Management and Outcome of COVID-19 Infection Using Nirmatrelvir/Ritonavir in Kidney Transplant Patients.

BACKGROUND: Nirmatrelvir/ritonavir has been shown to reduce the risk of COVID-19 related complications in patients at high risk for severe COVID-19. However, clinical experience of nirmatrelvir/ritonavir in the transplant recipient population is scattered due to the complex management of drug-drug interactions with calcineurin inhibitors. We describe the clinical experience with nirmatrelvir/ritonavir at The Ottawa Hospital kidney transplant program. METHODS: Patients who received nirmatrelvir/ritonavir between April and June 2022 were included and followed up 30 days after completion of treatment. Tacrolimus was withheld for 24 hours and resumed 72 hours after the last dose of nirmatrelvir/ritonavir (on Day 8) based on drug level the day before. The first 30 patients had their dose adjusted according to drug levels performed twice in the first week and as needed thereafter. Subsequently, a simplified algorithm with less frequent calcineurin inhibitor level monitoring was implemented. Outcomes including tacrolimus level changes, serum creatinine and acute kidney injury (AKI, defined as serum creatinine increase by 30%) and clinical outcomes were described globally and compared between algorithms. RESULTS: Fifty-one patients received nirmatrelvir/ritonavir. Tacrolimus levels drawn at the first timepoint, 7 days after withholding of calcineurin inhibitor and 2 days after discontinuing nirmatrelvir/ritonavir were within the therapeutic target in 17/44 (39%), subtherapeutic in 21/44(48%) and supratherapeutic in 6/44 (14%). Two weeks after, 55% were within the therapeutic range, 23% were below, and 23% were above it. The standard and simplified algorithms provided similar tacrolimus level (median 5.2 ug/L [4.0, 6.2] versus 4.8 ug/L [4.3, 5.7] p=0.70). There were no acute rejections or other complications. CONCLUSIONS: Withholding tacrolimus starting the day before initiation of nirmatrelvir/ritonavir with resumption 3 days after completion of therapy resulted in a low incidence of supratherapeutic levels but a short period of subtherapeutic levels for many patients. AKI was infrequent. The data are limited by the small sample size and short follow-up.

Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Early Experience with Modified Dose Nirmatrelvir/Ritonavir in Dialysis Patients with Coronavirus Disease 2019.

BACKGROUND: Nirmatrelvir/ritonavir was approved for use in high-risk outpatients with coronavirus disease 2019 (COVID-19). However, patients with severe CKD were excluded from the phase 3 trial, and the drug is not recommended for those with GFR <30 ml/min per 1.73 m 2 . On the basis of available pharmacological data, we developed a modified low-dose regimen of nirmatrelvir/ritonavir 300/100 mg on day 1, followed by 150/100 mg daily from day 2 to 5. In this study, we report our experience with this modified dose regimen in dialysis patients in the Canadian province of Ontario. METHODS: We included dialysis patients who developed COVID-19 and were treated with the modified dose nirmatrelvir/ritonavir regimen during a 60-day period between April 1 and May 31, 2022. Details of nirmatrelvir/ritonavir use and outcomes were captured manually, and demographic data were obtained from a provincial database. Data are presented with descriptive statistics. The principal outcomes we describe are 30-day hospitalization, 30-day mortality, and required medication changes with the modified dose regimen. RESULTS: A total of 134 dialysis patients with COVID-19 received nirmatrelvir/ritonavir during the period of study. Fifty-six percent were men, and the mean age was 64 years. Most common symptoms were cough and/or sore throat (60%). Medication interactions were common with calcium channel blockers, statins being the most frequent. Most patients (128, 96%) were able to complete the course of nirmatrelvir/ritonavir, and none of the patients who received nirmatrelvir/ritonavir died of COVID-19 in the 30 days of follow-up. CONCLUSIONS: A modified dose of nirmatrelvir/ritonavir use was found to be safe and well tolerated, with no serious adverse events being observed in a small sample of maintenance dialysis patients.

A Unified Citywide Dashboard for Allocation and Scheduling Dialysis for COVID-19 Patients on Maintenance Hemodialysis.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has caused significant global disruption, especially for chronic care like hemodialysis treatments. Approximately 10,000 end-stage kidney disease (ESKD) patients are receiving maintenance hemodialysis (MHD) at 174 dialysis centers in Greater Mumbai. Because of the fear of transmission of infection and inability to isolate patients in dialysis centers, chronic hemodialysis care was disrupted for COVID-19-infected patients. Hence, we embarked on a citywide initiative to ensure uninterrupted dialysis for these patients. Materials and Methods: The Municipal Corporation of Greater Mumbai (MCGM) designated 23 hemodialysis facilities as COVID-positive centers, two as COVID-suspect centers, and the rest continued as COVID-negative centers to avoid transmission of infection and continuation of chronic hemodialysis treatment. Nephrologists and engineers of the city developed a web-based-portal so that information about the availability of dialysis slots for COVID-infected patients was easily available in real time to all those providing care to chronic hemodialysis patients. Results: The portal became operational on May 20, 2020, and as of December 31, 2020, has enrolled 1,418 COVID-positive ESKD patients. This initiative has helped 97% of enrolled COVID-infected ESKD patients to secure a dialysis slot within 48 hours. The portal also tracked outcomes and as of December 31, 2020, 370 (27%) patients died, 960 patients recovered, and 88 patients still had an active infection. Conclusions: The portal aided the timely and smooth transfer of COVID-19-positive ESKD patients to designated facilities, thus averting mortality arising from delayed or denied dialysis. Additionally, the portal also documented the natural history of the COVID-19 pandemic in the city and provided information on the overall incidence and outcomes. This aided the city administration in the projected resource needs to handle the pandemic.

Review of Early Immune Response to SARS-CoV-2 Vaccination Among Patients With CKD.

The effects of the coronavirus disease-2019 (COVID-19) pandemic, particularly among those with chronic kidney disease (CKD), who commonly have defects in humoral and cellular immunity, and the efficacy of vaccinations against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are uncertain. To inform public health and clinical practice, we synthesized published studies and preprints evaluating surrogate measures of immunity after SARS-CoV-2 vaccination in patients with CKD, including those receiving dialysis or with a kidney transplant. We found 35 studies (28 published, 7 preprints), with sample sizes ranging from 23 to 1140 participants and follow-up ranging from 1 week to 1 month after vaccination. Seventeen of these studies enrolled a control group. In the 22 studies of patients receiving dialysis, the development of antibodies was observed in 18% to 53% after 1 dose and in 70% to 96% after 2 doses of mRNA vaccine. In the 14 studies of transplant recipients, 3% to 59% mounted detectable humoral or cellular responses after 2 doses of mRNA vaccine. After vaccination, there were a few reported cases of relapse or de novo glomerulonephritis, and acute transplant rejection, suggesting a need for ongoing surveillance. Studies are needed to better evaluate the effectiveness of SARS-CoV-2 vaccination in these populations. Rigorous surveillance is necessary for detection of long-term adverse effects in patients with autoimmune disease and transplant recipients. For transplant recipients and those with suboptimal immune responses, alternate vaccination platforms and strategies should be considered. As additional data arise, the NephJC COVID-19 page will continue to be updated (http://www.nephjc.com/news/covid-vaccine).

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

AIM: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence. DESIGN: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included. MAIN OUTCOME MEASURES: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed. RESULTS: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation. CONCLUSION: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.

Canadian Association of Paediatric Nephrologists COVID-19 Rapid Response: Guidelines for Management of Acute Kidney Injury in Children.

PURPOSE: This article provides guidance on managing acute kidney injury (AKI) and kidney replacement therapy (KRT) in pediatrics during the COVID-19 pandemic in the Canadian context. It is adapted from recently published rapid guidelines on the management of AKI and KRT in adults, from the Canadian Society of Nephrology (CSN). The goal is to provide the best possible care for pediatric patients with kidney disease during the pandemic and ensure the health care team's safety. INFORMATION SOURCES: The Canadian Association of Paediatric Nephrologists (CAPN) COVID-19 Rapid Response team derived these rapid guidelines from the CSN consensus recommendations for adult patients with AKI. We have also consulted specific documents from other national and international agencies focused on pediatric kidney health. We identified additional information by reviewing the published academic literature relevant to pediatric AKI and KRT, including recent journal articles and preprints related to COVID-19 in children. Finally, our group also sought expert opinions from pediatric nephrologists across Canada. METHODS: The leadership of the CAPN, which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric AKI and acute KRT. The goal was to adapt the guidelines recently adopted for Canadian adult patients for pediatric-specific settings. These included specific COVID-19-related themes relevant to AKI and KRT in a Canadian setting, as determined by a group of kidney disease experts and leaders. An expert group of clinicians in pediatric AKI and acute KRT reviewed the revised pediatric guidelines. KEY FINDINGS: (1) Current Canadian data do not suggest an imminent threat of an increase in acute KRT needs in children because of COVID-19; however, close coordination between nephrology programs and critical care programs is crucial as the pandemic continues to evolve. (2) Pediatric centers should prepare to reallocate resources to adult centers as needed based on broader health care needs during the COVID-19 pandemic. (3) Specific suggestions pertinent to the optimal management of AKI and KRT in COVID-19 patients are provided. These suggestions include but are not limited to aspects of fluid management, KRT vascular access, and KRT modality choice. (4) Considerations to ensure adequate provision of KRT if resources become scarce during the COVID-19 pandemic. LIMITATIONS: We did not conduct a formal systematic review or meta-analysis. We did not evaluate our specific suggestions in the clinical environment. The local context, including how the provision of care for AKI and acute KRT is organized, may impede the implementation of many suggestions. As knowledge is advancing rapidly in the area of COVID-19, suggestions may become outdated quickly. Finally, most of the literature for AKI and KRT in COVID-19 comes from adult data, and there are few pediatric-specific studies. IMPLICATIONS: Given that most acute KRT related to COVID-19 is likely to be required in the pediatric intensive care unit initial setting, close collaboration and planning between critical care and pediatric nephrology programs are needed. Our group will update these suggestions with a supplement if necessary as newer evidence becomes available that may change or add to the recommendations provided.

Proliferation of Papers and Preprints During the Coronavirus Disease 2019 Pandemic: Progress or Problems With Peer Review?

The coronavirus disease 2019 (COVID-19) pandemic has spread exponentially throughout the world in a short period, aided by our hyperconnected world including global trade and travel. Unlike previous pandemics, the pace of the spread of the virus has been matched by the pace of publications, not just in traditional journals, but also in preprint servers. Not all publication findings are true, and sifting through the firehose of data has been challenging to peer reviewers, editors, as well as to consumers of the literature, that is, scientists, healthcare workers, and the general public. There has been an equally exponential rise in the public discussion on social media. Rather than decry the pace of change, we suggest the nephrology community should embrace it, making deposition of research into preprint servers the default, encouraging prepublication peer review more widely of such preprint studies, and harnessing social media tools to make these actions easier and seamless.

Preprint Servers in Kidney Disease Research: A Rapid Review.

Preprint servers, such as arXiv and bioRxiv, have disrupted the scientific communication landscape by providing rapid access to research before peer review. medRxiv was launched as a free online repository for preprints in the medical, clinical, and related health sciences in 2019. In this review, we present the uptake of preprint server use in nephrology and discuss specific considerations regarding preprint server use in medicine. Distribution of kidney-related research on preprint servers is rising at an exponential rate. Survey of nephrology journals identified that 15 of 17 (88%) are publishing original research accepted submissions that have been uploaded to preprint servers. After reviewing 52 clinically impactful trials in nephrology discussed in the online Nephrology Journal Club (NephJC), an average lag of 300 days was found between study completion and publication, indicating an opportunity for faster research dissemination. Rapid review of papers discussing benefits and risks of preprint server use from the researcher, publisher, or end user perspective identified 53 papers that met criteria. Potential benefits of biomedical preprint servers included rapid dissemination, improved transparency of the peer review process, greater visibility and recognition, and collaboration. However, these benefits come at the risk of rapid spread of results not yet subjected to the rigors of peer review. Preprint servers shift the burden of critical appraisal to the reader. Media may be especially at risk due to their focus on "late-breaking" information. Preprint servers have played an even larger role when late-breaking research results are of special interest, such as during the global coronavirus disease 2019 pandemic. Coronavirus disease 2019 has brought both the benefits and risks of preprint servers to the forefront. Given the prominent online presence of the nephrology community, it is poised to lead the medicine community in appropriate use of preprint servers.

COVID-19 Extrapulmonary illness - The Impact of COVID-19 on Nephrology care.

Coronavirus disease-2019 (COVID-19) has caused a pandemic that has affected millions of people worldwide. COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and is spread by close contact and by respiratory droplets. It has also impacted different aspects of caring for people with kidney disease, including those with acute kidney injury (AKI), chronic kidney disease (CKD), those requiring kidney replacement therapy (KRT), and those with a kidney transplant. All of these patients are considered high risk. The lessons learned from the COVID-19 pandemic will hopefully serve to protect patients with kidney disease in a similar situation in the future.

CSN COVID-19 Rapid Review Program: Management of Acute Kidney Injury.

PURPOSE: Severe acute kidney injury (AKI) is a potential complication of COVID-19-associated critical illness. This has implications for the management of COVID-19-associated AKI and the resulting increased need for kidney replacement therapy (KRT) in the intensive care unit (ICU) and elsewhere in the hospital. The Canadian Society of Nephrology COVID-19 Rapid Review Team has sought to collate and synthesize currently available resources to inform ethically justifiable decisions. The goal is the provision of the best possible care for the largest number of patients with kidney disease while considering how best to ensure the safety of the health care team. INFORMATION SOURCES: Local, provincial, national, and international guidance and planning documents related to the COVID-19 pandemic; guidance documents available from nephrology and critical care-related professional organizations; recent journal articles and preprints related to the COVID-19 pandemic; expert opinion from nephrologists from across Canada. METHODS: A working group of kidney specialist physicians was established with representation from across Canada. Kidney physician specialists met via teleconference and exchanged e-mails to refine and agree on the proposed suggestions in this document. KEY FINDINGS: (1) Nephrology programs should work with ICU programs to plan for the possibility that up to 30% or more of critically ill patients with COVID-19 admitted to ICU will require kidney replacement therapy (KRT). (2) Specific suggestions pertinent to the optimal management of AKI and KRT in patients with COVID-19. These suggestions include, but are not limited to, aspects of fluid management, KRT vascular access, and KRT modality choice. (3) We describe considerations related to ensuring adequate provision of KRT, should resources become scarce during the COVID-19 pandemic. LIMITATIONS: A systematic review or meta-analysis was not conducted. Our suggestions have not been specifically evaluated in the clinical environment. The local context, including how the provision of acute KRT is organized, may impede the implementation of many suggestions. Knowledge is advancing rapidly in the area of COVID-19 and suggestions may become outdated quickly. IMPLICATIONS: Given that most acute KRT related to COVID-19 is likely to be required initially in the ICU setting, close collaboration and planning between critical care and nephrology programs is required. Suggestions may be updated as newer evidence becomes available.