Establishing surrogate kidney endpoints for lupus nephritis clinical trials: development and validation of a novel approach to predict future kidney outcomes

Objective: Endpoints currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long‐term kidney survival. The objective of this investigation was to identify short‐term endpoints that predict long‐term kidney outcomes for use in clinical trials. Methods: A database of 944 LN patients was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long‐term outcomes in a 36 month follow‐up period. The long‐term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). Hazard Index Tools (HITs) to predict risk for each outcome were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects 54 CKD, 55 SKI and 22 RRT events occurred. Variables in the final CKD HIT were prediction period CKD status, 12‐month proteinuria and12‐month serum creatinine (SCr). The SKI HIT included prediction period CKD status, ISN Class, 12‐month proteinuria, 12‐month SCr, race and an interaction between ISN Class and 12‐month proteinuria. The RRT HIT included age at diagnosis, 12‐month proteinuria and 12‐month SCr. Each HIT validated well internally (c‐indices 0.84‐0.92) and in an independent LN cohort (c‐indices 0.83‐0.92). Conclusion: HITs, derived from short‐term kidney responses to treatment correlate with long‐term kidney outcomes, and now must be validated as surrogate endpoints for LN clinical trials.</p

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

OBJECTIVE: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials

COVID-19 Vaccination and New Onset Glomerular Disease: Results from the IRocGN2 International Registry

UnknownNot hel

Mechanisms of adhesion and subsequent actions of a haematopoietic stem cell line, HPC-7, in the injured murine intestinal microcirculation in vivo

Although haematopoietic stem cells (HSCs) migrate to injured gut, therapeutic success clinically remains poor. This has been partially attributed to limited local HSC recruitment following systemic injection. Identifying site specific adhesive mechanisms underpinning HSC-endothelial interactions may provide important information on how to enhance their recruitment and thus potentially improve therapeutic efficacy. This study determined (i) the integrins and inflammatory cyto/chemokines governing HSC adhesion to injured gut and muscle (ii) whether pre-treating HSCs with these cyto/chemokines enhanced their adhesion and (iii) whether the degree of HSC adhesion influenced their ability to modulate leukocyte recruitment.Adhesion of HPC-7, a murine HSC line, to ischaemia-reperfused (IR) injured mouse gut or cremaster muscle was monitored intravitally. Critical adhesion molecules were identified by pre-treating HPC-7 with blocking antibodies to CD18 and CD49d. To identify cyto/chemokines capable of recruiting HPC-7, adhesion was monitored following tissue exposure to TNF-α, IL-1β or CXCL12. The effects of pre-treating HPC-7 with these cyto/chemokines on surface integrin expression/clustering, adhesion to ICAM-1/VCAM-1 and recruitment in vivo was also investigated. Endogenous leukocyte adhesion following HPC-7 injection was again determined intravitally.IR injury increased HPC-7 adhesion in vivo, with intestinal adhesion dependent upon CD18 and muscle adhesion predominantly relying on CD49d. Only CXCL12 pre-treatment enhanced HPC-7 adhesion within injured gut, likely by increasing CD18 binding to ICAM-1 and/or CD18 surface clustering on HPC-7. Leukocyte adhesion was reduced at 4 hours post-reperfusion, but only when local HPC-7 adhesion was enhanced using CXCL12.This data provides evidence that site-specific molecular mechanisms govern HPC-7 adhesion to injured tissue. Importantly, we show that HPC-7 adhesion is a modulatable event in IR injury and further demonstrate that adhesion instigated by injury alone is not sufficient for mediating anti-inflammatory effects. Enhancing local HSC presence may therefore be essential to realising their clinical potential

COVID-19 Vaccination and New Onset Glomerular Disease : Results from the IRocGN2 International Registry

Background Patients with de novo glomerular disease (GD) with various renal histologies have been reported after vaccination against SARS-CoV-2. Causality has not been established, and the long-term outcomes are not known. To better characterize the GDs and clinical courses/outcomes, we created the International Registry of COVID-19 vaccination and Glomerulonephritis to study in aggregate patients with de novo GN suspected after COVID-19 vaccine exposure.Methods A REDCap survey was used for anonymized data collection. Detailed information on vaccination type and timing and GD histology were recorded in the registry. We collected serial information on laboratory values (before and after vaccination and during follow-up), treatments, and kidney-related outcomes.Results Ninety-eight patients with GD were entered into the registry over 11 months from 44 centers throughout the world. Median follow-up was 89 days after diagnosis. IgA nephropathy (IgAN) and minimal change disease (MCD) were the most common kidney diseases reported. Recovery of kidney function and remission of proteinuria were more likely in IgAN and MCD at 4-6 months than with pauci-immune GN/vasculitis and membranous nephropathy.Conclusions The development of GD after vaccination against SARS-CoV-2 may be a very rare adverse event. Temporal association is present for IgAN and MCD, but causality is not firmly established. Kidney outcomes for IgAN and MCD are favorable. No changes in vaccination risk-benefit assessment are recommended based on these findings.Peer reviewe