Dennis A. Hesselink

Bio: Dennis A. Hesselink is an academic researcher from Erasmus University Rotterdam. The author has contributed to research in topics: Transplantation & Kidney transplantation. The author has an hindex of 38, co-authored 210 publications receiving 6216 citations. Previous affiliations of Dennis A. Hesselink include Paul Sabatier University & Erasmus University Medical Center.

Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus

Abstract: Background The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1. Objective Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics. Methods Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype. Results Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P < .0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P = .003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations. Conclusion As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes. Clinical Pharmacology & Therapeutics (2003) 74, 245–254; doi: 10.1016/S0009-9236(03)00168-1

Duration and key determinants of infectious virus shedding in hospitalized patients with coronavirus disease-2019 (COVID-19).

Abstract: Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients (17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5–11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4–17.2). Multivariate analyses identify viral loads above 7 log10 RNA copies/mL (odds ratio [OR] of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report

Abstract: Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

Shedding of infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key determinants

Abstract: Background Long-term shedding of viral RNA in COVID-19 prevents timely discharge from the hospital or de-escalation of infection prevention and control practices. Key questions are the duration and determinants of infectious virus shedding. We assessed these questions using virus cultures of respiratory tract samples from hospitalized COVID-19 patients as a proxy for infectious virus shedding. Methods Clinical and virological data were obtained from 129 hospitalized COVID-19 patients (89 intensive care, 40 medium care). Generalized estimating equations were used to identify if viral RNA load, detection of viral subgenomic RNA, serum neutralizing antibody response, duration of symptoms, or immunocompromised status were predictive for a positive virus culture. Findings Infectious virus shedding was detected in 23 of the 129 patients (17,8%). The median duration of shedding was 8 days post onset of symptoms (IQR 5 – 11) and the probability of detecting infectious virus dropped below 5% after 15,2 days post onset of symptoms (95% confidence interval (CI) 13,4 – 17,2). Multivariate analyses identified viral loads above 7 log10 RNA copies/mL (odds ratio [OR]; CI 14,7 (3,57-58,1; p Interpretation Infection prevention and control guidelines should take into account that patients with severe or critical COVID-19 may shed infectious virus for longer periods of time compared to what has been reported for in patients with mild COVID-19. Infectious virus shedding drops to undetectable levels below a viral RNA load threshold and once serum neutralizing antibodies are present, which warrants the use of quantitative viral RNA load assays and serological assays in test-based strategies to discontinue or de-escalate infection prevention and control precautions. Research in context Evidence before this study We searched PubMed, bioRxiv, and medRxiv for articles that reported on shedding of infectious virus in COVID-19 patients using the search terms (“coronavirus” OR “SARS” OR “SARS-CoV-2” OR “COVID-19”) AND (“shedding” OR “infectivity” OR “infectious” OR “virus culture”) with no language or time restrictions. A detailed study on nine patients with mild COVID-19 reported that infectious virus could not be isolated after more than eight days of symptoms. The probability of isolating infectious virus was less than 5% when viral loads dropped below 6,51 Log10 RNA copies/mL. Similar results were obtained with a larger diagnostic sample set, but that study did not report on clinical parameters such as disease severity. Finally there is a report of a single patient shedding infectious virus up to 18 days after onset of symptoms. No published works were found on the shedding of infectious virus in patients with severe or critical COVID-19, and no published works were found on factors independently associated with shedding of infectious virus. Added value of this study We assessed the duration and determinants of infectious virus shedding in 129 patients with severe or critical COVID-19. The duration of infectious virus shedding ranged from 0 to 20 days post onset of symptoms (median 8 days, IQR 5 – 11). The probability of detecting infectious virus dropped below 5% after 15,2 days post onset of symptoms (95% confidence interval (CI) 13,4 – 17,2). Viral loads above 7 log10 RNA copies/mL were independently associated with detection of infectious SARS-CoV-2 from the respiratory tract (odds ratio [OR]; CI 14,7 (3,57-58,1; p Implications of all the available evidence Infection prevention and control guidelines should take into account that patients with severe or critical COVID-19 may shed infectious virus for longer periods of time compared to what has been reported for in patients with mild COVID-19. Quantitative viral RNA load assays and serological assays should be used for test-based strategies to discontinue or de-escalate infection prevention and control precautions.

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Abstract: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Post-acute COVID-19 syndrome.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue

Abstract: The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.