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This preclinical feasibility study investigates the potential of utilizing the hinotori™ robot system for esophagectomy. In three human cadaver models, the esophagus was successfully mobilized and resected using the hinotori™ system, with a mean thoracic procedure time of 57 minutes. The system allowed for precise dissection and radical lymphadenectomy without arm collision, attributed to its versatile design and docking-free trocars. Standard robot-specific patient positioning, including a 35° left lateral inclination, and trocar placement in a posterior axillary line configuration were employed. Notably, trocars suitable for both laparoscopy and the hinotori™ robot were utilized, providing flexibility in trocar selection. Unique features, such as the ergonomic console and pointer-based pivot point identification system, contributed to procedural success. While these findings highlight the promising potential of the hinotori™ system in advancing esophageal surgery, further clinical studies are warranted to validate its reproducibility and clinical utility. Additionally, enhancements to the pivot point identification system and evaluation of the arm base's features may further optimize surgical outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Minimally invasive esophagectomies, including robot-assisted procedures, have demonstrated superiority over traditional open surgery. Despite the prevalence of transhiatal and transthoracic approaches, cervical access is less common in minimally invasive esophageal surgery. Advancements in robotic systems, such as the da Vinci Single Port (SP), enable controlled transcervical extrapleural mediastinoscopic access, potentially reducing pulmonary complications and extending surgical options to patients with comorbidities. The da Vinci SP robot-assisted cervical esophagectomy (SP-RACE) employs an SP and laparoscopic approach, demonstrating feasibility with comparable lymphadenectomy and recurrent nerve palsy rates to transthoracic methods. This technique, performed for the first time in Europe at the University Hospital Mainz, involves a transcervical SP phase that allows for effective mediastinal dissection and esophageal mobilization. Despite technical challenges due to limited space, robotic systems enhance controlled access and eliminate arm collision. The da Vinci SP platform's advantages include improved triangulation, fewer interferences, and better control of instruments in confined spaces. This novel approach shows promise for patients with high esophageal tumors and those unsuitable for transthoracic surgery, warranting further investigation into its clinical utility and reproducibility., Competing Interests: P.P.G. serves as a proctor for Intuitive Surgical. All other authors declare no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Significance Statement: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available., Background: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification., Methods: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234)., Results: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU., Conclusions: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis., (Copyright © 2023 by the American Society of Nephrology.)

Background: Liver transplantation is the only promising treatment for end-stage liver disease and patients with hepatocellular carcinoma. However, too many organs are rejected for transplantation., Methods: We analyzed the factors involved in organ allocation in our transplant center and reviewed all livers that were declined for transplantation. Reasons for declining organs for transplantation were categorized as major extended donor criteria (maEDC), size mismatch and vascular problems, medical reasons and risk of disease transmission, and other reasons. The fate of the declined organs was analyzed., Results: 1086 declined organs were offered 1200 times. A total of 31% of the livers were declined because of maEDC, 35.5% because of size mismatch and vascular problems, 15.8% because of medical reasons and risk of disease transmission, and 20.7% because of other reasons. A total of 40% of the declined organs were allocated and transplanted. A total of 50% of the organs were completely discarded, and significantly more of these grafts had maEDC than grafts that were eventually allocated (37.5% vs. 17.7%, p < 0.001)., Conclusion: Most organs were declined because of poor organ quality. Donor-recipient matching at time of allocation and organ preservation must be improved by allocating maEDC grafts using individualized algorithms that avoid high-risk donor-recipient combinations and unnecessary organ declination.

Split-liver transplantation offers a solution to the organ shortage problem. However, the outcomes of extended right lobe liver transplantation (ERLT) and whether it is a suitable alternative to full-size liver transplantation (FSLT) remain controversial. We compared the outcomes of ERLT and FSLT in adult recipients of 43,409 first deceased donor liver transplantations using Cox regression. We also analyzed 612 ERLT and 1224 FSLT 1:2 matched cases to identify factors that affect ERLT outcome. The risk of graft loss was significantly higher following ERLT than following FSLT during the first posttransplantation year in the matched and unmatched collective (hazard ratio [HR], 1.39 and 1.27 and P = 0.01 and 0.006, respectively). Every additional hour of cold ischemia time (CIT) increased the risk of 1-year graft loss by 10% in the ERLT group compared with only 3% in the FSLT group (P = 0.003 and <0.001, respectively). Importantly, the outcome of ERLT and FSLT did not differ significantly if the CIT was below 10 hours (HR, 0.71; P = 0.22). One-year graft and patient survival were lower in high-risk ERLT recipients with a Model for End-Stage Liver Disease (MELD) score of ≥20 (HR, 1.88; P = 0.03 and HR, 2.03; P = 0.02). In the male recipient-male donor combination, ERLT recipients had a higher risk of 1-year graft loss than FSLT recipients (HR, 2.44; P = 0.006). This was probably because of the significantly higher MELD score in ERLT recipients (P = 0.004). ERLT in adults is an adequate alternative to FSLT and offers an elegant solution to the problem of organ shortage as long as the cold storage is less than 10 hours and the recipient's MELD score is <20., (© 2021 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Patients with hepatocellular carcinoma (HCC) are selected for transplantation if they have a low tumour burden and low risk of recurrence. The morphometric Milan criteria have been the cornerstone for patient selection, but dynamic morphological and biological tumour characteristics surfaced as an encouraging tool to refine the selection of patients with HCC and to support the expansion of the Milan criteria. The outcomes of the most prevalent models that select patients with HCC for liver transplantation were analysed in this study, which aimed to identify the selection model that offered the best recurrence-free and overall survival after transplantation., Methods: Studies that compared Milan, University of California San Francisco (UCSF), up-to-seven (UPTS), alpha-fetoprotein (AFP), and MetroTicket 2.0 (MT2) models were included. One-year, 3-year, and 5-year recurrence-free and overall survival rates of patients selected for transplantation using different models were analysed., Results: A total of 60 850 adult patients with HCC selected for liver transplantation using Milan, UCSF, UPTS, AFP, or MT2 criteria were included. Patients selected for transplantation using the MT2 model had the highest 1-, 3-, and 5-year recurrence-free survival. In addition, patients selected for transplantation using MT2 criteria had the best 1- and 3-year overall survival, whereas patients selected for transplantation using the Milan criteria had the best 5-year overall survival rates., Conclusion: The MT2 model offered the best post-transplant outcomes in patients with HCC, highlighting the importance of considering tumour morphology and biology when selecting patients with HCC for liver transplantation., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

This study aimed to identify cutoff values for donor risk index (DRI), Eurotransplant (ET)-DRI, and balance of risk (BAR) scores that predict the risk of liver graft loss. MEDLINE and Web of Science databases were searched systematically and unrestrictedly. Graft loss odds ratios and 95% confidence intervals were assessed by meta-analyses using Mantel-Haenszel tests with a random-effects model. Cutoff values for predicting graft loss at 3 months, 1 year, and 3 years were analyzed for each of the scores. Measures of calibration and discrimination used in studies validating the DRI and the ET-DRI were summarized. DRI ≥ 1.4 (six studies, n = 35 580 patients) and ET-DRI ≥ 1.4 (four studies, n = 11 666 patients) were associated with the highest risk of graft loss at all time points. BAR > 18 was associated with the highest risk of 3-month and 1-year graft loss (n = 6499 patients). A DRI cutoff of 1.8 and an ET-DRI cutoff of 1.7 were estimated using a summary receiver operator characteristic curve, but the sensitivity and specificity of these cutoff values were low. A DRI and ET-DRI score ≥ 1.4 and a BAR score > 18 have a negative influence on graft survival, but these cutoff values are not well suited for predicting graft loss., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Incisional hernia is a frequent consequence of major surgery. Most repairs augment the abdominal wall with artificial meshes fixed to the tissues with sutures, tacks, or glue. Pain and recurrences plague at least 10-20% of the patients after repair of the abdominal defect. How should a repair of incisional hernias be constructed to achieve durability? Incisional hernia repair can be regarded as a compound technique. The biomechanical properties of a compound made of tissue, textile, and linking materials vary to a large extent. Tissues differ in age, exercise levels, and comorbidities. Textiles are currently optimized for tensile strength, but frequently fail to provide tackiness, dynamic stiction, and strain resistance to pulse impacts. Linking strength with and without fixation devices depends on the retention forces between surfaces to sustain stiction under dynamic load. Impacts such a coughing or sharp bending can easily overburden clinically applied composite structures and can lead to a breakdown of incisional hernia repair. Our group developed a bench test with tissues, fixation, and textiles using dynamic intermittent strain (DIS), which resembles coughing. Tissue elasticity, the size of the hernia under pressure, and the area of instability of the abdominal wall of the individual patient was assessed with low-dose computed tomography of the abdomen preoperatively. A surgical concept was developed based on biomechanical considerations. Observations in a clinical registry based on consecutive patients from four hospitals demonstrate low failure rates and low pain levels after 1 year. Here, results from the bench test, the application of CT abdomen with Valsalva's maneuver, considerations of the surgical concept, and the clinical application of our approach are outlined., Competing Interests: FK has received research grants from Baxter®, Dahlhausen®, Ethicon®, and Medtronic® not related to the research perspective described in the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kallinowski, Gutjahr, Harder, Sabagh, Ludwig, Lozanovski, Löffler, Rinn, Görich, Grimm, Vollmer and Nessel.)

The outcomes of split-liver transplantation are controversial. This study compared outcomes and morbidity after extended right lobe liver transplantation (ERLT) and whole liver transplantation (WLT) in adults. MEDLINE and Web of Science databases were searched systematically and unrestrictedly for studies on ERLT and its impact on graft and patient survival, and postoperative complications. Graft loss and patient mortality odds ratios (OR) and 95% confidence intervals (CI) were assessed by meta-analyses using Mantel-Haenszel tests with a random-effects model. Vascular and biliary complications, primary nonfunction, 3-month, 1-, and 3-year graft and patient survival, and retransplantation after ERLT and WLT were analyzed. The literature search yielded 10 594 articles. After exclusion, 22 studies (n = 75 799 adult transplant patients) were included in the analysis. ERLT was associated with lower 3-month (OR = 1.43, 95% CI = 1.09-1.89, P = 0.01), 1-year (OR = 1.46, 95% CI = 1.08-1.97, P = 0.01), and 3-year (OR = 1.37, 95% CI = 1.01-1.84, P = 0.04) graft survival. WL grafts were less associated with retransplantation (OR = 0.57; 95% CI = 0.41-0.80; P < 0.01), vascular complications (OR = 0.53, 95% CI = 0.38-0.74, P < 0.01) and biliary complications (OR = 0.67; 95% CI = 0.47-0.95; P = 0.03). Considering ERLT as major Extended Donor Criteria is justified because ERL grafts are associated with vasculobiliary complications and the need for retransplantation, and have a negative influence on graft survival., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood., Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry., Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P =6.35×10 -8 ) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract ( WDPCP, OTX1, BMP5, VANGL1, and WNT5A ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P =1.86×10 -9 ). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis., Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR., (Copyright © 2021 by the American Society of Nephrology.)

In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65-year-old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65- to 74-year-old donors can also be allocated to 55- to 64-year-old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with short survival and limited therapeutic options. Broccoli sulforaphane is a promising new treatment due to the results of recent epidemiological, experimental and patient studies. Upon approval from the ethics committee and registration at ClinicalTrials.gov, 40 patients with palliative chemotherapy were placed into a placebo and treatment group in an unblinded fashion. Fifteen capsules with pulverized broccoli sprouts containing 90 mg/508 μmol sulforaphane and 180 mg/411 μmol glucoraphanin or methylcellulose were administered daily for up to 1 year. Twenty-nine patients were included in the treatment group and 11 patients were in the placebo group; these patients were followed for up to 1 year. The patient characteristics, overall survival and feasibility were assessed. Compared to those of the placebo group, the mean death rate was lower in the treatment group during the first 6 months after intake (day 30: 0%/18%, day 90: 0%/25%, and day 180: 25%/43%), and Kaplan-Meier analysis revealed a higher survival rate. There was a high drop-out rate (72% in the treatment group and 55% in the placebo group) after 1 year. We concluded from the Karnofsky index that the broccoli sprouts did not impact patient's self-care and overall abilities severely. The intake of 15 capsules daily was difficult for some patients, and the broccoli sprouts sometimes increased digestive problems, nausea and emesis. We did not obtain statistically significant results (p = 0.291 for the endpoint at day 180), but the knowledge about the feasibility is the basis for the development of new sulforaphane drugs.

Introduction: Despite increasing awareness of the negative impact of cold ischemia time (CIT) in liver transplantation, its precise influence in different subgroups of liver transplant recipients has not been analyzed in detail. This study aimed to identify liver transplant recipients with an unfavorable outcome due to prolonged cold ischemia. Methods: 40,288 adult liver transplantations, performed between 1998 and 2017 and reported to the Collaborative Transplant Study were analyzed. Results: Prolonged CIT significantly reduced graft and patient survival only during the first post-transplant year. On average, each hour added to the cold ischemia was associated with a 3.4% increase in the risk of graft loss (hazard ratio (HR) 1.034, P < 0.001). The impact of CIT was strongest in patients with hepatitis C-related (HCV) cirrhosis with a 24% higher risk of graft loss already at 8-9 h (HR 1.24, 95% CI 1.05-1.47, P = 0.011) and 64% higher risk at ≥14 h (HR 1.64, 95% CI 1.30-2.09, P < 0.001). In contrast, patients with hepatocellular cancer (HCC) and alcoholic cirrhosis tolerated longer ischemia times up to <10 and <12 h, respectively, without significant impact on graft survival ( P = 0.47 and 0.42). In HCC patients with model of end-stage liver disease scores (MELD) <20, graft survival was not significantly impaired in the cases of CIT up to 13 h. Conclusion: The negative influence of CIT on liver transplant outcome depends on the underlying disease, patients with HCV-related cirrhosis being at the highest risk of graft loss due to prolonged cold ischemia. Grafts with longer cold preservation times should preferentially be allocated to recipients with alcoholic cirrhosis and HCC patients with MELD <20, in whom the effect of cold ischemia is less pronounced., (Copyright © 2020 Lozanovski, Döhler, Weiss, Mehrabi and Süsal.)

The major extended donor criteria (maEDC; steatosis >40%, age >65 years, and cold ischemia time >14 h) influence graft and patient outcomes after liver transplantation. Despite organ shortages, maEDC organs are often considered unsuitable for transplantation. We investigated the outcomes of maEDC organ liver transplantation in patients with hepatocellular carcinoma (HCC). Two hundred and sixty-four HCC liver transplant patients were eligible for analysis. Risk factor analysis was performed for early allograft dysfunction; primary nonfunction; 30-day and 90-day graft failure; and 30-day, 90-day, and 1-year patient mortality. One-year graft survival was higher in recipients of no-maEDC grafts. One-year patient survival did not differ between the recipients of no-maEDC and maEDC organs. The univariate and multivariate analyses revealed no association between maEDC grafts and one-year patient mortality. Graft survival differed between the recipients of no-maEDC and maEDC organs after correcting for a laboratory model of end-stage liver disease (labMELD) score with a cut-off value of 20, but patient survival did not. Patient survival did not differ between recipients who did and did not meet the Milan criteria and who received grafts with and without maEDC. Instead of being discarded, maEDC grafts may expand the organ pool for patients with HCC without impairing patient survival or recurrence-free survival.

In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Introduction: Numerous extended donor criteria (EDC) have been identified in liver transplantation (LT), but different EDC have different impacts on graft and patient survival. This study aimed to identify major EDC (maEDC) that were best able to predict the outcome after LT and to examine the plausibility of an allocation algorithm based on these criteria., Methods: All consecutive LTs between 12/2006 and 03/2014 were included (n = 611). We analyzed the following EDC: donor age > 65 years, body mass index > 30, malignancy and drug abuse history, intensive care unit stay/ventilation > 7 days, aminotransferases > 3 times normal, serum bilirubin > 3 mg/dL, serum Na + > 165 mmol/L, positive hepatitis serology, biopsy-proven macrovesicular steatosis (BPS) > 40%, and cold ischemia time (CIT) > 14 h. We analyzed hazard risk ratios of graft failure for each EDC and evaluated primary non-function (PNF). In addition, we analyzed 30-day, 90-day, 1-year, and 3-year graft survival. We established low- and high-risk graft (maEDC 0 vs. ≥ 1) and recipient (labMELD < 20 vs. ≥ 20) groups and compared the post-LT outcomes between these groups., Results: BPS > 40%, donor age > 65 years, and CIT > 14 h (all p < 0.05) were independent predictors of graft failure and patient mortality and increased PNF, 30-day, 90-day, 1-year, and 3-year graft failure rates. Three-year graft and patient survival decreased in recipients of ≥ 1 maEDC grafts (all p < 0.05) and LT of high-risk grafts into high-risk recipients yielded worse outcomes compared with other groups., Conclusion: Donor age > 65 years, BPS > 40%, and CIT > 14 h are major EDC that decrease short and 3-year graft survival, and 3-year patient survival. An allocation algorithm based on maEDC and labMELD is therefore plausible.

Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia.Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.

Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown., Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice., Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10 -14 ). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies., Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Background: The objective of this study was to assess clinical course and outcome of children with congenital anomalies of the kidney and urinary tract (CAKUT) who had an attack of acute poststreptococcal glomerulonephritis (PSGN)., Method: Renal status including blood pressure, proteinuria and glomerular filtration rate was retrospectively analyzed in five children with CAKUT and PSGN at the presentation and during the follow up., Results: In the period 2004-2013, 678 patients were diagnosed and recruited in our CAKUT cohort. During this period, 188 patients were hospitalized with the diagnosis of PSGN. A total of five patients had CAKUT and an episode of PSGN (2.6%). Analysis of the follow-up data revealed that three children fully recovered (bilateral vesicoureteral reflux n = 1, ectopic/hypodysplastic kidney n = 1, ureteropelvic junction obstruction n = 1). One child with bilateral hypodysplasia had progressive worsening of the renal function and has been prepared for renal replacement therapy. Another child with single kidney has stable renal function but has significant rising proteinuria, which was not evident on the routine analysis 2 months before the attack of PSGN., Conclusion: Poststreptococcal glomerulonephritis in children is generally benign disease with low mortality in acute stage and excellent medium and long-term prognosis. We analyzed our series of PSGN patients and found that 2.6% had anomaly of the urinary tract. The unfavorable outcome was noted in children with single kidney and bilateral renal impairment.

Background and Aims: Liver transplantation is the only curative treatment for end-stage liver disease. While waiting list mortality can be predicted by the MELD-score, reliable scoring systems for the postoperative period do not exist. This study's objective was to identify risk factors that contribute to postoperative mortality., Methods: Between December 2006 and March 2011, 429 patients underwent liver transplantation in our department. Risk factors for postoperative mortality in 266 consecutive liver transplantations were identified using univariate and multivariate analyses. Patients who were <18 years, HU-listings, and split-, living related, combined or re-transplantations were excluded from the analysis. The correlation between number of risk factors and mortality was analyzed., Results: A labMELD ≥20, female sex, coronary heart disease, donor risk index >1.5 and donor Na+>145 mmol/L were identified to be independent predictive factors for postoperative mortality. With increasing number of these risk-factors, postoperative 90-day and 1-year mortality increased (0-1: 0 and 0%; 2: 2.9 and 17.4%; 3: 5.6 and 16.8%; 4: 22.2 and 33.3%; 5-6: 60.9 and 66.2%)., Conclusions: In this analysis, a simple score was derived that adequately identified patients at risk after liver transplantation. Opening a discussion on the inclusion of these parameters in the process of organ allocation may be a worthwhile venture.

Background: Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with marked resistance to chemo- and radiotherapy. PDA-cancer stem cells (CSCs) are not targeted by current therapies and may be a reason for poor prognosis. Studies indicate that diets rich in cabbage, broccoli, and cauliflower offer cancer preventative and therapeutic benefits. Recent experimental studies have confirmed these findings and demonstrated that isothiocyanate, sulforaphane, and the polyphenol, quercetin, effectively reduced tumor growth and enhanced the sensitivity of the cancer cells to current chemotherapeutics. The aim of the present study is to test the feasibility of a randomized controlled trial on the application of freeze-dried broccoli sprouts in patients with advanced PDA., Methods and Study Design: The study is designed as a prospective randomized, double-blinded pilot trial with a treatment and a placebo-controlled arm in a single center setting. A total number of forty patients (18 years or older) in two parallel groups with advanced, surgically non-resectable PDA under palliative chemotherapy are planned for recruitment. Patients in the treatment group will receive fifteen capsules of the study substance per day (90 mg of active sulforaphane) during the chemotherapy treatment course. Patients in the placebo group will receive the same capsule size and portion distribution with inactive substances (mainly methylcellulose). The follow-up duration is one year. Feasibility of the study substance, adverse effects, and patient compliance, as well as levels of serum tumor markers (CEA, CA 19-9), quality of life, and patient overall survival rates will be assessed at defined points of time., Discussion: The POUDER trial is expected to transfer promising experimental and epidemiological data into a clinical pilot study to assess the effectiveness of broccoli sprout extracts in the treatment of advanced PDA. The study objectives will provide data on the clinical feasibility and acceptability of a supportive treatment option accompanying palliative chemotherapy. Based on these results, future clinical studies to create further evidence in this field are possible., Trial Registration: The POUDER trial has been registered at ClinicalTrials.gov with an ID NCT01879878 and WHO with an ID U1111-1144-2013 on June 13th 2013.

Background: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood., Methods: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies., Results: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases., Conclusions: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Oculocerebrorenal (Lowe) syndrome is an X-linked multisystem disease characterized by renal proximal tubulopathy, mental retardation, and congenital cataracts. We present a 19-year-old boy who was found to have low molecular weight proteinuria, hypercalciuria, mild generalized hyperaminoaciduria and intermittent microscopic hematuria at the age of 3., Methods: Standard clinical and biochemical examinations and mutational analysis of the CLNC5 and OCRL1 gene were performed for the patient., Results: The patient fulfilled diagnostic criteria for Dent disease, but lacked mutation in CLCN5. Sequencing of candidate genes revealed a mutation in his OCRL1 gene, which encodes for enzyme PIP2 5-phosphatase. The enzyme was not detected by western blot analysis, and decreased activity of the enzyme PIP2 5-phosphatase was observed in cultured skin fibroblasts. The boy had only mild mental retardation, mildly elevated muscle enzymes, but no neurological deficit or congenital cataracts, which are typical for Lowe syndrome., Conclusions: Children with Dent phenotype who lack CLCN5 mutation should be tested for OCRL1 mutation. OCRL1 mutations may present with mild clinical features and are not necessarily associated with congenital cataracts.

OCRL mutations, which are a hallmark of Lowe syndrome, have recently been found in patients with isolated renal phenotype (Dent-2 disease). In this report, we describe clinical and laboratory features in five Macedonian children with mutations in the OCRL gene. Children with a clinical diagnosis of Lowe syndrome or Dent disease underwent complete neurological and ophthalmological examination, imaging of the kidney and urinary tract, assessment of renal tubular function, and mutation analysis of the OCRL gene. Two children (18 months and 11 years, respectively) were diagnosed with Lowe syndrome on the basis of congenital cataracts, severe psychomotor retardation, and renal dysfunction. Both children had low molecular weight proteinuria (LMWP) and hypercalciuria, but not Fanconi syndrome. The older one had bilateral nephrolithiasis due to associated hypocitraturia and mild hyperoxaluria. Three children with asymptomatic proteinuria were diagnosed with Dent-2 disease; none had cataracts or neurological deficit. One child showed mild mental retardation. All had LMWP, hypercalciuria, and elevated enzymes (creatine phosphokinase, lactic dehydrogenase). All three children had an abnormal Tc-99m DMSA scan revealing poor visualization of the kidneys with a high radionuclide content in the bladder; none had nephrolithiasis or nephrocalcinosis. In conclusion, children with OCRL mutations may present with very mild phenotype (asymptomatic proteinuria with/without mild mental retardation) or severe classic oculocerebrorenal syndrome of Lowe. Elevated enzymes and abnormal results on the Tc-99m DMSA scan may be useful indicators for Dent-2 disease.

Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria.

Idiopathic renal hypouricaemia is an inherited form of hypouricaemia, associated with abnormal renal handling of uric acid. There is excessive urinary wasting of uric acid resulting in hypouricaemia. Patients may be asymptomatic, but the persistent urinary abnormalities may manifest as renal stone disease, and hypouricaemia may manifest as exercise induced acute kidney injury. Here we have identified Macedonian and British patients with hypouricaemia, who presented with a variety of renal symptoms and signs including renal stone disease, hematuria, pyelonephritis and nephrocalcinosis. We have identified heterozygous missense mutations in SLC22A12 encoding the urate transporter protein URAT1 and correlate these genetic findings with functional characterization. Urate handling was determined using uptake experiments in HEK293 cells. This data highlights the importance of the URAT1 renal urate transporter in determining serum urate concentrations and the clinical phenotypes, including nephrolithiasis, that should prompt the clinician to suspect an inherited form of renal hypouricaemia.

Rare diseases (RDs) pose a significant set of problems for patients, since their disease and general social and health situation are often not recognized by the medical community and shunned by health insurance. The sheer number of RDs (5000-8000) and the number of patients (6-8% of the population) are challenging for every society. We wanted to get a better understanding of the rare diseases affecting the kidneys and urinary tract (RDAKUT) in the Republic of Macedonia and we investigated principally the PubMed Central articles of Macedonian medical professionals dealing with RDAKUT, but we also used information on RDAKUT from local sources. A significant number of RDs have been published, demonstrating the awareness and skill of Macedonian medical professionals despite pretty limited diagnostic facilities. We still feel that RDAKUT are underdiagnosed (e.g. Fabry's disease has not yet been reported), and that many patients with RDs have a long way to go before an accurate diagnosis. Increased awareness and ameliorated education are needed by the physicians; while health insurance must include RDAKUT covering their diagnosis and treatment costs. Neonatal screening for ~30 diseases (instead of just hypothyroidism) is also required. Patients' organizations exist and they are active in promoting their interests before of the health authorities.