Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets.

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Lipid disorders before and after successful liver transplantation.

INTRODUCTION: Liver transplantation (LTx) is the only successful treatment for end-stage liver disease. The results of liver transplantation depend not only on graft survival but may be also affected by superimposed cardiovascular morbidities. The aim of this retrospective study was to assess the prevalence of lipid disorders as one of the important cardiovascular risk factors in patients before and after successful LTx. MATERIAL AND METHODS: One hundred eleven patients who underwent liver transplantation because of liver cirrhosis and survived at least 2 years with functioning graft between November 2005 and May 2014 were included in this retrospective analysis. The mean age of the patients at the time of liver transplantation was 49.7±12.2 years. The prevalence of dyslipidemia was assessed before and two years after liver transplantation. This was analyzed in relation to the etiology of liver disease, including alcohol toxicity, viral or autoimmune diseases. RESULTS: The prevalence of hypertriglyceridemia before and after LTx was 13.5% and 40.5%, respectively (P<0.001). Similarly, hypercholesterolemia was noted in 17.1% and 51.4% respectively (P<0.001). The annual incidence of hypertriglyceridemia and hypercholesterolemia during the first two years after LTx was 16.2% and 20.7%, respectively. The prevalence of hypertriglyceridemia (18.5% vs 66.7%, P<0.001) and hypercholesterolemia (29.6% vs 70.0%, P=0.002) was significantly lower in patients with the autoimmune cause of liver cirrhosis in comparison to patients with the alcoholic liver disease. CONCLUSIONS: The prevalence of dyslipidemia is increased after liver transplantation. The prevalence of dyslipidemia may be related to the cause of liver injury before LTx.

Modelling of transverse vibration of conveyor belt in aspect of the trough angle.

The transverse vibration of conveyor belts is a crucial aspect in their proper and safe design, as the correct determination of vibration frequencies is essential to avoid unsafe operating conditions and premature wear of components. This study presents the Moving Compressed Beam (MCB) transverse vibration model, that is based on the interpretation of a conveyor belt as a beam known from the literature. This approach allows you to include in the model the transverse flexural rigidity of a troughed belt-a parameter that is closely related to the belt geometry. While not commonly used in engineering practice, the MSB model was compared with other models during the laboratory tests based on changing of trough geometry. This study emphasizes the significance of considering the transverse flexural rigidity of conveyor belts during the design process, and the MCB model which offers a promising approach in aspect of vibration control.

Clinical Outcomes of Transplanted Kidneys from Deceased Donors Using Different Generic Preservation Solutions.

Background and Objectives: StoreProtect Plus® is a preserving solution for cold organ storage, with a composition identical to Institute Georges Lopez (IGL-1) solution. The aim of this single center study was to compare the clinical performance of StoreProtect Plus with the generic counterpart of University of Wisconsin preservation fluid, named SPS-1®. Materials and Methods: The clinical outcomes of 168 consecutive organs preserved with StoreProtect Plus solution and 167 organs preserved with SPS-1 solution were compared. During an 18-month post-transplant follow-up period, kidney graft function, the frequency of acute rejection, post-transplant diabetes, and infectious complications, as well as patient and graft survival were analyzed. Results: There was significantly more immediate graft function (IGF) (39.3 vs. 24.0%; p < 0.01) and less slow graft function (SGF) (38.7 vs. 51.5%; p < 0.05) in the StoreProtect Plus group in comparison with the SPS-1 group, whereas the occurrence of DGF was similar in both groups. Long-term kidney graft function was comparable. Multivariate regression analysis showed that the use of StoreProtect Plus vs. SPS-1 solution (rpartial = 0.217; p < 0.001) and the amount of residual diuresis (rpartial = 0.147; p < 0.001) independently increased the occurrence of IGF, whereas Scr > 1.5 mg/dL prior to organ procurement (rpartial = −0.198; p < 0.001), longer CIT (rpartial = −0.170; p < 0.01), and CVD donor death (rpartial = −0.214; p < 0.001) were associated with SGF. Conclusions: The higher occurrence of IGF was found in kidney transplant recipients whose organs were preserved using StoreProtect Plus solution as compared with SPS-1 solution. The two groups did not differ in kidney graft function, the frequency of post-transplant complications, as well as patient and graft survival.

Analysis of surgical outcomes in 102 patients with renal cell carcinoma with venous tumor thrombus: A retrospective observational single-center study.

The aim of the study was to assess short- and long-term results following radical nephrectomy with renal vein and inferior vena cava thrombectomy in patients with renal cell cancer with venous thrombus and to investigate impact of various demographical, clinical and histological factors on overall survival (OS). The medical records of 102 adult patients with renal cell cancer with venous thrombus admitted for surgery in Department of General, Vascular and Transplant Surgery from 2012 to 2019 were retrospectively analyzed. The tumor was more frequently located on the right side compared to the left one (55 vs. 47). According to Neves Zincke classification, the levels of venous thrombus were as follows: 1 to 48 (47%), 2 to 47 (46%), 3 to 6 (6%), and 4 to 1 (1%). Postoperative complications were noted in 16 (15.7%) patients. One (3%) patient (Neves Zincke 2) died of intraoperative pulmonary embolism during hospitalization. Clear cell carcinoma was the most common pathological type reported in 92 (90.2%) patients. Thirty nine (38.2%) patients were alive at the time of last follow-up. The median OS was 21.50 (0-101.17) months. The 1-year OS was 75.5%. Significantly better OS (median 38.03 months) was noted in patients with RCC Neves Zincke 1 compared to OS (median 14.79 months) in patients with Neves Zincke 2-4 VT (P = .008). Higher tumor staging (T3 vs. T4) (P = .038), nodal staging (N0 vs. N1) (P = .0008), Fuhrman histological grading (G1-2 vs. G3-4) (P = .033) were associated with a shorter OS. Patients with renal cell cancer with venous thrombus, with an acceptable perioperative risk, should be treated surgically, because radical nephrectomy with thrombectomy performed in a high volume surgical center is a safe procedure. Neves Zincke 2-4 venous thrombus, higher tumor and nodal staging, as well higher Fuhrman histological grading are associated with a shorter OS.

Evaluation of Early and Late Effects of Surgical Treatment of Early Hepatic Artery Thrombosis After Liver Transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is the most severe vascular complication after liver transplantation and one of the major causes of early graft loss and mortality after transplantation. The number of retransplantations and recipient deaths can be decreased with an urgent thrombectomy of the hepatic artery. The aim of the study was to analyze the early and long-term outcomes of the surgical revascularization of early hepatic artery thrombosis after liver transplantation. METHODS: Four hundred eleven orthotopic liver transplantations in 380 patients were performed at our center between 2005 and 2020. A Doppler evaluation of the graft vessels patency was performed daily for the first 5 days after transplantation in all recipients. After angio-computed tomography confirmation, most of the cases of HAT qualified for surgical revascularization. RESULTS: Early HAT was diagnosed in 20 cases (4.9%), occurring most frequently between the first and third day after transplantation. Sixteen patients underwent revascularization surgery. Among them, in the early post-transplantation period, 4 died and 2 more had retransplantation. Of the remaining 10 recipients, 2 had no biliary complications, 1 had bile leakage, and 7 had common bile duct stenosis, all treated endoscopically. Among 4 nonoperated patients, 1 died and the other 2 had retransplantation in the early post-transplantation period; the last of these 4 recipients had bile duct stenosis. CONCLUSIONS: The urgent surgical revascularization in liver recipients with early HAT allows the avoidance of early retransplantation. However, these patients require intensified surveillance owing to the high risk of biliary complications that may affect shortened graft and patient survival.

Analysis of Complications and Recipients' and Graft Survival in Patients 60 Years of Age and Older in the Long-Term Follow-up Period After Kidney Transplant: A Single-Center, Paired Kidney Analysis.

BACKGROUND: Long-term results of kidney transplant (KTx) in older patients may differ from younger recipients owing to increased cardiovascular comorbidities. The study aimed to analyze surgical and nonsurgical complications that develop in the long-term follow-up period after KTx, and factors that influence results of KTx in recipients aged 60 years and older (≥60) compared with younger recipients (<60). METHODS: One hundred seventy-five patients aged ≥60 years and 175 patients aged <60 years who received a kidney graft from the same deceased donor were enrolled in the study. In the long-term follow-up period (3 months to 5 years after KTx) the incidence of surgical and nonsurgical complications, as well as patient and kidney graft survival, were compared. Additionally, the influence of early complications on patients and kidney graft survival was assessed. RESULTS: There were no differences between recipients aged ≥60 years compared with recipients aged <60 years in occurrence of surgical complications (graft artery stenosis: 0.6% vs 2.3%; ureter stenosis: 3.4% vs 1.1%; lymphocele: 6.9% vs 3.4%) and nonsurgical complications (urinary tract infection: 19.4% vs 23.4%; pneumonia: 8.6% vs 8.6%; cytomegalovirus infection: 6.3% vs 8%; new-onset diabetes after transplant: 16.6% vs 17.1%; cancer incidence: 5.7% vs 4.6%; acute rejection episode: 13.1% vs 17.1%). Five-year recipient survival was lower in a group of patients aged ≥60 years (death, 15.4% vs 8%; death with functioning graft, 12% vs 5.1%). CONCLUSIONS: The incidence of surgical and nonsurgical complications, as well as kidney-graft survival, in recipients aged ≥60 years in a 5-year follow-up period is comparable to younger recipients aged <60 years.

Consequences of Changes in the Liver Allocation System for Transplantation in the Silesian Voivodeship and in the Transplantation Center in Katowice.

BACKGROUND: For a number of years, the system of procured livers for transplantation by transplant centers in a fixed order, regardless of the location of the procurement site, was in force in Poland. In mid-2018, priority was introduced in the collection of livers by a team from a given province. The aim of the study was to evaluate the impact of changing the liver transplantation allocation system at the Katowice Transplant Center (KTW) on the number of transplanted livers and on the selected parameters of donors from which the liver was procured. METHODS: The rates and cold ischemia time (CIT) of procured livers were analyzed. RESULTS: The rate of livers procured by the KTW transplant team increased from 36.6% to 53.3%, and at the same time the rate of livers procured by this team and sent for transplantation in other transplant centers increased. The rate of livers transplanted in the KTW, which were procured in the Silesian Voivodeship, increased from 37.4% to 61.0%, and the rate of livers procured outside the Silesian Voivodeship decreased from 54.8% to 36.4%. The CIT of livers transplanted in the KTW was reduced from 407.5 to 360.0 minutes. The comparative analysis of donor parameters of livers procured by the KTW transplant team and transplanted in Katowice revealed no differences regarding analyzed clinical and biochemical parameters. CONCLUSION: The change in the allocation system increased the number of livers procured by the local team and shortened CIT of livers transplanted at the KTW.

First in Poland Simultaneous Liver-Lung Transplantation With Liver-First Approach for Recipient Due to Cystic Fibrosis: A Case Report.

Cystic fibrosis is an autosomal progressive disease affecting the lung, pancreas, and liver. Some patients develop end-stage respiratory and liver failure. For such patients, combined lung-liver transplantation remains the only therapeutic option. In this article we present the first simultaneous lung-liver transplantation in Poland, as well as in Central and Eastern Europe, with detailed clinical history, surgical aspects, and postoperative course.

Kidney Graft Failure and Patient Survival Modelling Based on Competing Risks Under Nonproportional Hazards.

We analyze data on Silesian patients after kidney transplantation under competing events scenarios where time to death and time to graft failure are considered as absorbing competing events. Our objectives are to use model diagnostics in identifying violations of proportionality assumption under the framework of subdistribution and cause-specific hazards. We use the Fine-Gray proportional hazards model for the subdistribution. Under the cause-specific hazards (CSH) scenario we use the Cox proportional hazards model and Gray's time-varying coefficients model and available model diagnostics. We show that violation of proportional subdistribution hazards assumption may be conveniently identified using residual diagnostics and properly accounted for by involving time interactions with appropriate model predictors. We also show that although the nonproportional effects on cumulative incidence do not necessarily translate in those on cause-specific hazards, they often take place simultaneously, and a violation of the proportionality assumption needs to be checked rigorously. Time-varying effects have a profound impact on clinical inference under competing risks. They do not translate directly between the frameworks of subdistribution and cause-specific hazards because the cumulative incidence is obtained via integrating the cause-specific hazard weighted by the overall survival function. Also, a different definition of the risk set is in place under the cumulative incidence and CSH framework, respectively. However, a simultaneous violation of the proportionality assumption under both frameworks is still possible. Clinical inference may change considerably when such a violation occurs. Nonproportional effects may be properly identified under each framework using available model diagnostics.

Vascular Resection in Pancreatectomy-Is It Safe and Useful for Patients with Advanced Pancreatic Cancer?

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with poor prognosis and increased incidence. Surgical resection R0 remains the most important treatment to prolong survival in PDAC patients. In borderline and locally advanced cancer, vascular resection and reconstruction during pancreatectomy enables achieving R0 resection. This study is a comprehensive review of the literature regarding the role of venous and arterial resection with vascular reconstruction in the treatment of pancreatic cancer. The literature review is focused on the use of venous and arterial resection with immediate vascular reconstruction in pancreaticoduodenectomy. Different types of venous and arterial resections are widely described. Different methods of vascular reconstructions, from primary vessel closure, through end-to-end vascular anastomosis, to interposition grafts with use autologous veins (internal jugular vein, saphenous vein, superficial femoral vein, external or internal iliac veins, inferior mesenteric vein, and left renal vein or gonadal vein), autologous substitute grafts constructed from various parts of parietal peritoneum including falciform ligament, cryopreserved and synthetic allografts. The most attention was given to the most common venous reconstructions, such as end-to-end anastomosis and interposition graft with the use of an autologous vein. Moreover, we presented mortality and morbidity rates as well as vascular patency and survival following pancreatectomy combined with vascular resection reported in cited articles.

Type 1 Diabetic Patients After Simultaneous Pancreas and Kidney Transplantation Have Less Intense Periodontal Inflammation Compared to Kidney Recipients Treated with Insulin.

BACKGROUND Long-term diabetes predisposes to pathological changes in periodontal tissues. Improvement in this respect can be expected in patients after pancreas transplantation. The aim of this study was to assess and compare the intensity of periodontium pathological lesions and inflammation markers concentration in gingival crevicular fluid (GCF) in patients with type 1 diabetes (T1D) after kidney (KTx) or simultaneous pancreas and kidney transplantation (SPK). MATERIAL AND METHODS The study included 20 T1D patients after SPK and 16 after KTx, and 15 non-diabetic kidney recipients (control). Periodontal clinical parameters and concentration of selected biochemical markers of inflammation in GCF were assessed. The following tests were used in statistical data analysis: Shapiro-Wilk test, the t test, the Mann-Whitney U tests, one-way ANOVA with Tukey's post hoc test, and χ² test (also with Yate's correction). Moreover, linear regression and Pearson or Spearman correlation coefficient was used. RESULTS There were no differences in modified Sulcus Bleeding Index (mSBI) and GCF volume between the SPK group and control group, whereas values of these parameters in the KTx group were higher than in the SPK and control groups. Maximal clinical attachment loss and pocket depth and Periotest values were higher in diabetic recipients compared to controls, and did not differ between SPK and KTx. The concentration of IL-1ß, MMP-8, resistin, TNFalpha, and YKL40 in the GCF in the KTx group was higher than in the SPK and control groups. In the combined group of T1D patients, there was a correlation between blood HbA1c and mSBI, GCF volume, and resistin, TNF-alpha and YKL40 concentrations, and between resistin concentration and mSBI. CONCLUSIONS T1D patients after SPK show lower levels of inflammatory markers in GCF and present reduced intensity of periodontitis compared to kidney recipients treated with insulin. The severity of morphological changes in periodontium in T1D patients after KTx or SPK is higher than in non-diabetic kidney recipients.

Beneficial Effect of Successful Simultaneous Pancreas-Kidney Transplantation on Plasma Profile of Metalloproteinases in Type 1 Diabetes Mellitus Patients.

It is not fully elucidated whether the restoring of normal glucose metabolism after successful simultaneous pancreas-kidney transplantation (SPK) improves vascular wall morphology and function in type 1 diabetic (T1D) patients. Therefore, we compared arterial stiffness, assessed by pulse wave velocity (PWV), carotid intima-media thickness (IMT), and biomarkers of arterial wall calcification in T1D patients after SPK or kidney transplantation alone (KTA). In 39 SPK and 39 KTA adult patients of similar age, PWV, IMT, circulating matrix metalloproteinases (MMPs) and calcification biomarkers were assessed at median 83 months post transplantation. Additionally, carotid plaques were visualized and semi-qualitatively classified. Although PWV and IMT values were similar, the occurrence of atherosclerotic plaques (51.3 vs. 70.3%, p < 0.01) and calcified lesions (35.9 vs. 64.9%, p < 0.05) was lower in SPK patients. There were significantly lower concentrations of MMP-1, MMP-2, MMP-3, and osteocalcin in SPK subjects. Among the analyzed biomarkers, only logMMP-1, logMMP-2, and logMMP-3 concentrations were associated with log HbA1c. Multivariate stepwise backward regression analysis revealed that MMP-1 and MMP-3 variability were explained only by log HbA1c. Normal glucose metabolism achieved by SPK is followed by the favorable profile of circulating matrix metalloproteinases, which may reflect the vasoprotective effect of pancreas transplantation.

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Absence of the celiac trunk and anomalous very low origin of the common hepatic artery arising independently from the abdominal aorta just above aortic bifurcation in patient undergoing radical pancreaticoduodenectomy.

PURPOSE: Knowledge of anomalies of the celiac trunk is very important during various surgical procedures (such as pancreatic and gastric resections including Appleby operation, liver resections and liver transplantations) and as well as radiologic procedures (such as chemoembolization of pancreatic and hepatic tumors). METHODS: A 77-years-old woman was admitted to our department for surgical treatment of ampullary adenocarcinoma G2 confirmed in endoscopic retrograde cholangiopancreatography (ERCP) with papillotomy and ampullary biopsy. In the contrast-enhanced computed tomography, the ampullary tumor was not visible, but the main pancreatic duct within pancreatic head and isthmus was dilated (indirect radiological tumor signs). An absence of the celiac trunk (CT) was established via computed tomography. Therefore, computed tomography-based angiography (angio-CT) of the abdominal aorta (AA) was performed before operation. RESULTS: Angio-CT confirmed an extremely rare vascular anomaly: an absence of CT. The left gastric (LGA), splenic (SA), and common hepatic (CHA) arteries connected above origin of the superior mesenteric artery (SMA) from the AA. Pylorus-preserving pancreaticoduodenectomy (PD) was performed. This anomaly was also confirmed intraoperatively. The postoperative course was uneventful and the patient was discharged on postoperative day 10. There were no signs of recurrence of the tumor during the 6 months follow-up. CONCLUSION: The proper preoperative identification of anomalies within major abdominal vessels and its relationship to the tumor is very important to avoid intraoperative vascular injury and major postoperative complications.

COVID-19 infection in solid organ transplant recipients: A single-center experience with patients immediately after transplantation.

In our transplant center, infection with SARS-CoV-2 virus was confirmed in 4 organ transplant recipients (3 kidney and 1 liver transplant recipients) during their early post-transplant hospital stay. In this paper, we report the basic characteristics, management, clinical course, and outcomes of these patients.

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

Tests of Belt Linear Speed for Identification of Frictional Contact Phenomena.

In the locations where driving forces are transmitted, the changing tensile forces cause rapid elastic deformations of the belt. The deformation changes the belt speed. Measurement of the belt speed on the friction contact sections is essential to identify elastic slippage. However, the scale of the phenomenon is small, so it is necessary to use precise measuring equipment. The article presents measurements of the linear belt speed with the use of various sensors and measuring devices. A measurement error was determined for each of the presented measurement methods. The method with the highest accuracy was used to identify the elastic slippage on the drive pulley.