The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Initially, the pandemic COVID-19, caused by SARS-CoV-2, was considered to be an exclusive lung disease, eventually leading to serious respiratory symptoms 1 . In the meantime, accumulating experimental and clinical studies have suggested that SARS-CoV-2 may also cause lesions in the kidneys, heart, brain, and gastrointestinal and endocrine organs [2][3][4][5][6][7] . SARS-CoV-2 tropism towards distinct tissues is governed by cellular factors expressed on target cells such as the viral entry receptor angiotensin-converting enzyme 2 (ACE2) 8 and the transmembrane serine protease 2 (TMPRSS2) 8 . ACE2 messenger RNA 9-13 and protein 12-14 expression within the islets of Langerhans has been reported, but not yet been shown, to allow SARS-CoV-2 entry 9,12,15 . Diabetes mellitus presents Janus like in 16 ): first, pre-existing diabetes is a highly prevalent comorbidity observed in 11-22% of patients and as such increases the risk of a severe disease, requiring more intense interventions and increasing mortality [17][18][19][20][21][22] . Second, SARS-CoV-2 infection seems to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients 23 , and pancreatic enlargement and abnormal amylase or lipase levels in 7.5-17% of patients 9,22 . Third, metabolic dysregulation has been observed in patients with COVID-19 as:(1) increased hyperglycaemia in patients with type 2 diabetes 24 ; (2) ketoacidosis in 2-6.4% of diabetic and non-diabetic patients 18,25 ; and (3), in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by (4) new-onset type 1 diabetes mellitus (T1DM) in the absence of autoantibodies [26][27][28] . In a cohort study of patients with diabetes, hyperglycaemia was reported in more than 50% of all cases, and almost a third experienced diabetic ketoacidosis 29 . Finally, a multicentre study found an 80% increase of new-onset T1DM in children during the COVID-19 pandemic 30 . In accordance, a recent meta-analysis summarizes that severe SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

Mouse embryonic stem (ES) cells differentiate into cells of all three primary germ layers including endodermal cells that produce insulin in vitro.We show that constitutive expression of Pax4 (Pax4 ؉ ), and to a lesser extent Pdx1 (Pdx1 ؉ ), affects the differentiation of ES cells and significantly promote the development of insulin-producing cells. In Pax4 overexpressing R1 ES cells, isl-1, ngn3, insulin, islet amyloid polypeptide, and glucose transporter 2 (Glut-2) mRNA levels increase significantly. The number of nestinexpressing (nestin؉) cells also increases. Constitutive Pax4 expression combined with selection of nestin؉ cells and histotypic culture conditions give rise to spheroids containing insulin-positive granules typical of embryonal and adult ␤ cells. In response to glucose, Pax4 ؉ and wild-type ES-derived cells release insulin. Transplantation of these cells into streptozotocin-treated diabetic mice results in a normalization of blood glucose levels. We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin.

The nuclear factor of activated T cell (NFAT) proteins are a family of Ca 2 þ /calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation and cardiac valve development. We demonstrate that NFATc1 is commonly overexpressed in pancreatic carcinomas and enhances the malignant potential of tumor cells through transcriptional activation of the c-myc oncogene. Activated NFATc1 directly binds to a specific element within the proximal c-myc promoter and upregulates c-myc transcription, ultimately resulting in increased cell proliferation and enhanced anchorageindependent growth. Conversely, c-myc transcription and anchorage-dependent and -independent cell growth is significantly attenuated by inhibition of Ca 2 þ /calcineurin signaling or siRNA-mediated knock down of NFATc1 expression. Together, these results demonstrate that ectopic activation of NFATc1 and the Ca 2 þ /calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer.

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CUTL1, also known as CDP, Cut, or Cux-1, is a homeodomain transcriptional regulator known to be involved in development and cell cycle progression. Here we report that CUTL1 activity is associated with increased migration and invasiveness in numerous tumor cell lines, both in vitro and in vivo. Furthermore, we identify CUTL1 as a transcriptional target of transforming growth factor beta and a mediator of its promigratory effects. CUTL1 activates a transcriptional program regulating genes involved in cell motility, invasion, and extracellular matrix composition. CUTL1 expression is significantly increased in high-grade carcinomas and is inversely correlated with survival in breast cancer. This suggests that CUTL1 plays a central role in coordinating a gene expression program associated with cell motility and tumor progression.

ObjectiveThe generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment.DesignWe designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.ResultsExtensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids.ConclusionsTaken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.

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