Neutrophil gelatinase-associated lipocalin in kidney and liver transplantation

Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) complicating kidney transplant outcome. Liver transplant recipients are at an increased risk for kidney injury both before and after transplantation and renal dysfunction strongly associates with morbidity and mortality. Identifying kidney injury early is crucial in achieving favorable outcome after transplantation. However, there are currently no reliable methods for predicting kidney damage in transplant patients. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel marker for acute kidney injury. The aim of the study was thus to test whether kidney donor and recipient urine and serum NGAL could predict DGF and prolonged DGF lasting >14 days, and whether plasma NGAL obtained prior to liver transplantation could predict prolonged kidney injury. The studies included 99 deceased kidney donors and their 176 adult recipients and 203 consecutive liver transplant recipients. DGF was seen in 39% of the kidney grafts and the duration of DGF was prolonged in 26 cases. Long-term graft function was significantly decreased in prolonged DGF grafts. NGAL correlated with other markers that describe kidney function such as serum creatinine and GFR. Based on the results measuring serum or urine NGAL the following morning after transplantation predicts DGF and prolonged DGF. Donor urine NGAL correlated with prolonged DGF. In the liver transplant recipients, pretransplant NGAL could not predict posttransplant kidney injury. However, it predicted irreversibility of pretransplant kidney dysfunction, which is helpful in optimizing patient care and deciding whether combined liver-kidney transplantation is needed. In conclusion, measuring blood (serum or plasma) NGAL is useful in assessing kidney function after kidney and liver transplantation.Viivästynyt siirteen käynnistyminen on merkittävä munuaissiirron pitkäaikaisennustetta heikentävä tekijä koskettaen noin kolmannesta munuaissiirroista. Sen ilmaantumista ja kestoa ei voi ennustaa. Sen määrä lisääntyy kun siirrettäväksi hyväksytään yhä vanhempien henkilöiden munuaisia. Maksan vajaatoimintaan liittyy usein myös munuaisten vajaatoiminta. Ennen maksansiirtoa on vaikea ennustaa kenen munuaiset toipuvat ja kuka jää dialyysiriippuvaiseksi maksansiirron jälkeen. Mikäli tätä voitaisiin ennustaa tälle potilasryhmälle voitaisiin tehdä kombinoitu munuaisen ja maksansiirto. NGAL (Neutrophil Gelatinase-Associated Lipocalin) on seerumista ja virtsasta mitattavissa oleva proteiini, jonka on todettu ennustavan akuuttia munuaisten vajaatoimintaa paremmin kuin tällä hetkellä muuten käytössä olevien menetelmien, kuten kreatiniinin. Tässä tutkimuksessa selvitettiin NGAL proteiinin kykyä ennustaa viivästynyttä käyntiinlähtöä, luovuttajan munuaisten laatua, sekä munuaisten vajaatoiminnan kestoa maksansiirron yhteydessä. Varhainen diagnoosi mahdollistaisi yksilöllisen hoidonsuunnittelun ja terapeuttisten interventioiden kehittämisen, jolla viivästynyttä käyntiinlähtöä pystyttäisiin jopa estämään. Munuaissiirtotutkimus koostuu 99 perättäisestä elinluovuttajasta ja heidän munuaistensa vastaanottajista (n=176). Maksatutkimuksessa on mukana kaikki maksansiirtopotilaat vuosilta 2005-2010. NGAL proteiinin pitoisuus määritettiin munuaisten luovuttajien ja vastaanottajien seerumi- ja virtsanäytteistä eri aikapisteissä ja maksansiirtopotilaiden plasmasta ennen maksansiirtoa. Tutkimuksessa 39% munuaissiirteistä käynnistyi viiveellä. Siirteen pitkäaikaisennuste heikkeni merkittävästi kun viivästynyt käyntiinlähtö pitkittyi yli 14vrk kestäväksi. Tutkimuksen tulosten perusteella siirteen käynnistymistä voi ennustaa mittaamalla seerumin ja virtsan NGAL pitoisuutta munuaissiirron jälkeisenä aamuna. Luovuttajan virtsan NGAL korreloi muiden munuaisten toimintaa kuvaavien mittareiden kanssa, kuten seerumin kreatiniini ja GFR. Luovuttajan virtsan NGAL puolestaan ennusti pitkittyvää viivästynyttä käyntiinlähtöä. Sen sijaan seerumin NGAL ei kuvastanut luovuttajan munuaisten toimintaa. Maksansiirtopotilailla ennen siirtoa mitattu plasman NGAL ei ennustanut kenelle kehittyy heti siirron jälkeen munuaisten vajaatoiminta mutta oli riippumaton ennusarvo kenelle munuaisten vajaatoiminta jää pysyväksi siirron jälkeen ja näin voisi auttaa arviossa tarvitaanko kombinaatiosiirto. Veren (seerumin tai plasman) NGAL pitoisuusmääritystä voidaan käyttää arvioitaessa munuaisten toimintaa munuais- ja maksansiirron jälkeen

Serum neutrophil gelatinase-associated lipocalin and recovery of kidney graft function after transplantation

Peer reviewe

Inhibition of Vascular Endothelial Growth Factor Receptors 1 and 2 Attenuates Natural Killer Cell and Innate Immune Responses in an Experimental Model for Obliterative Bronchiolitis

Funding Information: Supported by the Helsinki University Hospital , the Sigrid Juselius Foundation , the Academy of Finland , Finska Läkaresällskapet , the Research and Science Foundation of Farmos , The Paulo Foundation , Jalmari and Rauha Ahokas Foundation , Aarne Koskelo Foundation , Päivi and Sakari Sohlberg Foundation , Finnish Pulmonary Association , Biomedicum Helsinki Foundation , Jane and Aatos Erkko Foundation , and the University of Helsinki . Funding Information: Supported by the Helsinki University Hospital, the Sigrid Juselius Foundation, the Academy of Finland, Finska L?kares?llskapet, the Research and Science Foundation of Farmos, The Paulo Foundation, Jalmari and Rauha Ahokas Foundation, Aarne Koskelo Foundation, P?ivi and Sakari Sohlberg Foundation, Finnish Pulmonary Association, Biomedicum Helsinki Foundation, Jane and Aatos Erkko Foundation, and the University of Helsinki. Publisher Copyright: © 2022 American Society for Investigative PathologyObliterative bronchiolitis (OB) after lung transplantation is a nonreversible, life-threatening complication. Herein, the role of vascular endothelial growth factor receptor (Vegfr)-1 and -2 was investigated in the development of obliterative airway disease (OAD), an experimental model for OB. The nonimmunosuppressed recipients underwent transplantation with fully major histocompatibility complex mismatched heterotopic tracheal allografts and received Vegfr1 and -2-specific monoclonal antibodies either alone or in combination, or rat IgG as a control. The treatment with Vegfr1- or -2-blocking antibody significantly decreased intragraft mRNA expression of natural killer cell activation markers early after transplantation. This was followed by reduced infiltration of Cd11b thorn cells and Cd4 thorn T cells as well as down-regulated mRNA expression of proinflammatory chemokines and profibrotic growth factors. However, blocking of both Vegfr1 and -2 was necessary to reduce luminal occlusion. Furthermore, concomitant inhibition of the calcineurin activation pathway almost totally abolished the development of OAD. This study proposes that blocking of Vegf receptors blunted natural killer cell and innate immune responses early after transplantation and attenuated the development of OAD. The results of this study suggest that further studies on the role of Vegfr1 and -2 blocking in development of obliterative airway lesions might be rewarding. (Am J Pathol 2022, 192: 254-269; https://doi.org/10.1016/ j.ajpath.2021.10.018)Peer reviewe

Virtual communication is commonly used in Finnish interstitial lung disease multidisciplinary meetings

Multidisciplinary meeting (MDM) is a core element in the diagnosis of interstitial lung diseases (ILD). The aim of the study was to investigate the implementation and key elements related to ILD MDMs in Finnish specialized care, which is characterized by long travel distances and a large number of small centers treating patients suffering from ILDs. An electronic questionnaire was sent to ILD experts working at five academic centers of Finland regarding the implementation of ILD MDMs with the focus on utilization of virtual communication. Responses were received from all academic centers of Finland (n = 5) whose catchment areas cover all of Finland. ILD MDMs were organized in each center approximately every two weeks and the core participants included a radiologist, respiratory physicians, junior staff, pathologist and a rheumatologist. All non-academic centers could refer their patients to be evaluated in ILD MDM of an academic center. Virtual communication was utilized by all academic centers in the implementation of ILD MDMs, being most common among small centers located in Eastern and Northern Finland. Virtual access to ILD MDM of an academic center was available in most parts of Finland, enabling small centers to benefit from the ILD expertise of academic centers.Peer reviewe

Cell Death or Survival Promoted by Alternative Isoforms of ErbB4

The report demonstrates that two distinct isoforms of the ErbB4 receptor tyrosine kinase stimulate either proliferation or apoptosis by mechanisms involving differential transcriptional regulation of the PDGFRA gene. These data have implications for developing approaches to target ErbB4 signaling in cancer

Intricate macrophage-colorectal cancer cell communication in response to radiation

Both cancer and tumour-associated host cells are exposed to ionizing radiation when a tumour is subjected to radiotherapy. Macrophages frequently constitute the most abundant tumour-associated immune population, playing a role in tumour progression and response to therapy. The present work aimed to evaluate the importance of macrophage-cancer cell communication in the cellular response to radiation. To address this question, we established monocultures and indirect co-cultures of human monocyte-derived macrophages with RKO or SW1463 colorectal cancer cells, which exhibit higher and lower radiation sensitivity, respectively. Mono- and co-cultures were then irradiated with 5 cumulative doses, in a similar fractionated scheme to that used during cancer patients' treatment (2 Gy/fraction/day). Our results demonstrated that macrophages sensitize RKO to radiation-induced apoptosis, while protecting SW1463 cells. Additionally, the co-culture with macrophages increased the mRNA expression of metabolism- and survival-related genes more in SW1463 than in RKO. The presence of macrophages also upregulated glucose transporter 1 expression in irradiated SW1463, but not in RKO cells. In addition, the influence of cancer cells on the expression of pro- and anti-inflammatory macrophage markers, upon radiation exposure, was also evaluated. In the presence of RKO or SW1463, irradiated macrophages exhibit higher levels of pro-inflammatory TNF, IL6, CCL2 and CCR7, and of anti-inflammatory CCL18. However, RKO cells induce an increase of macrophage pro-inflammatory IL1B, while SW1463 cells promote higher pro-inflammatory CXCL8 and CD80, and also anti-inflammatory VCAN and IL10 levels. Thus, our data demonstrated that macrophages and cancer cells mutually influence their response to radiation. Notably, conditioned medium from irradiated co-cultures increased non-irradiated RKO cell migration and invasion and did not impact on angiogenesis in a chicken embryo chorioallantoic membrane assay. Overall, the establishment of primary human macrophage-cancer cell co-cultures revealed an intricate cell communication in response to ionizing radiation, which should be considered when developing therapies adjuvant to radiotherapy

Evaluation of CPAP mask performance during 3 years of mask usage : time for reconsideration of renewal policies?

Background Continuous positive airway pressure (CPAP) mask renewal policies vary inside and between countries. There are no independent studies on the optimal mask renewal frequency. We aimed to evaluate CPAP mask function over time in a real-life clinical setting, and to compare the results against current renewal policies. Methods Daily performance data of 1846 CPAP masks (65% nasal, 22% nasal pillows, 12% oronasal) were recorded from 450 participants (68% male, mean age 59 years) with obstructive sleep apnoea. The unintentional leak, Apnoea-Hypopnoea Index (CPAP-AHI) and usage data were exported from the CPAP device. Results Of 656 324 nights of CPAP usage, the mean renewal time was 497 days (SD 327), mean leak 5.7 L/min (SD 8.1) and CPAP-AHI 3.8 events/h (SD 3.6). The difference in mean leak between one (5.2 L/min, SD 7.5), 12 (6.0 L/min, SD 10.2) and 24 months (5.8 L/min, SD 7.5) was minimal (p=0.59). Mean CPAP-AHI remained normal and unchanged in nasal masks and pillows up to 30 months, and was highest in oronasal masks. Different mask manufacturers performed similarly. Masks' daily or total usage did not affect the results. Shifting the mask renewal policy to 24 months could reduce the mask-related cost up to 50%-88%. Conclusions Nasal masks and pillows could be used at least 2 years without significant changes in unintentional leak and CPAP-AHI. We suggest updating the mask renewal policies of nasal masks and pillows; results on oronasal masks and other manufacturers CPAP devices need further verification.Peer reviewe

Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation

Delayed graft function (DGF), especially long-lasting DGF, complicates kidney transplant outcome. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute kidney injury marker; therefore, we tested whether urine NGAL could predict DGF, prolonged DGF (lasting over 14 days), or the quality of kidney function in transplant recipients without DGF (non-DGF). We collected urine samples from 176 recipients transplanted with deceased donor kidneys before and various days after transplantation. A total of 70 transplantations had DGF, of which 26 were prolonged. Patients who developed DGF had a significantly slower decrease in urinary NGAL compared with those without DGF, such that day 1 NGAL predicted DGF (area under the curve (AUC) 0.75) and predicted DGF in 15 of 112 cases with day 1 urine output over 1l (AUC 0.70) and in 19 of 86 cases with a day 1 decrease in creatinine over 50μmol/l (AUC 0.74). The urinary NGAL level on day 1 predicted prolonged DGF (AUC 0.75), which had significantly worse 1-year graft survival (73%), compared with shorter DGF (100%). In non-DGF, high day 3 NGAL (greater than the mean) was associated with significantly worse kidney function at 3 weeks compared with low NGAL, but not at 3 months and 1 year. NGAL did not correlate with long-term function in DGF. Hence, day 1 urinary NGAL predicted DGF even when it was not clinically expected early on, and importantly, it predicted prolonged DGF that led to worse graft survival