Radiologic imaging has the potential to identify several functional and/or structural biomarkers of acute and chronic kidney diseases that are useful diagnostics to guide patient management. A renal ...ultrasound examination can provide information regarding the gross anatomy and macrostructure of the renal parenchyma, and ultrasound imaging modalities based on Doppler or elastography techniques can provide haemodynamic and structural information, respectively. CT is also able to combine morphological and functional information, but the use of CT is limited due to the required exposure to X-ray irradiation and a risk of contrast-induced nephropathy following intravenous injection of a radio-contrast agent. MRI can be used to identify a wide range of anatomical and physiological parameters at the tissue and even cellular level, such as tissue perfusion, oxygenation, water diffusion, cellular phagocytic activity, tissue stiffness, and level of renal filtration. The ability of MRI to provide valuable information for most of these parameters within a renal context is still in development and requires more clinical experience, harmonization of technical procedures, and an evaluation of reliability and validity on a large scale.
Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether ...the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR <30 ml/min per 1.73 m(2) (hazard ratio HR, 3.56; 95% confidence interval CI, 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss.
Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with ...limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts.
While direct measurements of glomerular filtration rate (GFR) provide the most accurate evaluation of pre-donation kidney function, guidelines do not systematically require the use of a reference ...method. We evaluated whether and to what extent relying upon creatinine-based estimating equations (eGFR) rather than direct measurement of GFR (mGFR) alters the selection of potential living donors. We compared the impact of 4 equations (the MDRD study equation, the CKD-EPI equation, the revised Lund-Malmö equation, and the full age spectrum FAS equation) on the evaluation of 2733 potential donors with GFR measured by reference methods. We also considered the impact of using either absolute or age-adapted GFR thresholds. The CKD-EPI and FAS equations had the best performances (P10 of 50.6% and 47.8%; P30 of 94.4% and 93.1%, respectively) and led to the lowest proportion of improperly evaluated candidates. Misclassification was more frequent when GFR adequacy was defined as an absolute threshold of 90 ml/min/1.73m2 as compared to an age-adapted definition (26% and 5%, respectively). Interpretation of eGFR according to an absolute threshold of 90 ml/min/1.73m2 identified 1804 candidates eligible to donate, compared to 2648 when mGFR was interpreted with age-adapted thresholds. We conclude that creatinine-based estimates cannot substitute for direct GFR measurement to evaluate candidates for kidney donation. When reference methods for direct GFR measurement are not available, our data suggest that a strategy based on age-adapted eGFR values estimated with either the CKD-EPI or FAS equation should be preferred.
mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in ...high‐risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R−) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan–Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 95% confidence interval (CI), 0.913–2.973; log‐rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 95% CI, 0.574–4.007; log‐rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 95% CI, 0.340–5.552; log‐rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni‐ and multivariate time‐dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease.
It is widely accepted that HLA donor-specific antibodies (DSA) are associated with antibody-mediated rejection and graft loss. However, in many transplant programs, preformed anti-HLA-Cw and ...anti-HLA-DP DSA are not considered in organ allocation policies because their clinical relevance is still uncertain.
We analyzed the clinical impact of Cw/DP DSA through a retrospective study, comparing 48 patients transplanted with isolated preformed Cw/DP DSA (Cw/DP DSA group) with (i) 104 matched HLA-sensitized kidney transplant recipients with No DSA at D0 (No DSA group) and (ii) 47 kidney transplant recipients with preformed A, -B, -DR, -DQ DSA (A/B/DR/DQ DSA group).
A positive flow cytometry crossmatch in the Cw/DP DSA group was more frequent than in the No DSA group and as frequent as in the A/B/DR/DQDSA group. Two years after transplantation, the biopsy-proven acute rejection-free survival was worse in the Cw/DP and A/B/DR/DQ DSA groups than in the No DSA group (65%, 84%, 93%, P = 0.001 and P = 0.05, respectively). Accordingly, graft survival was lower in the Cw/DP and the A/B/DR/DQ DSA groups than in the No DSA group (87%, 89%, 95%, P = 0.02 and P = 0.1, respectively).
These results suggest that preformed anti-HLA-Cw and anti-HLA-DP DSA are as deleterious as anti-HLA A/B/DR/DQ DSA. It justifies their inclusion in kidney allocation programs and in immunological risk stratification algorithms.
Pathogenicity of donor-specific antibodies (DSAs) can be assessed using the single-antigen flow beads (SAFB) assays through mean fluorescence intensity (MFI) with or without serum ...ethylenediaminetetraacetic acid (EDTA) treatment, measurement of C1q or C3d binding and/or their intragraft detection graft-bound donor-specific antibody (gDSA). We aimed to investigate which of these markers best associates with antibody-mediated rejection (ABMR) and kidney allograft loss at the time of a for-cause biopsy.
This retrospective, single-centre study included 77 kidney transplant recipients who underwent a for-cause biopsy between December 2004 and July 2013. All displayed serum DSAs were identified on the same day as the biopsy. Sera were tested in parallel with the classical SAFB assay with or without serum EDTA treatment, C1q- and C3d-binding assays. gDSAs were eluted from biopsy fragments and identified with SAFB.
The median time between transplantation and biopsy was 25 months (range 0.5-251). The median follow-up was 36 months (range 0-140). ABMR was histologically proven in 40% of recipients. The sensitivity and specificity of C1q, C3d and gDSA assays for predicting ABMR were 68% and 61%, 52% and 70% and 64.5% and 56.5%, respectively. At the time of biopsy, only the DSA MFI after EDTA treatment and C3d positivity were associated with graft loss. In multivariate analyses, glomerular filtration rate, transplant glomerulopathy and C4d positivity were the only factors associated with graft loss.
Our findings weaken the rationale for systematically implementing C1q, C3d or gDSA assays in this situation, because they do not independently predict ABMR and graft loss.
Our objective was to calculate an immunosuppressant possession ratio (IPR) to diagnose non-adherence at the time of antibody-mediated rejection (ABMR). IPR was defined as the ratio of number of pills ...collected at the pharmacy to the number of pills prescribed over a defined period. In a first cohort of 91 kidney transplant recipients (KTRs), those with an IPR < 90% had more frequently a tacrolimus through level coefficient of variation >30% than patients with an IPR = 100% (66.7% vs. 29.4%,
= 0.05). In a case-control study, 26 KTRs with ABMR had lower 6 months IPRs than 26 controls (76% vs. 99%,
< 0.001). In KTRs with ABMR, non-adherence was more often diagnosed by a 6 months IPR < 90% than by clinical suspicion (73.1% vs 30.8%,
= 0.02). In the multivariable analysis, only
DSA and 6 months IPR < 90% were independently associated with ABMR, whereas clinical suspicion was not (odds ratio, 4.73; 95% CI, 1.17-21.88;
= 0.03; and odds ratio, 6.34; 95% CI, 1.73-25.59;
= 0.007, respectively). In summary, IPR < 90% is a quantifiable tool to measure immunosuppressant non-adherence. It is better associated with ABMR than clinical suspicion of non-adherence.
Abstract
Background
Preventing ischemia‒reperfusion injury (IRI) is a major issue in kidney transplantation, particularly for transplant recipients receiving a kidney from extended criteria donors ...(ECD). The main consequence of IRI is delayed graft function (DGF). Hypoxia is one of the key factors in IRI, suggesting that the use of an oxygen carrier as an additive to preservation solution may be useful. In the OxyOp trial, we showed that the organs preserved using the oxygen carrier HEMO2life® displayed significantly less DGF. In the OxyOp2 trial, we aim to definitively test and quantify the efficacy of HEMO2life® for organ preservation in a large population of kidney grafts.
Methods
OxyOp2 is a prospective, multicenter, randomized, comparative, single-blinded, parallel-group study versus standard of care in renal transplantation. After the selection of a suitable donor according to the inclusion/exclusion criteria, both kidneys will be used in the study. Depending on the characteristics of the donor, both kidneys will be preserved either in static cold storage (standard donors) or on machine perfusion (for ECD and deceased-after-cardiac-death donors (DCD)). The kidneys resulting from one donor will be randomized: one to the standard-of-care arm (organ preserved in preservation solution routinely used according to the local practice) and the other to the active treatment arm (HEMO2life® on top of routinely used preservation solution). HEMO2life® will be used for ex vivo graft preservation at a dose of 1 g/l preservation solution. The primary outcome is the occurrence of DGF, defined as the need for renal replacement therapy during the first week after transplantation.
Discussion
The use of HEMO2life® in preservation solutions is a novel approach allowing, for the first time, the delivery of oxygen to organs. Improving graft survival by limiting ischemic lesions is a major public-health goal in the field of organ transplantation.
Trial registration
ClinicalTrials.gov, ID:
NCT04181710
. registered on November 29, 2019.
•This study explored tuberculosis (TB): management of contact patients with kidney disease or transplant.•TB treatment was given to contacts of circle 1 or with positive IGRA.•No case of TB disease ...occurred in this cohort of immunocompromised patients.•Systematic TB prophylaxis on highly vulnerable contact is questionable.
To describe the investigation, follow-up, management, and outcomes in a cohort of chronic kidney disease (CKD) and kidney transplant recipients (KTR) exposed to a case of pulmonary tuberculosis (TB).
Contacts were investigated following a concentric circles approach and followed-up according to their level of priority. In those with evidence of latent TB infection, treatment decision was based on the level of exposure, individual vulnerability, as well as the results of an interferon-gamma release assay.
A total of 130 patients with CKD and 180 KTR were identified as contacts and followed-up over a 2-year period. Few vulnerable high-priority contacts received anti-TB treatment, including the two (100%) highly exposed patients in circle 1, 11/78 (14.1%) CKD patients and 4/142 (2.8%) KTR in circle 2, and 10/52 (19.2%) CKD patients and 2/36 (5.6%) KTR in circle 3; all had a positive interferon-gamma release assay result. No incident cases of TB disease occurred.
These findings suggest that latent TB treatment, as recommended in European guidelines, might be reasonably avoided in vulnerable high-priority contacts of circle 2, with a negative interferon-gamma release assay and in countries with low prevalence of TB.
PDF
