De-novo malignancies after kidney transplantation: A long-term observational study

Background: De-novo malignancies after kidney transplantation represent one major cause for mortality after transplantation. However, most of the studies are limited due to small sample size, short follow-up or lack of information about cancer specific mortality. Methods: This long-term retrospective analysis included all adult patients with complete follow-up that underwent kidney transplantation between 1995 and 2016 at our centre. All patients with diagnosis of malignancy excluding non-melanoma skin cancer (NMSC) were identified and a matched control group was assigned to the kidney transplant recipients with post-transplant malignancies. Results: 1417 patients matched the inclusion criteria. 179 malignancies posttransplant were diagnosed in 154 patients (n = 21 with two, n = 2 patients with three different malignancies). Mean age at cancer diagnosis was 60.3±13.3 years. Overall incidence of de-novo malignancies except NMSC was 1% per year posttransplant. Renal cell carcinoma was the most common entity (n = 49, incidence 4.20 per 1000 patient years; cancer specific mortality 12%), followed by cancer of the gastro-intestinal tract (n = 30, 2.57; 50%), urinary system (n = 24, 2.06; 13%), respiratory system (n = 18, 1.54; 89%), female reproductive system (n = 15, 1.29; 13%), posttransplant lymphoproliferative disorders and haematological tumours (n = 14, 1.20; 21%), cancers of unknown primary (n = 7, 0.60 100%) and others (n = 22, 1.89; 27%). Male sex, re-transplantation and time on dialysis were associated with de-novo malignancies after transplantation. Conclusion: De-novo malignancies continue to be a serious problem after kidney transplantation. To improve long-term outcome after Kidney transplantation, prevention and cancer screening should be more tailored and intensified

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

The interferon pathway, a key antiviral defense mechanism, is being considered as a therapeutic target in COVID-19. Both, substitution of interferon and JAK/STAT inhibition to limit cytokine storms have been proposed. However, little is known about possible abnormalities in STAT signaling in immune cells during SARS-CoV-2 infection. We investigated downstream targets of interferon signaling, including STAT1, STAT2, pSTAT1 and 2, and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID-19, 17 with mild, and 13 with severe infection. We report upregulation of STAT1 and IRF9 in mild and severe COVID-19 cases, which correlated with the IFN-signature assessed by Siglec-1 (CD169) expression on peripheral monocytes. Interestingly, Siglec-1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe cases compared to mild cases. Contrary to the baseline STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID-19 cases, indicating a dysbalanced JAK/STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN-alpha and IFN-gamma stimulation of PBMCs from patients with severe COVID-19. Data suggest impaired STAT1 transcriptional upregulation among severely infected patients may represent a potential predictive biomarker and would allow stratification of patients for certain interferon-pathway targeted treatments

Point-of-care lung ultrasound in COVID-19 patients: inter- and intra-observer agreement in a prospective observational study

With an urgent need for bedside imaging of coronavirus disease 2019 (COVID-19), this study's main goal was to assess inter- and intraobserver agreement in lung ultrasound (LUS) of COVID-19 patients. In this single-center study we prospectively acquired and evaluated 100 recorded ten-second cine-loops in confirmed COVID-19 intensive care unit (ICU) patients. All loops were rated by ten observers with different subspeciality backgrounds for four times by each observer (400 loops overall) in a random sequence using a web-based rating tool. We analyzed inter- and intraobserver variability for specific pathologies and a semiquantitative LUS score. Interobserver agreement for both, identification of specific pathologies and assignment of LUS scores was fair to moderate (e.g., LUS score 1 Fleiss' kappa =0.27; subpleural consolidations Fleiss' kappa =0.59). Intraobserver agreement was mostly moderate to substantial with generally higher agreement for more distinct findings (e.g., lowest LUS score 0 vs. highest LUS score 3 (median Fleiss' kappa =0.71 vs. 0.79) or air bronchograms (median Fleiss' kappa =0.72)). Intraobserver consistency was relatively low for intermediate LUS scores (e.g. LUS Score 1 median Fleiss' kappa =0.52). We therefore conclude that more distinct LUS findings (e.g., air bronchograms, subpleural consolidations) may be more suitable for disease monitoring, especially with more than one investigator and that training material used for LUS in point-of-care ultrasound (POCUS) should pay refined attention to areas such as B-line quantification and differentiation of intermediate LUS scores

Inzidenz und Outcome der Zitratakkumulation bei kritisch kranken Patienten mit kontinuierlicher Nierenersatztherapie und regionaler Zitratantikoagulation

Continuous renal replacement therapy (CRRT) is increasingly applied in critically ill patients with acute kidney injury who requires renal support. CRRT is often preferred to intermittent dialysis because of better hemodynamic stability and metabolic control. Regional citrate anticoagulation (RCA) during CRRT (RCA-CRRT) is a common alternative to systemic heparin anticoagulation, especially by patients with increased bleeding risk. Indeed, in recently published guidelines RCA is now recommended as the anticoagulation strategy of choice in patients undergoing CRRT without contraindication to citrate. According to KDIGO guidelines, the major contraindications for RCA are: severely impaired liver function or shock with muscle hypoperfusion, both representing a risk of citrate accumulation. Citrate accumulation is a serious complication of CRRT with RCA. It could cause severe metabolic acidosis, decrease cardiac contractility or cause arrhythmias, as symptoms of systemic ionized hypocalcemia. Acute or chronic impaired liver function, shock with arterial hypoxia and reduced tissue perfusion are the major risk factors for citrate accumulation. Unfortunately measurement of citrate concentration in blood is not available on a daily routine basis, and, at least in Germany, available test kits are not approved for clinical use. There are however commonly accepted markers for citrate accumulation, such as: metabolic acidosis with or without increased anion gap, ionized hypocalcemia with simultaneous increased levels of total calcium and, an increased total calcium to ionized calcium ratio (tCa/iCa). Those laboratory parameters do not confirm citrate accumulation in all cases, and often lead to false positive results, what makes the diagnosis of citrate accumulation a complex clinical issue. More over, information about the incidence of citrate accumulation in general cohort of ICU patients undergoing RCA-CRRT is relatively limited, due to the fact that patients with risk factors for citrate accumulation were usually whether excluded from the prospective trials, or the observation of those patients were limited to the study period. In this monocentric retrospective study we collected and analyzed all patients on RCA-CRRT over a three-year period (from 2008 to 2010) to identify risk factors for citrate accumulation. The primary objective was to reveal the incidence rate of citrate accumulation in cohort of non-selected critically ill patients receiving RCA-CRRT. The secondary objective was to assess the clinical characteristics and outcome related to citrate accumulation based on a representative population of patients. The results of the present research show that the incidence of metabolic disarrangements consistent with citrate accumulation was rather low since it affected only 2.99% of all RCA-CRRT patients. Our findings show that RCA during CRRT is feasible and complications are uncommon independently of a liver function, shock or presented muscle hypoperfusion. Diagnosis of citrate accumulation was found exclusively in severely ill patients with multiorgan failure and severe lactic acidosis, thus representing a group of patients with a very poor prognosis per se. All patients with suspected citrate accumulation died during their ICU stay. Our findings suggest that citrate accumulation occurs secondary to severe disability of cellular respiration and that citrate accumulation could be interpreted as a strong indicator for patient's poor outcome. We suggest that close attention should be paid to patients treated with RCA-CRRT who have a severe lactic acidosis and an elevated demand for calcium substitution.Die kontinuierliche Nierenersatztherapie wird beim Großteil der kritisch kranken Patienten mit dialysepflichtigen akutem Nierenversagen auf Intensivstationen verwendet. Die kontinuierliche Nierenersatztherapie wird insbesondere bei hämodynamisch instabilen patienten gegenüber der intermittierenden Dialyse wegen der schonenderen Ultrafiltration und der besseren Stoffwechselkontrolle bevorzugt. Die regionale Zitratantikoagulation während der kontinuierlichen Nierenersatztherapie ist eine zunehmend häufiger eingesetzte Alternative zur systemischen Antikoagulation, insbesondere bei Patienten mit erhöhtem Blutungsrisiko. In den kürzlich veröffentlichten Leitlinien zur Antikoagulation bei kontinuierlicher Nierensesartztherapie (KDIGO 2012) wird die regionale Zitratantikoagulation empfohlen als die Antikoagulation der Wahl bei Patienten ohne Kontraindikation für Zitratantikoagulation und ohne systemische Antikoagulation aus anderen patientenbezogenen Gründen. Die wichtigsten Kontraindikationen für RCA laut den KDIGO Leitlinien sind folgende: stark eingeschränkte Leberfunktion oder Schock mit Muskelminderdurchblutung. Beide Risikofaktoren entsprechen den Risikofaktoren der Zitratakkumulation. Die systemische Zitratakkumulation stellt eine Komplikation kontinuierlichen Nierenersatzverfahrens mit regionaler Zitratantikoagulation dar. Die möglichen klinischen Folgen der Zitratakkumulation sind schwere metabolische Azidose, verminderte Herzkontraktilität und Herzrhythmusstörungen. Leider ist die Messung der Zitratkonzentration im Blut im klinischen Alltag nicht verfügbar. Allgemein anerkannte Marker der Zitratakkumulation sind rasch fallende Konzentration des ionisierten Kalziums bei gleichzeitig steigendem Kalziumsubstitutionsbedarf, erhöhter Quotient aus Gesamtkalzium zu ionisierten Kalzium, sowie metabolische Azidose mit oder ohne erweiterter Anionenlücke. Diese Laborparameter bestätigen die Zitratakkumulation nicht in allen Fällen und führen häufig zu falschen positiven Ergebnissen. Somit ist die Diagnose der Zitratakkumulation ein komplexes klinisches Problem. Weiterhin ist die Information über die Inzidenz der Zitratakkumulation in allgemeiner Kohorte von dialysepflichtigen kritisch kranken Patienten auf der Intensivstation gering, weil die Patienten mit Risikofaktoren für Zitratakkumulation in der Regel aus den bisherigen prospektiven Studien ausgeschlossen wurden oder der Beobachtungszeitraum vergleichsweise kurz war. In dieser monozentrischen retrospektiven Studie wurden alle Patienten die mit kontinuierlicher Nierenersatztherapie mit regionaler Zitratantikoagulation auf der Intensivstationen behandelt worden über einen Zeitraum von drei Jahren (von 2008 bis 2010) identifiziert und analysiert. Das primäre Ziel war es, die Häufigkeit der Zitratakkumulation in einer Kohorte von nicht selektierten kritisch kranken Patienten, die mit RCA- CRRT behandelt wurden, zu ermitteln. Das weitere Ziel war es, die klinischen Merkmale sowie das Outcome der Zitratakkumulation aufgrund einer repräsentativen Patientenpopulation zu bewerten. Die Ergebnisse der vorliegenden Arbeit zeigen, dass die Inzidenz der Zitratakkumulation mit 2.99 % gering war. Die Ergebnisse zeigen weiterhin, dass die Zitratantikoagulation während der kontinuierlichen Nierenersatztherapie, unabhängig von einer Leberfunktion, Schock oder Muskelminderdurchblutung, möglich sowie komplikationsarm ist. Die Zitratakkumulation ist auschließlich bei Patienten mit schwerster Laktatazidose bei Multiorganversagens und starkeingeschränkter Prognose aufgetreten. Die Ergebnisse deuten auf das Auftreten der Zitratakkumulation als Folge des schwerwiegenden Versagens der Zellatmung hin. Die Zitratakkumulation könnte damit als ein starker Prädiktor für eine schlechte Prognose des Patienten interpretiert werden. Die Patienten, die mit RCA-CRRT behandelt werden und gleichzeitig eine schwere Laktatazidose mit erhöhtem Kalziumsubstitutionsbedarf haben, sind besonderes zu beachten

Measuring parathyroid hormone (PTH) in patients with oxidative stress--do we need a fourth generation parathyroid hormone assay?

Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7% of traditionally measured PTH was free of oxidation, whereas in other patients 34% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis

Analysis of Risk Factors and Long-Term Outcomes in Kidney Transplant Patients with Identified Lymphoceles

The collection of lymphatic fluids (lymphoceles) is a frequent adverse event following renal transplantation. A variety of surgical and medical factors has been linked to this entity, but reliable data on risk factors and long-term outcomes are lacking. This retrospective single-center study included 867 adult transplant recipients who received a kidney transplantation from 2006 to 2015. We evaluated for patient and graft survival, rejection episodes, or detectable donor-specific antibodies (dnDSA) in patients with identified lymphoceles in comparison to controls. We identified 305/867 (35.2%) patients with lymphocele formation, of whom 72/867 (8.3%) needed intervention. Multivariate analysis identified rejection episode as an independent risk factor (OR 1.61, CI 95% 1.17-2.21, p = 0.003) for lymphocele formation, while delayed graft function was independently associated with symptomatic lymphoceles (OR 1.9, CI 95% 1.16-3.12, p = 0.011). Interestingly, there was no difference in detectable dnDSA between groups with a similar graft and patient survival in all groups after 10 years. Lymphoceles frequently occur after transplantation and were found to be independently associated with rejection episodes, while symptomatic lymphoceles were associated with delayed graft function in our cohort. As both are inflammatory processes, they might play a causative role in the formation of lymphoceles. However, development or intervention of lymphoceles did not lead to impaired graft survival in the long-term

Clinical Characteristic of the patients on dialysis.

<p>Clinical Characteristic of the patients on dialysis.</p

We measured intact PTH using the intact PTH assay as described in the method section in 18 patients on dialysis (blue bars), for further detail see also <b>table 2</b>.

<p>When removing the oxidized forms of PTH from the sample as illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040242#pone-0040242-g006" target="_blank">figure 6</a>, the results were completely different (red bars). The effect of oxidation of PTH is highly variable among these patients requiring dialysis. There is only a very weak correlation between traditionally measured PTH and PTH data considering the oxidation of this hormone.</p