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Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure–response relationship between mycophenolic acid 12-hour area under the curve (AUC 0–12h) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination – long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC 0–12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC 0–12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79–0.97; P = 0.010) and 0.89 (95% CI, 0.85–0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC 0–12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure–response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.

Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemo-lytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy. Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treat-ment were evaluated. In addition, an extensive cost-consequence analysis was conducted. Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight. Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.

Aims Immunosuppressant and kidney function monitoring are crucial for kidney transplant recipient follow-up. Microsamples enable remote sampling and minimise patient burden as compared to conventional venous sampling at the clinic. We developed a liquid chromatography-tandem mass spectrometry assay to quantify tacrolimus, mycophenolic acid (MPA), creatinine and iohexol in dried blood spot (DBS), and volumetric absorptive microsample (VAMS) samples. Methods The assay was successfully validated analytically for all analytes. Clinical validation was conducted by direct comparison of paired DBS, VAMS and venous reference samples from 25 kidney transplant recipients. Patients received iohexol 5-15 minutes before immunosuppressant intake and were sampled 0, 1, 2 and 3 hours thereafter, enabling tacrolimus and MPA area under the concentration-time curve (AUC) and creatinine-based and iohexol-based glomerular filtration rate (GFR) estimation. Method agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and the percentages of values within 15-30% of the reference (P-15-P-30) with a P-20 acceptance threshold of 80%. Results For DBS samples, method agreement was excellent for tacrolimus trough concentrations (n = 25, P-15 = 92.0%) and AUCs (n = 25; P-20 = 95.8%) and adequate for creatinine-based GFR trend monitoring (n = 25; P-20 = 80%). DBS-based MPA AUC assessment showed suboptimal agreement (n = 16; P-20 = 68.8%), but was considered acceptable given its P-30 of 100%. The assay performed inadequately for DBS-based iohexol GFR determination (n = 24; P-20 = 75%). The VAMS technique generally showed inferior performance, but can be considered for certain situations. Conclusion The assay was successfully validated for tacrolimus, MPA and creatinine quantification in DBS samples, enabling simultaneous remote kidney function trend monitoring and immunosuppressant therapeutic drug monitoring in kidney transplant recipients.

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued during a COVID-19 infection. However, clinical signs of calcineurin toxicity have been described in multiple COVID-19 positive KTRs. In this report we describe the course of tacrolimus exposure prior to, during, and post COVID-19 in observations from three clinical cases as well as four KTRs from a controlled trial population. We postulate inflammation driven downregulation of the CYP3A metabolism as a potential mechanism for higher tacrolimus exposure. To mitigate the risk of tacrolimus overexposure and toxicity therapeutic drug monitoring is recommended in KTRs with COVID-19 both in the in-, out-patient and home monitoring setting.

Background COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Trial registration The study protocol has been registered in clinicaltrials.gov(NCT04841785). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

As part of the innate immune system, the complement system is an important mechanism in our first line of defence, but it can also contribute to the onset of various diseases. In renal diseases, the dysregulation of the complement system is often caused by mutations in-and autoantibodies directed against-members of the complement system, and contributes to disease onset and severity. As the only known positive regulator of the complement system, the role of properdin in complement-mediated diseases is largely unknown. In this review, we provide an overview of the detection of properdin in kidney biopsies and urine, serum or plasma samples from patients with complement-mediated renal diseases, such as immune complex-mediated glomerulonephritis and C3 glomerulopathy. Advances towards a better understanding of the role of properdin in ( local) complement activation will provide insight into its potential role and offer opportunities to improve diagnosis and therapeutic interventions.

This dissertation aimed to broaden our understanding of patient-relevant outcomes after kidney transplantation with a special focus on the patients’ perspectives. By conducting different studies in Dutch kidney transplant recipients and by synthesizing existing evidence, we explored several post-transplant patient-relevant outcomes (e.g. health-related quality of life, symptom burden, illness perceptions, medication non-adherence and hospital readmission) and investigated pathways to improve these outcomes, hereby adding to the existing body of knowledge in kidney transplantation. In Chapter 1, we briefly introduced the status quo of patient-relevant outcomes in kidney transplant recipients, discussed potential pathways to improve patient-relevant outcomes in kidney transplant recipients, and provided an overview of the studies presented in this dissertation. In Chapter 7, we provided a summary of our main findings from different studies described in Chapter 2 - 6, the clinical implication of our main findings, and suggestions for future research.

The aim of this thesis was to evaluate quantitative MRI techniques in reno-cardiovascular health, and to study the links between obesity and reno-cardiovascular health using quantitative MRI metrics. Furthermore, we aimed to address novel insights on the safety of contrast media with regard to the use of gadolinium. The general introduction (Chapter 1) of this thesis introduces the concept of quantitative MRI, its application in epidemiological research, reno-cardiovascular health, and in obesity. In addition, the general introduction addresses the safety of gadolinium as an MRI contrast agent. Following the general introduction a review of the clinical application and technical considerations of quantitative MRI using T1 and T2(*) mapping in cardiac and renal imaging was provided in Chapter 2. Part 1 of this thesis focused on the reproducibility and clinical validity of T1 mapping and proton magnetic resonance spectroscopy (1H-MRS) in renal imaging. Part 2, described different studies evaluating the association between obesity and reno-cardiovascular function which was analyzed in population-based imaging studies using different quantitative MRI metrics. Part 3, provides an overview of the safety profile of gadolinium containing contrast agents, and reflection on the recent EMA recommendations.

The aim of this thesis was to develop advanced body MR techniques that can contribute to the knowledge of the metabolic syndrome (MetS). Such techniques are important since the incidence of the metabolic syndrome is reaching pandemic proportions. We looked In the first part of this thesis, consisting of chapters 2, 3 and 4, new techniques for body MR were developed. Firstly high dielectric passive shimming was developed and applied on liver imaging to increase image quality. Furthermore, the required power was reduced by applying the passive shimming method. Secondly MR spectroscopy was optimized to reliably measure lipid levels in the heart and kidney. By looking at the various parameters and optimizing them individually very high measurement reproducibility was reached. Even though MR spectroscopy is a great tool for studying MetS the complexity of the technique hampers broad application therefore, extra emphasis was placed on the ease of use of the developed protocol. In the second part of the thesis the previously mentioned methods were applied in a more clinical setting.