according to the French DKT program based on donor eGFR: DKT for eGFR between 30 and 60, SKT for eGFR between 60 and 90 mL/min/1.73 m2. Recipients younger than 65 years or with a panel-reactive antibody percentage ≥25% were excluded.
Results
The first analysis included 461 DKT and 1131 SKT. DKT donors were significantly older (77.6 versus 74 years), had a more frequent history of hypertension and a lower eGFR (55.1 versus 63.6 mL/min/1.73 m2). While primary nonfunction and delayed graft function did not differ between SKT and DKT, 1-year eGFR was lower in SKT recipients (39 versus 49 mL/min/1.73 m2, P < 0.001). Graft survival was significantly better in DKT, even after adjustment for recipient and donor risk factors. Nevertheless, patient survival did not differ between these groups. The second analysis included 293 DKT and 687 SKT adequately allocated with donor eGFR and displayed similar results but with a smaller benefit in terms of graft survival.
Conclusions
In a context of organ shortage, DKT is a good option for optimizing the use of kidneys from very expanded criteria donors.
Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE ...(VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 13.7 years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 0.60-1.48; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 0.07-0.86, P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background and Aims
Hepatitis B virus (HBV) reactivation in kidney transplant recipients may be associated with liver failure and graft loss, especially in anti-HBc antibody (HBcAb)-positive ...HBs antigen (HBsAg)-negative patients. Belatacept, a selective costimulation blocker, has been used in kidney transplantation for some time and has been associated with reactivation of other viruses as BK or CMV. However, there are few data on HBV reactivation among kidney recipients treated with belatacept.
Method
We performed a retrospective study in two French kidney transplantation centres including all transplant recipients receiving belatacept. Among HBcAb-positive patients, we analyzed HBV reactivation rate, outcomes and risks factors.
Results
135 patients treated with belatacept were included, and 32 were HBcAb-positive. Seven patients reactivated HBV (21.9% of HBcAb-positive patients), including 5 HBsAg-negative patients (16.7%); reactivation occurred 54.8 (± 70.9) months after transplantation. There was no significant difference in survival between patients that reactivated HBV and patients that did not: 5-year patient survival of 100% (28.6; 100) and 83.4% (67.6; 100), respectively (p = 0.363) and 5-year graft survival of 100% (28.6; 100) and 79.8% (61.7; 100), respectively (p = 0.335). No factor, including HBsAb positivity and antiviral prophylaxis, was statistically associated with the risk of HBV reactivation.
Conclusion
Compared to the few studies that exist in this area, the HBV reactivation rate was high in patients treated with belatacept in our study. Our findings suggest that systematic antiviral prophylaxis for anti-HBc antibody (HBcAb)-positive HBs antigen (HBsAg)-negative patients should be considered and that there should be close monitoring of HBV serology and viral load in these patients to detect early HBV reactivation.
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