Volume Retention, Metabolism, and Cellular Composition of Human Fat Xenografts

Background:. To optimize the take of transferred fat, better understanding of fat graft morphology and growth properties in vivo is critical. We aim to evaluate survival, volume retention, metabolism, and cellular composition of various aliquots of human fat xenografts. Methods:. Twenty athymic nude mice were injected subcutaneously in opposing flanks with 0.1 ml (small) and 1.0 ml (large) aliquots of human fat graft. Volume (ultrasound) of fat aliquots was measured at baseline, 1, 3, and 12 weeks after implantation. Tissue metabolism (18F-FDG), Hematoxylin and Eosin, special stains, and immunohistochemical analysis were performed at 3 and 12 weeks to determine graft viability, cell origin, and proliferative activity. Results:. Only 1 of 10 small grafts were detected after 12 weeks by ultrasound and 5 of 10 were found at necropsy. Volume of large grafts decreased significantly from baseline at 3 (827 ± 195 mm3 versus 953 ± 122 mm3; P = 0.004) and 12 weeks (515 ± 163 mm3 versus 953 ± 122 mm3; P = 0.0001). Metabolism increased with time in small (0.6 ± 0.4%ID/g versus 2.0 ± 1.1%ID/g, P = 0.01) and large grafts (0.4 ± 0.3%ID/g versus 1.4 ± 0.9 %ID/g; P = 0.005). Large grafts viability decreased between 3 and 12 weeks (72 ± 20% versus 31 ± 30%; P = 0.012) although small graft viability remained unchanged. Viable and proliferating human and mouse adipocytes and chimeric blood vessels were seen within grafts at both time points. Conclusions:. Larger graft aliquot was associated with better volume retention by ultrasound but lower viability by histology. Graft metabolism increased with time irrespective of aliquot size potentially due to regenerative processes of both donor and recipient origin

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics