Kristian Horsman Hansen

Background: Monitoring IGF-I concentration is recommended during GH therapy in children. Supranormal levels of total IGF-I have raised concerns of long-term risks. Aim: To evaluate bioactive and total IGF-I in healthy and in GH-treated children and adolescents. Materials and methods: A reference population of 570 children (59% girls) from the Copenhagen Puberty Study III and 126 short children (36% girls) with GH deficiency (GHD) and other non-GHD conditions. We established pediatric, sex-specific reference ranges of serum concentrations of bioactive IGF-I (KIRA) and compared with total IGF-I and IGF-I/IGFBP-3 molar ratio (iSYS) and total IGF-I, -II, IGFBP-3, and acid labile subunit (liquid chromatography-tandem mass spectrometry) in a subgroup. Further, we compared IGF-I bioactivity with total IGF-I, IGFBP-3 (iSYS) and IGF-I/IGFBP-3 molar ratio during GH therapy. Results: Bioactive IGF-I increased with age in healthy children and correlated positively with total IGF-I and IGF-I/IGFBP-3 in healthy males (r = 0.61 and r = 0.57; P < .001) and females (r = 0.58 and r = 0.59; P < .001) and with IGF-I, BP-3, and acid labile subunit (liquid chromatography-tandem mass spectrometry) (r = 0.56, r = 0.29, and r = 0.38; P < .001). Bioactive IGF-I and IGF-II (r = -0.29; P < .001) correlated negatively. In 13% (17/126) of the patients, bioactive IGF-I was above +2SD, whereas total IGF-I was above +2SD in 25% (32/126) patients. Nine patients had both total and bioactive IGF-I above +2SD. In the non-GHD groups, bioactive IGF-I SDS were lower than IGF-I SDS (P = .015). Conclusion: Bioactive IGF-I was within reference ranges in the majority of GH-treated children. Monitoring bioactive IGF-I may help optimize GH dosing in specific patient subgroups.

Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40–0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26–3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22–3.30) and HR: 1.78 (1.24–2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08–1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis.

Oxidative stress contributes to the progression of chronic kidney disease (CKD) and CKD-related mortality. The nuclear factor erythroid 2-related factor 2 (Nrf2) is essential in the regulation of cellular redox status, and Nrf2-activating therapies are under evaluation in several chronic diseases, including CKD. It is therefore inevitable to understand how Nrf2 behaves in advancing CKD. We analyzed Nrf2 protein concentrations in patients with varying extents of CKD but without renal replacement therapy, and in healthy subjects. Compared to healthy controls, Nrf2 protein was upregulated in mild to moderate kidney function impairment (G1–3). Within the CKD population, we found a significant positive correlation between Nrf2 protein concentration and kidney function (estimated glomerular filtration rate). In severe kidney function impairment (G4,5), Nrf2 protein was reduced compared to mild to moderate kidney function impairment. We conclude that Nrf2 protein concentration in severe kidney function impairment is reduced relative to the mild to moderate kidney function impairment where increased Nrf2 protein concentrations prevail. With respect to the implementation of Nrf2 targeted therapies, it will be necessary to explore in which population of patients with CKD such therapies are able to effectively add to the endogenous Nrf2 activity.