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Vitamin K deficiency is common among kidney transplant recipients (KTRs) and likely contributes to progressive vascular calcification and stiffness. In this single-center, randomized, double-blind, placebo-controlled trial, we aimed to investigate the effects of vitamin K supplementation on the primary end point, serum calcification propensity (calciprotein particle maturation time, T50), and secondary end points arterial stiffness (pulse wave velocity [PWV]) and vitamin K status in 40 vitamin K-deficient KTRs (plasma dephosphorylated uncarboxylated matrix Gla protein [dp-ucMGP] ≥500 pmol/L). Participants (35% female; age, 57 ± 13 years) were randomized 1:1 to vitamin K2 (menaquinone-7, 360 μg/day) or placebo for 12 weeks. Vitamin K supplementation had no effect on calcification propensity (change in T50 vs baseline +2.3 ± 27.4 minutes) compared with placebo (+0.8 ± 34.4 minutes; Pbetween group = .88) but prevented progression of PWV (change vs baseline -0.06 ± 0.26 m/s) compared with placebo (+0.27 ± 0.43 m/s; Pbetween group = .010). Vitamin K supplementation strongly improved vitamin K status (change in dp-ucMGP vs baseline -385 [-631 to -269] pmol/L) compared with placebo (+39 [-188 to +183] pmol/L; Pbetween group < .001), although most patients remained vitamin K-deficient. In conclusion, vitamin K supplementation did not alter serum calcification propensity but prevented progression of arterial stiffness, suggesting that vitamin K has vascular effects independent of calciprotein particles. These results set the stage for longer-term intervention studies with vitamin K supplementation in KTRs.TRIAL REGISTRY: EU Clinical Trials Register (EudraCT Number: 2019-004906-88) and the Dutch Trial Register (NTR number: NL7687).

Contains fulltext : 290620.pdf (Publisher’s version ) (Open Access) BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. AIM: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. METHODS: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 μg/g), safety, and discontinuation rate. RESULTS: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. CONCLUSION: Tofacitinib was effective in 31.8% of patients after 24 months of treatment. 01 januari 2023

BACKGROUND: Survival of kidney transplant recipients (KTR) is low compared with the general population. Low muscle mass and muscle strength may contribute to lower survival, but practical measures of muscle status suitable for routine care have not been evaluated for their association with long-term survival and their relation with each other in a large cohort of KTR.METHODS: Data of outpatient KTR ≥ 1 year post-transplantation, included in the TransplantLines Biobank and Cohort Study (ClinicalTrials.gov Identifier: NCT03272841), were used. Muscle mass was determined as appendicular skeletal muscle mass indexed for height 2 (ASMI) through bio-electrical impedance analysis (BIA), and by 24-h urinary creatinine excretion rate indexed for height 2 (CERI). Muscle strength was determined by hand grip strength indexed for height 2 (HGSI). Secondary analyses were performed using parameters not indexed for height 2. Cox proportional hazards models were used to investigate the associations between muscle mass and muscle strength and all-cause mortality, both in univariable and multivariable models with adjustment for potential confounders, including age, sex, body mass index (BMI), estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: We included 741 KTR (62% male, age 55 ± 13 years, BMI 27.3 ± 4.6 kg/m 2), of which 62 (8%) died during a median [interquartile range] follow-up of 3.0 [2.3-5.7] years. Compared with patients who survived, patients who died had similar ASMI (7.0 ± 1.0 vs. 7.0 ± 1.0 kg/m 2; P = 0.57), lower CERI (4.2 ± 1.1 vs. 3.5 ± 0.9 mmol/24 h/m 2; P < 0.001) and lower HGSI (12.6 ± 3.3 vs. 10.4 ± 2.8 kg/m 2; P < 0.001). We observed no association between ASMI and all-cause mortality (HR 0.93 per SD increase; 95% confidence interval [CI] [0.72, 1.19]; P = 0.54), whereas CERI and HGSI were significantly associated with mortality, independent of potential confounders (HR 0.57 per SD increase; 95% CI [0.44, 0.81]; P = 0.002 and HR 0.47 per SD increase; 95% CI [0.33, 0.68]; P < 0.001, respectively), and associations of CERI and HGSI with mortality remained independent of each other (HR 0.68 per SD increase; 95% CI [0.47, 0.98]; P = 0.04 and HR 0.53 per SD increase; 95% CI [0.36, 0.76]; P = 0.001, respectively). Similar associations were found for unindexed parameters. CONCLUSIONS: Higher muscle mass assessed by creatinine excretion rate and higher muscle strength assessed by hand grip strength are complementary in their association with lower risk of all-cause mortality in KTR. Muscle mass assessed by BIA is not associated with mortality. Routine assessment using both 24-h urine samples and hand grip strength is recommended, to potentially target interdisciplinary interventions for KTR at risk for poor survival to improve muscle status.

Background: Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD).Aims: To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD.Methods: Serological biomarkers of type III/IV collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP) or granzyme-B (GrzB)-mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope protein fingerprint assays in 101 patients with CD (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 controls. Patients were followed up until their last outpatient visit to monitor stricturing/penetrating disease progression and recurrence and the occurrence of surgical interventions.Results: C1M, C3M and C4M were significantly reduced in patients with stricturing disease (Montreal B2) and accurately differentiated them from patients with either non-stricturing, non-penetrating (B1) or penetrating (B3) disease (all p Conclusions: Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing CD. Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating CD.

BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs.METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength.RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. β = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. β = 0.22, P < 0.001), handgrip strength (std. β = 0.15, P < 0.001), and worse FTSTS test scores (std. β = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001).CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC-4 trial. Real-world data on the effectiveness of gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015-2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8-40.7) for GEMCAP and 22.1 months (95% CI 20.6-25.0) for GEM (HR: 0.71, 95% CI 0.56-0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57-0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.

Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFRCr), muscle mass-independent cystatin C (eGFRCys), and the combination of creatinine and cystatin C (eGFRCr-Cys) and predicted probabilities of discordant classification given age, sex, and CER index. Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFRCr 2 when eGFRCys was 2. Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed. Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (Pdifference Cr and eGFRCys disagreed by 24.7 mL/min/1.73 m2 (and 30.1 mL/min/1.73 m2 when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8–22.1%) and 15.2% (11.4–18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFRCr and eGFRCys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m2 (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m2 when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively. Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFRCr. Muscle wasting may cause spurious overestimation of repeatedly measured eGFRCr. Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches.

Background: A plasma-based clot lysis time (CLT) assay is an established research test to assess plasma fibrinolytic potential, with application in hyperfibrinolytic or hypofibrinolytic conditions. Interprotocol variations make comparisons between laboratories challenging. The aim of this study was to compare the results of 2 different CLT assays performed by 2 distinct research laboratories by using their own protocol. Methods: We evaluated fibrinolysis in the plasma of 60 patients undergoing hepatobiliary surgery and in plasma from a healthy donor that was spiked with commonly used anticoagulant drugs (enoxaparin, dabigatran, and rivaroxaban) in 2 distinct laboratories (Aarhus and Groningen) by using 2 different assays that differ, among others, in tissue plasminogen activator (tPA) concentration. Results: Overall conclusions on fibrinolytic potential in patients undergoing hepatobiliary surgery were similar between the 2 CLT assays, with hyperfibrinolytic and hypofibrinolytic profiles identified at the same time points during and after surgery. Severe hypofibrinolysis was less commonly reported in the Aarhus assay (36/319 samples; 11%) than in the Groningen assay (55/319 samples; 17%). No clot formation was observed in 31 of 319 samples in the Aarhus assay vs 0 of 319 samples in the Groningen assay. Clotting times increased much more profoundly on the addition of all 3 anticoagulants in the Aarhus assay. Conclusions: Despite the differences in laboratory, protocol, reagents, operator, data processing, and analysis, overall conclusions on fibrinolytic capacity are similar between the 2 laboratories. With a higher concentration of tPA in the Aarhus assay, the test becomes less sensitive for the detection of hypofibrinolysis and is more sensitive to the addition of anticoagulants.

Background: Patients with cirrhosis are increasingly using direct oral anticoagulants (DOACs) in therapeutic doses for the treatment of portal vein thrombosis or for concomitant atrial fibrillation. DOACs may affect routine diagnostic tests of coagulation including the international normalized ratio (INR). The INR is a part of the model of end-stage liver disease (MELD) score, a validated score that predicts the mortality risk in patients with cirrhosis and is used to prioritize patients for liver transplantation. DOAC–induced increases in the INR may thus lead to artificial inflation of the MELD score. Objective: We studied the effect of DOACs on INR prolongation in patients with cirrhosis. Methods: We spiked plasma from 20 healthy individuals and 20 patients at the start of liver transplantation with DOACs in concentrations representing peak therapeutic levels. In addition, we studied INR increases in healthy controls and patients with mild cirrhosis who received the DOAC edoxaban for 1 week for study purposes. Results: In controls and patients, the INR increased by an ex vivo addition of a DOAC, and the INR increase in patients was proportional to the baseline INR values. The increase in INR translated to a median increase of between 3 and 10 MELD points, depending on the DOAC used. In controls and patients alike, the INR increased on the ingestion of edoxaban, which translated to an increase in 5 MELD points. Conclusions: Taken together, DOACs result in an INR increase that translates to clinically meaningful increases in MELD points in patients with cirrhosis, and precautions to avoid artificial inflation of the MELD score in these patients are warranted.

Background & AimsPatients with liver disease may acquire substantial changes in their hemostatic system, which are most pronounced in patients who are critically ill. Changes in the quality of the fibrin clot in critically ill patients have not been studied in detail. Here we assessed markers of fibrin clot quality and effects of coagulation factor concentrates in patients with acutely decompensated (AD) cirrhosis and acute on chronic liver failure (ACLF).MethodsWe measured plasma levels of fibrinogen, factor XIII, prothrombin and performed thrombin generation assays in 52 AD patients, 58 ACLF patients and 40 controls. In addition, we examined the effects of coagulation factor concentrates on functional assays of fibrin quality.ResultsWe found increased thrombin generating capacity in both AD and ACLF in comparison with healthy controls. Plasma levels of prothrombin, fibrinogen, and factor XIII were lower in patients compared to controls, appeared lower in ACLF compared to AD patients, and were related to clinical outcomes. Fibrinogen concentrate, but not factor XIII or prothrombin complex concentrate, improved clot quality in vitro. Prothrombin complex concentrate increased the resistance of the clot to break down.ConclusionsWe have demonstrated elevated thrombin generation but decreased plasma levels of prothrombin, fibrinogen and FXIII in acutely ill patients with cirrhosis. In addition, we showed that fibrinogen concentrate and PCCs, but not factor XIII concentrate, improve clot properties in patient plasma. Whether there is true clinical benefit from coagulation factor concentrates in prevention or treatment of bleeding requires further study.Lay summaryPatients with liver diseases are at risk of bleeding, but mechanisms involved in this bleeding risk are incompletely understood. We studied components that determine the stability of the blood clot and found that concentrations of certain proteins involved in clot stability are present in low levels in acutely ill patients with liver disease. We furthermore demonstrated that some clinically available drugs improve the stability of blood clots from these patients in a test tube.

Background Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all-cause mortality.Methods Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population-based PREVEND study. A fatty liver index (FLI) >= 60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all-cause mortality were investigated using Cox regression analyses.Results The study included 6,297 participants aged 54 +/- 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153-259] vs 170 [133-243] mu mol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8-8.9] years of follow-up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06-1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12-1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all-cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).Conclusion Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all-cause mortality.

Background Despite the fact that primary percutaneous catheter drainage has become standard practice, some patients with pancreatic fistula after pancreatoduodenectomy ultimately undergo a relaparotomy. The aim of this study was to compare completion pancreatectomy with a pancreas-preserving procedure in patients undergoing relaparotomy for pancreatic fistula after pancreatoduodenectomy. Methods This retrospective cohort study of nine institutions included patients who underwent relaparotomy for pancreatic fistula after pancreatoduodenectomy from 2005–2018. Furthermore, a systematic review and meta-analysis were performed according to the PRISMA guidelines. Results From 4877 patients undergoing pancreatoduodenectomy, 786 (16 per cent) developed a pancreatic fistula grade B/C and 162 (3 per cent) underwent a relaparotomy for pancreatic fistula. Of these patients, 36 (22 per cent) underwent a completion pancreatectomy and 126 (78 per cent) a pancreas-preserving procedure. Mortality was higher after completion pancreatectomy (20 (56 per cent) versus 40 patients (32 per cent); P = 0.009), which remained after adjusting for sex, age, BMI, ASA score, previous reintervention, and organ failure in the 24 h before relaparotomy (adjusted odds ratio 2.55, 95 per cent c.i. 1.07 to 6.08). The proportion of additional reinterventions was not different between groups (23 (64 per cent) versus 84 patients (67 per cent); P = 0.756). The meta-analysis including 33 studies evaluating 745 patients, confirmed the association between completion pancreatectomy and mortality (Mantel–Haenszel random-effects model: odds ratio 1.99, 95 per cent c.i. 1.03 to 3.84). Conclusion Based on the current data, a pancreas-preserving procedure seems preferable to completion pancreatectomy in patients in whom a relaparotomy is deemed necessary for pancreatic fistula after pancreatoduodenectomy.

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course.METHODS: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death.RESULTS: A total of 66 patients from 26 centers fulfilling the inclusion criteria with a mean (±SD) age of 45.0±21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow-up of 9.6 years, tumor-related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (p=0.031). Four B-catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision.CONCLUSIONS: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well-differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

Thrombosis after liver transplantation substantially impairs graft‐ and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome‐wide association study (GWAS) and meta‐analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis‐susceptible polymorphisms. By performing a meta‐GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611‐T, p = 4.22 × 10−05) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696‐C, p = 2.62 × 10−05) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia‐related variants, are associated with increased risk of thrombosis after liver transplantation., A meta‐analysis of two genome‐wide association studies of adult and pediatric liver transplants identifies three common candidate risk loci in the donor, but not previously known thrombophilia‐related variants, were newly associated with increased risk of thrombosis after liver transplantation.

Muscle mass is essential for performing physical activity, and low muscle mass (sarcopenia) has been found to have a strong association with all-cause mortality in patients with type 2 diabetes (T2D).1 However, muscle mass is not routinely assessed in clinical practice and low muscle mass can easily go unnoticed in obese patients (sarcopenic obesity), which was emphasized in previous DIALECT findings.2 The current definition of sarcopenia requires presence of either low muscle mass, low muscle strength or poor physical performance rather than low muscle mass alone.3 Two methods for estimating muscle mass independent of kidney function in clinical practice are the 24 h urinary creatinine excretion rate (CER) and bioelectric impedance analysis (BIA), but their association with physical performance and function is unclear.4 In this study we investigate whether CER or BIA-derived predicted muscle mass also indicate physical performance and function in patients with T2D, in order to indirectly screen patients on sarcopenia.

Disturbances in calcium‐phosphate homeostasis are common after kidney transplantation. We aimed to assess the relationship between deregulations in plasma calcium and phosphate over time and mortality and death‐censored graft failure (DCGF). In this prospective cohort study, we included kidney transplant recipients with ≥2 plasma calcium and phosphate measurements. Data were analyzed using time‐updated Cox regression analyses adjusted for potential confounders including time‐updated kidney function. We included 2769 patients (mean age 47 ± 14 years, 42.3% female) with 138 496 plasma calcium and phosphate levels (median [IQR] 43 [31–61] measurements per patient). During follow‐up of 16.3 [8.7–25.2] years, 17.2% developed DCGF and 7.9% died. Posttransplant hypercalcemia was associated with an increased risk of mortality (1.63 [1.31–2.00], p, This prospective cohort study shows that, in patients with preserved kidney function, hypercalcemia is associated with increased mortality risk.

Patients with liver diseases acquire complex alterations in their hemostatic system that may lead to abnormalities in routine diagnostic test of hemostasis. Thrombocytopenia, prolongations in the prothrombin time and activated partial thromboplastin time, and decreased plasma fibrinogen are common in patients with advanced liver disease. Historically, liver diseases therefore have been classified as an acquired bleeding disorder. Laboratory and clinical observations have demonstrated that although routine diagnostic tests of hemostasis suggest a hypocoagulable state, patients with liver disease also tend to develop thrombotic events. Overall, patients have commensurate changes in both pro‐ and antihemostatic pathways. This new hemostatic balance, however, appears much more fragile than the hemostatic balance in individuals with normal liver function, and patients with liver disease can readily experience both hemostasis‐related bleeding and thrombotic events. These insights into the hemostatic balance in patients with liver disease have led to revised recommendations for clinical management of hemostasis. In 2020, an SSC working group within the ISTH has been founded with the aim to disseminate new concepts on prevention and treatment of bleeding and thrombosis in patients with liver disease. The current document will outline the hemostatic changes in patients with liver disease, the limitations of routine diagnostic tests of hemostasis, and the concept of rebalanced hemostasis.

Essentials Liver diseases are associated with profound hemostatic changes proportional to severity of illness.Hemostatic changes in acute‐on‐chronic liver failure (ACLF) may in part reflect critical illness.Hemostatic changes in ACLF partly overlap with those in sepsis, with rebalanced hemostasis in both.Patients with sepsis had hyperfibrinogenemia, associated with a thrombogenic clot structure. Abstract Background Even the sickest patients with chronic liver disease (CLD), such as those with acute‐on‐chronic liver failure (ACLF) remain in hemostatic balance due to a concomitant decline in pro‐ and antihemostatic factors. Objectives We aimed to study whether the hemostatic status in ACLF is merely an exaggeration from the status in patients with compensated and acutely decompensated cirrhosis, or whether sepsis‐associated hemostatic changes contribute. Methods We performed extensive hemostatic profiling in 31 adult patients with ACLF, 20 patients with sepsis without underlying CLD, and 40 healthy controls. Results We found similarly elevated plasma levels of the platelet adhesive protein von Willebrand factor (VWF) and decreased levels of the VWF‐regulating protease ADAMTS13 in both groups compared to healthy controls. In vivo markers of activation of coagulation (thrombin‐antithrombin III, D‐dimer) were similarly elevated in both groups compared to controls, but ex vivo thrombin‐generating capacity was similar between patients and controls, despite a much more profound international normalized ratio elevation in ACLF. Plasma fibrinogen levels were much higher in septics, which was accompanied by a decreased ex vivo clot permeability and an increase in ex vivo resistance to clot lysis. All hemostatic parameters were remarkably stable over the first 10 days after admission. Conclusions We have found hemostatic changes in ACLF to partially overlap with that of patients with sepsis, and evidence of preserved hemostatic capacity in both patient groups. The notable difference was a profound hyperfibrinogenemia, associated with a thrombogenic clot structure and a marked ex vivo resistance to fibrinolysis in patients with sepsis.

BACKGROUND: In vitro efficacy of pro- and antihemostatic drugs is profoundly different in patients with compensated cirrhosis and in those who have cirrhosis and are critically ill.OBJECTIVES: Here we assessed the efficacy of pro- and anticoagulant drugs in plasma of patients undergoing hepato-pancreato-biliary (HPB) surgery, which is associated with unique hemostatic changes.METHODS: We performed in vitro analyses on blood samples of 60 patients undergoing HPB surgery and liver transplantation: 20 orthotopic liver transplantations, 20 partial hepatectomies, and 20 pylorus-preserving pancreaticoduodenectomies. We performed thrombin generation experiments before and after in vitro addition of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), low molecular weight heparin (LMWH), unfractionated heparin, dabigatran, and rivaroxaban.RESULTS: We showed that patients undergoing HPB surgery are in a hypercoagulable state by thrombin generation testing. FFP and rFVIIa had minimal effects on thrombin generation, whereas PCC had a more pronounced procoagulant effect in patients compared with controls. Dabigatran showed a more pronounced anticoagulant effect in patients compared with controls, whereas rivaroxaban and LMWH had a decreased anticoagulant effect in patients.CONCLUSION: We demonstrate profoundly altered in vitro efficacy of commonly used anticoagulants, in patients undergoing HPB surgery compared with healthy controls, which may have implications for anticoagulant dosing in the early postoperative period. In the correction of perioperative bleeding complications, PCCs appear much more potent than FFP or rFVIIa, and PCCs may require conservative dosing and caution in use in patients undergoing HPB surgery.

Background: Thrombosis after liver transplantation is a leading cause of graft loss, morbidity, and mortality. Several known recipient- and surgery-related characteristics have been associated with increased risk of thrombosis after transplantation. Potential donor-related risk factors, however, remain largely undefined. Objectives: We aimed to identify risk factors for early post-transplantation thrombosis ('90 days) and to determine the impact of early postoperative thrombosis on long-term graft and patient survival. Patients/Methods: A post hoc analysis was performed of an observational cohort study including all primary, adult liver transplantations performed between 1993 and 2018. Donor-, recipient-, and surgery-related characteristics were collected. Competing risk model analyses and multivariable regression analyses were performed to identify risk factors for developing early post-transplant thrombosis and graft failure. Results: From a total of 748 adult liver transplantations, 58 recipients (7.8%) developed a thrombosis after a median of 7 days. Post-transplantation thrombotic events included 25 hepatic artery thromboses, 13 portal vein thromboses, and 22 other thrombotic complications. Donor history of smoking was independently associated with early postoperative thrombosis (odds ratio [OR] 2.42; 95% confidence interval [CI], 1.29-4.52). Development of early post-transplant thrombosis was independently associated with patient mortality (hazard ratio [HR] 3.61; 95% CI 1.54-8.46) and graft failure (HR 5.80, 95% CI 3.26-10.33), respectively. Conclusion: Donor history of smoking conveys a more than two-fold increased risk of thrombosis after liver transplantation, independent of other factors. Post-transplant thrombosis was independently associated with decreased patient and graft survival.

Acquired bleeding disorders can accompany hematological, neoplastic, autoimmune, cardiovascular or liver diseases, but can sometimes also arise spontaneously. They can manifest as single factor deficiencies or as complex hemostatic abnormalities. This review addresses (a) acquired hemophilia A, an autoimmune disorder characterized by inhibitory autoantibodies against coagulation factor VIII; (b) acquired von Willebrand syndrome in patients with cardiovascular disorders, where shear stress abnormalities result in destruction of von Willebrand factor; and (c) liver function disorders that comprise complex changes in pro- and anti-hemostatic factors, whose clinical implications are often difficult to predict. The article provides an overview on the pathophysiology, diagnostic tests and state-of-the-art treatment strategies.

Background and aimsNon-O blood type (BT) is a risk factor for thromboses, which has been attributed to its effects on von Willebrand factor (VWF)/factor VIII (FVIII) levels. Although high VWF/FVIII may be risk factors for portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD), the impact of BT on PVT is unknown. We aimed to assess (I) whether non-O-BT is a risk factor for PVT and (II) whether non-O-BT impacts VWF/factor VIII in patients with ACLD.MethodsRetrospective analysis comprising two cohorts: (I) "US" including all adult liver transplantations in the US in the MELD era and (II) "Vienna" comprising patients with a hepatic venous pressure gradient (HVPG) >= 6 mmHg.Results(I) The "US cohort" included 84 947 patients (non-O: 55.43%). The prevalence of PVT at the time of listing (4.37% vs 4.56%; P = .1762) and at liver transplantation (9.56% vs 9.33%; P = .2546) was similar in patients with O- and non-O-BT. (II) 411 patients were included in the "Vienna cohort" (non-O: 64%). Mean HVPG was 18(9) mmHg and 90% had an HVPG >= 10 mmHg. Patients with non-O-BT had slightly increased VWF levels (318(164)% vs 309(176)%; P = .048; increase of 23.8%-23.9% in adjusted analyses), but this difference was driven by patients with less advanced disease. However, non-O-BT explained only 1% of the variation in VWF and had no effect on FVIII.ConclusionsAlthough non-O-BT impacts VWF in patients with early stage ACLD, its contribution to VWF variation is considerably smaller than in the general population. Moreover, non-O-BT had no impact on FVIII. These findings may explain the absence of an association between non-O-BT and PVT in patients with advanced cirrhosis.

BACKGROUND: High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow.AIM: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response.METHODS: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD.RESULTS: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses.CONCLUSIONS: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.

Aim: To assess rheumatoid arthritis (RA)-associated autoantibodies in the gingivocrevicular fluid (GCF) of RA patients and healthy controls with or without periodontal disease, as chronic mucosal inflammation in periodontal disease is hypothesized to contribute to the formation of these autoantibodies. Materials and methods: Anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and their IgA isotypes were assessed in the serum and GCF of RA patients (n = 72) and healthy controls (HC, n = 151). The presence and levels of these antibodies were studied in relation to interleukin (IL)-8 and periodontal disease. Results: In contrast to the HC, the levels of ACPA and RF in the serum and GCF of the RA patients were strongly correlated (p

Background and Aims Patients with cirrhosis have a rebalanced hemostasis, often with normal or elevated thrombin-generating (TG) capacity in plasma. Whole blood (WB) TG allows faster determination and, importantly, includes the influence of all circulating blood cells. We aimed to study the TG profile of patients with cirrhosis in WB and in platelet poor plasma.Methods Thrombin-generating capacity in WB and plasma were assessed with a near-patient WB-TG assay and the calibrated automated thrombinography assay, respectively. TG assays were tested in presence and absence of thrombomodulin. Conventional coagulation tests were also performed.Results Thirty-four patients with cirrhosis and twenty-two controls were analyzed. Compared with controls, patients had substantially deranged results in conventional coagulation tests. Comparable WB-TG capacity (endogenous thrombin potential until peak, ETPp) but significantly lower peak thrombin were found in patients, and these results persisted when thrombomodulin was present. TG of the patients was more resistant to thrombomodulin than controls in both WB and plasma, although the inhibitory effect of thrombomodulin was drastically weaker in WB than in plasma. The peak of WB-TG in patients correlated moderately with their hematocrit and platelet count. Significant correlations were found between TG results in WB and plasma.Conclusions The WB-TG assay shows a normal to hypocoagulable state in patients with cirrhosis with a decreased anticoagulant activity of TM compared to plasma-TG. The clinical value of this assay needs further validation.

Angiogenic T (Tang) cells are mediators of vascular repair, and are characterized by surface expression of CXCR4. This receptor for stromal cell-derived factor-1α (SDF-1α) is cleaved by dipeptidyl peptidase-4 (DPP-4). Tang cell levels were investigated in people with type 2 diabetes mellitus (T2DM) compared with matched healthy controls and after treatment with the DPP-4 inhibitor Linagliptin. People with T2DM were randomized to 5 mg/day Linagliptin (n = 20) or placebo (n = 21) for 26 weeks. Tang cell frequency was identified in peripheral blood mononuclear cells (CD3+CD31+CXCR4+) and levels of endothelial progenitor cells (EPCs) (CD34+CD133+KDR+) were also assessed in whole blood. Circulating Tang cell levels were significantly lower in people with T2DM compared with the healthy control group. SDF-1α levels increased significantly in Linagliptin-treated people with T2DM compared to placebo, and a trend was observed in change of Tang cell levels, while EPC count did not change. In conclusion, circulating Tang cell levels were considerably lower in people with T2DM, while a trend was observed in recruitment of Tang cells after 26 weeks of treatment with Linagliptin. These data suggest that DPP-4 inhibitors may potentially exert beneficial effects on bone marrow-driven vascular repair.

BACKGROUND & AIMS: Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ-induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI.METHODS: Patients diagnosed with drug-induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow-up data were analysed.RESULTS: Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54-70) years. The median latency period was 45 (range, 29-90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow-up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation.CONCLUSIONS: BGZ-induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end-stage liver disease or died.

In the general population we recently reported a consistent association between plasma sodium and volume markers, suggesting that individuals with higher plasma sodium have higher extracellular fluid volume (ECFV). To test this hypothesis, we analyzed the association between plasma sodium and directly measured ECFV (iothalamate distribution volume) in healthy men. Second, we studied whether plasma sodium is associated with blood pressure. We analyzed data from 70 men (age 24 ± 7 years) at the end of two 7‐day periods on a low‐sodium diet (LS, 50 mmol Na/24 h) and a high‐sodium diet (HS, 200 mmol Na/24 h), respectively. The association of plasma sodium with blood pressure was assessed in the combined data of the different sodium intakes by linear mixed effects models. A positive univariable association between plasma sodium and ECFV was found during HS (β = 0.24, p = 0.042) and LS (β = 0.23, p = 0.058), respectively. Individual values of plasma sodium on LS and HS diet were strongly correlated (β = 0.68, p, Plasma sodium concentration is positively associated with ECFV on both LS and HS intake. Our data confirm and extend prior data on individual regulation of plasma sodium and suggest that this is associated with individuality of the regulation of ECFV. Finally, plasma sodium level is associated with SBP, independent of ECFV and diet.

Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:22 issue:1 pages:144-153 ispartof: location:United States status: published

Hepatocyte nuclear factor 1A (HNF1A) maturity-onset diabetes of the young (MODY) is a monogenetic, autosomal dominantly inherited form of diabetes. HNF1A-MODY is associated with HNF1A-inactivated hepatocellular adenoma (H-HCA) formation. Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co-occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus. Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA-related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before. HNF1A-MODY should be considered in (non-)diabetic (male) patients with H-HCA. We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A-MODY patients.

BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women.METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years).RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women.CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing, with concomitant high incidence of lipoprotein abnormalities. Cardiovascular disease (CVD) is the main cause of death in subjects with NAFLD and management of dyslipidemia is pivotal for prevention. We aimed to determine cardiovascular risk and indication for statin therapy in subjects with NAFLD.METHODS: Cross sectional analysis of the population-based Lifelines Cohort Study of 34,240 adult individuals. Subjects with reported use of lipid-lowering drugs were excluded. Suspected NAFLD was defined as Fatty Liver Index (FLI) ≥60 and advanced hepatic fibrosis as NAFLD fibrosis score (NFS) >0.676. Cardiovascular risk and indication for statin therapy were defined according to the European Society of Cardiology and European Atherosclerosis Society Guideline for the Management of Dyslipidemias.RESULTS: FLI≥60 was present in 7,067 (20.6%) participants and coincided with increased prevalence of type 2 diabetes mellitus, metabolic syndrome, CVD and impaired renal function (all P0.676 (73.2% vs. 30.6%, P0.676 (OR 5.03, 95%CI: 2.76-9.17%, PCONCLUSIONS: Because of increased cardiovascular risk, substantial proportions of subjects with suspected NAFLD and/or fibrosis have an indication for lipid-lowering treatment and could benefit from statin therapy. This article is protected by copyright. All rights reserved.

BACKGROUND & AIMS: Hepatocellular Adenomas (HCA) are rare, hormone driven, benign liver tumors. HCA >50mm are associated with hemorrhage and malignant transformation. Guidelines recommend cessation of oral contraceptive pills (OCP) for size reduction, however, it is currently unknown how HCA respond to cessation of OCP. We sought to investigate the effect of OCP cessation on HCA size.METHODS: A retrospective cohort study was performed including HCA patients who stopped OCP intake within six months of imaging between 2005-2018. Biometrics and hormonal medication use were evaluated with self-designed questionnaires. Response of the largest HCA was evaluated according to Response Evaluation Criteria in Solid Tumors (RECISTv1.1). Cox regression was performed for analysis of factors influencing HCA regression.RESULTS: Seventy-eight HCA patients were included, diagnosed at a median (IQR) age of 32 (26-41) years. Follow-up was 1.6 (0.4-2.9) years. HCA size at diagnosis ranged 10-167mm. After a median time of 1.3 (0.6 - 2.6) years after OCP cessation, 37.2% of HCA showed >30% regression, 5.1% complete regression, 56.4% stability, and 1.3% progression. No HCA induced complications were observed during follow-up. Cox regression analysis demonstrated a significant association of HCA size with rate of regression; 50≤HCA100mm (HR 8.3, 95% CI 3.3-21.6; pCONCLUSIONS: Ninety-eight percent of HCA remained stable or regressed after OCP cessation. A longer wait-and-see period was associated with a larger proportion of regressing HCA, without HCA related complications during follow-up. This article is protected by copyright. All rights reserved.

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation., This clinical cohort study indicates that a combination of hypo‐ and normothermic machine perfusion, using a preservation fluid containing an hemoglobin‐based oxygen carrier, is feasible and provides a tool to resuscitate and select initially declined high‐risk donor livers that can be transplanted successfully.

Currently, there are no tools to predict postsurgery outcome after kidney transplantation. This study assesses whether frailty influence 30-day postoperative complications after kidney transplantation. One-hundred and fifty kidney transplantations were prospectively included. Frailty was assessed using a frailty indicator, consisting of 15 questions, covering most domains of functioning. Postoperative complications were measured by the Comprehensive Complication Index (CCI). Using a linear regression model, 30-day postoperative complications and frailty correlation were adjusted for confounders, including sex, age, ASA Score, Charlson Comorbidity Index, hypertension, BMI, smoking, dialysis, duration of dialysis, type of transplantation, and retransplantation. The mean frailty score was 2.07(+/- 1.6) and 23 patients were classified as frail (GFI >= 4). The mean CCI-score was 18(+/- 15.6), the mean CCI-score for "frail" patients 30.1(+/- 17.2) compared to 15.5 (+/- 14.2) for "non-frail" patients (N = 116). In a regression analysis, a significant relationship between CCI-score and frailty (beta = 13.3; 95% CI 5.7-20.9; P = 0.0007) and transplantation type (beta = 4.9; 95% CI: 0.72-9.16; P = 0.02) was found, independent of confounders. In conclusion, frailty and type of transplantation are independent factors associated with an increased risk of postoperative complications.

Background: Inotrope score has been proposed as a marker of clinical outcome after adult heart transplantation (HTx) but is rarely used in practice.Methods: Inotrope score during the first 48 h after HTx was calculated in 81 patients as: dopamine + dobutamine + amrinone + milrinone (dose × 15) + epinephrine (dose × 100) + norepinephrine (dose × 100) + enoximone + isoprenaline (dose × 100), with each drug in µg/kg/min. Determinants of inotrope score were identified with linear regression. Cox regression was used to determine the association of inotrope score with mortality.Results: The mean recipient age was 52 ± 11 years, and 32 (39.5%) patients were female. Determinants of inotrope score were preoperative C-reactive protein, serum urea, congenital heart disease, and donor cardiac arrest (R2 = .30). Inotrope score was associated with 5-year mortality, independent of recipient age and gender (HR 1.03, 95% CI 1.00-1.07). This association was attenuated when adjusting for female-to-male transplant and ischemia time. Inotrope score was also strongly associated with continuous veno-venous hemofiltration (OR 1.07, 95% CI 1.03-1.12).Conclusion: High inotrope score post-HTx was observed in recipient congenital heart disease and was associated with a higher risk of mortality and acute kidney injury.

Background In the failing heart, energy metabolism is shifted towards increased ketone body oxidation. Nevertheless, the association of beta-hydroxybutyrate (beta-OHB) with development of heart failure (HF) remains unclear. We investigated the association between plasma beta-OHB and the risk of HF in a prospective population-based cohort. Design Plasma beta-OHB concentrations were measured in 6134 participants of the PREVEND study. Risk of incident HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction was estimated using multivariable-adjusted Cox regression models. Results During median follow-up for 8.2 years, 227 subjects were diagnosed with HF (137 with HFrEF; 90 with HFpEF). Cox regression analyses revealed a significant association of higher beta-OHB concentrations with incident HF (HR per 1 standard deviation increase, 1.40 (95% CI: 1.21-1.63; P

Background Type 2 diabetes is associated with both impaired insulin action at target tissues and impaired insulin secretion in pancreatic beta cells. Mitochondrial dysfunction may play a role in both insulin resistance and impaired insulin secretion. Plasma creatine has been proposed as a potential marker for mitochondrial dysfunction. We aimed to investigate the association between plasma creatine and incident type 2 diabetes. Methods We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the general population‐based PREVEND study. The study outcome was incident type 2 diabetes, defined as a fasting plasma glucose ≥7.0 mmol/L (126 mg/dl); a random sample plasma glucose ≥11.1 mmol/L (200 mg/dl); self‐report of a physician diagnosis or the use of glucose‐lowering medications based on a central pharmacy registration. Associations of plasma creatine with type 2 diabetes were quantified using Cox proportional hazards models and were adjusted for potential confounders. Results We included 4735 participants aged 52 ± 11 years, of whom 49% were male. Mean plasma creatine concentrations were 36.7 ± 17.6 µmol/L, with lower concentrations in males than in females (30.4 ± 15.1 µmol/L vs. 42.7 ± 17.7 µmol/L; p for difference, Clinical Endocrinology, 94 (4), ISSN:1365-2265, ISSN:0300-0664

In brain‐dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We aimed to investigate whether brain death (BD)‐induced lung injury is complement dependent and dissected the contribution of the complement activation pathways. BD was induced and sustained for 3 hours in wild‐type (WT) and complement deficient mice. C3−/− mice represented total complement deficiency, C4−/− mice represented deficiency of the classical and lectin pathway, and factor properdin (P)−/− mice represented alternative pathway deficiency. Systemic and local complement levels, histological lung injury, and pulmonary inflammation were assessed. Systemic and local complement levels were reduced in C3−/− mice. In addition, histological lung injury and inflammation were attenuated, as corroborated by influx of neutrophils and gene expressions of interleukin (IL)‐6, IL‐8–like KC, TNF‐α, E‐selectin, and MCP‐1. In C4−/− mice, complement was reduced on both systemic and local levels and histological lung injury and inflammatory status were ameliorated. In P−/− mice, histological lung injury was attenuated, though systemic and local complement levels, IL‐6 and KC gene expressions, and neutrophil influx were not affected. We demonstrated that BD‐induced lung injury is complement dependent, with a primary role for the classical/lectin activation pathway., In a mouse model, brain death–induced lung injury is complement‐dependent, elucidating a primary role for the classical/lectin complement activation pathway.

Background COVID-19 is associated with a substantial risk of venous thrombotic events, even in the presence of adequate thromboprophylactic therapy. Objectives We aimed to better characterize the hypercoagulable state of COVID-19 patients in patients receiving anticoagulant therapy. Methods We took plasma samples of 23 patients with COVID-19 who were on prophylactic or intensified anticoagulant therapy. Twenty healthy volunteers were included to establish reference ranges. Results COVID-19 patients had a mildly prolonged prothrombin time, high von Willebrand factor levels and low ADAMTS13 activity. Most rotational thromboelastometry parameters were normal, with a hypercoagulable maximum clot firmness in part of the patients. Despite detectable anti-activated factor X activity in the majority of patients, ex vivo thrombin generation was normal, and in vivo thrombin generation elevated as evidenced by elevated levels of thrombin-antithrombin complexes and D-dimers. Plasma levels of activated factor VII were lower in patients, and levels of the platelet activation marker soluble CD40 ligand were similar in patients and controls. Plasmin-antiplasmin complex levels were also increased in patients despite an in vitro hypofibrinolytic profile. Conclusions COVID-19 patients are characterized by normal in vitro thrombin generation and enhanced clot formation and decreased fibrinolytic potential despite the presence of heparin in the sample. Anticoagulated COVID-19 patients have persistent in vivo activation of coagulation and fibrinolysis, but no evidence of excessive platelet activation. Ongoing activation of coagulation despite normal to intensified anticoagulant therapy indicates studies on alternative antithrombotic strategies are urgently required.

The SARS‐CoV‐2 pandemic has led to worldwide research aiming to identify the risk factors for developing critical illness and mortality caused by COVID‐19. It quickly became apparent that besides older age, obesity is one of the most important risk factors for a more severe course of COVID‐19, although the mechanisms remain largely unknown [1‐3]. Notably, with respect to acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), evidence is mounting that obesity is a risk factor for ARDS/ALI, but among people with ARDS/ALI, obesity is associated with better outcome, a phenomenon which has been called the “obesity paradox” [4,5].

Main Problem: Following cold aortic flush in a deceased organ donation procedure, kidneys never reach the intended 0–4°C and stay ischemic at around 20°C in the donor’s body until actual surgical retrieval. Therefore, organ extraction time could have a detrimental influence on kidney transplant outcome.Materials and Methods: We analyzed the association between extraction time and kidney transplant outcome in multicenter data of 5,426 transplant procedures from the Dutch Organ Transplantation Registry (NOTR) and 15,849 transplant procedures from the United Network for Organ Sharing (UNOS).Results: Extraction time was grouped per 10-min increment. In the NOTR database, extraction time was independently associated with graft loss [HR 1.027 (1.004–1.050); p = 0.022] and with DGF [OR 1.043 (1.021–1.066); p < 0.005]. An extraction time >80 min was associated with a 27.4% higher hazard rate of graft failure [HR 1.274 (1.080–1.502); p = 0.004] and such kidneys had 43.8% higher odds of developing DGF [OR 1.438, (1.236–1.673); p < 0.005]. In the UNOS database, increasing extraction times in DCD donors were associated with DGF [OR 1.036 (1.016–1.055); p < 0.005]. An extraction time >30 min was associated with 14.5% higher odds of developing DGF [OR 1.145 (1.063–1.233); p < 0.005].Discussion: Prolonged kidney extraction time negatively influenced graft survival in Dutch donors and increased DGF risk in all deceased donor recipients.

Ischemia/reperfusion injury (IRI) is the main cause of complications following liver transplantation. Reactive oxygen species (ROS) were thought to be the main regulators of IRI. However, recent studies demonstrate that ROS activate the cytoprotective mechanism of autophagy promoting cell survival. Liver IRI initially damages the liver endothelial cells (LEC), but whether ROS-autophagy promotes cell survival in LEC during IRI is not known. Primary human LEC were isolated from human liver tissue and exposed to an in vitro model of IRI to assess the role of autophagy in LEC. The role of autophagy during liver IRI in vivo was assessed using a murine model of partial liver IRI. During IRI, ROS specifically activate autophagy-related protein (ATG) 7 promoting autophagic flux and the formation of LC3B-positive puncta around mitochondria in primary human LEC. Inhibition of ROS reduces autophagic flux in LEC during IRI inducing necrosis. In addition, small interfering RNA knockdown of ATG7 sensitized LEC to necrosis during IRI. In vivo murine livers in uninjured liver lobes demonstrate autophagy within LEC that is reduced following IRI with concomitant reduction in autophagic flux and increased cell death. In conclusion, these findings demonstrate that during liver IRI ROS-dependent autophagy promotes the survival of LEC, and therapeutic targeting of this signaling pathway may reduce liver IRI following transplantation.

Author(s): Brunt, Elizabeth; Aishima, Shinichi; Clavien, Pierre-Alain; Fowler, Kathryn; Goodman, Zachary; Gores, Gregory; Gouw, Annette; Kagen, Alex; Klimstra, David; Komuta, Mina; Kondo, Fukuo; Miksad, Rebecca; Nakano, Masayuki; Nakanuma, Yasuni; Ng, Irene; Paradis, Valerie; Nyun Park, Young; Quaglia, Alberto; Roncalli, Massimo; Roskams, Tania; Sakamoto, Michiie; Saxena, Romil; Sempoux, Christine; Sirlin, Claude; Stueck, Ashley; Thung, Swan; Tsui, WMS; Wang, Xin-Wei; Wee, Aileen; Yano, Hirohisa; Yeh, Matthew; Zen, Yoh; Zucman-Rossi, Jessica; Theise, Neil | Abstract: Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation.ConclusionIt is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (HaE); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).

BACKGROUND & AIMS: A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.METHODS: We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.RESULTS: Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients.CONCLUSIONS: These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.

Background & Aims The long-term impact of sustained virological response (SVR) after direct-acting antivirals (DAAs) on the hypercoagulability associated with HCV cirrhosis is unknown. We longitudinally evaluated the effect of DAAs treatment on cirrhotic coagulopathy. Methods Results Pro- and anticoagulant factor levels and thrombin generation were assessed in patients with HCV-related cirrhosis at baseline, end of therapy (EOT), at 12, 24 and 48 weeks (W) after EOT. Fifty-eight patients were enrolled (86% Child's A). SVR was 100%. Median factor VIII activity significantly decreased at EOT, 12 weeks and 24 weeks compared with baseline, whereas protein C significantly increased at 24 weeks and 48 weeks. Cirrhotic patients showed a slight but sustained increase in endogenous thrombin potential (ETP) with a statistically significant difference at EOT, 12 weeks, 24 weeks and 48 weeks compared with baseline. Conversely, thrombomodulin-modified ETP was elevated before treatment and decreased over time to normal levels at 24 weeks and 48 weeks. The ETP ratio decreased slowly at EOT and 12 weeks, and was significantly decreased at 24 weeks and 48 weeks compared with baseline (P