Publications by authors named "Dirk Kuypers"

259 Publications

Liver and/or Kidney Transplantation After SARS-CoV-2 Infection: Prevalence, Short-Term Outcome and Kinetics of Serum IgG Antibodies.

Transplantation 2021 Sep 16. Epub 2021 Sep 16.

Department of Gastroenterology & Hepatology, University Hospitals Leuven; Laboratory of Hepatology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium Clinical Department of Laboratory Medicine and National Reference Center for Respiratory Pathogens, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Abdominal Transplant Surgery, University Hospitals Leuven; Transplantation Research Group, Lab of Abdominal Transplantation, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium Department of Respiratory Diseases, University Hospitals Leuven; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium. Department of Cardiology, University Hospitals Leuven; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium Department of Nephrology & Renal Transplantation, University Hospitals Leuven; Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: There is paucity of data on the prevalence, adequate timing and outcome of solid organ transplantation after SARS-CoV-2 infection and the kinetics of IgG antibodies in these patients.

Methods: SARS-CoV-2 anti-nucleocapsid (N) IgG and PCR via nasopharyngeal swab were analyzed in all patients within 24h before liver and/or kidney transplantation. Kinetics of IgG antibodies were analysed and compared with an immune-competent cohort.

Results: Between May 1st 2020 and March 18th 2021, 168 patients underwent liver and/or kidney transplantation in our centre, of which 11 (6.54%) patients with previous SARS-CoV-2 infection were identified. Median interval between SARS-CoV-2 infection and transplantation was 4.5 months (range 0.9-11). After a median post-transplant follow-up of 4.9 months, 10 out of 11 patients were alive without clinical signs of viral shedding or recurrent or active infection. One patient without symptom resolution at time of transplantation died after combined liver-kidney transplantation. In 9 out of 11 patients with previously PCR confirmed infection, SARS-CoV-2 anti-N and anti-spike (S) IgG were detectable at day of transplantation. Absolute levels of anti-N and anti-S IgG were positively correlated, declined over time in all patients and were significantly lower compared with immune-competent individuals. All patients remained anti-S IgG positive until last post-transplant follow-up, while three patients became anti-N negative.

Conclusions: We observed an uncomplicated course of liver and/or kidney transplantation after SARS-CoV-2 infection in selected patients. Although having lower absolute IgG antibody levels than immune-competent individuals, all seroconverted patients remained anti-S IgG positive. These encouraging data need validation in larger studies.
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http://dx.doi.org/10.1097/TP.0000000000003955DOI Listing
September 2021

Letermovir exposure in transplant patients with end-stage renal disease on renal replacement therapy.

J Antimicrob Chemother 2021 Sep 2. Epub 2021 Sep 2.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1093/jac/dkab316DOI Listing
September 2021

Determination of tacrolimus, three mono-demethylated metabolites and a M1 tautomer in human whole blood by liquid chromatography - tandem mass spectrometry.

J Pharm Biomed Anal 2021 Aug 3;205:114296. Epub 2021 Aug 3.

University Hospitals Leuven, Department of Nephrology and Renal Transplantation, B-3000, Leuven, Belgium. Electronic address:

The immunosuppressant tacrolimus is the primary drug used in kidney transplantation to prevent organ rejection. A sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to measure tacrolimus and its three known mono-demethylated metabolites 13-O-desmethyl tacrolimus (M1), 31-O-desmethyl tacrolimus (M2), 15-O-desmethyl tacrolimus (M3). By generating the metabolites to use as standards after incubation of tacrolimus with rat liver microsomes, we discovered multiple M1 peaks which we identified as two tautomers of M1. The M1 tautomer II was also successfully validated in this method. The separation and purification of the metabolites and tautomers were performed by semi-preparative liquid chromatography with UV-detection, while confirmation was done by UPLC-MS/MS and Nuclear Magnetic Resonance. For quantification an easy sample preparation was performed with zinc sulfate and acetonitrile as cell lyses and precipitation. Detection was performed in positive electrospray ionization. By better characterization of the metabolites and the tautomers, we could possibly explain insight into the clinical condition and thus adjust the immunosuppressant therapy individually per patient. Calibration curves were linear for all compounds. Precision was assessed according to the NCCLS EP5-T guideline, being below 15 % and mean recoveries were between 93 and 110 % for tacrolimus, its three metabolites and the M1 tautomer II. The validated method was successfully applied in a cohort of 20 patients after kidney transplantation.
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http://dx.doi.org/10.1016/j.jpba.2021.114296DOI Listing
August 2021

Patterns of renal osteodystrophy one year after kidney transplantation.

Nephrol Dial Transplant 2021 Aug 12. Epub 2021 Aug 12.

Department of Microbiology, Immunology and Transplantation; Nephrology and Renal Transplantation Research Group, KU, Leuven, Belgium.

Background: Renal osteodystrophy is considered common, but is not well characterized, in contemporary kidney transplant recipients. This study reports extensively on bone phenotype by bone histomorphometry, bone densitometry, and novel bone biomarkers 1 year after kidney transplantation.

Methods: A transiliac bone biopsy and dual energy x-ray absorptiometry were performed in 141 unselected kidney transplant recipients in this observational cohort study. Blood and 24 hr urine samples were collected simultaneously.

Results: Median age was 57 ± 11 years, 71% were men, and all were of Caucasian ethnicity. Bone turnover was normal in 71% of patients, low in 26%, and high in just four cases (3%). Hyperparathyroidism with hypercalcemia was present in 13% of patients, of which one had high bone turnover. Delayed bone mineralization was detected in 16% of patients, who were characterized by hyperparathyroidism (137 vs. 53 ρg/mL), a higher fractional excretion of phosphate (40 vs. 32%), and lower levels of phosphate (2.68 vs 3.18 mg/dL) and calcidiol (29 vs. 37 ng/mL) compared to patients with normal bone mineralization. Osteoporosis was present in 15-46% of patients, with the highest prevalence at the distal skeleton. The proportion of osteoporotic patients was comparable across categories of bone turnover and mineralization.

Conclusion: The majority of kidney transplant recipients, including patients with osteoporosis, have a normal bone turnover at 1-year post-transplant. Low bone turnover is seen in a substantial subset, while high bone turnover is rare. Vitamin D deficiency and hypophosphatemia represent potential interventional targets to improve bone health post-transplant.
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http://dx.doi.org/10.1093/ndt/gfab239DOI Listing
August 2021

Strategies for asymmetrical triacetate dialyser heparin-free effective haemodialysis: the SAFE study.

Clin Kidney J 2021 Aug 28;14(8):1901-1907. Epub 2020 Nov 28.

Division of Nephrology, UZ Leuven, Leuven, Belgium.

Background: In haemodialysis, maintaining patency of the extracorporeal circuit requires the use of anticoagulants. Although (low molecular weight) heparins are the mainstay, these are not well tolerated in all patients. Alternative approaches include saline infusion, citrate-containing dialysate, regional citrate anticoagulation or the use of heparin-coated membranes. Asymmetric cellulose triacetate (ATA) dialysers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialysers. The aim of this study was to test the clotting propensity of ATA when used without systemic anticoagulation.

Methods: We performed a Phase II pilot study in maintenance dialysis patients. The 'Strategies for Asymmetrical Triacetate dialyzer heparin-Free Effective hemodialysis' (SAFE) study was a two-arm open-label crossover study. In Arm A, patients were dialysed using 1.9 m ATA membranes in combination with a citrate-containing dialysate (1 mM). In Arm B, the ATA membrane was combined with high-volume predilution haemodiafiltration (HDF) without any other anticoagulation. The primary endpoint was the success rate to complete 4 h of haemodialysis without preterm clotting. Secondary endpoints included time to clotting and measures of dialysis adequacy.

Results: We scheduled 240 dialysis sessions (120/arm) in 20 patients. Patients were randomized 1:1 to start with Arm A or B. All patients crossed to the other arm halfway through the study. A total of 232 (96.7%) study treatments were delivered. Overall, 23 clotting events occurred, 7 in Arm A and 16 in Arm B. The success rate in Arm A (ATA + citrate-containing dialysate) was 90.8/94.0% [intention to treat (ITT)/as treated]. The success rate in Arm B (ATA + predilution HDF) was 83.3/86.2% (ITT/as treated). Time to clotting was borderline significantly better in Arm A (Mantel-Cox log rank P = 0.05).

Conclusion: ATA dialysers have a low clotting propensity and both predilution HDF and a citrate-containing dialysate resulted in high rates of completed dialysis sessions.
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http://dx.doi.org/10.1093/ckj/sfaa228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323132PMC
August 2021

Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation.

Sci Rep 2021 Aug 2;11(1):15606. Epub 2021 Aug 2.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.
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http://dx.doi.org/10.1038/s41598-021-95201-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329201PMC
August 2021

Missing Self-Induced Microvascular Rejection of Kidney Allografts: A Population-Based Study.

J Am Soc Nephrol 2021 Aug 22;32(8):2070-2082. Epub 2021 Jul 22.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium

Background: Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I-mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage , and has been associated with HLA-DSA-negative MVI. However, missing self's clinical importance as a nonhumoral trigger of allograft rejection remains unclear.

Methods: In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene.

Results: We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio [HR], 1.78; 95% confidence interval [95% CI], 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA-associated MVI.

Conclusion: Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA-negative MVI and might be relevant for improved diagnostic classification and patient risk stratification.
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http://dx.doi.org/10.1681/ASN.2020111558DOI Listing
August 2021

The evolution of histological changes suggestive of antibody-mediated injury, in the presence and absence of donor-specific anti-HLA antibodies.

Transpl Int 2021 Jul 1. Epub 2021 Jul 1.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

The interplay between donor-specific anti-HLA antibodies (HLA-DSA), histology of active antibody-mediated rejection (aABMR ), transplant glomerulopathy (cg), and graft failure in kidney transplantation remains insufficiently understood. We performed a single-center cohort study (n = 1000) including 2761 protocol and 833 indication biopsies. Patients with pretransplant HLA-DSA were more prone to develop aABMRh (OR 22.7, 95% CI, 11.8-43.7, P < 0.001), cg (OR 5.76, 95% CI, 1.67-19.8, P = 0.006), and aABMRh/cg (OR 19.5, 95% CI, 10.6-35.9, P < 0.001). The negative impact of pre-transplant HLA-DSA on graft survival (HR 2.12, 95% CI, 1.41-3.20, P < 0.001) was partially mediated through aABMRh and cg occurrence. When adjusted for time-dependent HLA-DSA (HR 4.03, 95% CI, 2.21-7.15, P = 0.002), graft failure was only affected by aABMR when cg was evident. In HLA-DSA negative patients, aABMR was associated with impaired graft outcome only when evolving to cg (HR 1.32, 95% CI, 1.07-1.61, P = 0.008). We conclude that the kinetics of HLA-DSA are important to estimate the rate of graft failure, and that histological follow-up is necessary to discover, often subclinical, ABMR and cg. In the absence of HLA-DSA, patients experience similar histological lesions and the evolution to transplant glomerulopathy associates with impaired graft outcome.
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http://dx.doi.org/10.1111/tri.13964DOI Listing
July 2021

Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels.

Bone 2021 11 18;152:116066. Epub 2021 Jun 18.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Belgium; Department of Medicine, Division of Nephrology, University Hospitals Leuven, Belgium. Electronic address:

A bone biopsy with prior tetracycline labeling is the gold standard to diagnose renal osteodystrophy. In cases of missing tetracycline labels, it is still paramount to gain clinically relevant information from the extracted bone sample, by evaluating the static histomorphometry. This study investigates the diagnostic performance of static histomorphometry for the evaluation of high and low bone turnover. Transiliac bone biopsies taken pre- or post- kidney transplantation, of sufficient quality for a full histomorphometric analysis were included (n = 205). The cohort was randomly split to provide separate exploration and validation subsets. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover, and all were significant predictors of both high and low bone turnover (AUC 0.71-0.84). Diagnostic performance was very good for high turnover, as a combination of static parameters resulted in negative and positive predictive values (NPV and PPV) of 80% and 96%, respectively. For low turnover, the combined model resulted in PPV of 71% and NPV of 82%. We conclude that in the absence of tetracycline labels, static histomorphometry provide an acceptable alternative for a diagnosis of bone turnover in renal osteodystrophy.
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http://dx.doi.org/10.1016/j.bone.2021.116066DOI Listing
November 2021

Therapeutic concentrations of calcineurin inhibitors do not deregulate glutathione redox balance in human renal proximal tubule cells.

PLoS One 2021 30;16(4):e0250996. Epub 2021 Apr 30.

Laboratory of Peroxisome Biology and Intracellular Communication, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.

The calcineurin inhibitors (CNI) cyclosporine A and tacrolimus comprise the basis of immunosuppressive regimes in all solid organ transplantation. However, long-term or high exposure to CNI leads to histological and functional renal damage (CNI-associated nephrotoxicity). In the kidney, proximal tubule cells are the only cells that metabolize CNI and these cells are believed to play a central role in the origin of the toxicity for this class of drugs, although the underlying mechanisms are not clear. Several studies have reported oxidative stress as an important mediator of CNI-associated nephrotoxicity in response to CNI exposure in different available proximal tubule cell models. However, former models often made use of supra-therapeutic levels of tissue drug exposure. In addition, they were not shown to express the relevant enzymes (e.g., CYP3A5) and transporters (e.g., P-glycoprotein) for the metabolism of CNI in human proximal tubule cells. Moreover, the used methods for detecting ROS were potentially prone to false positive results. In this study, we used a novel proximal tubule cell model established from human allograft biopsies that demonstrated functional expression of relevant enzymes and transporters for the disposition of CNI. We exposed these cells to CNI concentrations as found in tissue of stable solid organ transplant recipients with therapeutic blood concentrations. We measured the glutathione redox balance in this cell model by using organelle-targeted variants of roGFP2, a highly sensitive green fluorescent reporter protein that dynamically equilibrates with the glutathione redox couple through the action of endogenous glutaredoxins. Our findings provide evidence that CNI, at concentrations commonly found in allograft biopsies, do not alter the glutathione redox balance in mitochondria, peroxisomes, and the cytosol. However, at supra-therapeutic concentrations, cyclosporine A but not tacrolimus increases the ratio of oxidized/reduced glutathione in the mitochondria, suggestive of imbalances in the redox environment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250996PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087105PMC
April 2021

Data and optimisation requirements for Kidney Exchange Programs.

Health Informatics J 2021 Apr-Jun;27(2):14604582211009918

Ente Ospedaliero Cantonale, Switzerland.

Kidney Exchange Programs (KEP) are valuable tools to increase the options of living donor kidney transplantation for patients with end-stage kidney disease with an immunologically incompatible live donor. Maximising the benefits of a KEP requires an information system to manage data and to optimise transplants. The data input specifications of the systems that relate to key information on blood group and Human Leukocyte Antigen (HLA) types and HLA antibodies are crucial in order to maximise the number of identified matched pairs while minimising the risk of match failures due to unanticipated positive crossmatches. Based on a survey of eight national and one transnational kidney exchange program, we discuss data requirements for running a KEP. We note large variations in the data recorded by different KEPs, reflecting varying medical practices. Furthermore, we describe how the information system supports decision making throughout these kidney exchange programs.
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http://dx.doi.org/10.1177/14604582211009918DOI Listing
August 2021

Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering.

J Am Soc Nephrol 2021 05 9;32(5):1084-1096. Epub 2021 Mar 9.

Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

Background: Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure.

Methods: The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance.

Results: Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters.

Conclusions: A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.
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http://dx.doi.org/10.1681/ASN.2020101418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259675PMC
May 2021

Risk factors, histopathological features, and graft outcome of transplant glomerulopathy in the absence of donor-specific HLA antibodies.

Kidney Int 2021 08 3;100(2):401-414. Epub 2021 Mar 3.

KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Electronic address:

Transplant glomerulopathy is established as a hallmark of chronic antibody-mediated rejection in kidney transplant patients with donor-specific HLA antibodies (HLA-DSA). The clinical importance of transplant glomerulopathy in the absence of HLA-DSA is not well established. To help define this, 954 patients (encompassing 3744 biopsies) who underwent kidney transplantation 2004-2013 were studied with retrospective high-resolution HLA genotyping of both donors and recipients. The risk factors, histopathological appearance and prognosis of cases with transplant glomerulopathy in the absence of HLA-DSA were compared to those cases with HLA-DSA, and the impact of the PIRCHE-II score and eplet mismatches on development of transplant glomerulopathy evaluated. In this cohort, 10.3% developed transplant glomerulopathy, on average 3.2 years post-transplant. At the time of glomerulopathy, 23.5% had persistent pre-transplant or de novo HLA-DSA, while 76.5% were HLA-DSA negative. Only HLA-DSA was identified as a risk factor for glomerulopathy development as eplet mismatches and the PIRCHE-II score did not associate. HLA-DSA negative biopsies with glomerulopathy had less interstitial inflammation, less glomerulitis, and less C4d deposition in the peritubular capillaries compared to the HLA-DSA positive biopsies with glomerulopathy. While graft function was comparable between the two groups, HLA-DSA positive glomerulopathy was associated with a significantly higher risk of graft failure compared to HLA-DSA negative glomerulopathy (Hazard Ratio 3.84; 95% confidence interval 1.94-7.59). Landmark analysis three-years post-transplant showed that HLA-DSA negative patients with glomerulopathy still had a significant increased risk of graft failure compared to patients negative for glomerulopathy (2.62; 1.46-4.72). Thus, transplant glomerulopathy often occurs in the absence of HLA-DSA, independent of HLA molecular mismatches, and represents a different phenotype with less concomitant inflammation and better graft survival compared to that developed in the presence of HLA-DSA.
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http://dx.doi.org/10.1016/j.kint.2021.01.029DOI Listing
August 2021

Does kidney transplantation with a standard or expanded criteria donor improve patient survival? Results from a Belgian cohort.

Nephrol Dial Transplant 2021 04;36(5):918-926

Department of Medical Informatics, ERA-EDTA Registry, Amsterdam UMC, Academic Medical Center, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.

Background: Changes in recipient and donor factors have reopened the question of survival benefits of kidney transplantation versus dialysis.

Methods: We analysed survival among 3808 adult Belgian patients waitlisted for a first deceased donor kidney transplant from 2000 to 2012. The primary outcome was mortality during the median waiting time plus 3 years of follow-up after transplantation or with continued dialysis. Outcomes were analysed separately for standard criteria donor (SCD) and expanded criteria donor (ECD) kidney transplants. We adjusted survival analyses for recipient age (20-44, 45-64 and ≥65 years), sex and diabetes as the primary renal disease.

Results: Among patients ≥65 years of age, only SCD transplantation provided a significant survival benefit compared with dialysis, with a mortality of 16.3% [95% confidence interval (CI) 13.2-19.9] with SCD transplantation, 20.5% (95% CI 16.1-24.6) with ECD transplantation and 24.6% (95% CI 19.4-29.5) with continued dialysis. Relative mortality risk was increased in the first months after transplantation compared with dialysis, with equivalent risk levels reached earlier with SCD than ECD transplantation in all age groups.

Conclusions: The results of this study suggest that older patients might gain a survival benefit with SCD transplantation versus dialysis, but any survival benefit with ECD transplantation versus dialysis may be small.
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http://dx.doi.org/10.1093/ndt/gfab024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075371PMC
April 2021

Revisiting the changes in the Banff classification for antibody-mediated rejection after kidney transplantation.

Am J Transplant 2021 07 4;21(7):2413-2423. Epub 2021 Mar 4.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

The Banff classification for antibody-mediated rejection (ABMR) has undergone important changes, mainly by inclusion of C4d-negative ABMR in Banff'13 and elimination of suspicious ABMR (sABMR) with the use of C4d as surrogate for HLA-DSA in Banff'17. We aimed to evaluate the numerical and prognostic repercussions of these changes in a single-center cohort study of 949 single kidney transplantations, comprising 3662 biopsies that were classified according to the different versions of the Banff classification. Overall, the number of ABMR and sABMR cases increased from Banff'01 to Banff'13. In Banff'17, 248 of 292 sABMR biopsies were reclassified to No ABMR, and 44 of 292 to ABMR. However, reclassified sABMR biopsies had worse and better outcome than No ABMR and ABMR, which was mainly driven by the presence of microvascular inflammation and absence of HLA-DSA, respectively. Consequently, the discriminative performance for allograft failure was lowest in Banff'17, and highest in Banff'13. Our data suggest that the clinical and histological heterogeneity of ABMR is inadequately represented in a binary classification system. This study provides a framework to evaluate the updates of the Banff classification and assess the impact of proposed changes on the number of cases and risk stratification. Two alternative classifications introducing an intermediate category are explored.
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http://dx.doi.org/10.1111/ajt.16474DOI Listing
July 2021

Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV).

Clin Infect Dis 2021 08;73(3):e661-e671

Leuven University Vaccinology Centre, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Background: The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant.

Methods: This is a phase III investigator-initiated study in 100 persons living with HIV (age 18-45 years) and 171 SOT recipients (age 18-55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs).

Results: All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study.

Conclusions: Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.
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http://dx.doi.org/10.1093/cid/ciaa1897DOI Listing
August 2021

Apixaban in patients on haemodialysis: a single-dose pharmacokinetics study.

Nephrol Dial Transplant 2021 04;36(5):884-889

Division of Nephrology, UZ Leuven, Leuven, Belgium.

Background: Apixaban, a direct oral anticoagulant inhibiting factor Xa, has been proven to reduce the risk of atrial fibrillation-related stroke and thromboembolism in patients with mild to moderate renal insufficiency. Patients on renal replacement therapy, however, were excluded from randomized controlled trials. Therefore, uncertainty remains concerning benefits, dosing and timing of intake in haemodialysis population.

Methods: We conducted a Phase II pharmacokinetics study in which 24 patients on maintenance haemodialysis were given a single dose (2.5 mg or 5 mg) of apixaban, either 30 min before or immediately after dialysis on the mid-week dialysis day.

Results: Apixaban 5 mg resulted in higher area under the curve (AUC0-48) in comparison with 2.5 mg, although significance could only be reached for dosing pre-dialysis (2.5 mg versus 5 mg, P = 0.008). In line, peak concentrations (Cmax) after dosing pre-dialysis were significantly higher in the 5 mg than in the 2.5 mg groups (P = 0.02). In addition, dialysis resulted in significant reduction of drug exposure. AUC0-48 pre-dialysis were on average 48% (2.5 mg) and 26% (5 mg) lower than the AUC0-48 post-dialysis, in line with Cmax. As a result, a dose of 2.5 mg post-dialysis and a dose of 5 mg pre-dialysis resulted in similar AUC0-48. In contrast, significant differences were found between the 5 mg group post-dialysis and the 2.5 mg group pre-dialysis (P = 0.02).

Conclusions: Our data suggest that exposure to apixaban in patients on maintenance haemodialysis is dependent not only on drug dose but also on timing of intake relative to the haemodialysis procedure.
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http://dx.doi.org/10.1093/ndt/gfaa351DOI Listing
April 2021

Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the United States: A Comparison of International Transplant Practices and Outcomes.

J Am Soc Nephrol 2021 02 15;32(2):397-409. Epub 2020 Dec 15.

Université de Paris, Institut National de la Santé et de la Recherche Médicale U970, Paris Translational Research Centre for Organ Transplantation, Paris, France

Background: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown.

Methods: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival.

Results: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years.

Conclusions: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.
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http://dx.doi.org/10.1681/ASN.2020040464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054891PMC
February 2021

Discrepancies between bioimpedance spectroscopy devices in haemodialysis patients.

Clin Kidney J 2020 Oct 22;13(5):906-908. Epub 2019 Oct 22.

Department of Immunology and Microbiology, Laboratory of Nephrology and Renal Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1093/ckj/sfz147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577755PMC
October 2020

Measures of Loop Diuretic Efficiency and Prognosis in Chronic Kidney Disease.

Cardiorenal Med 2020 29;10(6):402-414. Epub 2020 Oct 29.

Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

Background: The evolution and prognostic impact of loop diuretic efficiency according to chronic kidney disease (CKD) severity is unclear.

Methods: This retrospective cohort study includes 783 CKD patients on oral loop diuretic therapy with a 24-h urine collection available. Acute kidney injury and history of renal replacement therapy were exclusion criteria. Patients were stratified according to Kidney Disease Improving Global Outcomes (KDIGO) glomerular filtration rate class. Loop diuretic efficiency was calculated as urine output, natriuresis, and chloruresis, each adjusted for loop diuretic dose, and compared among strata. Risk for onset of dialysis and all-cause mortality was evaluated.

Results: Loop diuretic efficiency metrics decreased from KDIGO class IIIB to IV in furosemide users and from KDIGO class IV to V with all loop diuretics (p value <0.05 for all comparisons). The correlation between loop diuretic efficiency and creatinine clearance was moderate at best (Spearman's ρ 0.298-0.436; p value <0.001 for all correlations). During median follow-up of 45 months, 457 patients died (58%) and 63 received kidney transplantation (8%), while dialysis was started before in 328 (42%). All loop diuretic efficiency metrics were significantly and independently associated with both the risk for dialysis and all-cause mortality. In KDIGO class IV/V patients, low loop diuretic efficiency (i.e., urine output adjusted for loop diuretic dose ≤1,000 mL) shortened median time to dialysis with 24 months and median time to all-cause mortality with 23 months.

Conclusion: Low loop diuretic efficiency is independently associated with a shorter time to dialysis initiation and a higher risk for all-cause mortality in CKD.
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http://dx.doi.org/10.1159/000509741DOI Listing
August 2021

Replicative senescence and arteriosclerosis after kidney transplantation.

Nephrol Dial Transplant 2020 11;35(11):1984-1995

Department of Microbiology and Immunology, KU Leuven - University of Leuven, Leuven, Belgium.

Background: Replicative senescence is associated with telomere shortening. In native kidneys, obtained prior to transplantation, we recently described and validated a significant association between shorter intrarenal telomere length and renal arteriosclerosis. After renal transplantation, animal experiments suggested that ischaemia-reperfusion injury, acute rejection episodes and cytomegalovirus disease associate with accelerated renal allograft senescence. The association between post-transplant events and replicative senescence has not yet been evaluated in a human setting.

Methods: In a cohort of 134 kidney allograft recipients, we performed protocol-specified renal allograft biopsies at 3 months, 1 year, 2 years and 5 years after transplantation (n = 579 biopsies). We used quantitative real-time polymerase chain reaction to measure intrarenal relative average telomere length (T/S ratio). The association between donor and recipient demographic factors, post-transplant clinical/histological events, renal allograft histological evolution by 5 years post-transplant and intrarenal telomere length at 5 years after transplantation was studied using multiple regression models.

Results: At 5 years after transplantation, shorter intrarenal telomere length was associated with male donor gender, older donor age, donor history of hypertension and donor cardiovascular risk, which confirms the associations observed in native kidneys. Recipient characteristics and post-transplant events like delayed graft function, acute rejection episodes, presence of donor-specific antibodies, cytomegalovirus disease and immunosuppressive regimen did not associate with alterations of intrarenal telomere length at 5 years. Independent of donor age and donor cardiovascular risk, intrarenal arteriosclerosis in protocol biopsies obtained at 5 years after transplantation and progressive arteriosclerosis over time after transplantation associated with shorter telomere length, while this was not the case for other histological lesions. Moreover, telomere attrition augments the association between older donor age and the presence of severe arteriosclerosis. In the group with the oldest donor age and shortest telomere length, there was significantly more severe arteriosclerosis (43%) in protocol biopsies at 5 years after transplantation, compared with other combinations (13-28%) (P = 0.001). Intrarenal arteriosclerosis at 5 years after transplantation did not associate with post-transplant clinical events.

Conclusions: We demonstrate that intrarenal telomere length at 5 years after transplantation, as a marker for replicative senescence, associates with renal arteriosclerosis and reflects kidney donor characteristics, but not post-transplant events.
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http://dx.doi.org/10.1093/ndt/gfaa151DOI Listing
November 2020

The effect of universal infant vaccination on the prevalence of hepatitis B immunity in adult solid organ transplant candidates.

J Viral Hepat 2021 01 14;28(1):105-111. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.

Background: Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region.

Methods: Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986.

Results: The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18-2.66, P = .006) were associated with increased HBV immunity.

Conclusion: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.
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http://dx.doi.org/10.1111/jvh.13414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756211PMC
January 2021

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Front Immunol 2020 26;11:1886. Epub 2020 Aug 26.

Institute of Immunology, Heidelberg University Hospital, Heidelberg, Germany.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.
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http://dx.doi.org/10.3389/fimmu.2020.01886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489336PMC
April 2021

The effect of IGL-1 preservation solution on outcome after kidney transplantation: A retrospective single-center analysis.

Am J Transplant 2021 02 12;21(2):830-837. Epub 2020 Oct 12.

Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium.

Institut Georges Lopez-1 (IGL-1) solution is increasingly used for kidney preservation, although little information on outcomes is available. Outcomes of all deceased donor kidneys preserved by IGL-1, University of Wisconsin solution (UW), or histidine-tryptophan-ketoglutarate (HTK) and transplanted in our center (2000-2018) were analyzed. Multivariable analysis for delayed graft function (DGF), functional DGF, estimated glomerular filtration rate (eGFR, CKD-EPI equation), proteinuria, acute rejection, death-censored graft loss, and patient survival were performed. A double robust approach, consisting of propensity score weighting and correction for confounders, minimized the risk of bias. In total, 1943 transplants were included: 234 with IGL-1, 1046 with UW, and 663 with HTK. As IGL-1 was only introduced in 2014, a prespecified sensitivity analysis of 917 kidneys (2010-2018) was performed using the same statistical approach. After weighting, IGL-1 retained a higher proportion of kidneys donated after circulatory death (DCD). IGL-1 was not independently associated with any of the outcomes when compared to UW or HTK. Sensitivity analysis between 2010 and 2018 showed similar results. In this retrospective analysis, using robust methodology to reduce the risk of bias, IGL-1 preservation results in equal outcomes compared to UW or HTK, despite more DCD transplants in the IGL-1 group.
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http://dx.doi.org/10.1111/ajt.16302DOI Listing
February 2021

The Histological Picture of Indication Biopsies in the First 2 Weeks after Kidney Transplantation.

Clin J Am Soc Nephrol 2020 10 10;15(10):1484-1493. Epub 2020 Aug 10.

Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium

Background And Objectives: In preclinical studies, ischemia-reperfusion injury and older donor age are associated with graft inflammation in the early phase after transplantation. In human kidney transplantation, impaired allograft function in the first days after transplantation is often adjudicated to donor- and procedure-related characteristics, such as donor age, donor type, and ischemia times.

Design: In a cohort of 984 kidney recipients, 329 indication biopsies were performed within the first 14 days after transplantation. The histologic picture of these biopsies and its relationship with alloimmune risk factors and donor- and procedure-related characteristics were studied, as well as the association with graft failure. Multivariable Cox models were applied to quantify the cause-specific hazard ratios for early rejection and early inflammatory scores, adjusted for potential confounders. For quantification of hazard ratios of early events for death-censored graft failure, landmark analyses starting from day 15 were used.

Results: Early indication biopsy specimens displayed microvascular inflammation score ≥2 in 30% and tubulointerstitial inflammation score ≥2 in 49%. Rejection was diagnosed in 186 of 329 (57%) biopsies and associated with the presence of pretransplant donor-specific HLA antibodies and the number of HLA mismatches, but not nonimmune risk factors in multivariable Cox proportional hazards analysis. In multivariable Cox proportional hazards analysis, delayed graft function, the graft dysfunction that prompted an early indication biopsy, HLA mismatches, and pretransplant donor-specific HLA antibodies were significantly associated with a higher risk for death-censored graft failure, whereas early acute rejection was not.

Conclusions: Indication biopsies performed early after kidney transplantation display inflammatory changes related to alloimmune risk factors. Nonimmune risk factors for ischemia-reperfusion injury, such as cold and warm ischemia time, older donor age, and donor type, were not identified as strong risk factors for early inflammation after human kidney transplantation.
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http://dx.doi.org/10.2215/CJN.04230320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536761PMC
October 2020

Eplet Mismatch Load and Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study.

J Am Soc Nephrol 2020 09 6;31(9):2193-2204. Epub 2020 Aug 6.

Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit (KU) Leuven, University of Leuven, Leuven, Belgium

Background: In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes.

Methods: To evaluate the effect of number of eplet mismatches (mismatch load) on formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches.

Results: DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch.

Conclusions: Eplet mismatches in HLA-DQ confer substantial risk for DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA and DQB alleles could also help to minimize DSA formation and potentially improve transplant outcomes.
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http://dx.doi.org/10.1681/ASN.2020010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461684PMC
September 2020

Transcriptional Changes in Kidney Allografts with Histology of Antibody-Mediated Rejection without Anti-HLA Donor-Specific Antibodies.

J Am Soc Nephrol 2020 09 8;31(9):2168-2183. Epub 2020 Jul 8.

Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium

Background: Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype.

Methods: In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status.

Results: Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFN-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences.

Conclusions: ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.
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http://dx.doi.org/10.1681/ASN.2020030306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461663PMC
September 2020

Antibody-mediated rejection with and without donor-specific anti-human leucocyte antigen antibodies: performance of the peripheral blood 8-gene expression assay.

Nephrol Dial Transplant 2020 08;35(8):1328-1337

KU Leuven Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, Leuven, Belgium.

Background: Recently a peripheral blood 8-gene expression assay was developed for non-invasive detection of antibody-mediated rejection (ABMR) after kidney transplantation. Its value has not yet been evaluated in detail in clinical scenarios with different baseline disease probability [human leucocyte antigen donor-specific antibodies (HLA-DSA)-positive versus HLA-DSA-negative cases at the time of stable graft function versus graft dysfunction].

Methods: Here we investigated the diagnostic accuracy of the 8-gene expression assay for histology of ABMR (ABMRh) with or without HLA-DSA in a cross-sectional cohort study of 387 blood samples with a concomitant graft biopsy.

Results: In patients with HLA-DSA (n = 64), the 8-gene expression assay discriminated DSA-positive ABMRh (DSAposABMRh) cases (n = 16) with good diagnostic performance {area under the receiver operating characteristic curve [AUROC] 83.1% [95% confidence interval (CI) 70.8-95.3]}. Also, in HLA-DSA-negative samples (n = 323), a clinically relevant diagnostic performance for DSAnegABMRh cases was found (n = 30) with an AUROC of 75.8% (95% CI 67.4-84.4). The 8-gene assay did not discriminate DSAposABMRh cases from DSAnegABMRh cases. There was a net benefit for clinical decision-making when adding the 8-gene expression assay to a clinical model consisting of estimated glomerular filtration rate, proteinuria, HLA-DSA and age.

Conclusion: The 8-gene expression assay shows great potential for implementation in the clinical follow-up of high-risk HLA-DSA-positive patients and clinical relevance in HLA-DSA-negative cases.
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http://dx.doi.org/10.1093/ndt/gfaa096DOI Listing
August 2020

The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study.

PLoS Med 2020 06 15;17(6):e1003140. Epub 2020 Jun 15.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven and Nephrology & Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Background: Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs.

Methods And Findings: We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7-9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38-2.52, P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality (HR 1.68, 95% CI 1.21-2.33, P = 0.002). Moreover, the HR for mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48-3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23-2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation.

Conclusions: We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs.

Trial Registration: ClinicalTrials.gov Identifier: NCT02811835, NCT01331668.
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http://dx.doi.org/10.1371/journal.pmed.1003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295199PMC
June 2020

Comparison of 2 Serum-Free Light-Chain Assays in CKD Patients.

Kidney Int Rep 2020 May 30;5(5):627-631. Epub 2020 Jan 30.

Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium.

Introduction: Quantification of serum-free light chains (FLCs) is important in the diagnosis and monitoring of paraprotein-related diseases. There are currently 2 FLC assays available: the Freelite assay (Binding Site) and the N Latex assay (Siemens). There is emerging evidence that these assays give different results, but it is not established how kidney dysfunction affects these assays differently.

Methods: In this study, we measured and compared serum FLCs in patients with mild-to-moderate chronic kidney disease (CKD) using both assays.

Results: Although κ FLCs are higher by Freelite, λ FLCs are higher by N Latex. Both κ and λ FLCs correlate inversely with estimated glomerular filtration rate (eGFR) in the 2 assays, but this effect is more pronounced in λ-free light-chain measurement by N Latex. Consequently, although the κ/λ ratio by Freelite is inversely correlated by eGFR, the κ/λ ratio by N Latex is positively correlated with eGFR.

Conclusion: Our results clearly demonstrate that the 2 available FLC assays cannot be used interchangeably in patients with CKD.
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http://dx.doi.org/10.1016/j.ekir.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210599PMC
May 2020
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