Hepatitis C virus (HCV) infection can lead to hepatic fibrosis. The advent of direct-acting antivirals (DAAs) has substantially improved sustained virological response (SVR) rates. In this context, kidney transplant recipients (KTRs) are of particular interest due to their higher HCV infection rates and uncertain renal excretion and bioavailability of DAAs. We investigated liver stiffness after DAA treatment in 15 HCV-infected KTRs using ultrasound shear wave elastography (SWE) in comparison with magnetic resonance elastography (MRE). KTRs were treated with DAAs (daclatasvir and sofosbuvir) for three months and underwent SWE at baseline, end of therapy (EOT), and 3 (EOT+3) and 12 months (EOT+12) after EOT. Fourteen patients achieved SVR12. Shear wave speed (SWS)—as a surrogate parameter for tissue stiffness—was substantially lower at all three post-therapeutic timepoints compared with baseline (EOT: −0.42 m/s, p < 0.01; CI = −0.75–−0.09, EOT+3: −0.43 m/s, p < 0.01; CI = −0.75–−0.11, and EOT+12: −0.52 m/s, p < 0.001; CI = −0.84–−0.19), suggesting liver regeneration after viral eradication and end of inflammation. Baseline SWS correlated positively with histopathological fibrosis scores (r = 0.48; CI = −0.11–0.85). Longitudinal results correlated moderately with APRI (r = 0.41; CI = 0.12–0.64) but not with FIB-4 scores (r = 0.12; CI = −0.19–0.41). Although higher on average, SWE-derived measurements correlated strongly with MRE (r = 0.64). In conclusion, SWE is suitable for non-invasive therapy monitoring in KTRs with HCV infection.

ABSTRACT Background The most common definition of delayed graft function (DGF) relies on dialysis during the first week post-transplant and does not consider DGF severity. The impact of DGF severity on long-term graft outcome remains controversial. Methods We analysed 627 deceased-donor kidney transplant recipients (KTRs) transplanted in 2005–2015 at our centre for DGF severity, associated risk factors and long-term consequences of DGF. Results We found 349 (55.7%) KTRs with DGF, which were classified into four groups according to DGF duration (0–1, 2–7, 8–14, >14 days) and were compared with KTR with no DGF. A longer duration of DGF was associated with progressive worsening of 10-year death-censored graft survival {no DGF: 88.3% [95% confidence interval (CI) 82.4–94.2]; 0–1 day: 81.3% [95% CI 68.2–94.4], 2–7 days: 61.5% [95% CI 43.1.1–79.9], 8–14 days: 66.6% [95% CI 47.4–85.8], >14 days: 51.2% [95% CI 33–69.4]; P < 0.001}. In kidneys with a Kidney Donor Profile Index (KDPI) ≥85%, all DGF severity groups demonstrated reduced graft survival. However, in the <85% KDPI kidneys, only >14 days DGF duration showed worse outcomes. Conclusions DGF had a duration-dependent effect on graft survival, which varied depending on the KDPI. Of note, 0- to 1-day DGF showed comparable results to no DGF in the whole cohort.

Besides the liver, hepatitis C virus (HCV) infection also affects kidney allografts. The aim of this study was to longitudinally evaluate viscoelasticity changes in the liver and in kidney allografts in kidney transplant recipients (KTRs) with HCV infection after treatment with direct-acting antiviral agents (DAAs). Fifteen KTRs with HCV infection were treated with DAAs (daclatasvir and sofosbuvir) for 3 months and monitored at baseline, end of treatment (EOT), and 3 (FU1) and 12 (FU2) months after EOT. Shear-wave speed (SWS) and loss angle of the complex shear modulus (φ), reflecting stiffness and fluidity, respectively, were reconstructed from multifrequency magnetic resonance elastography data with tomoelastography post-processing. After virus elimination by DAAs, hepatic stiffness and fluidity decreased, while kidney allograft stiffness and fluidity increased compared with baseline (hepatic stiffness change at FU1: −0.14 m/s, p < 0.01, and at FU2: −0.11 m/s, p < 0.05; fluidity at FU1: −0.05 rad, p = 0.04 and unchanged at FU2: p = 0.20; kidney allograft stiffness change at FU1: +0.27 m/s, p = 0.01, and at FU2: +0.30 m/s, p < 0.01; fluidity at FU1 and FU2: +0.06 rad, p = 0.02). These results suggest the restoration of mechanically sensitive structures and functions in both organs. Tomoelastography can be used to monitor the therapeutic results of HCV treatment non-invasively on the basis of hepatic and renal viscoelastic parameters.

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4-weekly doses; 12 weeks), followed by a 9-month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose-adjusted C0 levels (C0 /D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4-weekly intervals. IL-6 and C-reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL-6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21-7.84] versus 4.22 [1.99-8.18] μg/ml*h, P = 0.36) or calcineurin inhibitor C0 /D ratios (tacrolimus: 1.49 [1.17-3.20] versus 1.37 [0.98-2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57-0.85] versus 1.08 [0.52-1.38] ng/ml/mg, P = 0.47). We conclude that IL-6 blockade in ABMR - in absence of systemic inflammation - may have no meaningful effect on CYP metabolism.

BACKGROUND:Preliminary data suggest that COVID-19 has reduced access to solid organ transplantation. However, the global consequences of the COVID-19 pandemic on transplantation rates and the effect on waitlisted patients have not been reported. We aimed to assess the effect of the COVID-19 pandemic on transplantation and investigate if the pandemic was associated with heterogeneous adaptation in terms of organ transplantation, with ensuing consequences for waitlisted patients. METHODS:In this population-based, observational, before-and-after study, we collected and validated nationwide cohorts of consecutive kidney, liver, lung, and heart transplants from 22 countries. Data were collected from Jan 1 to Dec 31, 2020, along with data from the same period in 2019. The analysis was done from the onset of the 100th cumulative COVID-19 case through to Dec 31, 2020. We assessed the effect of the pandemic on the worldwide organ transplantation rate and the disparity in transplant numbers within each country. We estimated the number of waitlisted patient life-years lost due to the negative effects of the pandemic. The study is registered with ClinicalTrials.gov, NCT04416256. FINDINGS:Transplant activity in all countries studied showed an overall decrease during the pandemic. Kidney transplantation was the most affected, followed by lung, liver, and heart. We identified three organ transplant rate patterns, as follows: countries with a sharp decrease in transplantation rate with a low COVID-19-related death rate; countries with a moderate decrease in transplantation rate with a moderate COVID-19-related death rate; and countries with a slight decrease in transplantation rate despite a high COVID-19-related death rate. Temporal trends revealed a marked worldwide reduction in transplant activity during the first 3 months of the pandemic, with losses stabilising after June, 2020, but decreasing again from October to December, 2020. The overall reduction in transplants during the observation time period translated to 48 239 waitlisted patient life-years lost. INTERPRETATION:We quantified the impact of the COVID-19 pandemic on worldwide organ transplantation activity and revealed heterogeneous adaptation in terms of organ transplantation, both at national levels and within countries, with detrimental consequences for waitlisted patients. Understanding how different countries and health-care systems responded to COVID-19-related challenges could facilitate improved pandemic preparedness, notably, how to safely maintain transplant programmes, both with immediate and non-immediate life-saving potential, to prevent loss of patient life-years. FUNDING:French national research agency (INSERM) ATIP Avenir and Fondation Bettencourt Schueller.

Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity.

Based on data of the SPRINT trial, American hypertension guidelines recently reduced the blood pressure goal from 140/90 mmHg to 130/80 mmHg for subjects with chronic kidney disease (CKD), whereas European guidelines recommend a systolic blood pressure (SBP) of 130–139 mmHg. The present analysis investigates whether a SBP < 130 mmHg is associated with an additional benefit in renal transplant recipients. We performed a retrospective analysis of 815 renal transplant recipients who were stratified according to mean office SBP values < 130 mmHg, 130–139 mmHg or ≥140 mmHg. Patient and graft survival was defined as composite endpoint, follow-up was limited to 120 months. Mean SBP of the follow-up was significantly associated with the composite endpoint (n = 218) with better survival for a SBP < 130 mmHg and 130–139 mmHg compared to ≥140 mmHg (p < 0.001). The differences in the combined endpoint remained significant in Cox regression analysis adjusted for age, gender and eGFR (p = 0.007, HR = 0.58, 95%CI = 0.41–0.53), but not for graft survival alone. Renal transplant recipients with SBP < 130 mmHg had a lower mortality than those with the conservative blood pressure goal <140 mmHg. These data suggest that the new AHA BP targets are safe for renal transplant recipients and – with all limitations of a retrospective analysis - might even be associated with improved outcome.

Zusammenfassung Die Stadt Oaxaca de Juárez in Mexiko verfügt über eine reiche Kultur- und Bibliothekslandschaft, die in hohem Maße von privaten Initiativen geprägt ist. In diesem Artikel werden die Forschungs- und Spezialbibliotheken sowie Öffentliche Bibliotheken der Stadt mit ihrer Geschichte und ihren Beständen vorgestellt sowie deren Bedeutung für die Einwohnerinnen und Einwohner Oaxacas aufgezeigt.

Antibody-mediated rejection (ABMR) is an important barrier to long-term success after renal transplantation.[1][1] Early (<1 year) ABMR is rare in patients without preformed donor-specific antibodies (DSAs), but it occurs in up to 40% of patients after desensitization. Most importantly, maintenance

BACKGROUND:The use of belatacept is not yet approved for maintenance in kidney transplant patients. This retrospective multicenter European study aimed to assess the efficacy and safety of conversion to belatacept in a large cohort of patients in a real-life setting and to identify the predictive factors for improved kidney function after the switch. METHODS:Two hundred nineteen maintenance kidney transplant patients from 5 European kidney transplant centers were converted to belatacept at 21.2 months (0.1-337.1 months) posttransplantation, mainly because of impaired kidney function. Thirty-two patients were converted to belatacept within the first 3 months posttransplantation. The mean duration of follow-up was 21.9 ± 20.2 months. RESULTS:The actuarial rate of patients still on belatacept-based therapy was 77.6%. Mean estimated glomerular filtration rate increased from 32 ± 16.4 at baseline to 38 ± 20 mL/min per 1.73 m (P < 0.0001) at last follow-up. Conversion to belatacept before 3 months posttransplantation was the main predictive factor for a significant increase in estimated glomerular filtration rate (of 5 and 10 mL/min per 1.73 m at 3 and 12 months after the switch, respectively). Eighteen patients (8.2%) presented with an acute rejection episode after conversion; 3 developed a donor-specific antibody. Overall efficacy and safety were good, including for the 35 patients that had a donor-specific antibody at conversion. CONCLUSIONS:The conversion to belatacept was effective, especially when performed early after transplantation.

Background Monitoring of renal allograft function is essential for early identification of dysfunction and improvement of kidney transplant (KTX) outcome. Purpose To non-invasively assess renal stiffness in KTX recipients using ultrasound shear wave elastography (USE) in correlation with multifrequency magnetic resonance elastography (MRE), renal allograft function, and renal microvascular flow determined using a novel ultrasound microvascular imaging technique. Material and Methods This prospective study investigated 25 KTXs (functional KTX [FCT], n = 14; chronic KTX insufficiency [DYS], n = 11) in 20 KTX recipients (mean age = 43 ± 14 years). USE was performed using a high-frequency broadband linear transducer and compared with MRE. Shear wave velocity (SWV) was correlated with the estimated glomerular filtration rate (eGFR). Qualitative differences in renal microvascular flow were obtained using SMI. Results FCT had higher SWV than DYS in both cortex and pyramids (cortex, FCT: 3.75 ± 0.82 m/s vs. DYS: 2.79 ± 0.73 m/s, P = 0.0002; pyramid, FCT: 2.89 ± 0.46 m/s vs. DYS: 2.39 ± 0.34 m/s, P = 0.044). Cutoff values of 3.265 m/s for cortex, 2.535 m/s for pyramids, and 2.985 m/s for combined non-hilar parenchyma provided sensitivities of 72.7%, 77.8%, and 90.9% and specificities of 71.4%, 78.6%, and 85.7% for detecting renal allograft dysfunction with area under the receiver operating characteristic curve (AUC) values of 0.831, 0.841, 0.925 (95% confidence interval [CI] = 0.67–0.99, 0.66–1.02, 0.83–1.03). USE correlated positively with eGFR ( r = 0.741, P = 0.0004) and with MRE-derived SWV ( r = 0.562, P = 0.004). Renal microvascular flow was decreased in DYS. Conclusion USE is sensitive to renal allograft dysfunction, which is characterized by reduced SWV and renal perfusion. USE has higher image resolution than MRE, while MRE has slightly better diagnostic accuracy.

Transplant patients are at increased risk for developing severe norovirus (NoV) infections with secondary complications such as rejection episodes and acute transplant failure. This single-center retrospective study included all kidney transplant patients tested positive for NoV RNA between January 2007 and December 2011. Data were compared to a control group of 528 kidney transplant patients without NoV infection. Sixty-five kidney transplant patients were recorded NoV RNA positive. Of these, 26 patients (40%) presented with acute transplant failure (AKI). In 43 patients (66.2%), dose reduction in immunosuppression was performed, and of 22 patients receiving tacrolimus, four patients (18.2%) showed toxic trough levels above 15 ng/mL at time of diagnosis. In three patients (4.6%), indicated therapeutic procedures had to be postponed due to prolonged severe diarrhea. Ten patients (15.4%) developed chronic NoV infection. One-year patient and graft survival in NoV patients and controls was 92.3% and 96.4%, respectively (n.s.). Compared to controls, eGFR was already significantly lower before NoV infection and loss of eGFR relative to baseline over 12 and 36 months was significantly higher in NoV-infected patients. In particular, patients initially presenting with AKI experienced a long-term loss of transplant function. Risk factors for NoV infection were immunosuppression containing steroids and antirejection therapy.

AIMS To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

During the period of perestroika, and since then, renewed attention has been paid to earlier Russian-American comparative research on the cultures of the peoples spanning both sides of the Bering Sea region. With the exhibitions Crossroads of Continents (Fitzhugh and Crowell, eds., 1988) and Drawing Shadows to Stones (Kendall, Mathé and Miller 1997), the significant results of the Jesup North Pacific Expedition (1897–1902) were made known to a broader international public. At the same time, a comprehensive research program called “Jesup 2” explored the legacy of that expedition (Krupnik and Fitzhugh, eds., 2001). Further aspects of this grand venture were discussed at a symposium in Bonn (Germany) more recently in 2011 (Dahlmann, Ordubadi, Winterschladen, eds., 2016). These academic projects aroused great interest, especially in the hitherto far less known northeast Asian part of the expedition, which was directed by Waldemar Jochelson.2 His work resulted, not least, in the publication of the present two volume edition dealing with the Koryak. This monograph of Jochelson, together with the works of his colleague Waldemar Bogoras on the Chukchi, marks the beginning of a new era. They were the first thorough and insightful descriptions of that region to focus on anthropological themes. Most notably, they adopted or tested novel methodological approaches to this new and emerging scientific discipline. This contrasts with reports from a number of 18th and 19th century ventures that explored the North Pacific rim. Driven by the mercantile interests of the Russian Empire, they resulted in comprehensive and detailed descriptions of the natural environments and cultures of the region. The researchers who were invited to accompany the expeditions and record their observations mainly had professional backgrounds in the natural sciences. At that time, ethnology or cultural anthropology had not yet been established as a discipline in its own right. Hence, these earlier scientists were inclined to view indigenous peoples and their cultures from a relatively broad perspective (Kasten, ed., 2013). Most of those who visited Kamchatka before Jochelson were of German or German-Baltic origin. While working in the service of Russian authorities, they established transnational research networks that stretched from Western Europe to the Russian Far East. When Jochelson arrived, along with the associated scientists of the Jesup North Pacific Expedi-