Introduction:
Specific alleles in human leukocyte antigens (HLAs) are associated with an increased risk of developing drug hypersensitivity reactions induced by abacavir, allopurinol, carbamazepine, ...oxcarbazepine, phenytoin, lamotrigine, or flucloxacillin. Transplant patients are genotyped for HLA as a routine practice to match a potential donor to a recipient. This study aims to investigate the feasibility and potential impact of repurposing these HLA genotype data from kidney transplant patients to prevent drug hypersensitivity reactions.
Methods:
A cohort of 1347 kidney transplant recipients has been genotyped in the Leiden University Medical Center (LUMC) using next-generation sequencing (NGS). The risk alleles
HLA-A*31:01, HLA-B*15:02, HLA-B*15:11, HLA-B*57:01,
and
HLA-B*58:01
were retrieved from the NGS data. Medical history, medication use, and allergic reactions were obtained from the patient’s medical records. Carrier frequencies found were compared to a LUMC blood donor population.
Results:
A total of 13.1% of transplant cohort patients carried at least one of the five
HLA
risk alleles and therefore had an increased risk of drug-induced hypersensitivity for specific drugs.
HLA-A*31:01
,
HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01
were found in carrier frequencies of 4.61%, 1.19%, 4.46%, and 3.35% respectively. No
HLA-B*15:11
carrier was found. In total nine
HLA-B*57:01
carriers received flucloxacillin and seven
HLA-B*58:01
carriers within our cohort received allopurinol.
Discussion:
Our study shows that repurposing HLA genotype data from transplantation patients for the assignment of HLA risk alleles associated with drug hypersensitivity is feasible. The use of these data by physicians while prescribing drugs or by the pharmacist when dispensing drugs holds the potential to prevent drug hypersensitivity reactions. The utility of this method was highlighted by 13.1% of the transplant cohort patients carrying an actionable HLA allele.
An increasing number of elderly patients (≥65 years) receive a donor kidney from elderly donors after brain death (DBD) or after circulatory death (DCD). These organs are allocated within the ...Eurotransplant Senior Program, but outcomes must be evaluated. From the Dutch Organ Transplantation Registry, we selected 3597 recipients (≥18 years) who received a first DBD or DCD kidney during 2002-2012, and categorized them as young or elderly recipients receiving a graft from either a young or elderly donor, stratified by donor type. In multiple logistic regression analysis, elderly recipients of elderly DCD kidneys experienced more delayed graft function and acute rejection than did elderly recipients of young DBD kidneys (odds ratios 10.43 95% confidence interval (95% CI), 5.75 to 18.91 and 2.78 95% CI, 1.35 to 5.73, respectively). In Cox regression analysis, elderly recipients of elderly DCD kidneys had a 5-year mortality risk higher than that of elderly recipients of young DBD kidneys (hazard ratio, 1.86; 95% CI, 1.15 to 3.02). Elderly recipients of elderly kidneys had a 5-year mortality rate comparable to that of waitlisted elderly patients remaining on dialysis. Among elderly recipients, 63.8% of those who received elderly DCD kidneys, 45.5% of those who received elderly DBD kidneys, and approximately 26% of those who received young DBD or DCD kidneys had an eGFR<30 ml/min per 1.73 m
(including primary nonfunction) after 1 year. In conclusion, improving donor selection and preservation is warranted if the allocation of elderly DCD grafts to elderly recipients is to be expanded.
Hospital readmission after transplantation is common in kidney transplant recipients (KTRs). In this study, we aim to compare the risk of 3-month hospital readmission after kidney transplantation ...with different donor types in the overall population and in both young (< 65 years) and elderly (≥65 years) KTRs.
We included all first-time adult KTRs from 2016 to 2018 in the Netherlands Organ Transplant Registry. Multivariable logistic regression models were used to estimate the effect while adjusting for baseline confounders.
Among 1917 KTRs, 615 (32.1%) had at least one hospital readmission. Living donor kidney transplantation (LDKT) recipients had an adjusted OR of 0.76 (95%CI, 0.61 to 0.96; p = 0.02) for hospital readmission compared to deceased donor kidney transplantation (DDKT) recipients. In the young and elderly, the adjusted ORs were 0.69 (95%CI, 0.52 to 0.90, p = 0.01) and 0.93 (95%CI, 0.62 to 1.39, p = 0.73) and did not differ significantly from each other (p-value for interaction = 0.38). In DDKT, the risk of hospital readmission is similar between recipients with donation after cardiac death (DCD) or brain death (DBD) and the risk was similar between the young and elderly.
A lower risk of post-transplant 3-month hospital readmission was found in recipients after LDKT compared to DDKT, and this benefit of LDKT might be less dominant in elderly patients. In DDKT, having either DCD or DBD donors is not associated with post-transplant 3-month hospital readmission, regardless of age. Tailored patient management is needed for recipients with DDKT and elderly KTRs.
New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal ...transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.
The ESOT TLJ 3.0. consensus conference brought together leading experts in transplantation to develop evidence-based guidance on the standardization and clinical utility of pre-implantation kidney ...biopsy in the assessment of grafts from Expanded Criteria Donors (ECD). Seven themes were selected and underwent in-depth analysis after formulation of PICO (patient/population, intervention, comparison, outcomes) questions. After literature search, the statements for each key question were produced, rated according the GRADE approach Quality of evidence: High (A), Moderate (B), Low (C); Strength of Recommendation: Strong (1), Weak (2). The statements were subsequently presented in-person at the Prague kick-off meeting, discussed and voted. After two rounds of discussion and voting, all 7 statements reached an overall agreement of 100% on the following issues: needle core/wedge/punch technique representatively B,1, frozen/paraffin embedded section reliability B,2, experienced/non-experienced on-call renal pathologist reproducibility/accuracy of the histological report A,1, glomerulosclerosis/other parameters reproducibility C,2, digital pathology/light microscopy in the measurement of histological variables A,1, special stainings/Haematoxylin and Eosin alone comparison A,1, glomerulosclerosis reliability
other histological parameters to predict the graft survival, graft function, primary non-function B,1. This methodology has allowed to reach a full consensus among European experts on important technical topics regarding pre-implantation biopsy in the ECD graft assessment.
•COVID-19 associated with long-lasting symptoms in patients with advanced kidney disease.•Post COVID-19 condition (PCC) occurs in 24% of patients with advanced kidney disease.•Less likelihood of PCC ...if higher SARS-CoV-2 vaccine induced antibody levels.•More likelihood of PCC if previously hospital admitted during COVID-19.
The burden of post COVID-19 condition (PCC) is not well studied in patients with advanced kidney disease.
A large prospective cohort of SARS-CoV-2 vaccinated patients with chronic kidney disease stages G4–G5 (CKD G4/5), on dialysis, and kidney transplant recipients (KTR) were included. Antibody levels were determined after vaccination. Presence of long-lasting symptoms was assessed in patients with and without prior COVID-19 and compared using logistic regression. In patients with prior COVID-19, PCC was defined according to the WHO definition.
Two hundred sixteen CKD G4/5 patients, 375 dialysis patients, and 2005 KTR were included. Long-lasting symptoms were reported in 204/853 (24%) patients with prior COVID-19 and in 297/1743 (17%) patients without prior COVID-19 (aOR: 1.45 (1.17–1.78), P < 0.001). PCC was prevalent in 29% of CKD G4/5 patients, 21% of dialysis patients, and 24% of KTR. In addition, 69% of patients with PCC reported (very) high symptom burden. Odds of PCC was lower per 10-fold increase in antibody level after vaccination (aOR 0.82 0.70–0.96, P = 0.01) and higher in case of COVID-19 related hospital admission (aOR 4.64 2.61–8.25, P = 0.003).
CKD G4/5 patients, dialysis patients, and KTR are at risk for PCC with high symptom burden after SARS-CoV-2 vaccination, especially if antibody levels are low and in case of hospitalization due to COVID-19.
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Human leukocyte antigen (HLA) antibodies are induced by pregnancy, transfusion, or transplantation. Serum from transplant recipients is regularly screened for IgG HLA antibodies because of their ...clinical relevance for transplant outcome. While other isotypes of HLA antibodies, such as IgA may also contribute to the alloimmune response, validated detection assays for IgA HLA antibody detection are lacking. Therefore, we modified the commonly used luminex screening assay for IgG HLA antibody detection (IgG‐LMX) into an IgA HLA antibody screening assay (IgA‐LMX). Optimization and validation was performed with IgG, IgA1, and IgA2 isotype variants of HLA‐specific human recombinant monoclonal antibodies (mAbs). Reactivity patterns of IgA1 and IgA2 isotype HLA‐specific mAbs in IgA‐LMX were identical to those of the IgG isotype. Cross‐reactivity with IgG and IgM antibodies and nonspecific binding to the beads were excluded. Further assay validation showed the absence of IgA HLA antibodies in serum from individuals without alloantigen exposure (n = 18). When the IgA‐LMX assay was applied to sera from 289 individuals with known alloantigen exposure through pregnancy (n = 91) or kidney transplantation (n = 198), IgA HLA antibodies were detected in 3.5% of individuals; eight patients on the kidney retransplant waitlist and two women immunized through pregnancy. The majority (90%) of IgA HLA antibodies were directed against HLA class II and were always present in conjunction with IgG HLA antibodies. Results of this study show that this validated IgA‐LMX method can serve as a screening assay for IgA HLA antibodies and that the incidence of IgA HLA antibodies in alloantigen exposed individuals is low.
The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic ...pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.
To assess the feasibility of renal proton magnetic resonance spectroscopy for quantification of triglyceride content and to compare spectral quality and reproducibility without and with respiratory ...motion compensation in vivo.
The Institutional Review Board of our institution approved the study protocol, and written informed consent was obtained. After technical optimization, a total of 20 healthy volunteers underwent renal proton magnetic resonance spectroscopy of the renal cortex both without and with respiratory motion compensation and volume tracking. After the first session the subjects were repositioned and the protocol was repeated to assess reproducibility. Spectral quality (linewidth of the water signal) and triglyceride content were quantified. Bland-Altman analyses and a test by Pitman were performed.
Linewidth changed from 11.5±0.4 Hz to 10.7±0.4 Hz (all data pooled, p<0.05), without and with respiratory motion compensation respectively. Mean % triglyceride content in the first and second session without respiratory motion compensation were respectively 0.58±0.12% and 0.51±0.14% (P = NS). Mean % triglyceride content in the first and second session with respiratory motion compensation were respectively 0.44±0.10% and 0.43±0.10% (P = NS between sessions and P = NS compared to measurements with respiratory motion compensation). Bland-Altman analyses showed narrower limits of agreement and a significant difference in the correlated variances (correlation of -0.59, P<0.05).
Metabolic imaging of the human kidney using renal proton magnetic resonance spectroscopy is a feasible tool to assess cortical triglyceride content in humans in vivo and the use of respiratory motion compensation significantly improves spectral quality and reproducibility. Therefore, respiratory motion compensation seems a necessity for metabolic imaging of renal triglyceride content in vivo.
Abstract Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for ...therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration—time curve (AUC). However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long‐term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed. In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients.
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