Indicators of Cardiometabolic Function in Pregnancy and Long-Term Risk of COVID-19: Population-Based Cohort Study.

BACKGROUND: Pregnancy increases a woman's susceptibility to severe COVID-19, especially those with metabolic dysfunction. It is unknown if markers of metabolic dysfunction commonly assessed around pregnancy are associated with COVID-19 illness after pregnancy. AIM: The aim of this study is to evaluate the indicators of metabolic dysfunction collected in pregnancy and the future risk of severe COVID-19 after pregnancy. METHODS: This population-based cohort study was completed in all of Ontario, comprising 417,713 women aged 15-49 years with a hospital birth between April 2007 and March 2018. The main exposure was each 1-kg/m2 higher body mass index (BMI), 1-mmol/L higher glucose concentration at the 50-g glucose challenge test, and one-week earlier gestational week at delivery. The main outcome was severe COVID-19 illness or death, from the start of the pandemic period on March 1, 2020, till December 31, 2021. RESULTS: The adjusted hazard ratio (aHR) of COVID-19 illness increased per 1-kg/m2 higher BMI (1.05, 95% CI 1.04-1.06), per 1-mmol/L higher serum glucose concentration (1.16, 95% CI 1.10-1.22), and for each one-week earlier gestational week at delivery (1.12, 95% CI 1.03-1.23). Relative to women with no dichotomized risk factors, the aHR for severe COVID-19 was 1.60 (95% CI 1.28-2.01) with one factor, 3.34 (95% CI 2.51-4.44) with two factors, and 4.52 (95% CI 2.11-9.67) with three factors. CONCLUSIONS: The number, and degree, of standard metabolic indicators measured around pregnancy predict the future risk of severe COVID-19 remotely after that pregnancy.

Renal Autologous Cell Therapy in Type 2 Diabetes with Late Stage 4 Diabetes-Related Chronic Kidney Disease: Trial Design and Early Analysis.

INTRODUCTION: Cell-based therapies potentially delay the trajectory toward end-stage kidney disease (ESKD) in late stage 4 diabetic chronic kidney disease (DKD). We describe the trial design, baseline patient characteristics, and early results of an IRB-approved phase II multicenter clinical trial, utilizing Renal Autologous Cell Therapy (REACT) in adults with pre-ESKD due to type 2 DKD. The trial objectives were safety and tolerability of REACT by assessment of the procedure, product administration, and renal-specific adverse events in addition to evaluate the impact on renal function following injection. METHODS: Ten adults with an eGFR of 14-20 mL/min/1.73 m2 were enrolled in a single-arm open-label trial. Following a percutaneous kidney biopsy, an ex vivo expansion of selected renal cells that form the REACT was injected into the cortex of the biopsied kidney with CT image guidance. Each participant received two doses of the REACT product at 6-month intervals. A 6-month observation pre-trial was required to establish patients' "own" baseline and rate of DKD progression. RESULTS: Five men and 5 women underwent 19 REACT injections (1 participant received only one injection). Their baseline characteristics were as follows: 3 Hispanic/Latino, 7 non-Hispanic, 7 white; mean (SD) age: 58.9 years (5.22), BMI 35.8 (8.2), eGFR (sCR) 15.5 (2.72), eGFR (sCR + Cys-C) 17.7 (3.67) mL/min/1.73 m2, sCr 3.6 mg/mL (0.73), Cys-C 2.6 mg/mL (0.52), and log random UACR 7.9 mg/g (1.01). The pre- and post-injection eGFR slope was -6.5 mL/min/1.73 m2 and -3.9 mL/min/1.73 m2. No cell-related adverse events occurred, and two procedure-related hematomas required observation without transfusion or angiographic interventions. Dialysis was delayed a mean of 16 months (range 6-28 months). At 15 months, 2 patients (20%) have eGFR slope stability and have not commenced renal replacement therapy. CONCLUSION: Trials that include patients with an eGFR of <20 mL/min/1.73 m2 are uncommon, and none to date involve autologous homologous cell-based treatments. REACT has the potential to stabilize or delay dialysis in high-risk late stage 4 DKD.

Renal Autologous Cell Therapy to Stabilize Function in Diabetes-Related Chronic Kidney Disease: Corroboration of Mechanistic Action With Cell Marker Analysis.

Introduction: Chronic kidney disease (CKD) is a worldwide disease without cure. Selected renal cells (SRCs) can augment kidney function in animal models. This study correlates the phenotypical characteristics of autologous homologous SRCs (formulated product called Renal Autologous Cell Therapy [REACT]) injected into patients' kidneys with advanced type 2 diabetes-related CKD (D-CKD) to clinical and laboratory findings. Methods: A total of 22 adults with type 2 D-CKD underwent a kidney biopsy followed by 2 subcortical injections of SRCs, 7 ± 3 months apart. There were 2 patients who had only 1 injection. We compared annualized estimated glomerular filtration rate (eGFR) slopes pre- and post-REACT injection using the 2009 CKD-EPI formula for serum creatinine (sCr) and the 2012 CKD-EPI Creatinine-Cystatin C equation and report clinical/laboratory changes. Fluorescent Activated Cell Sorting (FACS) Analysis for renal progenitor lineages in REACT and donor vascular endothelial growth factor A (VEGF-A) analysis were performed. Longitudinal parameter changes were analyzed with longitudinal linear mixed effects model. Results: At baseline, the mean diabetes duration was 18.4 ± 8.80 years, glycated hemoglobin (Hgb) was 7.0 ± 1.05, and eGFR was 40.3 ± 9.35 ml/min per 1.73 m2 using the 2012 CKD-EPI cystatin C and sCr formulas. The annualized eGFR slope (2012 CKD-EPI) was -4.63 ml/min per 1.73 m2 per year pre-injection and improved to -1.69 ml/min per 1.73 m2 per year post-injection (P = 0.015). There were 7 patients who had an eGFR slope of >0 ml/min per 1.73 m2 postinjection. SRCs were found to have cell markers of ureteric bud, mesenchyme cap, and podocyte sources and positive VEGF. There were 2 patients who had remote fatal adverse events determined as unrelated with the biopsies/injections or the REACT product. Conclusion: Our cell marker analysis suggests that SRCs may enable REACT to stabilize and improve kidney function, possibly halting type 2 D-CKD progression.