Anders Åsberg

• Ludvigsen, Lene Ugilt Pagter; Thomsen, Marianne Kragh; Kro, Grete Anette Birkeland; Pedersen, Rune Micha; Gramkow, Ann Maria & Åsberg, Anders [Show all 16 contributors for this article] (2026). Epstein-Barr virus infection monitoring in kidney transplant recipients (EVITA study)—investigating the clinical significance of EBV-DNAemia and the risk of early-onset PTLD. American Journal of Transplantation. ISSN 1600-6135. p. 1–15. doi: 10.1016/j.ajt.2026.07.012. Full text in Research Archive
• Averina, Maria; Brun, Atle; Skadberg, Øyvind; Løfblad, Lena; Michaelsen, Anette Kristine & Bergan, Stein [Show all 15 contributors for this article] (2026). Performance of the European Kidney Function Consortium (EKFC) creatinine-based eGFR equation and other eGFR equations in a north European population. A multicentre study in Norway. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. doi: 10.1515/cclm-2026-0464. Full text in Research Archive Show summary

  Objectives Accurate estimation of glomerular filtration rate (eGFR) is necessary for early detection and staging of chronic kidney disease (CKD), risk stratification, and guiding therapies that prevent complications and progression to advanced CKD. This study aimed to evaluate the performance of different eGFR equations in a large national cohort. Methods This multicentre study was conducted at six university hospitals in Norway. Retrospective data from patient’s medical records from 2005 to 2024 for 5,552 adults and 2,981 children were used to validate several creatinine-based eGFR equations against measured GFR (mGFR) by Iohexol clearance. Performance was assessed using median bias and P30 accuracy (proportion of eGFR within ±30 % of mGFR). Results The European Kidney Function Consortium (EKFC) creatinine-based eGFR equation outperformed the CKD-EPI 2009 and 2021, the Modification of Diet in Renal Disease (MDRD) in adults, the Schwarts bedside and the CKiD U25 equations in children ≥2 years and was comparable to the Lund-Malmö equation (LM) in adults. Both CKD-EPI equations had the lowest accuracy and were overestimating GFR in young people (<25 years) and elderly patients (≥65 years). Replacing the CKD-EPI equations with the EKFC equation will result in lower eGFR values and a higher prevalence of CKD stages 3–5. Replacing the LM and MDRD with the EKFC equation will result in higher eGFR and a lower prevalence of CKD stages 3–5. Conclusions The EKFC equation was overall the best suited creatinine-based eGFR equation for this Norwegian population from 2 years of age. Clinicians should be informed about clinical implications of shifting from other equations to the EKFC equation.

• Boffel, Laura; Baets, Hanna De; Heughebaert, Liesl; Rispens, Theo; Åsberg, Anders & Shipkova, Maria [Show all 11 contributors for this article] (2026). To Convert or Not to Convert? Official International Association of Therapeutic Drug Monitoring and Clinical Toxicology Guideline: Considerations and Recommendations for Converting Capillary Blood Microsampling Concentrations to Plasma Concentrations. Therapeutic Drug Monitoring. ISSN 0163-4356. 48(1), p. 1–26. doi: 10.1097/ftd.0000000000001393. Full text in Research Archive Show summary

  Background: Capillary blood microsampling enables the sampling of small blood volumes, making it suitable for vulnerable populations, remote collection, and repeated sampling. Owing to its minimal invasiveness, blood microsampling has emerged as an alternative to venipuncture in many fields. However, as capillary blood differs from venous blood in composition and analytes vary in their distribution between the blood cell and plasma fractions, plasma and capillary blood concentrations may differ. Because plasma is often the standard matrix for routine analyses, this discrepancy can compromise the clinicians' interpretation of capillary blood results. Hence, to ensure comparability with results obtained through plasma-based assays and reference ranges, accurate conversion to plasma concentrations may be required, which may improve the reliability and validity of microsampling-based outcomes. Despite its relevance, guidance on whether conversion is appropriate or desired and on how to translate and validate the translation of capillary blood microsampling results to plasma concentrations is lacking. Method: To address this gap, members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) expert committees have prepared this guideline to discuss the “what, when, and how” of converting capillary to plasma concentrations and provide guidance on the decision of fit-for-purpose conversion. In addition, guidance to assess capillary blood results when the reference matrix is whole blood and to assess liquid capillary plasma results is provided. The included topics, as well as considerations and recommendations presented in this guideline, were based on a previously published dried blood spot-based IATDMCT guideline, literature review and expert opinions of the authors. Results and conclusions: Key points include the importance of conducting a comprehensive clinical validation study to fully understand capillary blood microsampling results. In addition, the performance of the conversion method should be evaluated case by case, as it depends on both the microsampling-based method and analyte of interest. Furthermore, an independent set of paired capillary and venous samples should be used to validate an established conversion formula. Finally, a key point for future studies is to focus on the clinical impact of (converted) capillary blood concentrations in comparison with decisions based on results in the reference matrix to guarantee any microsampling-based outcome.

• Slon-Roblero, Maria Fernanda; Stel, Vianda S.; Sanchez-Alvarez, Emilio; Escola, Joaquín Manrique; Dias, Bruno José Fraga & Auñón, Antonio Sarrión [Show all 28 contributors for this article] (2025). Trends in home dialysis over the last decade in Europe: an ERA Registry study. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 41(3), p. 457–475. doi: 10.1093/ndt/gfaf171. Full text in Research Archive Show summary

  Background Home dialysis therapies could offer benefits to individuals undergoing dialysis. This study examines trends of home dialysis, including home haemodialysis (HHD) and peritoneal dialysis (PD) across European countries from 2012 to 2021, and evaluates transitions between home dialysis and other kidney replacement therapies (KRT). Methods Data from adult patients undergoing KRT in 13 European countries were obtained from the European Renal Association Registry. Trends in home dialysis initiation, the number of patients receiving home dialysis by 31 December of each year, and transitions before and after home dialysis were analysed. Results Between 2012 and 2021, 65 246 adults initiated PD and 7878 HHD. Over the last decade, HHD initiation rates and prevalence increased, while those for PD declined, resulting in a stable overall home dialysis initiation rate and prevalence. Home dialysis accounted for 5.8% of the total KRT prevalence. Most HHD patients transitioned from in-centre HD (ICHD, 76.6%), whereas 86.9% of PD patients had no prior KRT. Two years after initiation, 53.2% of HHD patients remained on HHD, 20.9% received a kidney transplant (KT), 16.6% transitioned to ICHD, 8.1% died while on HHD and 0.6% switched to PD. Among PD patients, 39.6% remained on PD, 22.6% transitioned to ICHD, 18.3% received a KT, 17.4% died while on PD and 0.3% switched to HHD. Conclusions While the use of HHD over the past decade increased in some European countries, the use of PD has declined. The prevalence of both HHD and PD remains low, with limited transitions from other KRT options to home dialysis and between home dialysis modalities. These findings highlight the need for more effective, region-specific strategies to improve access to these modalities for patients who may benefit from it.

• Ali, Hatem; Casula, Anna Maria; Paola, Andre; Åsberg, Anders; Gudmundsdottir, Helga & Waldum-Grevbo, Bård Endre [Show all 10 contributors for this article] (2025). "PD-PREDICT": A Machine Learning Model for Patient Survival in Peritoneal Dialysis. ASAIO journal (1992). ISSN 1058-2916. 72(3), p. 263–271. doi: 10.1097/MAT.0000000000002563. Full text in Research Archive
• Risnes, Louise Fremgaard; Brottveit, Margit; Robertsen, Ida; Ibsen, Jostein Holen; Aabakken, Lars & Johannesen, Marie Kongshaug [Show all 12 contributors for this article] (2025). Research Communication: Teriflunomide Does Not Affect Gluten-Specific T-Cell Activity in Coeliac Disease—A Randomised, Placebo-Controlled Trial. Alimentary Pharmacology and Therapeutics. ISSN 0269-2813. 62(10), p. 1027–1031. doi: 10.1111/apt.70301. Full text in Research Archive Show summary

  Coeliac disease is an autoimmune disorder driven by gluten and managed through a strict gluten-free diet. We tested teriflunomide, a drug known for its ability to alter T-cell activity, in a phase 2a trial of 15 patients with coeliac disease. Participants received teriflunomide or placebo including a loading dose, followed by a 3-day oral gluten challenge to monitor T-cell responses. The main aim was to observe attenuation of gluten-specific T-cell activation markers after gluten exposure. We found no significant differences in T-cell activity between groups, concluding that teriflunomide is ineffective as a non-dietary treatment for coeliac disease

• Sagedal, Solbjørg; Hovd, Markus; Åsberg, Anders; Mollnes, Tom Eirik; Klingenberg, Olav Inge & Heldal, Torbjørn Fossum [Show all 10 contributors for this article] (2025). Increased levels of ficolin-1 and of C3dg are independently associated with high risk of infection in patients with chronic kidney disease: a prospective cohort study. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1645347. Full text in Research Archive Show summary

  Background and hypothesis: Infection is a leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). The complement system provides crucial first-line defense against pathogens. Mannose-binding lectin (MBL), ficolins (1, 2 and 3), and collectin-LK 1 (CL-LK) are pattern recognition molecules (PRMs) of the lectin pathway (LP) that recognize microbial surfaces and activate complement. C3dg is a complement cleavage fragment indicating complement activation. The aim of the study was to investigate whether levels of PRMs and C3dg are associated with the risk of significant infections requiring hospitalization in patients with CKD. Methods: This prospective cohort study included 518 patients ≥18 years with CKD (eGFR<60 mL/min/1.73 m2), consecutively recruited between 2008-2022. About half (270/518) were in dialysis at inclusion. None of the patients were previously transplanted with any organ or stem cells. The primary endpoint was non-access-related infections requiring hospitalization. Patients were followed until kidney transplantation or death or until 31.12.2024. Plasma concentrations of the biomarkers were measured at inclusion. Time-to-event analyses using Cox regression were employed to assess associations with infection, adjusting for age, sex, diabetes, dialysis status, and dialysis vintage. Results: During a median (interquartile range [IQR]) time of follow-up of 1.24 (0.49-2.76) years, 182 patients (35%) were hospitalized due to non-access infection. Higher baseline levels of ficolin-1 and C3dg were independently associated with infection risk, HR 3.05, 95% CI 1.25-7.43, p=0.01 and HR 2.97, 95% CI 1.37-6.44, p=0.006, respectively, for each log10 unit increase. In multivariable models including all biomarkers, only C3dg remained independently associated with infection (HR 2.81, 95% CI 1.23-6.43, p=0.01). Conclusions: High levels of complement activation (C3dg) and ficolin-1 were independently associated with increased infection risk in patients with CKD. A dysregulated complement activation rather than PRM deficiency seems to be a key pathogenic mechanism resulting in increased infection risk in advanced CKD.

• Nguyen, Mai Uyen T.; Neely, Michael N.; Åsberg, Anders; Boge, Craig L.K. & Downes, Kevin J. (2025). A Matched Case-Control Study to Evaluate Predicted Drug Exposures and Neutropenia during Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients. Transplant Infectious Disease. ISSN 1398-2273. doi: 10.1111/tid.70146. Full text in Research Archive
• Fløde, Mari; Hermann, Monica; Igland, Jannicke; Hernar, Ingvild; Sigurdardottir, Arun K. & Søfteland, Eirik [Show all 9 contributors for this article] (2025). Hypoglycaemia and its associations with diabetes and age-related factors in older home-dwelling people with diabetes. BMC Geriatrics. 25(1). doi: 10.1186/s12877-025-06732-9. Full text in Research Archive Show summary

  Background Studies have shown high rates of hypoglycaemia among home-dwelling older people receiving home care services. Hypoglycaemia can lead to severe consequences and in worst case, death. Therefore, knowledge about the factors associated with the occurrence of hypoglycaemia in this patient group is important. This study aimed to investigate the associations between hypoglycaemia and relevant diabetes and age-related factors among individuals with diabetes aged ≥ 65 years who received home care services. Methods This prospective observational study included data from blinded continuous glucose monitoring to identify hypoglycaemia and glycaemic variability. Further, data from blood tests (HbA1c, serum creatinine), medication lists, and questionnaires on cognitive function, functional status with need of assistance, and nutritional status were collected. Data analysis was performed using Fisher’s exact tests and unadjusted logistic regression analyses. Results In total, 56 individuals participated (52% men, median age 82 years). We identified a statistically significant association between hypoglycaemia and glycaemic variability ( p  < 0.001). All participants with a coefficient of variation (CV) ≥ 36% had undergone at least one hypoglycaemic event during the study period. Also, participants with CV ≥ 27% had higher risk of hypoglycaemia than those with CV < 27% (OR 5.3, 95% CI 1.6, 17.7). Among the 34 participants with HbA1c ≥ 53 mmol/mol, 32% experienced hypoglycaemia. In total, 93% were treated with medications that potentially interfered with the effect of their diabetes medications, and 64% were treated with medications that potentially affected their ability to detect symptoms of hypoglycaemia. The associations between hypoglycaemia and cognitive, functional, or nutritional status is uncertain due to limitations in sample size. Conclusions This study highlights a significant association between glycaemic variability and hypoglycaemia among older home-dwelling adults with diabetes receiving home care services. The prevalence of drug-drug interactions raises concerns about diabetes treatment and emphasise the need for targeted interventions to improve safety and care for this vulnerable group of patients.

• Drevland, Ole Martin; Skadberg, Eline Supannee Setu; Tran, Lan Anh; Åsberg, Anders; Midtvedt, Karsten & Robertsen, Ida (2025). Development and Clinical Validation of a Volumetric Absorptive Capillary Microsampling Method for Quantification of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Kidney Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 47(6), p. 790–798. doi: 10.1097/FTD.0000000000001330. Full text in Research Archive
• Kotton, Camille N; Kumar, Deepali; Manuel, Oriol; Chou, Sunwen; Hayden, R T & Danziger-Isakov, Lara [Show all 9 contributors for this article] (2025). The Fourth International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation. ISSN 0041-1337. 109(7), p. 1066–1110. doi: 10.1097/TP.0000000000005374. Full text in Research Archive
• Gopalakrishnan, Vancheswaran; Kumar, Chanchal; Robertsen, Ida; Morehouse, Christopher; Sparklin, Ben & Khader, Shameer [Show all 19 contributors for this article] (2025). A multi-omics microbiome signature is associated with the benefits of gastric bypass surgery and is differentiated from diet induced weight loss through 2 years of follow-up. Mucosal Immunology. ISSN 1933-0219. 18(4), p. 825–835. doi: 10.1016/j.mucimm.2025.04.002. Full text in Research Archive Show summary

  Roux-en-Y gastric bypass (GBP) surgery is an effective treatment for reducing body weight and correcting metabolic dysfunction in individuals with severe obesity. Herein, we characterize the differences between very low energy diet (VLED) and GBP induced weight loss by multi-omic analyses of microbiome and host features in a non-randomized, controlled, single-center study. Eighty-eight participants with severe obesity were recruited into two arms – GBP versus VLED with matching weight loss for 6 weeks and 2-years of follow-up. A dramatic shift in the distribution of gut microbial taxa and their functional capacity was seen in the GBP group at Week 2 after surgery and was sustained through 2 years. Multi-omic analyses were performed after 6 weeks of matching weight loss between the GBP and VLED groups, which pointed to microbiome derived metabolites such as indoxyl sulphate as characterizing the GBP group. We also identified an inverse association between Streptococcus parasanguinis (an oral commensal) and plasma levels of tryptophan and tyrosine. These data have important implications, as they reveal a significant robust restructuring of the microbiome away from a baseline dysbiotic state in the GBP group. Furthermore, multi-omics modelling points to potentially novel mechanistic insights at the intersection of the microbiome and host.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Soeren & Mollnes, Tom Eirik [Show all 11 contributors for this article] (2025). Systemic inflammation is an important risk factor and predictor of graft loss and mortality one year after kidney transplantation. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1529812. Full text in Research Archive
• Gosset, Clement; Barbosa, Susana; Destere, Alexandre; Cuozzo, Sebastien; Albano, Laetitia & Morelon, Emmanuel [Show all 25 contributors for this article] (2025). Maximum cold ischemia duration for a kidney allograft: a prediction model for allograft failure at the time of organ allocation. EClinicalMedicine. 85. doi: 10.1016/j.eclinm.2025.103322. Full text in Research Archive Show summary

  Background Many determinants of kidney allograft failure are established at the time of allocation by organ distribution agencies. At this point, the main modifiable factor is the duration of cold ischemia (CIT). Currently, no practical tool exists to determine the maximum permissible cold ischemia time for a specific recipient at allocation. Methods We analyzed two prospective cohorts of kidney transplant recipients from European centers: a derivation cohort of 7040 patients from 10 centers (Barcelona; Leuven; Oslo; Paris Necker, Lyon, Nantes, Nancy, Montpellier, Nice, Paris Saint Louis) with data collected between 2005 and 2020, and a validation cohort of 6131 patients from 6 French centers (Paris Necker, Lyon, Nantes, Nancy, Montpellier, Nice) with data collected between 2008 and 2019. The main outcome was allograft failure (return to dialysis or pre-emptive retransplantation). We assessed 26 determinants of allograft failure available at the time of allograft allocation including cold ischemia time as a modifiable factor. Prediction models were developed using a classical survival analysis and a competing risk framework. Findings Allograft failure occurred in 16% (1113) of the derivation cohort and 14% (832) of the validation cohort. Independent determinants of allograft failure were donor age (HR 2.2 [1.9–2.6] for donors above 65 years old), previous allografts (HR 1.5 [1.3–1.6]), dialysis history (HR 1.7 [1.3–2] for Hemodialysis), diabetes (HR 1.4 [1.2–1.6]), vascular disease (HR 1.3 [1.1–1.5]), HLA-DR incompatibility (HR 1.2 [1.1–1.3]), donor serum creatinine (HR 1 [1–1]), and cold ischemia time (HR 1 [1–1]). Donor age was the strongest contributor, while cold ischemia was the only modifiable factor. These factors were combined into two predictive models of kidney allograft failure (Cox regression and Fine Gray) showing accurate calibration, and discrimination with a C-Index of 0.66 (95% CI: 0.63–0.70 at year one) on the validation cohort for the Fine Gray model. The Fine–Gray model, which accounts for the competing risks between allograft failure and patient death, was used to develop a practical tool for predicting allograft failure based on cold ischemia. Interpretation Prediction model at the time of allocation provides a simple and practical tool which may guide organ distribution agencies and medico-surgical teams by customizing cold ischemia time for a kidney allograft transplantation. Funding Centaure Foundation (SIREN 499,947,398–http://www.fondation-centaure.org) none of the funding sources had any role in study.

• Vasstrand, Hilde Jæger; Raki, Melinda; Skrunes, Rannveig; Leh, Sabine; Thomsen, Janne & Gudmundsdottir, Helga [Show all 11 contributors for this article] (2025). Epidemiology and clinical presentation of kidney amyloidosis have changed over the past three decades: a nationwide population-based study. BMC Nephrology. 26. doi: 10.1186/s12882-025-04136-w. Full text in Research Archive Show summary

  Background: Early diagnosis of kidney amyloidosis is essential for optimal treatment and improved outcomes. This large, nationwide cohort spanning three decades, explores the changing epidemiology and clinical presentation of kidney amyloidosis in Norway, aiming to raise amyloid awareness. Methods: In the 30-year period (1988–2017), we identified 479 patients with biopsy-confirmed kidney amyloidosis from national registries. Past medical records were reviewed for additional amyloid relevant data and cases were divided into groups of non-AA and AA amyloidosis. Results: Overall amyloid biopsy incidence in the registries was stable around 4%, but a shift in types occurred. The AL-dominated non-AA group increased from 1.9% to 2.8% (p = 0.014) while the AA group decreased from 2.6% to 1.3% (p < 0.001). The change in AA was related to less rheumatic disease, partly compensated by an increase in AA in people who inject drugs. The scope and accuracy of amyloid typing improved in the study period, significantly reducing undetermined cases (p < 0.001) and providing more robust diagnoses. Clinical presentation was diverse, but proteinuria was present in 94%. Non-AA patients more often than AA had nephrotic syndrome (70% vs 51%, p < 0.001) and better-preserved kidney-function (median (IQR) eGFR 53(55) vs 27(34) ml/min/1.73 m2, p < 0.001). AA patients were younger (p < 0.001) with higher prevalence of hypertension (53% vs 38%, p < 0.001). Notably, AA in people who inject drugs was more advanced and near half presented with end-stage kidney disease. In recent years, non-AA presented with significantly improved serum albumin (p = 0.002), haemoglobin (p = 0.020) and erythrocyte sedimentation ratio (p = 0.029). Additionally, the percentage of non-AA with end-stage kidney disease fell from 26.8% to 8.7% (p = 0.005), possibly indicating earlier diagnosis. Conclusion: The epidemiology of kidney amyloidosis has changed over the past 30 years. Biopsy incidence of non-AA is increased, and findings may suggest an earlier diagnosis. Amyloid typing has improved over time and is reflected in more precise amyloid diagnoses and reduced number of undetermined cases in recent years. Although AA related to rheumatic disease is declining, AA amyloidosis in people who inject drugs represents a growing challenge. The changing epidemiology of kidney amyloidosis may impact clinical presentation and future healthcare needs, emphasising the need for amyloid awareness.

• Ludvigsen, Lene Ugilt Pagter; Åsberg, Anders; Spetalen, Signe; Sørensen, Mia Dahl; Hamilton-Dutoit, Stephen & Gramkow, Ann-Maria [Show all 19 contributors for this article] (2025). Risk and prognosis of posttransplant lymphoproliferative disease in Epstein-Barr virus–seronegative kidney transplant recipients — an observational cohort study from Norway and western Denmark. American Journal of Transplantation. ISSN 1600-6135. 25(7), p. 1547–1560. doi: 10.1016/j.ajt.2025.01.035. Full text in Research Archive Show summary

  Posttransplant lymphoproliferative disorder (PTLD) poses a serious challenge in kidney transplant recipients. Epstein-Barr virus (EBV)-seronegative recipients have a significantly increased risk of PTLD, but few studies have investigated risk factors for PTLD in EBVseronegative recipients in the current era of immunosuppression. This cohort study from Norway and western Denmark included first-time kidney transplant recipients between 2007 and 2021 and estimated the cumulative incidence, risk, and prognosis of PTLD. In total, 80 of 5084 recipients developed biopsy-proven PTLD (median follow-up of 6.8 years). Two-year cumulative incidence of PTLD was 7.3% in EBV-seronegative adults and 14.1% in EBV-seronegative children. The age-adjusted hazard ratio (HR) for PTLD was 30.7 (95% CI, 13.9-67.9) in EBV-seronegative vs EBV-seropositive adults and 5.4 (95% CI, 1.1-26.9) in children. Recipients receiving induction therapy with antithymocyte globulin had an increased risk of PTLD (HR, 4.4; 95% CI, 1.8-10.6), while rituximab induction was associated with a lower risk of PTLD (HR, 0.20; 95% CI, 0.03-1.49). The age-adjusted mortality rate was higher in EBV-seronegative recipients with vs without PTLD (HR, 3.3; 95% CI, 1.3-8.3). In conclusion, the risk of PTLD in EBV-seronegative kidney transplant recipients is high in the contemporary era of immunosuppression. Induction therapy should be carefully considered in this high-risk population.

• Carlsen, Rasmus Kirkeskov; Åsberg, Anders; Svensson, My Hanna Sofia; Birkeland, Kåre Inge; Jørgensen, Hanne Skou & Bressendorff, Iain [Show all 10 contributors for this article] (2025). Hypomagnesemia, insulin secretion and action in patients without diabetes, 1 year after kidney transplantation. Frontiers in Medicine. 12. doi: 10.3389/fmed.2025.1492871. Full text in Research Archive
• Boenink, Rianne; Bonthuis, Marjolein; Boerstra, Brittany A.; Astley, Megan E.; Sousa, Iris R. Montez de & Helve, Jaakko [Show all 45 contributors for this article] (2025). The ERA Registry Annual Report 2022: Epidemiology of Kidney Replacement Therapy in Europe, with a focus on sex comparisons. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 18(2). doi: 10.1093/ckj/sfae405. Full text in Research Archive
• Skandalou, Eleni; Rivedal, Mariell Lossius; Marti, Hans Peter; Halden, Thea Anine Strøm; Jenssen, Trond & Vikse, Bjørn Egil [Show all 8 contributors for this article] (2025). Proteome of Renal Tubuli and Serum Differentiate Pre-Existing Type 2 Diabetes and Post-Transplant Diabetes in Kidney Transplant Recipients. PROTEOMICS - Clinical Applications. ISSN 1862-8346. 19(3). doi: 10.1002/prca.70000. Full text in Research Archive Show summary

  Purpose: Diabetes mellitus (DM) is a major cause of end-stage kidney disease (ESKD), with kidney transplantation being the preferred treatment. However, post-transplant diabetes mellitus (PTDM) increases mortality and graft loss. While PTDM and Type 2 diabetes mellitus (T2DM) share risk factors, their mechanisms differ, particularly in diabetic nephropathy (DN). This study aimed to investigate the molecular differences in PTDM by mapping the proteomes of proximal tubuli and serum in normoglycemic (NG), pre-transplant T2DM, and PTDM patients one year post-transplantation. Experimental Design Proteomic analysis was performed on microdissected proximal tubular cells and serum samples from kidney transplant recipients categorized as NG, pre-transplant T2DM, or PTDM at one year post-transplantation. Mass spectrometry was used to identify differentially expressed proteins. Data analyses were performed using gene ontology databases and pathway analysis. Results: Proteomic analysis revealed key differences, including significant dysregulation of mitochondrial proteins and lipid metabolism pathways in PTDM patients compared to T2DM and NG groups. Additionally, we observed distinct serum patterns of cholesterol metabolism dysregulation in PTDM, highlighting a complex interplay between fatty acid metabolism, mitochondrial dysfunction and systemic lipid dysregulation that may drive renal injury in PTDM-related DN. Conclusions and Clinical Relevance: This pilot study is the first to perform proteomic analysis on both microdissected tubular cells and serum from post-transplant PTDM, pre-transplant T2DM and NG transplant recipients. The proteomic differences between PTDM and T2DM could help to develop targeted therapies and early diagnostic markers, ultimately improving transplant outcomes and patient management. Further research is needed to validate these findings and explore their therapeutic potential.

• Drevland, Ole Martin; Muinck, Eric de; Trosvik, Pål; Hammerstad, Marta; Kvitne, Kine Eide & Midtvedt, Karsten [Show all 8 contributors for this article] (2025). Microbiome-derived reactivation of mycophenolate explains variations in enterohepatic recirculation in kidney transplant recipients. Microbiome. 13(1). doi: 10.1186/s40168-025-02142-6. Full text in Research Archive Show summary

  Background The pivotal role of microbes in drug metabolism is increasingly recognized, as variation in the gut microbiome composition between individuals has been shown to impact systemic drug exposure, efficacy and toxicity. Mycophenolate mofetil (MMF) is a cornerstone in immunosuppressive therapy following solid organ transplantation. However, dosing and tolerance are challenged by significant pharmacokinetic variability among patients, largely due to variable degrees of enterohepatic recirculation of mycophenolic acid (MPA), the active moiety of MMF. It is hypothesized that the variability in MPA recirculation is driven by gut microbiome-derived β-glucuronidase (β-GUS) mediated cleavage of MPA-glucuronide (MPAG) excreted in the bile. Here, we investigated the bidirectional interaction between MPA and the gut microbiome in kidney transplant recipients, using a combination of in vivo and in vitro data. Results We compared the fecal microbiomes of kidney transplant recipients (n = 21) both pre- and post-transplantation to healthy individuals (n = 15) using shotgun metagenomic sequencing. We also determined the individual microbiome-derived reactivation rate of MPAG to MPA and show a strong positive correlation between this reactivation rate and the degree of MPA enterohepatic recirculation in vivo. Through metagenomic analysis, the reactivation rate of MPA was linked to specific gut microbial species. In particular, specific β-GUS gene variants associated with Faecalibacterium prausnitzii showed a strong impact on the conversion of MPAG to MPA. Furthermore, our study confirmed a significant shift in microbial composition post-transplantation and revealed notable fluctuations in species such as F. prausnitzii and Akkermansia muciniphila across different time points after transplantation. Lastly, we provide evidence that the microbiome-derived reactivation rate of MPA is linked to specific beta-glucuronidase alleles. Conclusions We highlight for the first time that the ex vivo determined reactivation rate of MPA explains the variation of enterohepatic recirculation, emphasizing the important role of F. prausnitzii in this process. More broadly, our findings suggest that the gut microbiome significantly influences the degree of enterohepatic recirculation of MPA, providing valuable insights that could be relevant for optimizing individualized immunosuppressive drug dosing in transplant patients.

• Ponthier, Laure; Autmizguine, Julie; Franck, Benedicte; Åsberg, Anders; Ovetchkine, Philippe & Destere, Alexandre [Show all 9 contributors for this article] (2024). Optimization of Ganciclovir and Valganciclovir Starting Dose in Children by Machine Learning. Clinical Pharmacokinetics. ISSN 0312-5963. 63, p. 539–550. doi: 10.1007/s40262-024-01362-7. Full text in Research Archive
• Boerstra, Brittany A.; Boenink, Rianne; Astley, Megan E.; Bonthuis, Marjolein; ElHafeez, Samar Abd & Monzón, Federico Arribas [Show all 19 contributors for this article] (2024). The ERA Registry Annual Report 2021: a summary. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 17(2). doi: 10.1093/ckj/sfad281. Full text in Research Archive
• Drevland, Ole Martin; Grasdal, Marte; Carlsen, Rasmus Kirkeskov; Midtvedt, Karsten; Robertsen, Ida & Jenssen, Trond [Show all 10 contributors for this article] (2024). Patiromer Does Not Alter Tacrolimus Pharmacokinetics in Kidney Transplant Recipients When Administered Three Hours Post–Tacrolimus. Transplantation direct. 10(12). doi: 10.1097/TXD.0000000000001733. Full text in Research Archive Show summary

  Background. Hyperkalemia is common in kidney transplant (KTx) recipients. Patiromer, a potassium-binding polymer used to treat acute and chronic hyperkalemia, has the potential to bind charged particles in the gastrointestinal tract and thereby potentially affect the absorption of coadministered drugs. The immunosuppressive drug tacrolimus (Tac) has a narrow therapeutic window, is susceptible to drug-drug interactions (DDIs), and a potential gastrointestinal interaction with patiromer could elevate the risk of allograft rejection. We aimed to investigate the potential DDI between patiromer and Tac pharmacokinetics in KTx with hyperkalemia by sampling capillary blood using volumetric absorptive microsampling (VAMS). Methods. Thirteen KTx recipients on Tac twice daily (BID) with plasma potassium levels of >4.6 mmol/L were included. Two 12 h Tac pharmacokinetic investigations were performed with and without 8.4 mg patiromer/d for 1 wk. Oral Tac dose remained unchanged and patiromer was administered 3 h after Tac dose. Tac sampling was self-conducted using VAMS after mastering the technique. Results. Ten patients provided 2 evaluable pharmacokinetic profiles. The Tac area under the curve (AUC)0–12 ratio (AUCTac+patiromer/AUCTac) was 0.99 (90% confidence interval [CI], 0.86-1.14), and the Cmax ratio was 1.01 (90% CI, 0.86-1.19). Tac C0 and C12 fulfilled the bioequivalence criteria with a ratio of 0.98 (90% CI, 0.90-1.07) and 0.93 (90% CI, 0.83-1.04), respectively. Conclusions. When administered 3 h after the Tac morning dose, patiromer has no clinically relevant impact on Tac pharmacokinetics. We demonstrate that VAMS is a well-suited sampling method to simplify the execution of DDI studies.

• Helanterä, Ilkka; Dörje, Christina; Ortiz, Fernanda; Reisæter, Anna Varberg; Hammarström, Clara Louise & Lauronen, Jouni [Show all 11 contributors for this article] (2024). Very Low Frequency of Pathological Findings in One-year Protocol Biopsies of Uneventful Standard Risk Kidney Transplant Recipients: Results from the Nordic Protocol Biopsy Study. Transplantation direct. 10(5). doi: 10.1097/TXD.0000000000001621. Full text in Research Archive Show summary

  Background. The clinical significance of kidney transplant protocol biopsies has been debated. We studied the frequency of borderline changes and T cell–mediated rejection (TCMR) in 1-y protocol biopsies in standard risk kidney transplant recipients. Methods. Consecutive non-HLA-sensitized recipients of kidney transplants between 2006 and 2017, who underwent a protocol biopsy at 1 y in 2 national transplant centers were studied retrospectively (N = 1546). Donor-specific HLA antibodies (DSAs), graft function (plasma creatinine), and proteinuria were measured at the time of 1-y protocol biopsy. The occurrence of subclinical acute TCMR (i2t2v0 or higher) or borderline changes suspicious of TCMR (i1t1v0 or higher) in the protocol biopsy was studied, together with frequency of findings causing changes in the composite score iBox. Results. Subclinical acute TCMR was detected in 30 of 1546 (1.9%) of the protocol biopsies, and borderline or TCMR in 179 of 1546 (12%). Among patients with no history of acute rejection, and no proteinuria or DSA, TCMR was detected in only 1 of 974 (0.1%) and borderline or TCMR in only 48 of 974 (4.9%) patients at 1 y. In the absence of proteinuria (<30 mg/g, or equivalent as measured with a negative dipstick proteinuria) or DSA, or history of acute rejection, only 50 of 974 (5.1%) biopsies showed any lesions significant for the iBox score. Conclusions. The likelihood of pathological findings in 1-y protocol biopsies in non-HLA-sensitized patients without previous immunological events is low. Clinical usefulness of protocol biopsies seems limited in these patients.

• Strømmen, Ruth Cecilie; Godang, Kristin; Hovd, Markus; Finnes, Trine Elisabeth; Smerud, Knut Terje & Hartmann, Anders [Show all 9 contributors for this article] (2024). Hip geometry and strength remain stable the first year after kidney transplantation—an ibandronate/placebo post hoc analysis. Journal of Bone and Mineral Research. ISSN 0884-0431. 8(12). doi: 10.1093/jbmrpl/ziae130. Full text in Research Archive Show summary

  The sensitivity of bone mineral density (BMD) to identify patients with high fracture risk after kidney transplantation is low, therefore alternative tools are needed. Hip Structure Analysis (HSA) provides an estimation of hip structural geometry and strength based on conventional DXA scans for hip analyses. We aimed to investigate the effect of antiresorptive therapy on hip geometrical and strength parameters by HSA. In a post hoc analysis of a 12-month randomized, double-blind, placebo-controlled trial evaluating the effect of ibandronate in addition to active vitamin D and calcium in kidney transplant recipients (KTR), we re-analyzed dual total hip and femoral neck DXA scans to measure cortical bone thickness (CBT) in the femoral neck (CBTNECK), calcar (CBTCALCAR), and shaft (CBTSHAFT), along with femur neck width, hip axis length, and to estimate buckling ratio and strength index. DXA measurements were performed within 5 weeks after transplantation and repeated at 10 weeks and 1-year post-transplant. The study included a total of 127 de novo KTR with estimated glomerular filtration rate >30 mL/min at baseline. The 5 geometrical and the strength and stability hip parameters remained stable over the first post-transplant year irrespective of antiresorptive therapy. We detected no statistically significant between-group differences in any of the HSA measures. Change in geometrical hip parameters and buckling ratio over the study duration was not correlated with change in plasma parathyroid hormone or change in dual total hip BMD. In this study, the so far largest of HSA in KTR, antiresorptive therapy with ibandronate for 12 months did not affect measures of hip geometry or strength.

• Karlsson, Cecilia; Johnsen, Line Kristin; Greasley, Peter; Retterstøl, Kjetil; Hedberg, Jonatan & Hall, Martin [Show all 18 contributors for this article] (2024). Gastric Bypass vs Diet and Cardiovascular Risk Factors: A Nonrandomized Controlled Trial. JAMA Surgery. ISSN 2168-6254. 159(9), p. 971–980. doi: 10.1001/jamasurg.2024.2162. Full text in Research Archive Show summary

  Importance Roux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear. Objective To compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED). Design, Setting, and Participants This nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023. Interventions VLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED. Main Outcomes and Measures Between-group comparisons of 6-week changes in CV risk factors. Results Among 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were −17.7 mg/dL (95% CI, −27.9 to −7.5), −17.4 mg/dL (95% CI, −29.8 to −5.0) mg/dL, −9.94 mg/dL (95% CI, −15.75 to −4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups. Conclusions and Relevance This study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss. Trial Registration ClinicalTrials.gov Identifier: NCT02386917

• Kvitne, Kine Eide; Hjelmesæth, Jøran Sture; Hovd, Markus; Sandbu, Rune; Johnson, Line Kristin & Andersson, Shalini [Show all 11 contributors for this article] (2024). Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 16(3), p. 647–652. doi: 10.1002/cpt.3307. Full text in Research Archive Show summary

  This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein (P-gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity-related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow-up due to high inter- and intraindividual variability in these patients, particularly following RYGB.

• Ponthier, Laure; Franck, Bénédicte; Autmizguine, Julie; Labriffe, Marc; Ovetchkine, Philippe & Marquet, Pierre [Show all 8 contributors for this article] (2024). Application of machine-learning models to predict the ganciclovir and valganciclovir exposure in children using a limited sampling strategy. Antimicrobial Agents and Chemotherapy. ISSN 0066-4804. 68(10). doi: 10.1128/aac.00860-24. Full text in Research Archive
• Lindahl, Jørn Petter Hanto; Åsberg, Anders; Heldal, Kristian; Jenssen, Trond; Dörje, Christina & Skauby, Morten Heier [Show all 7 contributors for this article] (2024). Long-term Outcomes After Kidney Transplantation From DBD Donors Aged 70 y and Older. Transplantation direct. 10(7). doi: 10.1097/TXD.0000000000001660. Full text in Research Archive Show summary

  Background. Transplantation of kidneys from elderly donations after brain death (DBD) donors has increased owing to organ shortages. We aimed to assess the impact on long-term kidney transplant outcomes from DBD donors aged 70 y and older compared with kidneys from younger donors. Methods. From 2007 to 2022, 2274 first single kidney transplantations from DBD donors were performed at our center. Data from 1417 kidney transplant recipients receiving a DBD organ were included and categorized into 3 groups according to donor age: 70 y and older (n = 444, median age 74 y), 60–69 y (n = 527, median age 64 y), and a reference group consisting of donors aged 45–54 y (n = 446, median age 50 y). Kaplan-Meier plots and multivariate Cox regression with correction for recipient, donor, and transplant characteristics were used to investigate patient and kidney graft survival outcomes. Results. The median patient follow-up time was 9.3 y (interquartile range, 5.3–13.1). The adjusted hazard ratios for patient death in recipients of kidneys from DBD donors aged 70 y and older compared with 60–69 y and 45–54 y were 1.12 (95% confidence interval [CI], 0.92-1.36; P = 0.26) and 1.62 (95% CI, 1.26-2.07; P < 0.001), respectively. Compared with recipients of donors aged 60–69 y and 45–54 y, the adjusted hazard ratios for kidney graft loss in recipients of donors aged 70 y and older were 1.23 (95% CI, 1.02-1.48; P = 0.029) and 1.94 (95% CI, 1.54-2.45; P < 0.001), respectively. Conclusions. Transplantation of kidneys from DBD donors aged 70 y and older resulted in acceptable long-term outcomes and is encouraging.

• Vethe, Nils Tore; Åsberg, Anders; Bergan, Stein; Robertsen, Ida & Midtvedt, Karsten (2024). Implementation of Volumetric Finger-Prick Self-Sampling for Therapeutic Drug Monitoring of Immunosuppressants After Kidney Transplantation: Lessons Learned From the Practice. Therapeutic Drug Monitoring. ISSN 0163-4356. 47(1), p. 98–104. doi: 10.1097/FTD.0000000000001281. Full text in Research Archive
• Toapanta, Néstor; Comas, Jordi; Revuelta, Ignacio; Manonelles, Anna; Facundo, Carme & Perez-Saes, MJ [Show all 16 contributors for this article] (2024). Benefits of Living Over Deceased Donor Kidney Transplantation in Elderly Recipients. A Propensity Score Matched Analysis of a Large European Registry Cohort. Transplant International. ISSN 0934-0874. 37. doi: 10.3389/ti.2024.13452. Full text in Research Archive Show summary

  Although kidney transplantation from living donors (LD) offers better long-term results than from deceased donors (DD), elderly recipients are less likely to receive LD transplants than younger ones. We analyzed renal transplant outcomes from LD versus DD in elderly recipients with a propensity-matched score. This retrospective, observational study included the first single kidney transplants in recipients aged ≥65 years from two European registry cohorts (2013–2020, n = 4,257). Recipients of LD (n = 408), brain death donors (BDD, n = 3,072), and controlled cardiocirculatory death donors (cDCD, n = 777) were matched for donor and recipient age, sex, dialysis time and recipient diabetes. Major graft and patient outcomes were investigated. Unmatched analyses showed that LD recipients were more likely to be transplanted preemptively and had shorter dialysis times than any DD type. The propensity score matched Cox’s regression analysis between LD and BDD (387-pairs) and LD and cDCD (259-pairs) revealing a higher hazard ratio for graft failure with BDD (2.19 [95% CI: 1.16–4.15], p = 0.016) and cDCD (3.38 [95% CI: 1.79–6.39], p < 0.001). One-year eGFR was higher in LD transplants than in BDD and cDCD recipients. In elderly recipients, LD transplantation offers superior graft survival and renal function compared to BDD or cDCD. This strategy should be further promoted to improve transplant outcomes.

• ElHafeez, Samar Abd; Kramer, Anneke; Arici, Mustafa; Arnol, Miha; Åsberg, Anders & Bell, Samira [Show all 29 contributors for this article] (2024). Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 39(9), p. 1449–1460. doi: 10.1093/ndt/gfae034. Full text in Research Archive Show summary

  Background Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death. Methods We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence and survival. Results The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. Immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidences, of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had 5-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death [adjusted hazard ratio 1.8 (95% confidence interval 1.6–1.9)] compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%). Conclusion The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.

• Hariharan, Sundaram; Rogers, Natasha; Naesens, Maarten; Pestana, Juan M.; Ferreira, Gustavo & Require-Moura, LR [Show all 25 contributors for this article] (2024). Long-Term Kidney Transplant Survival Across the Globe. Transplantation. ISSN 0041-1337. 108(9), p. e254–e263. doi: 10.1097/TP.0000000000004977. Full text in Research Archive
• Olsen, Thomas; Elshorbagy, Amany; Stolt, Emma Theresia Kjelland; Åsberg, Anders; Zare, Hasse Khiabani & Bastani, Nasser Ezzatkhah [Show all 9 contributors for this article] (2024). Acute effects of oral mesna administration on the full amino acid profile and 3-methylhistidine: secondary results from the CYLOB dose-finding study. Amino Acids. ISSN 0939-4451. 56. doi: 10.1007/s00726-024-03398-2. Full text in Research Archive Show summary

  Plasma total cysteine (tCys) is strongly associated with fat mass in humans. Mesna lowers plasma tCys in a dose-dependent manner, but it is not known whether it interferes with metabolism of other amino acids or protein. In this Phase-1 study, we show that a single dose of mesna administered at 400, 800, 1200 or 1600 mg to 6–7 individuals per dose only slightly affects amino acid profiles, with increases in plasma valine across dose levels. There were no effects of mesna on 3-methylhistidine, a marker of protein breakdown.

• Blom, Kjersti Benedicte; Kro, Grete Anette Birkeland; Midtvedt, Karsten; Jenssen, Trond; Reisæter, Anna Varberg & Rollag, Halvor [Show all 14 contributors for this article] (2024). Cellular immunity against cytomegalovirus and risk of infection after kidney transplantation. Frontiers in Immunology. 15, p. 1–11. doi: 10.3389/fimmu.2024.1414830. Full text in Research Archive Show summary

  Introduction Cytomegalovirus (CMV) infection remains a challenge following kidney transplantation (KTx). Currently, CMV-IgG serostatus at transplantation is used to individualize CMV preventive strategies. We assessed the clinical utility of CMV-IGRA for predicting CMV infection following KTx. Methods We performed a nationwide prospective cohort study from August 2016 until December 2022. Data from all adult KTx recipients in Norway, n=1,546 (R+; n=1,157, D+/R-; n=260, D-/R-; 129), were included with a total of 3,556 CMV-IGRA analyses (1,375 at KTx, 1,188 at eight weeks, 993 one-year after KTx) and 35,782 CMV DNAemia analyses. Results In R+ recipients CMV-IGRA status, measured at any of the time-points, could not identify any differential risk of later CMV infection. D+/R- recipients remaining CMV-IGRA negative 1-year after transplantation (regardless of positive CMV DNAemia and/or CMV IgG status at that time) had increased risk of developing later CMV infection compared to D+/R- recipients who had become CMV-IGRA positive (14% vs. 2%, p=0.01). Conclusion Knowledge of pre-transplant CMV-IGRA status did not provide additional information to CMV-IgG serostatus that could improve current post-transplant CMV treatment algorithms. However, D+/R- recipients with a persisting negative CMV-IGRA one-year after transplantation remained at increased risk of experiencing later CMV infection. Therefore we advocate post-transplant CMV-IGRA monitoring in these patients.

• Kramer, Anneke; Jager, Kitty J.; Chesnaye, Nicholas C.; Kerschbaum, Julia; Hommel, Kristine & Farnés, Jordi Comas [Show all 27 contributors for this article] (2024). Changes in the epidemiology of kidney replacement therapy across Europe in 2020—the first year of the COVID-19 pandemic: an ERA Registry study. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 39(11), p. 1835–1845. doi: 10.1093/ndt/gfae043. Full text in Research Archive Show summary

  Background In 2020, the coronavirus disease 2019 (COVID-19) pandemic caused disruptions in kidney replacement therapy (KRT) services worldwide. The aim of this study was to assess the effect of the COVID-19 pandemic in 2020 on the incidence of KRT, kidney transplantation activity, mortality and prevalence of KRT across Europe. Methods Patients receiving KRT were included from 17 countries providing data to the European Renal Association Registry. The epidemiology of KRT in 2020 was compared with average data from the period 2017–2019. Changes occurring during the first and second waves of the pandemic were also explored. Results The incidence of KRT was 6.2% lower in 2020 compared with 2017–2019, with the lowest point (−22.7%) during the first wave in April. The decrease varied across countries, was smaller in males (−5.2%) than in females (−8.2%) and was moderate for peritoneal dialysis (−3.7%) and haemodialysis (−5.4%) but substantial for pre-emptive kidney transplantation (−23.6%). The kidney transplantation rate decreased by 22.5%, reaching a nadir of −80.1% during the first wave, and was greatest for living donor kidney transplants (−30.5%). While in most countries the kidney transplantation rate decreased, in the Nordic/Baltic countries and Greece there was no clear decrease. In dialysis patients, mortality increased by 11.4% and was highest in those 65–74 years of age (16.1%), in those with diabetes as the primary renal disease (15.1%) and in those on haemodialysis (12.4%). In transplant recipients, the mortality was 25.8% higher, but there were no subgroups that stood out. In contrast to the rising prevalence of KRT observed over the past decades across Europe, the prevalence at the end of 2020 (N = 317 787) resembled that of 2019 (N = 317 077). Conclusion The COVID-19 pandemic has had a substantial impact on the incidence of KRT, kidney transplant activity, mortality of KRT and prevalence of KRT in Europe with variations across countries.

• Boenink, Rianne; Kramer, Anneke; Tuinhout, Rosalie E.; Savoye, Emilie; Åsberg, Anders & Idrizi, Alma [Show all 38 contributors for this article] (2023). Trends in kidney transplantation rate across Europe: study from the ERA Registry. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 38(6), p. 1528–1539. doi: 10.1093/ndt/gfac333. Full text in Research Archive Show summary

  ABSTRACT Background The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. Methods The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. Results The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East–West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). Conclusions The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries.

• Hovd, Markus Herberg; Robertsen, Ida; Woillard, Jean-Baptiste & Åsberg, Anders (2023). A Method for Evaluating Robustness of Limited Sampling Strategies—Exemplified by Serum Iohexol Clearance for Determination of Measured Glomerular Filtration Rate. Pharmaceutics. 15(4). doi: 10.3390/pharmaceutics15041073. Full text in Research Archive Show summary

  In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitoring. However, it is not uncommon for the actual sample time to deviate from the optimal one. In this work, we evaluate the robustness of parameter estimations to such deviations in an LSS. A previously developed 4-point LSS for estimation of serum iohexol clearance (i.e., dose/AUC) was used to exemplify the effect of sample time deviations. Two parallel strategies were used: (a) shifting the exact sampling time by an empirical amount of time for each of the four individual sample points, and (b) introducing a random error across all sample points. The investigated iohexol LSS appeared robust to deviations from optimal sample times, both across individual and multiple sample points. The proportion of individuals with a relative error greater than 15% (P15) was 5.3% in the reference run with optimally timed sampling, which increased to a maximum of 8.3% following the introduction of random error in sample time across all four time points. We propose to apply the present method for the validation of LSS developed for clinical use.

• Kipp, Anne Christina; Marti, Hans Peter; Babickova, Janka; Nakken, Sigrid; Leh, Sabine & Halden, Thea Anine Strøm [Show all 11 contributors for this article] (2023). Glomerular proteomic profiling reveals early differences between preexisting and de novo type 2 diabetes in human renal allografts. BMC Nephrology. 24(1). doi: 10.1186/s12882-023-03294-z. Full text in Research Archive Show summary

  Background Diabetes mellitus (DM), either preexisting or developing after transplantation, remains a crucial clinical problem in kidney transplantation. To obtain insights into the molecular mechanisms underlying PTDM development and early glomerular damage before the development of histologically visible diabetic kidney disease, we comparatively analysed the proteome of histologically normal glomeruli from patients with PTDM and normoglycaemic (NG) transplant recipients. Moreover, to assess specificities inherent in PTDM, we also comparatively evaluated glomerular proteomes from transplant recipients with preexisting type 2 DM (T2DM). Methods Protocol biopsies were obtained from adult NG, PTDM and T2DM patients one year after kidney transplantation. Biopsies were formalin-fixed and embedded in paraffin, and glomerular cross-sections were microdissected. A total of 4 NG, 7 PTDM and 6 T2DM kidney biopsies were used for the analysis. The proteome was determined by liquid chromatography-tandem mass spectrometry. Relative differences in protein abundance and significantly dysregulated pathways were analysed. Results Proteins involved in cell adhesion, immune response, leukocyte transendothelial filtration, and cell localization and organization were less abundant in glomeruli from PTDM patients than in those from NG patients, and proteins associated with supramolecular fibre organization and protein-containing complex binding were more abundant in PTDM patients. Overall, proteins related to adherens and tight junctions and those related to the immune system, including leukocyte transendothelial migration, were more abundant in NG patients than in transplanted patients with DM, irrespective of the timing of its development. However, proteins included in cell‒cell junctions and adhesion, insulin resistance, and vesicle-mediated transport were all less abundant in PTDM patients than in T2DM patients. Conclusions The glomerular proteome profile differentiates PTDM from NG and T2DM, suggesting specific pathogenetic mechanisms. Further studies are warranted to validate these results, potentially leading to an improved understanding of PTDM kidney transplant pathophysiology and to the identification of novel biomarkers.

• Bleskestad, Inger Hjørdis; Skadberg, Øyvind; Åsberg, Anders & Gøransson, Lasse Gunnar (2023). Glycated albumin and post-transplant diabetes mellitus in kidney transplant recipients. Annals of Clinical Biochemistry. ISSN 0004-5632. 60(2), p. 109–116. doi: 10.1177/00045632231152074. Full text in Research Archive
• Fløde, Mari; Hermann, Monica; Haugstvedt, Anne; Søfteland, Eirik; Igland, Jannicke & Åsberg, Anders [Show all 8 contributors for this article] (2023). High number of hypoglycaemic episodes identified by CGM among home-dwelling older people with diabetes: an observational study in Norway. BMC Endocrine Disorders. 23. doi: 10.1186/s12902-023-01472-6. Full text in Research Archive Show summary

  Background A scoping review from 2021 identified a lack of studies on the incidence, prevention and management of hypoglycaemia in home-dwelling older people with diabetes. The aim of this study was to investigate the frequency and duration of hypoglycaemic episodes measured by continuous glucose monitoring (CGM) in older people with diabetes who received home care and who were treated with glucose-lowering medications, and to compare the frequency and duration of hypoglycaemic episodes between subgroups of the study population according to demographic and clinical variables. Methods This was an observational study investigating the occurrence of hypoglycaemia in people with diabetes aged ≥ 65 years. Data were collected using blinded continuous glucose monitoring (CGM, iPro2) for 5 consecutive days. Frequency and duration of hypoglycaemic episodes were assessed using a sensor glucose cut-off value of 3.9 mmol/L. A blood sample for measurement of HbA1c and creatinine-based eGFR (CKD-EPI) was obtained during the monitoring period. Demographic and clinical data were collected from electronic patient records. Results Fifty-six individuals were enrolled (median age 82 years and 52% were men). Of the 36 participants who were treated with insulin, 33% had at least one hypoglycaemic episode during the five-day period. Among 18 participants who neither used insulin nor sulfonylurea, but other glucose-lowering medications, 44% had at least one hypoglycaemicepisode. Of those with hypoglycaemic episodes, 86% lived alone. The median duration of the hypoglycaemia was 1 h and 25 min, ranging from 15 min to 8 h and 50 min. Conclusion This study identified an unacceptably high number of unknown hypoglycaemic episodes among older home-dwelling people with diabetes receiving home care, even among those not using insulin or sulfonylurea. The study provides essential knowledge that can serve as a foundation to improve the treatment and care for this vulnerable patient group. The routines for glucose monitoring and other prevention tasks need to be considered more comprehensively, also, among those treated with glucose-lowering medications other than insulin.

• Kared, Hassen; Alirezaylavasani, Amin; Lund, Kathrine Persgård; Chopra, Adity; Tietze, Lisa & Kasahara, Taissa de Matos [Show all 17 contributors for this article] (2023). Hybrid and SARS-CoV-2-vaccine immunity in kidney transplant recipients. EBioMedicine. 97. doi: 10.1016/j.ebiom.2023.104833. Full text in Research Archive Show summary

  Background Kidney transplant recipients (KTR) are at high risk for severe COVID-19 and have demonstrated poor response to vaccination, making it unclear whether successive vaccinations offer immunity and protection. Methods We conducted a serologically guided interventional study where KTR patients that failed to seroconvert were revaccinated and also monitored seroconversion of KTR following the Norwegian vaccination program. We analysed IgG anti-RBD Spike responses from dose 2 (n = 432) up to after the 6th (n = 37) mRNA vaccine dose. The frequency and phenotype of Spike-specific T and B cell responses were assessed in the interventional cohort after 3–4 vaccine doses (n = 30). Additionally, we evaluated the Specific T and B cell response to breakthrough infection (n = 32), measured inflammatory cytokines and broadly cross-neutralizing antibodies, and defined the incidence of COVID-19-related hospitalizations and deaths. The Norwegian KTR cohort has a male dominance (2323 males, 1297 females), PBMC were collected from 114 male and 78 female donors. Findings After vaccine dose 3, most KTR developed Spike-specific T cell responses but had significantly reduced Spike-binding B cells and few memory cells. The B cell response included a cross-reactive subset that could bind Omicron VOC, which expanded after breakthrough infection (BTI) and gave rise to a memory IgG+ B cell response. After BTI, KTR had increased Spike-specific T cells, emergent non-Spike T and B cell responses, and a systemic inflammatory signature. Late seroconversion occurred after doses 5–6, but 38% (14/37) of KTR had no detectable immunity even after multiple vaccine doses. Interpretation Boosting vaccination can induce Spike-specific immunity that may expand in breakthrough infections highlighting the benefit of vaccination to protect this vulnerable population.

• Strømmen, Ruth Cecilie; Godang, Kristin; Finnes, Trine Elisabeth; Smerud, Knut Terje; Reisæter, Anna Varberg & Hartmann, Anders [Show all 9 contributors for this article] (2023). Trabecular Bone Score Improves Early After Successful Kidney Transplantation Irrespective of Antiresorptive Therapy and Changes in Bone Mineral Density. Transplantation direct. 10(1), p. e1566–e1566. doi: 10.1097/TXD.0000000000001566. Full text in Research Archive Show summary

  Background. Trabecular bone score (TBS) is a new tool to assess trabecular bone microarchitecture based on standard dual-energy x-ray absorptiometry (DXA) of lumbar spine images. TBS may be important to assess bone quality and fracture susceptibility in kidney transplant recipients (KTRs). This study aimed to investigate the effect of different bone therapies on TBS in KTRs. Methods. We reanalyzed DXA scans to assess TBS in 121 de novo KTRs at baseline, 10 wk, and 1 y. This cohort, between 2007 and 2009, participated in a randomized, placebo-controlled trial evaluating the effect of ibandronate versus placebo in addition to vitamin D and calcium. Results. Although bone mineral density (BMD) Z scores showed a subtle decrease in the first weeks, TBS Z scores increased from baseline to 10 wk for both treatment groups, followed by a slight decline at 12 mo. When comparing treatment groups and adjusting for baseline TBS, there were no differences found in TBS at 12 mo (P = 0.419). Correlation between TBS and BMD at baseline was weak (Spearman’s ρ = 0.234, P = 0.010), and change in TBS was not correlated with changes in lumbar spine BMD in either of the groups (ρ = 0.003, P = 0.973). Conclusions. Treatment with ibandronate or vitamin D and calcium did not affect bone quality as measured by TBS in de novo KTRs, but TBS increased early, irrespective of intervention. Changes in TBS and BMD during the study period were not correlated, indicating that these measurements reflect different aspects of bone integrity. TBS may complement BMD assessment in identifying KTRs with a high fracture risk.

• Vethe, Nils Tore; Åsberg, Anders; Andersen, Anders Mikal; Skauby, Ragnhild Kristine Heier; Bergan, Stein & Midtvedt, Karsten (2023). Clinical performance of volumetric finger-prick sampling for the monitoring of tacrolimus, creatinine and haemoglobin in kidney transplant recipients. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(12), p. 3690–3701. doi: 10.1111/bcp.15870. Full text in Research Archive Show summary

  Aims Finger‐prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger‐prick sampling performed by healthcare professionals vs . self‐sampling, and differences between the two devices. Methods We compared finger‐prick and venous sampling in three settings: microsampling performed by healthcare personnel, self‐sampling under supervision, unsupervised self‐sampling. The finger‐prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples. Results Twenty‐five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%–96% for Capitainer and 77%–95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%–100% and 93%–100% for Capitainer and 79%–96% and 67%–92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%–96%), whereas Mitra showed 72%–88% and 52%–72% success rates with samples collected by healthcare personnel and the patients themselves. Conclusions Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self‐sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger‐prick self‐sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow‐up of KTx recipients.

• Kvitne, Kine Eide; Drevland, Ole Martin; Haugli, Nora; Skadberg, Eline Supannee Setu; Zare, Hasse Khiabani & Åsberg, Anders [Show all 7 contributors for this article] (2023). Intraindividual Variability in Absolute Bioavailability and Clearance of Midazolam in Healthy Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. 62(7), p. 981–987. doi: 10.1007/s40262-023-01257-z. Full text in Research Archive Show summary

  Background and Objective Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals without obesity. Methods This study included 33 healthy volunteers [28 ± 8 years, 21% males, body mass index (BMI) 23 ± 2.5 kg/m2] subjected to four pharmacokinetic investigations over a 2-month period (weeks 0, 2, 4, and 8). Semi-simultaneous oral (0 h) and intravenous (2 h later) midazolam dosing was used to assess absolute bioavailability and clearance of midazolam. Results At baseline, mean absolute bioavailability and clearance were 46 ± 18% and 31 ± 10 L/h, respectively. The mean coefficient of variation (CV, %) for absolute bioavailability and clearance of midazolam was 26 ± 15% and 20 ± 10%, respectively. Approximately one-third had a CV > 30% for absolute bioavailability, while 13% had a CV > 30% for clearance. Conclusions On average, intraindividual variability in absolute bioavailability and clearance of midazolam was low to moderate; however, especially absolute bioavailability showed considerable variability in a relatively large proportion of the individuals.

• Thorsen, Inga Strand; Bleskestad, Inger Hjørdis; Åsberg, Anders; Jonsson, Grete; Skadberg, Øyvind & Heldal, Kristian [Show all 7 contributors for this article] (2023). Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation. Transplantation direct. 9(9). doi: 10.1097/TXD.0000000000001522. Full text in Research Archive Show summary

  Background: Short-term survival after kidney transplantation is excellent but long-term survival remains suboptimal. The aim of the study was to explore the relationship between soluble α-Klotho (sKlotho) and intact fibroblast growth factor 23 (iFGF23) measured 8 wk and 1 y posttransplant with long-term graft- and patient survival in a cohort of kidney transplant recipients with deficient and nondeficient vitamin D (25[OH]D) levels. Methods: Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Results: Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. Conclusions: In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.

• Astley, Megan E; Boenink, Rianne; ElHafeez, Samar Abd; Trujillo-Aleman, Sara; Arribas, Federico & Åsberg, Anders [Show all 36 contributors for this article] (2023). The ERA Registry Annual Report 2020: a summary. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 16(8), p. 1330–1354. doi: 10.1093/ckj/sfad087. Full text in Research Archive Show summary

  ABSTRACT Background The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with ESKD. This paper is a summary of the ERA Registry Annual Report 2020, also including comparisons among primary renal disease (PRD) groups. Methods Data were collected from 52 national and regional registries from 34 European countries and countries bordering the Mediterranean Sea: 35 registries from 18 countries providing individual level data and 17 registries from 17 countries providing aggregated data. Using this data, KRT incidence and prevalence, kidney transplantation rates, expected remaining lifetimes and survival probabilities were calculated. Results A general population of 654.9 million people was covered by the ERA Registry in 2020. The overall incidence of KRT was 128 per million population (p.m.p.). In incident KRT patients, 54% were older than 65 years, 63% were men and the most common PRD was diabetes mellitus (21%). Regarding initial treatment modality in incident patients, 85% received haemodialysis (HD), 11% received peritoneal dialysis (PD) and 4% received a pre-emptive kidney transplant. On 31 December 2020, the prevalence of KRT was 931 p.m.p. In prevalent patients, 45% were older than 65 years, 60% were men and glomerulonephritis was the most common PRD (18%). Of these patients, 58% were on HD, 5% on PD and 37% were living with a kidney transplant. The overall kidney transplantation rate in 2020 was 28 p.m.p., with a majority of kidney grafts from deceased donors (71%). The unadjusted 5-year survival, based on incident dialysis patient from 2011–15, was 41.8%. For patients having received a deceased donor transplant, the unadjusted 5-year survival probability was 86.2% and for patients having received a living donor transplant it was 94.4%. When comparing data by PRD group, differences were found regarding the distribution of age groups, sex and treatment modality received.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Soeren & Mollnes, Tom Eirik [Show all 11 contributors for this article] (2023). Systemic inflammation early after kidney transplantation is associated with long-term graft loss: a cohort study. Frontiers in Immunology. 14. doi: 10.3389/fimmu.2023.1253991. Full text in Research Archive Show summary

  Background: Early graft loss following kidney transplantation is mainly a result of acute rejection or surgical complications, while long-term kidney allograft loss is more complex. We examined the association between systemic inflammation early after kidney transplantation and long-term graft loss, as well as correlations between systemic inflammation scores and inflammatory findings in biopsies 6 weeks and 1 year after kidney transplantation.<p> <p>Methods: We measured 21 inflammatory biomarkers 10 weeks after transplantation in 699 patients who were transplanted between 2009 and 2012 at Oslo University Hospital, Rikshospitalet, Norway. Low-grade inflammation was assessed with predefined inflammation scores based on specific biomarkers: one overall inflammation score and five pathway-specific scores. Surveillance or indication biopsies were performed in all patients 6 weeks after transplantation. The scores were tested in Cox regression models.<p> <p>Results: Median follow-up time was 9.1 years (interquartile range 7.6-10.7 years). During the study period, there were 84 (12.2%) death-censored graft losses. The overall inflammation score was associated with long-term kidney graft loss both when assessed as a continuous variable (hazard ratio 1.03, 95% CI 1.01-1.06, P = 0.005) and as a categorical variable (4th quartile: hazard ratio 3.19, 95% CI 1.43-7.10, P = 0.005). In the pathway-specific analyses, fibrogenesis activity and vascular inflammation stood out. The vascular inflammation score was associated with inflammation in biopsies 6 weeks and 1 year after transplantation, while the fibrinogenesis score was associated with interstitial fibrosis and tubular atrophy.<p> <p>Conclusion: In conclusion, a systemic inflammatory environment early after kidney transplantation was associated with biopsy-confirmed kidney graft pathology and long-term kidney graft loss. The systemic vascular inflammation score correlated with inflammatory findings in biopsies 6 weeks and 1 year after transplantation.

• Åsberg, Anders; Hovd, Markus Herberg; Kjellevold, Stig Arne; Stenehjem, Aud Eldrid; Wien, Tale Norbye & Broch, Lars Ulrik [Show all 15 contributors for this article] (2023). Humoral Response After 6 or More Successive Doses of SARS-CoV-2 mRNA Vaccines in Kidney Transplant Recipients-Should We Keep Vaccinating? Transplantation. ISSN 0041-1337. 107(10), p. e279–e280. doi: 10.1097/TP.0000000000004732. Full text in Research Archive
• Hovd, Markus Herberg; Robertsen, Ida; Johnson, Line Kristin; Krogstad, Veronica; Wegler, Christine & Kvitne, Kine Eide [Show all 16 contributors for this article] (2023). Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance. Clinical Pharmacokinetics. ISSN 0312-5963. 62(5), p. 725–735. doi: 10.1007/s40262-023-01235-5. Full text in Research Archive Show summary

  Introduction Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Methods Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). Results A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Conclusions Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

• Kindem, Ingvild Andrea; Åsberg, Anders; Midtvedt, Karsten & Bjerre, Anna Kristina (2023). Optimizing medication adherence with home-monitoring – A feasibility study using capillary microsampling and mHealth in solid organ-transplanted adolescents. Pediatric Transplantation. ISSN 1397-3142. 27(7). doi: 10.1111/petr.14590. Full text in Research Archive Show summary

  Abstract Background Reliable methods to detect and reduce medication nonadherence in solid organ‐transplanted (SOT) adolescents are warranted. We aimed to evaluate the feasibility of combining a medication‐manager application (TusenTac®‐app) with home‐sampling of tacrolimus (Tac) in young SOT recipients. Methods Kidney and combined SOT recipients between 14 and 25 years were included. During an 8‐week intervention period, the participants were instructed to use the transplant‐specific, age‐adapted TusenTac®‐app daily and to perform weekly at‐home Tac trough finger‐prick microsampling. Microsample Tac concentrations were controlled against timed venous samples twice. Medication implementation and persistence adherence were measured with BAASIS© questionnaires, TusenTac®‐registrations, Tac trough concentration coefficient of variation (CV%) and self‐reporting by interview. For comparison, venous Tac trough CV% were obtained from the year before and after the short‐term intervention. Results Twenty‐two recipients were included, two withdrawals, leaving 20; median age 17.9 (14.5–24.8) years, 12 females (60%). The participants registered their dosage intake 88% (1502/1703) of the expected times, and 90% (106/118) of the microsamples were obtained correctly. At inclusion, 11 recipients (55%) were nonadherent assessed with BAASIS© questionnaire, four of these (36%) turned adherent during the intervention period. At the end, 70% reported improved timing‐adherence at the interview. There was no significant change in TacCV% from the year before to the year after the short‐term intervention. Home‐sampling was reliable and measured Tac concentrations accurately. Conclusions Home‐monitoring, combining Tac finger‐prick microsampling and a medication‐manager app, is feasible in adolescent SOT recipients with 70% perceived improvement in medication timing‐adherence. There were no significant long‐term changes in TacCV% confirming the need for continuous use and individualized interventions.

• Hovd, Markus Herberg; Åsberg, Anders; Munthe, Ludvig Andre; Heldal, Kristian; Reisæter, Anna Varberg & Vaage, John T. [Show all 8 contributors for this article] (2023). Humoral vaccine response and breakthrough infections in kidney transplant recipients during the COVID-19 pandemic: a nationwide cohort study. EClinicalMedicine. 60. doi: 10.1016/j.eclinm.2023.102035. Full text in Research Archive Show summary

  Background Kidney transplant recipients (KTRs) experienced reduced SARS-CoV-2 vaccine response and were at increased risk of severe COVID-19. It is unknown if level of vaccine induced anti-receptor binding domain IgG (anti-RBD IgG) correlates with protection from and survival following COVID-19. We aimed to evaluate the effect of vaccine response on risk of breakthrough infections (BTI) and COVID-19 death in KTRs. Methods We performed a nationwide study, examining the competing risk of SARS-CoV-2 infection, COVID-19 related/unrelated death, and vaccine efficacy as assessed by level of anti-RBD IgG response 4–10 weeks after each vaccination. The study included all KTR in Norway alive and with a functioning graft on February 20th, 2020, and events after November 11th, 2022 were right-censored. A pre-pandemic reference-cohort from January 1st 2019 to January 1st 2020 was included to evaluate excess mortality. The study was conducted at Oslo University Hospital, Rikshospitalet, Norway. Findings The study included 3607 KTRs (59 [48–70] years) with a functioning graft at February 20th, 2020, who received (median [IQR]) 4 [3–4] vaccines (range 2–6, 99% mRNA). Anti-RBD IgG was measured in 12 701 serum samples provided by 3213 KTRs. Vaccine response was assessed 41 [31–57] days after vaccination. A total of 1090 KTRs were infected with SARS-CoV-2, 1005 (92%) were BTI, and vaccine response did not protect against BTI. The hazard ratio for COVID-19 related death 40 days post-infection was 1.71 (95% CI: 1.14, 2.56) comparing vaccine response levels (≥5 vs. ≥5000 BAU/mL). No excess non-COVID-19 mortality was registered in KTRs surviving SARS-CoV-2 infection compared to a 2019 pre-pandemic reference. Interpretation Our findings suggested that SARS-CoV-2 mRNA vaccine response did not predict protection against infection, but prevention of fatal disease progression in KTRs and greater vaccine response further reduced the risk of COVID-19 death. No excess non-COVID-19 mortality was seen during the pandemic.

• Drevland, Ole Martin; Robertsen, Ida; Gustavsen, Marte Theie; Kveim, Hanne Kamilla; Hovd, Markus Herberg & Midtvedt, Karsten [Show all 7 contributors for this article] (2023). Impact of Fasting Status and Circadian Variation on the Pharmacokinetics of Mycophenolate Mofetil and the Glucuronide Metabolite in Renal Transplant Recipients. Transplantation direct. 9(3). doi: 10.1097/TXD.0000000000001448. Full text in Research Archive Show summary

  Background. Mycophenolate mofetil (MMF) is an immunosuppressive prodrug often used to prevent allograft rejection following solid organ transplantation. After oral administration, MMF is rapidly hydrolyzed to the active metabolite mycophenolate acid (MPA), which is inactivated by glucuronosyltransferase to the mycophenolic acid glucuronide metabolite (MPAG). The aim was 2-fold: to investigate the impact of circadian variation and fasting versus nonfasting status on MPA and MPAG pharmacokinetics in renal transplant recipients (RTRs). Methods. RTRs with stable graft function treated with tacrolimus, prednisolone, and MMF (750 mg BID) were included in this open, nonrandomized study. Two 12-h pharmacokinetic investigations were conducted in succession following morning and evening doses, both in a fasting and in a real-life nonfasting condition. Results. A total of 30 (22 men) RTRs performed one 24-h investigation, and 16 repeated the investigation within 1 mo. In a real-life nonfasting state, MPA area under the curve (AUC)0–12 and C0 failed to meet the bioequivalence criteria. Following the evening dose, mean MPA AUC12–24 was 16% lower (P < 0.001) compared with AUC0–12, and a shorter Tmax was observed (P = 0.09). Under fasting conditions, MPA AUC12–24 was 13% lower than AUC0–12, and the absorption rate was slower after the evening dose (P < 0.05). MPAG displayed circadian variation only under real-life conditions with lower AUC0–12 following the evening dose (P < 0.001). Conclusions. Both MPA and MPAG showed circadian variation with somewhat lower systemic exposures following the evening dose with limited clinical relevance in the dosing of MMF in RTRs. Fasting status affects MMF absorption rate differently, but with similar results in systemic exposure.

• Handin, Niklas; Yuan, Di; Ölander, Magnus; Wegler, Christine; Karlsson, Cecilia & Jansson-Löfmark, Rasmus [Show all 10 contributors for this article] (2023). Proteome deconvolution of liver biopsies reveals hepatic cell composition as an important marker of fibrosis. Computational and Structural Biotechnology Journal. 21, p. 4361–4369. doi: 10.1016/j.csbj.2023.08.037. Full text in Research Archive Show summary

  Human liver tissue is composed of heterogeneous mixtures of different cell types and their cellular stoichiometry can provide information on hepatic physiology and disease progression. Deconvolution algorithms for the identification of cell types and their proportions have recently been developed for transcriptomic data. However, no method for the deconvolution of bulk proteomics data has been presented to date. Here, we show that proteomes, which usually contain less data than transcriptomes, can provide useful information for cell type deconvolution using different algorithms. We demonstrate that proteomes from defined mixtures of cell lines, isolated primary liver cells, and human liver biopsies can be deconvoluted with high accuracy. In contrast to transcriptome-based deconvolution, liver tissue proteomes also provided information about extracellular compartments. Using deconvolution of proteomics data from liver biopsies of 56 patients undergoing Roux-en-Y gastric bypass surgery we show that proportions of immune and stellate cells correlate with inflammatory markers and altered composition of extracellular matrix proteins characteristic of early-stage fibrosis. Our results thus demonstrate that proteome deconvolution can be used as a molecular microscope for investigations of the composition of cell types, extracellular compartments, and for exploring cell-type specific pathological events. We anticipate that these findings will allow the refinement of retrospective analyses of the growing number of proteome datasets from various liver disease states and pave the way for AI-supported clinical and preclinical diagnostics.

• Blom, Kjersti Benedicte; Kro, Grete Anette Birkeland; Midtvedt, Karsten; Jenssen, Trond; Reisæter, Anna Varberg & Rollag, Halvor [Show all 15 contributors for this article] (2023). Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management. Transplantation. ISSN 0041-1337. 107(8), p. 1846–1853. doi: 10.1097/TP.0000000000004615. Full text in Research Archive Show summary

  Background. Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R–). We performed a nationwide comparison of the 2 strategies in de novo D+/R– KT recipients accessing long-term outcomes. Methods. A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R– and R+ KT recipients were included. During the first 4 y, D+/R– recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. Results. A total of 2198 KT recipients (D+/R–, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1–15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection (P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era–related bias. Conclusions. There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R– kidney transplant recipients.

• Vinknes, Kathrine Jørgensen; Olsen, Thomas; Zare, Hasse Khiabani; Bastani, Nasser Ezzatkhah; Stolt, Emma Theresia Kjelland & Dahl, Anja Falkenhaug [Show all 11 contributors for this article] (2023). Cysteine-lowering treatment with mesna against obesity: Proof of concept and results from a human phase I, dose-finding study. Diabetes, obesity and metabolism. ISSN 1462-8902. 25(11), p. 3161–3170. doi: 10.1111/dom.15210. Full text in Research Archive Show summary

  Abstract Aim To investigate whether mesna—sodium‐2‐mercaptoethane sulfonate) can reduce diet‐induced fat gain in mice, and to assess the safety of single ascending mesna doses in humans to find the dose associated with lowering of plasma tCys by at least 30%. Methods C3H/HeH mice were shifted to a high‐fat diet ± mesna in drinking water; body composition was measured at weeks 0, 2 and 4. In an open, phase I, single ascending dose study, oral mesna (400, 800, 1200, 1600 mg) was administered to 17 men with overweight or obesity. Mesna and tCys concentrations were measured repeatedly for a duration of 48 hours postdosing in plasma, as well as in 24‐hour urine. Results Compared with controls, mesna‐treated mice had lower tCys and lower estimated mean fat mass gain from baseline (week 2: 4.54 ± 0.40 vs. 6.52 ± 0.36 g; week 4: 6.95 ± 0.35 vs. 8.19 ± 0.34 g; P overall  = .002), but similar lean mass gain. In men with overweight, mesna doses of 400‐1600 mg showed dose linearity and were well tolerated. Mesna doses of 800 mg or higher decreased plasma tCys by 30% or more at nadir (4h post‐dosing). With increasing mesna dose, tCys AUC 0‐12h decreased ( P trend  &lt; .001), and urine tCys excretion increased ( P trend  = .004). Conclusions Mesna reduces diet‐induced fat gain in mice. In men with overweight, single oral doses of mesna (800‐1600 mg) were well tolerated and lowered plasma tCys efficiently. The effect of sustained tCys‐lowering by repeated mesna administration on weight loss in humans deserves investigation.

• Bakkagloglu, Seven A; Vidal, Enrico; Bonthuis, Marjolein; Neto, Gisela; Paripovic, Dusan & Åsberg, Anders [Show all 12 contributors for this article] (2023). European chronic kidney disease registries for children not on kidney replacement therapy: tools for improving health systems and patient-centred outcomes. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 16(11), p. 1980–1985. doi: 10.1093/ckj/sfad204. Full text in Research Archive Show summary

  ABSTRACT Chronic kidney disease (CKD) in children, from birth to late adolescence, is a unique and highly challenging condition that requires epidemiological research and large-scale, prospective cohort studies. Since its first launch in 2007, the European Society for Paediatric Nephrology/European Renal Association (ESPN/ERA) Registry has collected data on patients on kidney replacement therapy (KRT). However, slowing the progression of CKD is of particular importance and thus the possibility to extend the current registry dataset to include patients in CKD stages 4–5 should be a priority. A survey was sent to the national representatives within the ESPN/ERA Registry to collect information on whether they are running CKD registries. All the representatives from the 38 European countries involved in the ESPN/ERA Registry participated in the survey. Eight existing CKD registries have been identified. General characteristics of the national registry and detailed data on anthropometry, laboratory tests and medications at baseline and at follow-up were collected. Results provided by this survey are highly promising regarding the establishment of an ESPN CKD registry linked to the ESPN/ERA KRT registry and subsequently linking it to the ERA Registry with the same patient identifier, which would allow us to monitor disease progression in childhood and beyond. It is our belief that through such linkages, gaps in patient follow-up will be eliminated and patient-centred outcomes may be improved.

• Kvitne, Kine Eide; Hovd, Markus; Johnsen, Line Kristin; Wegler, Christine; Karlsson, Cecilia & Artursson, Per [Show all 14 contributors for this article] (2023). Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. 63(1), p. 103–120. doi: 10.1007/s40262-023-01320-9. Full text in Research Archive Show summary

  Background and Objective Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. Methods This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. Results The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration–time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (−0.26 hours [95% CI −0.47, −0.05]), corresponding to a 25% reduction. Area under the concentration–time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [−0.94, 3.2]) or the diet group (0.94 µg h/L [−1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration–time curve from zero to infinity was −5.5 µg h/L [95% CI −8.5, −2.5] (−26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Show all 40 contributors for this article] (2022). Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants. npj Vaccines. 7(1). doi: 10.1038/s41541-022-00586-7. Full text in Research Archive Show summary

  Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

• Hemmelder, Marc H.; Noordzij, Marlies; Vart, Priya; Hilbrands, Luuk B.; Jager, Kitty J. & Abrahams, Alferso C. [Show all 233 contributors for this article] (2022). Recovery of dialysis patients with COVID-19: health outcomes 3 months after diagnosis in ERACODA. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 37(6), p. 1140–1151. doi: 10.1093/ndt/gfac008. Full text in Research Archive
• Rossignol, P; Duarte, K.; Bresso, E; Åsberg, Anders; Devignes, DM & Eriksson, N [Show all 22 contributors for this article] (2022). NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients. European Heart Journal Open (EHJ Open). 2(6). doi: 10.1093/ehjopen/oeac069. Full text in Research Archive Show summary

  Aims End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine. Methods and results The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths. Conclusions Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

• Kvitne, Kine Eide; Hole, Kristine; Krogstad, Veronica; Wollmann, Birgit Malene Tovik; Wegler, Christine & Johnson, Line Kristin [Show all 19 contributors for this article] (2022). Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. European Journal of Clinical Pharmacology. ISSN 0031-6970. 78(8), p. 1289–1299. doi: 10.1007/s00228-022-03336-9. Full text in Research Archive Show summary

  Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ =  − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ =  − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.

• Kvitne, Kine Eide; Krogstad, Veronica; Wegler, Christine; Johnson, Line Kristin; Kringen, Marianne K. & Hovd, Markus Herberg [Show all 19 contributors for this article] (2022). Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity. British Journal of Clinical Pharmacology. ISSN 0306-5251. 88(9), p. 4121–4133. doi: 10.1111/bcp.15349. Full text in Research Archive Show summary

  Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB −30 ± 6.9%, diet −3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference −0.30 [−0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.

• Wegler, Christine; Wisniewski, Jacek R.; Robertsen, Ida; Christensen, Hege; Hertel, Jens Kristoffer & Hjelmesæth, Jøran Sture [Show all 10 contributors for this article] (2022). Drug disposition protein quantification in matched human jejunum and liver from donors with obesity. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 111(5), p. 1142–1154. doi: 10.1002/cpt.2558. Full text in Research Archive Show summary

  Mathematical models, such as physiologically based pharmacokinetic (PBPK) models, are used to predict e.g., drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these inter-individual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug-metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (e.g., CYP2U1) and the amine oxidase [flavin-containing] (e.g., MAOA) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor-matched tissues. These proteins also do not correlate with physiological factors such as BMI, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, inter-individual differences were considerable, with implications for personalized prediction models and systems pharmacology.

• Khan, Sana Ahsan; Åsberg, Anders & Jenssen, Trond Geir (2022). Anticoagulation and safety of renal transplant biopsy. Clinical Transplantation. ISSN 0902-0063. 36(8). doi: 10.1111/ctr.14715. Full text in Research Archive
• Kindem, Ingvild Andrea; Bjerre, Anna Kristina; Hammarström, Clara Louise; Naper, Christian; Midtvedt, Karsten & Åsberg, Anders (2022). Kidney-transplanted Adolescents—Nonadherence and Graft Outcomes During the Transition Phase: A Nationwide Analysis, 2000–2020. Transplantation. ISSN 0041-1337. 107(5), p. 1206–1212. doi: 10.1097/TP.0000000000004431. Full text in Research Archive Show summary

  Background. The transition from pediatric to young adult care is a vulnerable period for the renal transplant patient. We aimed to identify medication nonadherence (noninitiation, nonimplementation, and nonpersistence) and graft loss rates among adolescents and young adults and elucidate the influence of the transition phase on transplant outcomes. Methods. A retrospective nationwide cohort analysis of all renal transplantations in Norway from 2000 to 2020 was performed. Data were retrieved from the Norwegian Renal Registry, and adherence data from hospital charts. Patients transplanted aged <50 y, with functioning graft at 6 mo, were included. Recipients transplanted aged <26 y were compared with recipients transplanted aged 26–50 y. Graft loss, acute rejection, and development of de novo donor-specific antibodies were assessed in relation to the transition phase, defined as 14–26 y. Results. Data from 1830 kidney recipients were included: 371 (20%) transplanted <26 y (64% male, 68% living donor) versus 1459 transplanted 26–50 y (63% male, 44% living donor). There were 298 graft losses, 78 (21%) in the <26-y group versus 220 (15%) in the 26- to 50-y group. During the transition phase, 36 grafts were lost, 29 (81%) after transfer to the adult service. Medication nonadherence was the reason for 58% (21 of 36) of the losses during the transition phase, versus 12% (27 of 220) in the 26- to 50-y group (P < 0.001). The 5-y graft survival rate was 89% (95% confidence interval, 85%-92%) and 94% (92%-95%), respectively (P = 0.01). Conclusions. Nonadherence was verified as the main cause of kidney graft loss in the transition phase.

• Tantisattamo, Ekamol; Imhof, Celine; Jager, Kitty J.; Hilbrands, Luuk B.; Guidotti, Rebecca & Islam, Mahmud [Show all 18 contributors for this article] (2022). Association of obesity with 3-month mortality in kidney failure patients with COVID-19. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 15(7), p. 1348–1360. doi: 10.1093/ckj/sfac083. Full text in Research Archive
• Duivenvoorden, Raphael; Vart, Priya; Noordzij, Marlies; Santos, Augusto C. Soares dos; Zulkarnaev, Alexey B. & Franssen, Casper F.M. [Show all 20 contributors for this article] (2022). Clinical, Functional, and Mental Health Outcomes in Kidney Transplant Recipients 3 Months After a Diagnosis of COVID-19. Transplantation. ISSN 0041-1337. 106(5), p. 1012–1023. doi: 10.1097/TP.0000000000004075. Full text in Research Archive
• Vart, Priya; Duivenvoorden, Raphaël; Adema, Aaltje; Covic, Adrian; Finne, Patrik & Braak, Nicole Heijtink-ter [Show all 235 contributors for this article] (2022). Sex differences in COVID-19 mortality risk in patients on kidney function replacement therapy. Scientific Reports. 12(1). doi: 10.1038/s41598-022-22657-4. Full text in Research Archive
• Tsarpali, Vasiliki; Midtvedt, Karsten; Lønning, Kjersti; Bernklev, Tomm; Åsberg, Anders & Fawad, Haris [Show all 10 contributors for this article] (2022). A Comorbidity Index and Pretransplant Physical Status Predict Survival in Older Kidney Transplant Recipients: A National Prospective Study. Transplantation direct. 8(4), p. e1307–e1307. doi: 10.1097/TXD.0000000000001307. Full text in Research Archive Show summary

  Kidney transplantation (KT) is considered the best treatment for end-stage kidney disease (ESKD). In the increasing elderly ESKD population, KT should be reserved for carefully selected candidates who are expected to experience favorable outcomes. We aimed to prospectively evaluate pretransplant recipient factors that may predict patient survival and can eventually guide therapeutic decisions in elderly with ESKD. Methods: Recipient factors were evaluated in KT candidates aged ≥65 y. Comorbidity was assessed at waitlisting according to the Liu comorbidity index (LCI). Health-related quality of life outcomes were measured using the Kidney Disease Quality of Life Short Form, version 1.3. The Cox proportional hazard regression was used to evaluate predictors of patient survival. Results: We included 192 recipients, with a mean age of 72.1 (4.1) y, who were transplanted with kidneys from deceased brain-dead donors. During a median observation period of 4.6 (3.2-6.3) y, 66 recipients died. Elevated LCI consistently predicted poor patient survival. In recipients with LCI ≥4, dialysis >2 y comprised a 2.5-fold increase in mortality risk compared with recipients on dialysis ≤2 y. Self-reported pretransplant physical function was also proven to be a significant positive predictor of survival. Conclusion: The implementation of LCI and a physical function score during the evaluation of older kidney transplant candidates may improve the selection and thereby optimize posttransplant outcomes.

• Heldal, Torbjørn Fossum; Åsberg, Anders; Ueland, Thor; Reisæter, Anna Varberg; Pischke, Søren Erik & Mollnes, Tom Eirik [Show all 10 contributors for this article] (2022). Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality. American Journal of Transplantation. ISSN 1600-6135. 22, p. 2016–2027. doi: 10.1111/ajt.17047. Full text in Research Archive Show summary

  In the general population low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. Hazard ratio (HR) for death was 4.71 (95% CI:2.85-7.81, p

• Gjerstad, Ann Christin; Skrunes, Rannveig; Tøndel, Camilla; Åsberg, Anders; Leh, Sabine & Klingenberg, Claus Andreas [Show all 9 contributors for this article] (2022). Kidney biopsy diagnosis in childhood in the Norwegian Kidney Biopsy Registry and the long-term risk of kidney replacement therapy: a 25-year follow-up. Pediatric nephrology (Berlin, West). ISSN 0931-041X. 38(4), p. 1249–1256. doi: 10.1007/s00467-022-05706-y. Full text in Research Archive Show summary

  Background There is scarce information on biopsy-verified kidney disease in childhood and its progression to chronic kidney disease stage 5 (CKD 5). This study aims to review biopsy findings in children, and to investigate risk of kidney replacement therapy (KRT). Methods We conducted a retrospective long-term follow-up study of children included in the Norwegian Kidney Biopsy Registry (NKBR) and in the Norwegian Renal Registry (NRR) from 1988 to 2021. Results In total, 575 children with a median (interquartile range, IQR) age of 10.7 (6.1 to 14.1) years were included, and median follow-up time (IQR) after kidney biopsy was 14.3 (range 8.9 to 21.6) years. The most common biopsy diagnoses were minimal change disease (MCD; n = 92), IgA vasculitis nephritis (IgAVN; n = 76), IgA nephropathy (n = 63), and focal and segmental glomerulosclerosis (FSGS; n = 47). In total, 118 (20.5%) of the biopsied children reached CKD 5, median (IQR) time to KRT 2.3 years (7 months to 8.4 years). Most frequently, nephronophthisis (NPHP; n = 16), FSGS (n = 30), IgA nephropathy (n = 9), and membranoproliferative glomerulonephritis (MPGN; n = 9) led to KRT. Conclusions The risk of KRT after a kidney biopsy diagnosis is highly dependent on the diagnosis. None of the children with MCD commenced KRT, while 63.8% with FSGS and 100% with NPHP reached KRT. Combining data from kidney biopsy registries with registries on KRT allows for detailed information concerning the risk for later CKD 5 after biopsy-verified kidney disease in childhood.

• Destere, Alexandre; Marquet, Pierre; Gandonnière, Charlotte Salmon; Åsberg, Anders; Loustaud-Ratti, Véronique & Carrier, Paul [Show all 10 contributors for this article] (2022). A Hybrid Model Associating Population Pharmacokinetics with Machine Learning: A Case Study with Iohexol Clearance Estimation. Clinical Pharmacokinetics. ISSN 0312-5963. 61(8), p. 1157–1165. doi: 10.1007/s40262-022-01138-x. Full text in Research Archive
• Kvitne, Kine Eide; Åsberg, Anders; Johnson, Line Kristin; Wegler, Christine; Hertel, Jens Kristoffer & Artursson, Per [Show all 14 contributors for this article] (2022). Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity. Clinical and Translational Science (CTS). ISSN 1752-8054. 15(11), p. 2685–2696. doi: 10.1111/cts.13394. Full text in Research Archive Show summary

  Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.

• Storås, Andrea; Åsberg, Anders; Halvorsen, Pål; Riegler, Michael Alexander & Strumke, Inga (2022). Predicting Tacrolimus Exposure in Kidney Transplanted Patients Using Machine Learning. In Shen, Linlin; González, Alejandro Rodríguez; Santosh, KC; Lai, Zhihui; Sicilia, Rosa; Almeida, João Rafael & Kane, Bridget (Ed.), 2022 IEEE 35th International Symposium on Computer-Based Medical Systems (CBMS). IEEE (Institute of Electrical and Electronics Engineers). ISSN 9781665467704. p. 38–43. doi: 10.1109/CBMS55023.2022.00014. Full text in Research Archive Show summary

  Tacrolimus is one of the cornerstone immunosup-pressive drugs in most transplantation centers worldwide following solid organ transplantation. Therapeutic drug monitoring of tacrolimus is necessary in order to avoid rejection of the transplanted organ or severe side effects. However, finding the right dose for a given patient is challenging, even for experienced clinicians. Consequently, a tool that can accurately estimate the drug exposure for individual dose adaptions would be of high clinical value. In this work, we propose a new technique using machine learning to estimate the tacrolimus exposure in kidney transplant recipients. Our models achieve predictive errors that are at the same level as an established population pharmacokinetic model, but are faster to develop and require less knowledge about the pharmacokinetic properties of the drug.

• Destere, Alexandre; Gandonniere, Charlotte Salmon; Åsberg, Anders; Loustaud-Ratti, Véronique; Carrier, Paul & Ehrmann, Stephan [Show all 9 contributors for this article] (2022). A single Bayesian estimator for iohexol clearance estimation in ICU, liver failure and renal transplant patients. British Journal of Clinical Pharmacology. ISSN 0306-5251. 88(6), p. 2793–2801. doi: 10.1111/bcp.15197. Full text in Research Archive
• Krogstad, Veronica; Elgstøen, Katja B. Prestø; Johnsen, Linda Flaa; Hartmann, Anders; Mørkrid, Lars & Åsberg, Anders (2022). High Plasma Oxalate Levels Early After Kidney Transplantation Are Associated With Impaired Long-Term Outcomes. Transplant International. ISSN 0934-0874. 35. doi: 10.3389/ti.2022.10240. Full text in Research Archive Show summary

  Background: Elevated levels of oxalate are common in renal failure patients and non-hyperoxaluria disease, and may cause damage after transplantation. We examined outcomes after 15 years for 167 kidney transplant recipients who had plasma oxalate measured early after transplantation. Analyses included plasma oxalate, recipient age, donor age, live donor, HLA-DR mismatch, mGFR, and smoking. Results: Median age was 52 years (range 18–81), 63% were male and 38% had live donors. Median plasma oxalate concentration 10 weeks after transplantation was 9.0 μmol/L (range 2.7–53.0), one third above the upper reference limit (11.0 μmol/L). Multivariable analysis revealed upper quartile plasma oxalate (>13.0 μmol/L, p = 0.008), recipient age (p < 0.001), deceased donor (p = 0.003), and current smoking (p < 0.001) as significant factors associated with patient survival. Upper quartile plasma oxalate (p = 0.021), recipient age (p = 0.001), deceased donor kidney (p = 0.001), HLA-DR mismatch (p = 0.015), and current smoking (p = 0.014) were also associated with graft loss. Factors associated with death censored graft losses were donor age (p = 0.012), deceased donor (p = 0.032), and HLA-DR mis-matched kidneys (p = 0.005) but plasma oxalate was not (p = 0.188). Conclusions: Plasma oxalate in the upper quartile early after transplantation was significantly associated with impaired long-term patient survival and graft losses, but not when censored for death.

• Rønning, Marit; Hjellvik, Vidar; Sakshaug, Solveig; Blix, Hege Salvesen; Midtvedt, Karsten & Reisæter, Anna Varberg [Show all 8 contributors for this article] (2022). Use of Statins in Kidney Transplant Recipients in Norway. International Journal of Environmental Research and Public Health (IJERPH). ISSN 1661-7827. 19(3). doi: 10.3390/ijerph19031370. Full text in Research Archive Show summary

  Kidney transplant recipients (KTRs) experience increased risk of cardiovascular disease. Guidelines recommend HMG-CoA reductase inhibitor (statin) therapy when tolerated. We aimed to study changes in the prescription of statins and patients’ adherence to treatment over time. A population-based observational study utilizing linked data from the Norwegian Renal Registry (national coverage of 99.9%) and the Norwegian Prescription Database was performed. Data from a total of 2250 first KTRs were included (mean age—54 years, 69% men). Dispensed prescriptions of statins and immunosuppressants for the period 2004–2016 for all first KTRs engrafted in the period 2005–2015 were analyzed. Seventy-two percent received statins the first year after kidney transplantation and the proportion increased with age. The proportion receiving a statin varied according to the time frame of transplantation (77% in 2005–2010 vs. 66% in 2012–2015). Among new users of statins, 82% of the patients were adherent both the second and third year after kidney transplantation, while the corresponding figure for those already receiving statins before transplantation was 97%. Statin continuation rates in KTRs were high. In conclusion, our findings show a slightly lower overall proportion of patients receiving statins after kidney transplants than the national target level of 80%. The proportion of statin users increased with the age of the KTRs but showed a decreasing trend as time progressed.

• Tsarpali, Vasiliki; Midtvedt, Karsten; Lønning, Kjersti; Bernklev, Tomm; Åsberg, Anders & Lippe, Nanna von der [Show all 8 contributors for this article] (2022). Poor physical function trajectory predicts impaired patient survival in older recipients of deceased donor kidneys: A prospective cohort study. Transplantation direct. 8(11), p. e1374–e1374. doi: 10.1097/TXD.0000000000001374. Full text in Research Archive Show summary

  Optimized health-related quality of life (HRQOL) at the time of kidney transplantation (KT) is associated with improved survival. In older KT recipients, we aimed to prospectively evaluate if HRQOL evolution during the first posttransplant year was associated with long-term patient survival. Methods: Recipients older than 65 y at KT who received an organ from a deceased brain-dead donor and survived >12 mo posttransplant were eligible. HRQOL was assessed pre-KT, at 10 wk, 6 mo, and 12 mo post-KT, using the Kidney Disease Quality of Life Short Form version 1.3 survey. A mixed-effect model was used to explore HRQOL evolution during the first posttransplant year in long-term survivors compared with nonsurvivors. Distinct HRQOL clusters were identified using a group-based trajectory modeling and their association with patient survival was investigated with Cox proportional hazard regression models. Results: We included 192 elderly recipients of deceased brain-dead donor kidneys who were transplanted from 2013 to 2020. Eleven died during the first year leaving 181 for evaluation (male, 125; mean age at KT, 72 y [65-84 y]). During a median observation time post-KT of 4.9 y (11.1-8.5 y), 57 recipients died. In survivors, all the generic and kidney-specific HRQOL domains substantially improved during the first year, whereas in nonsurvivors HRQOL deteriorated. Three longitudinal HRQOL trajectories indicating poor, fair, and good HRQOL evolution were identified. Poor physical function trajectory was significantly associated with higher mortality risk independent of covariates, as compared with good physical trajectory (hazard ratio, 2.38; 95% confidence interval, 1.15-5.01). Conclusions: In elderly KT recipients, detection of declining posttransplant physical function may imply impaired survival. Systematic HRQOL monitoring following KT provides added value when evaluating mortality and may guide therapeutic decisions.

• Bleskestad, Kristiane Birkeland; Nordheim, Espen; Lindahl, Jørn Petter Hanto; Midtvedt, Karsten; Pihlstrøm, Hege K. & Horneland, Rune [Show all 10 contributors for this article] (2021). Insulin secretion and action after pancreas transplantation. A retrospective single-center study. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 81(5), p. 365–370. doi: 10.1080/00365513.2021.1926535. Full text in Research Archive Show summary

  We explored glucometabolic and renal function after engraftment in all 159 consecutive patients with type 1 diabetes who received pancreas transplantation alone (PTA, n = 80) or simultaneous pancreas and kidney transplantation (SPK, n = 79) in Norway from 2012 until 2017. We report fasting levels of plasma glucose (FPG), C-peptide, eGFR and the homeostasis model assessment of insulin sensitivity (HOMA2(%S)) and beta-cell function (HOMA2(%B)) measured one to three times weekly during the first 8 and at 52 weeks after transplantation. One year after engraftment, in the PTA and SPK groups 52 and 64 were normoglycaemic without exogenous insulin, and two and zero patients were dead. Data at the 52-week visit were missing for 5 and 6 patients in the respective groups. During the first 8 weeks, FPG was lower, C-peptide and HOMA2(%S) were higher and eGFR was lower in the SPK group as compared with the PTA group (all p < .05). 30 out of 157 living patients needed insulin treatment 52 weeks after transplantation, 9/79 in the SPK group and 21/78 in the PTA group (p = .02). In conclusion, patients who underwent SPK showed lower insulin sensitivity, but higher insulin secretory capacity and lower mean blood glucose levels the first 8 weeks after transplantation. Also, a higher proportion of patients in the SPK group were insulin-free after 1 year, compared with the PTA group.

• Ville, Simon; Lorent, Marine; Kerleau, Clarisse; Åsberg, Anders; Legendre, Chrostopher & Morelon, Emmanuel [Show all 18 contributors for this article] (2021). Timing of Kidney Clamping and Deceased Donor Kidney Transplant Outcomes. American Society of Nephrology. Clinical Journal. ISSN 1555-9041. 16(11), p. 1704–1714. doi: 10.2215/CJN.03290321. Full text in Research Archive
• Jager, Kitty J; Åsberg, Anders; Collart, Frédéric; Couchoud, Cécile; Evans, Marie & Finne, Patrik [Show all 9 contributors for this article] (2021). A snapshot of European registries on chronic kidney disease patients not on kidney replacement therapy. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 37(1), p. 8–13. doi: 10.1093/ndt/gfab252. Full text in Research Archive Show summary

  BACKGROUND Traditionally, renal registries collect and report population-based epidemiological data on patients with kidney failure who are treated by kidney replacement therapy (KRT), i.e. dialysis or transplantation. Over the past decade, a number of these registries have started to widen the inclusion of patients to those with kidney failure treated with comprehensive conservative management and in some cases to earlier stages of chronic kidney disease (CKD), leading to, for example, CKD Stages 4–5 registries. As a result, they are increasing their value by not only providing numbers on those receiving or refraining from extremely expensive therapies, but also to stages of CKD in which kidney failure may still be prevented. The European Renal Association (ERA) Registry currently collects data on patients treated by KRT and uses them for comparison and collaborative research. In this article we report the current status of CKD registries in Europe in relation to their data collection on patients not on KRT so that in the future we may investigate to what extent their data may be used for similar purposes, such as collaborative research on CKD trajectories and patient outcomes.

• Heldal, Kristian; Åsberg, Anders; Abedini, Sadollah; Jenssen, Trond Geir; Reisæter, Anna Varberg & Bergan, Stein [Show all 7 contributors for this article] (2021). Estimert glomerulær filtrasjonshastighet som mål på nyrefunksjon. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(1), p. 48–51. doi: 10.4045/tidsskr.21.0501. Full text in Research Archive Show summary

  Estimert glomerulær filtrasjonshastighet er etablert som klinisk rutinemål for nyrefunksjon, men estimatet har begrensninger og kan ikke brukes i alle kliniske situasjoner. Estimert glomerulær filtrasjonshastighet har en høy variasjonskoeffisient, og ved avvik i pasientens høyde, vekt eller muskelmasse kan estimatet bli unøyaktig. Hvis det er avgjørende å ha et nøyaktig mål på nyrefunksjonen, kan man måle glomerulær filtrasjonshastighet ved hjelp av en eksogen substans.

• Stillemans, Gabriel; Paquot, Adrien; Muccioli, Giulio G.; Hoste, Emilia; Panin, Nadtha & Åsberg, Anders [Show all 9 contributors for this article] (2021). Atorvastatin population pharmacokinetics in a real-life setting: Influence of genetic polymorphisms and association with clinical response. Clinical and Translational Science (CTS). ISSN 1752-8054. 15(3), p. 667–679. doi: 10.1111/cts.13185. Full text in Research Archive Show summary

  The purpose of this study was to investigate the potential clinical relevance of estimating the apparent clearance (CL/F) of atorvastatin through population pharmacokinetic (PopPK) modeling with samples collected in a real-life setting in a cohort of ambulatory patients at risk of cardiovascular disease by using an opportunistic sampling strategy easily accessible in clinical routine. A total of 132 pharmacokinetic (PK) samples at a maximum of three visits were collected in the 70 included patients. The effects of demographic, genetic, and clinical covariates were also considered. With the collected data, we developed a two-compartment PopPK model that allowed estimating atorvastatin CL/F relatively precisely and considering the genotype of the patient for SLCO1B1 c.521T>C single-nucleotide polymorphism (SNP). Our results indicate that the estimation of the CL/F of atorvastatin through our PopPK model might help in identifying patients at risk of myalgia. Indeed, we showed that a patient presenting a CL/F lower than 414.67 L h−1 is at risk of suffering from muscle discomfort. We also observed that the CL/F was correlated with the efficacy outcomes, suggesting that a higher CL/F is associated with a better drug efficacy (i.e., a greater decrease in total and LDL-cholesterol levels). In conclusion, our study demonstrates that PopPK modeling can be useful in daily clinics to estimate a patient’ atorvastatin clearance. Notifying the clinician with this information can help in identifying patients at risk of myalgia and gives indication about the potential responsiveness to atorvastatin therapy.

• Onsøien, Mari Olsen; Midtvedt, Karsten; Reisæter, Anna Varberg; Aasarød, Knut; Waldum-Grevbo, Bård & Vikse, Bjørn Egil [Show all 8 contributors for this article] (2021). Blood Pressure Treatment in Kidney Transplant Recipients—Can We Improve? Transplantation direct. 7(4), p. 1–7. doi: 10.1097/TXD.0000000000001142. Full text in Research Archive Show summary

  Background. Hypertension in kidney transplant (KTx) recipients is common, affecting both patient and graft survival. Annual data from the Norwegian Renal Registry reveal that <50% of adult (>18 y) KTx recipients reach target blood pressure (BP) ≤130/80 mm Hg. The aim of this study was to identify the determinants of failure to achieve BP control. Methods. In conjunction with the 2018 annual data reporting, additional questions were added for recipients with BP >130/80 mm Hg (treating physician´s target BP for each patient, reasons for not achieving target, method of measurement). Results. Annual forms were received from 98% (3407 of 3486) of KTx recipients, with 1787 (52%) reporting a BP >130/80 mm Hg (“above-target” group). These recipients were older, mostly male, with higher body mass index and serum creatinine levels (P < 0.05) compared with patients with controlled hypertension (“on-target” group). Valid survey answers were available for 84% of the “above-target” group (Survresp) with no significant demographic differences versus nonresponders (Survnonresp). Among Survresp, 32% were under antihypertensive dose titration, whereas dose-limiting side effects were reported in 7%. Target BP was confirmed to 130/80 mm Hg for 60% of Survresp. In recipients for whom the treating physician set target BP >130/80 mm Hg, 51% did not reach these individual targets. The number of antihypertensive drugs was significantly higher in the “above-target” group versus “on-target” group (mean 2.1 ± 1.2 versus 1.8 ± 1.3) and 36% versus 25% used ≥3 antihypertensive drugs (P < 0.05). Automatic attended BP measurement was utilized by 51%. Conclusions. In KTx recipients, a higher BP target achievement seems possible, potentially in the range of 75%-80%.

• Kramer, Anneke; Boenink, Rianne; Stel, Vianda S.; Pablos, Carmen Santiuste de; Tomovic, Filip & Golan, Eliezer [Show all 46 contributors for this article] (2021). The ERA-EDTA Registry Annual Report 2018: A summary. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 14(1), p. 107–123. doi: 10.1093/ckj/sfaa271. Full text in Research Archive
• Witczak, Bartlomiej J; Pischke, Søren E.; Reisæter, Anna V.; Midtvedt, Karsten; Ludviksen, Judith K & Heldal, Kristian [Show all 10 contributors for this article] (2021). Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.738927. Full text in Research Archive Show summary

  Background: The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored. Methods: We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5–10.6]. Results: Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% vs. 75.5%, P < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% vs. 67.3% (P < 0.002). Graft survival was also lower when censored for death; 81.5% vs. 87.3% (P = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02–1.91), P = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06–1.85), P = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06–2.71), P = 0.03] as were also HLA-DR mismatches and higher immunological risk. Conclusions: Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.

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• Kongerud, Ingrid Charlotte; Midtvedt, Karsten; Solbu, Marit Dahl; Øvrehus, Marius Altern; Eikrem, Øystein Solberg & Eide, Ivar Anders [Show all 10 contributors for this article] (2026). Can sodium-glucose cotransporter 2 (SGLT2) inhibition preserve renal structure and function in de novo kidney transplant recipients? Protocol for a randomised, double-blind, placebo-controlled trial assessing the efficacy of dapagliflozin on kidney structure, function and safety in kidney transplant recipients in Norway—the DEAK study. doi: 10.1136/bmjopen-2026-117263. Full text in Research Archive Show summary

  Introduction Recent studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease in people at high cardiovascular risk, with or without type 2 diabetes. To date, all published studies have excluded kidney transplant recipients (KTRs). The Dapagliflozin Early After Kidney Transplantation (DEAK) study aims to prospectively evaluate the effects of the SGLT2 inhibitor dapagliflozin on kidney function, histopathology and metabolic outcomes among de novo KTRs. Methods and analyses This nationwide, investigator-initiated, single-transplant-centre, randomised, placebo-controlled, prospective clinical trial with two parallel groups aims to enrol 330 de novo adult KTRs (aged 18–75 years) with an estimated glomerular filtration rate (eGFR) of at least 25 mL/min/1.73 m². Participants are enrolled 6–8 weeks after transplantation and randomised 1:1 to receive dapagliflozin 10 mg/day or placebo for 3 years. Recipients with conditions that may intermittently affect kidney function, such as recent acute rejection or ongoing infection, are ineligible for inclusion. The primary endpoint of the study is the difference in the chronic eGFR slope between treatment groups over 3 years, estimated using the European Kidney Function Consortium equation. Secondary and safety endpoints include changes in measured GFR (iohexol clearance), urinary albumin/creatinine ratio, blood pressure, infections and safety clinical chemistry. Exploratory endpoints evaluated after 1.5 years include changes in body composition and glucose tolerance; between-group differences in urinary metabolomics; transplant kidney biopsy inflammation and fibrosis scores (n=140) and kidney biopsy messenger RNA and protein expression (n=50). The protocol also includes a 10-year poststudy registry follow-up of eGFR slope, cardiovascular events and graft and patient survival. Ethics and dissemination The study protocol (EudraCT number: 2022-002428-10) has been approved by the Norwegian Medical Products Agency, the Regional Committee for Medical Research Ethics in Southeast Norway (REK Southeast number 426076) and by the data protection offices at the participating hospitals. The main results will be published in international, peer-reviewed scientific journals. Trial registration number NCT05788276.

• Åsberg, Anders; Midtvedt, Karsten; Lindahl, Jørn Petter Hanto; Pihlstrøm, Hege K.; Bollerslev, Jens & Godang, Kristin (2025). Impact of Potassium-Binders on the Interpretation of Bone Mineral Density Following Kidney Transplantation. Clinical Transplantation. ISSN 0902-0063. 39(10). doi: 10.1111/ctr.70352. Full text in Research Archive
• Fløde, Mari; Hermann, Monica; Igland, Jannicke; Hernar, Ingvild; Sigurdardottir, Arun Kristin & Søfteland, Eirik [Show all 9 contributors for this article] (2025). Hypoglykemi hos eldre med diabetes - samanhengar med diabetes- og aldersrelaterte faktorar. Full text in Research Archive
• Gripheim, Janne Marlene; Åsberg, Anders; Hagness, Morten; Heldal, Kristian & Midtvedt, Karsten (2023). Nyretransplantasjon – en pågående suksesshistorie. 143(11). doi: 10.4045/tidsskr.23.0383. Full text in Research Archive
• Tran, Trung; Vaage, Eline Benno; Mehta, Adi; Chopra, Adity; Tietze, Lisa & Kolderup, Heidi Anette [Show all 40 contributors for this article] (2023). Author Correction: Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants (npj Vaccines, (2022), 7, 1, (174), 10.1038/s41541-022-00586-7). npj Vaccines. 8(1). doi: 10.1038/s41541-023-00600-6. Full text in Research Archive
• Graue, Marit; Haugstvedt, Anne; Hermann, Monica; Søfteland, Eirik; Igland, Jannicke & Åsberg, Anders [Show all 7 contributors for this article] (2023). Hypoglykemi påvist med CGM hos eldre. Full text in Research Archive
• Helanterä, Ilkka; Snyder, Jon; Åsberg, Anders; Cruzado, Josep María; Bell, Samira & Legendre, Christophe [Show all 13 contributors for this article] (2022). Demonstrating Benefit-Risk Profiles of Novel Therapeutic Strategies in Kidney Transplantation: Opportunities and Challenges of Real-World Evidence. Transplant International. ISSN 0934-0874. 35. doi: 10.3389/ti.2022.10329. Full text in Research Archive Show summary

  While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

• Storås, Andrea; Riegler, Michael Alexander; Halvorsen, Pål; Åsberg, Anders & Strumke, Inga (2022). Predicting drug exposure in kidney transplanted patients using machine learning. Full text in Research Archive
• Midtvedt, Karsten; Vaage, John T.; Heldal, Kristian; Munthe, Ludvig Andre; Lund-Johansen, Fridtjof & Åsberg, Anders (2022). Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response. American Journal of Transplantation. ISSN 1600-6135. doi: 10.1111/ajt.17091. Full text in Research Archive
• Boenink, Rianne; Astley, Megan E; Huijben, Jilske A; Stel, Vianda S.; Kerschbaum, Julia & Ots-Rosenberg, Mai [Show all 41 contributors for this article] (2022). The ERA Registry Annual Report 2019: Summary and age comparisons. Clinical Kidney Journal (CKJ). ISSN 2048-8505. 15(3), p. 452–472. doi: 10.1093/ckj/sfab273. Full text in Research Archive
• Midtvedt, Karsten; Onsøien, Mari Olsen & Åsberg, Anders (2021). Posttransplant Hypertension Matters! Transplantation. ISSN 0041-1337. 10(105), p. e150–e150. doi: 10.1097/TP.0000000000003831. Full text in Research Archive
• Midtvedt, Karsten; Tran, Trung; Parker, Krystina; Marti, Hans Peter; Stenehjem, Aud Eldrid & Gøransson, Lasse Gunnar [Show all 12 contributors for this article] (2021). Low Immunization Rate in Kidney Transplant Recipients Also After Dose 2 of the BNT162b2 Vaccine: Continue to Keep Your Guard up! Transplantation. ISSN 0041-1337. 105(8), p. E80–E81. doi: 10.1097/TP.0000000000003856. Full text in Research Archive
• Robertsen, Ida; Åsberg, Anders; Jenssen, Trond Geir; Gence, Berfin; Vethe, Nils Tore & Midtvedt, Karsten [Show all 8 contributors for this article] (2021). Increased systemic exposure of once-daily tacrolimus in renal transplant recipients on marine omega-3 fatty acid supplementation. Transplant International. ISSN 0934-0874. doi: 10.1111/tri.13917. Full text in Research Archive

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