Sunday, July 09, 2023

COVID-19 Vaccines Linked to Kidney Disease Safety Signal—Fujita Health University Investigation

Clinical investigators across disciplines affiliated with Fujita Health University in Toyoake, Japan, south and west of Tokyo, review the large national pharmacovigilance database capturing real-world spontaneous adverse event (AE) reports to identify any signals involving the most common form of glomerular injury post-COVID-19 vaccination known as IgA nephropathy (IgAN).

Represented by corresponding author Mizuno Tomohiro in the Department of Clinical Pharmacy at Fujita Health University, the team sought to investigate the frequency of IgAN post-COVID-19 vaccination based on a designed study of the Japanese Adverse Drug Event Report (JADER) database. Reviewing a total of 697,885 cases, Tomohiro and colleagues detected safety signals for IgAN (ROR: 6.49, 95% CI: 4.38–9.61; IC: 2.27, 95% CI: 1.70–2.83). Identifying a total of 30 COVID-19 vaccine-associated IgAN cases, 16 of these had information about the cases at the time of onset.

Of these, 11 of the cases occurred 2 days after vaccination, and two occurred >28 days after vaccination. Safety issues are raised by these findings as the Japanese clinical investigators write “These results suggest that compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.”

The recent results of the study titled “COVID-19 mRNA Vaccination is associated with IgA nephropathy: an analysis of the Japanese adverse drug event report database” were published in the Journal of Pharmacy & Pharmaceutical Sciences.

Before delving into study findings, a brief overview of the condition—IgAN.

What is IgAN?

Also known as IgAN or Berger’s disease, IgA nephropathy is a chronic kidney disease characterized by the deposition of immunoglobulin A (IgA) antibodies in the glomeruli, which are the filtering units of the kidneys. It is the most common form of glomerulonephritis worldwide.

With this disease, there is an abnormal immune response where IgA antibodies, which are part of the immune system and normally help protect against infections, become deposited in the glomeruli instead of being cleared from the body. This deposition triggers an inflammatory response and can lead to kidney damage over time.

The study

This study team analyzed data on drug-associated AEs reported between April 2004, and May 2022, via the JADER database on the Pharmaceuticals and Medical Devices Agency website. The team calculated reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) using two-by-two contingency tables in the study team’s quest to evaluate the safety signals for the targeted AEs.


The authors report, “A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38–9.61; IC: 2.27, 95% CI: 1.70–2.83). Of 30 cases of IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination.” Note, 11 cases never recovered, at least not to date.


Canadian Investigators Discovery Unique Blood Plasma Protein Patterns in Long COVID Patients

A Canadian research unit may come up with a way to treat at least some long COVID patients more effectively. The condition has emerged since the pandemic as a real problem. With anywhere from 10-20% of people that have been infected with SARS-CoV-2 susceptible to long COVID, some estimate north of 14 million people in America alone struggling with the condition, which can last for many months. Often impacting the quality of life, symptoms from brain fog and fatigue to breathing difficulties can be outright debilitating.

Led by Dr. Douglas Faser, a professor in pediatrics at Schulich School of Medicine & Dentist, and physician at London Health Sciences Centre (LHSC) a team of Canadians designed a study using artificial intelligence (AI) as part of advanced research to discover unique patterns of blood plasma proteins in patients with suspected long COVID, with an aim on improving patient outcomes. Enter the “plasma proteome,” as the research centers on proteins identified in blood plasma, released by cells often playing a vital role in pathogen immune response.

With study results recently published in the Journal of Translational Medicine this study team sought out to better understand how these plasma cells impact patients with long COVID, and why some patients struggle more than others.

Corresponding authors Dr. Douglas Faser and Cristiana Losef, both with Children’s Health Research Institute, Victoria Research Laboratories, and colleagues investigated possible mechanisms, and to inform the prognosis and treatment of long COVID.

This technology allowed researchers to determine unique patterns in the blood proteins. The team discovered that people with suspected long COVID have prolonged inflammation associated with changes in their immune cells and blood vessels. These changes may lead to problems in specific organs, like the brain and the heart, as reported by Western University.

Called “the plasma proteome,” the proteins are found in blood plasma and are released by cells that often play an important role in the body’s immune response to viruses. The research team is studying how those proteins adapt and change in long COVID.

The study

With a green light from the local Ethics Committee (Western University), the study team enrolled patients from London Health Sciences Center in London, Ontario, Canada and St. Joseph's including patients diagnosed with long COVID as well as acutely ill COVID-19 patients.

Upon diagnosis of long COVID, study patients were referred to a specialist clinic based on prolonged, diffuse symptoms according to the author's account in the Journal of Translational Medicine.

Conducting a series of tests including venous blood work, the study team analyzed patient plasma. COVID-19 patients were approached when they were admitted to the hospital or medical ward or intensive care unit. Healthy subjects were included—persons without disease, acute illness or any prescription medicine, but previously banked by the Translational Research Center in London, Ontario.

All samples in the study were matched by age and gender (e.g., long COVID patients to acutely ill patients to healthy controls).


Unlike acutely ill COVID-19 patients as well as healthy subjects---both matched by age and sex—the long COVID outpatients evidenced natural killer cell redistribution with a dominant resting phenotype, opposite to active and neutrophils formed in extracellular traps.

The study team reports a possible “resetting of cell phenotypes” likely resulting from “prospective vascular events mediated by both angiopoietin (ANGPT1) and vascular endothelial growth factor-A (VEGFA).

Validating several biomarkers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) the authors report also that “Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300” pointed to both vascular inflammation as well as tumor necrosis factor- α driven pathways. The authors suggested that the progression from acute COVID-19 to long COVID was “a vascular proliferative state associated with hypoxia-inducible factor 1 pathway.”

Fraser and Losef write that this “vascular-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction.”

PI Point of View

Cristiana Losef, a research analyst at Children’s Health Research Institute (CHRI), a program of Lawson went on the record, “We used novel technologies for this study, allowing us to analyze more than 3,000 proteins in blood plasma at the same time with multiple patients.”

Losef continued:

“We used a novel bioinformatic pipeline, a form of artificial intelligence (AI), to analyze the proteins to determine the specific changes that occur in long COVID.”

Dr. Michael Nicholson, associate scientist at Lawson, and respirologist at St. Joseph’s Health Care London reports on the influence of this study, “Trying to understand this mechanism is quite important because it provides further insight into how patients are affected,” says Dr. Michael Nicholson. He continued, “This paper sheds further light on a possible mechanism that may provide insight into why some patients have certain symptoms.”

Michael Knauer, an associate scientist at Lawson shared for Western University, “The saved blood plasma samples we are using helped us determine the long-term responses to COVID-19; serial blood plasma samples from individuals that had a COVID-19 infection and now presumed long COVID will help us determine how proteins are changing over time.”

What’s the potential value from a therapeutic perspective?

Dr. Faser, a professor at Schulich Medicine, said the proteins discovered could act as a potential drug target. The team is now examining potential new drug therapies with the hopes of improving outcomes for these patients.

Fraser emphasized:

“When we identify these signaling patterns within the blood plasma, we can then take the information and screen drug databases to better understand which drugs would be best to target the changes we identified in long COVID patients.” Pointing to the potential of these findings, “With this understanding, the identified drugs may be used in future long COVID clinical trials.”

Key Point: This research, which used multiple state-of-the-art technologies, was enabled by existing expertise and infrastructure through Children’s Health Research Institute (CHRI). It reveals that the findings point to a “vascular-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc.). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.”




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