ABSTRACT
Hyperparathyroidism (HPT) with hypercalcemia, often deemed irreversible and detrimental to graft survival post-kidney transplantation (KT), prompts pre-transplant parathyroidectomy in hypercalcemic patients. In this retrospective analysis of 1212 kidney transplant recipients (KTRs) between 2006 and 2019, the incidence and effect of persistent HPT and hypercalcemia on graft and patient survival, and risk factors for persistence were analyzed until 60 months of follow up (FU). At KT, 5.7% (n = 69) had no HPT, 32.7% (n = 396) had HPT without hypercalcemia and 37.0% (n = 448) had HPT with hypercalcemia. At 2 years FU, 26.4% (n = 320) of patients had no HPT and 6% (n = 73) had HPT with hypercalcemia. Dialysis and dialysis duration were linked to HPT development, while dialysis, KT waiting time and donor type correlated with persisting hypercalcemia after KT. KTRs with normalized PTH and recovered hypercalcemia had improved death-censored graft survival (p < 0.001) and overall patient survival (p < 0.001). HPT with hypercalcemia is frequent at time of KT with normalization of PTH and calcium in a substantial proportion of patients after a KT. These findings question the routine pre-KT parathyroidectomy for suspected parathyroid autonomy. Persisting HPT, especially with hypercalcemia, adversely affects graft and patient survival, suggesting the need for more aggressive treatment of HPT, especially in cases of persisting hypercalcemia.
ABSTRACT
The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.