Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design.

BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. DISCUSSION: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

Successful management of T-cell mediated rejection in a recent kidney transplant recipient with COVID-19 associated severe acute respiratory syndrome.

COVID-19-associated vasculitis has been reported as a defining feature of systemic disease including acute kidney injury. However, the understanding of COVID-19 kidney transplant-related injuries is still evolving. We report a case of AKI with isolated vasculitis (v2 lesion) in a new kidney transplant recipient with COVID-19 pneumonia.

COVID-19-associated glomerulopathy and high-risk APOL1 genotype;Basis for a two-hit mechanism of injury? A narrative review on recent findings

Kidney is one of the most common organs affected by coronavirus disease 2019 (COVID-19) after the respiratory and immune systems. Among the renal parenchymal components, the tubulointerstitial compartment is presumed to be the prime target of injury in COVID-19. The main mechanism of renal tubular damage by COVID-19 is considered to be indirect, i.e., cytokine-mediated injury. A proportion of infected individuals mount a strong inflammatory response to the virus by an exaggerated immune response of the body, namely cytokine storm. Sudden and massive release of cytokines may lead to serious systemic hyper-inflammation and renal tubular injury and inflammation resulting in acute renal failure. In addition, a number of cases of glomerulopathies, particularly collapsing glomerulopathy (CG) have been reported, predominantly in people of African ancestry, as a rare form of kidney involvement by SARS-CoV-2 that may originate from the background genetic susceptibility in this population complicated by the second hit of SARS-CoV-2 infection, either directly or indirectly. It is noteworthy that renal injury in COVID-19 could be severe in individuals of African origin due to the aforementioned genetic susceptibility, especially the presence of high-risk apolipoprotein L1 (APOL1) genotypes. Although the exact mechanism of kidney injury by SARS-CoV-2 is as yet unknown, multiple mechanisms are likely involved in renal damage caused by this virus. This review was aimed to summarize the salient points of pathogenesis of kidney injury, particularly glomerular injury in COVID-19 disease in the light of published data. A clear understanding of these is imperative for the proper management of these cases. For this review, a search was made of Google Scholar, Web of Science, Scopus, EBSCO and PubMed for finding English language articles related to COVID-19, kidney injury and glomerulopathy. From the information given in finally selected papers, the key aspects regarding glomerular involvement in COVID-19 were drawn out and are presented in this descriptive review. [ABSTRACT FROM AUTHOR] Copyright of Journal of Nephropathology is the property of Isfahan University of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Use of Donor-Derived Cell-Free DNA for Assessment of Allograft Injury in Kidney Transplant Recipients During the Time of the Coronavirus Disease 2019 Pandemic.

BACKGROUND: Kidney allograft biopsy is the gold standard for diagnosis of rejection. Under the current extraordinary circumstances of the coronavirus disease 2019 (COVID-19), in which social distancing is key to limiting the spread of the virus, the model used to provide care to transplant recipients has undergone a very rapid transformation. In the spirit of medical distancing, we have been using the donor-derived cell-free DNA (dd-cfDNA) test for screening for rejection. METHODS: This article describes our experience with this approach between March 15th and May 20th, 2020. RESULTS: This test was obtained for-cause in 23 patients and for monitoring in 9 patients. Normal results aided in forgoing biopsy in 63% of the patients for whom the test was obtained in the outpatient setting. The test is neither 100% sensitive nor specific for rejection; however, when used in combination with the available clinical information, it can be used for determining whether bringing in a transplant recipient into a medical facility is necessary. CONCLUSIONS: In the event COVID-19 becomes a long-term challenge for our community, noninvasive biomarkers such as the dd-cfDNA may become more relevant than ever in enhancing our ability to care for our transplant patients while maximizing the distancing measures.

Early Report on Published Outcomes in Kidney Transplant Recipients Compared to Nontransplant Patients Infected With Coronavirus Disease 2019.

BACKGROUND: Kidney transplant recipients (KTR) present unique characteristics, including disease vintage, immunosuppression, and single functioning kidneys. We conducted preliminary analyses to assess the impact of coronavirus disease 2019 (COVID-19) on outcomes in KTR compared to nontransplant patients. METHODS: We evaluated published information in peer-reviewed journals between January 1, 2020, and April 24, 2020, with available data on acute kidney injury (AKI), renal replacement therapy (RRT), intensive care unit (ICU) stay, and death and compared clinical outcomes in KTR vs nontransplant recipients with COVID-19. RESULTS: A total of 19 published articles were identified, including a total of 88 KTR and 5342 nontransplant patients. The sample size varied between 2 and 2634. Mean age was 58.6 years vs 58.9 years in KTR vs nontransplant patients. Patient-level incidence of AKI (27.5% vs 13.3%, P < .001), RRT (15.4% vs 3.3%, P < .001), ICU stay (34.1% vs 15.1%, P < .001), and death (22.7% vs 16.2%, P = .10) was higher in KTR, representing relative risks of 2.06 (1.44, 2.96), 4.72 (2.62, 8.51), 2.25 (1.67, 3.03), and 1.41 (0.95, 2.08), respectively. CONCLUSION: Early results suggest that the KTR are at significantly higher risk of AKI, RRT, and ICU stay from SARS-CoV-19 infection compared to the general population. The risk of death may not be significantly different.

The care of kidney transplant recipients during a global pandemic: Challenges and strategies for success.

The global pandemic of severe acute respiratory coronavirus 2 (SARS-CoV-2), which causes the novel beta coronavirus 2019 disease (COVID-19), has become an unprecedented medical, economic, and psychosocial crisis. The pandemic and its management strategies have resulted in immense challenges for health systems, not only in caring for those with COVID-19 but also in the ongoing management of chronic medical conditions. Kidney transplant recipients present a unique challenge given their need for ongoing monitoring and management as well as their higher risk of COVID-19 infection. In the absence of clear guidelines, it is unclear how to best provide routine care to this unique patient population during the pandemic. Rigorous medical and psychosocial patient-centered risk stratification strategies are needed to avoid adverse outcomes in stable solid organ transplant recipients. This review will focus on the challenges faced by kidney transplant recipients and health care providers and provides strategies to address these issues.