Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Contains fulltext : 98302.pdf (publisher's version ) (Closed access)PURPOSE: Radiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of (111)In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated. METHODS: Groups of kidney-specific megalin-deficient mice and wild-type mice were injected with (111)In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured. RESULTS: Megalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% ((111)In-octreotide) to 65% ((111)In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation. CONCLUSION: Megalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice

High-flow nasal cannula oxygen therapy alone or with non-invasive ventilation during the weaning period after extubation in ICU: the prospective randomised controlled HIGH-WEAN protocol

INTRODUCTION: Recent practice guidelines suggest applying non-invasive ventilation (NIV) to prevent postextubation respiratory failure in patients at high risk of extubation failure in intensive care unit (ICU). However, such prophylactic NIV has been only a conditional recommendation given the low certainty of evidence. Likewise, high-flow nasal cannula (HFNC) oxygen therapy has been shown to reduce reintubation rates as compared with standard oxygen and to be as efficient as NIV in patients at high risk. Whereas HFNC may be considered as an optimal therapy during the postextubation period, HFNC associated with NIV could be an additional means of preventing postextubation respiratory failure. We are hypothesising that treatment associating NIV with HFNC between NIV sessions may be more effective than HFNC alone and may reduce the reintubation rate in patients at high risk. METHODS AND ANALYSIS: This study is an investigator-initiated, multicentre randomised controlled trial comparing HFNC alone or with NIV sessions during the postextubation period in patients at high risk of extubation failure in the ICU. Six hundred patients will be randomised with a 1:1 ratio in two groups according to the strategy of oxygenation after extubation. The primary outcome is the reintubation rate within the 7 days following planned extubation. Secondary outcomes include the number of patients who meet the criteria for moderate/severe respiratory failure, ICU length of stay and mortality up to day 90. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03121482

Pneumococcal purpura fulminans in asplenic or hyposplenic patients: a French multicenter exposed-unexposed retrospective cohort study

International audienceBACKGROUND: Pneumococcal infections remain the main cause of overwhelming post-splenectomy infections, and purpura fulminans may develop in almost 20% of patients with overwhelming post-splenectomy infection. We aimed at describing the impact of asplenia/hyposplenia on the clinical features and the outcomes of adult patients admitted to the intensive care unit (ICU) for pneumococcal purpura fulminans. METHODS: A 17-year national multicenter retrospective cohort study included adult patients admitted to 55 French ICUs for an infectious purpura fulminans from 2000 to 2016. Patients with pneumococcal purpura fulminans were analyzed according to the absence or presence of asplenia/hyposplenia. RESULTS: Among the 306 patients admitted to the ICU for purpura fulminans, 67 (22%) had a pneumococcal purpura fulminans, of whom 34 (51%) had asplenia (n = 29/34, 85%) or hyposplenia (n = 5/34, 15%) and 33 (49%) had eusplenia. The prevalence of pneumococcal purpura fulminans was seven times higher in asplenic/hyposplenic patients compared to eusplenic patients with purpura fulminans (n = 34/39, 87% vs. n = 33/267, 12%; p \textless 0.001). The median time interval between the occurrence of asplenia/hyposplenia and ICU admission was 20 [9-32] years. Pneumococcal vaccine coverage was 35% in asplenic/hyposplenic patients. Purpura was more frequently reported before ICU admission in asplenic/hyposplenic patients (n = 25/34, 73% vs. n = 13/33, 39%; p = 0.01). The rate of bacteremia did not differ between asplenic/hyposplenic and eusplenic patients (n = 31/34, 91% vs n = 27/33, 82%; p = 0.261). SAPS II (60 ± 14 vs. 60 ± 18; p = 0.244) and SOFA (13 [1-5] vs. 14 [1-4, 6]; p = 0.48) scores did not differ between asplenic/hyposplenic and eusplenic patients. There were no significant differences between asplenic/hyposplenic and eusplenic patients regarding the rate of limb amputation (n = 9/34, 26% vs. 15/33, 45%; p = 0.11) and hospital mortality (n = 20/34, 59% vs. n = 15/33, 45%; p = 0.27). CONCLUSIONS: Half of pneumococcal purpura fulminans episodes occurred in asplenic or hyposplenic patients. Pneumococcal vaccine coverage was reported in one third of asplenic/hyposplenic patients. Half of pneumococcal purpura fulminans episodes occurred more than 20 years after splenectomy. Outcomes of pneumococcal purpura fulminans did not show significant differences between patients with or without asplenia or hyposplenia, although the small number of patients included limited our power to detect potential differences between groups