Targeting alternative splicing of fibronectin in human renal proximal tubule epithelial cells with antisense oligonucleotides to reduce EDA+ fibronectin production and block an autocrine loop that drives renal fibrosis.

TGFβ1 is a powerful regulator of fibrosis; secreted in a latent form, it becomes active after release from the latent complex. During tissue fibrosis, the EDA + isoform of cellular fibronectin is overexpressed. In pulmonary fibrosis it has been proposed that the fibronectin splice variant including an EDA domain (FN EDA+) activates latent TGFβ.

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial.

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure.

Fludrocortisone Is an Effective Treatment for Hyperkalaemic Metabolic Acidosis in Kidney Transplant Recipients on Tacrolimus: A Case Series.

Background: Hyperkalaemia with metabolic acidosis is common but under-reported following kidney transplantation. Calcineurin inhibitors, such as tacrolimus, are widely used in the management of transplant patients and are associated with the development of hyperkalaemia. We report on 10 renal transplant patients, treated with fludrocortisone, following identification of hyperkalaemic metabolic acidosis.

Safety and Efficacy of Kidney Transplants From Older Adult Living Donors: A Comparative Analysis of Donor and Recipient Outcomes.

Objectives: We investigated the safety of donor nephrectomy from older adult donors (age ≥60 years), as well as long-term donor, recipient, and graft outcomes.

Materials And Methods: We retrospectively analyzed data from 307 living donor kidney transplants from 1996 to 2016 and defined 2 cohorts based on donor age. Cohort A comprised donors aged 60 years and older, and cohort B comprised donors from 18 to 59 years old.

Evaluation of Urinary Biomarkers of Proximal Tubular Injury, Inflammation, and Fibrosis in Patients With Albuminuric and Nonalbuminuric Diabetic Kidney Disease.

Introduction: Albuminuric and nonalbuminuric pathways contribute to diabetic kidney disease. Proximal tubule and inflammation play important roles in these processes. Urinary biomarker(s) to detect early kidney damage and predict progression are needed.

High glucose-induced Smad3 linker phosphorylation and CCN2 expression are inhibited by dapagliflozin in a diabetic tubule epithelial cell model.

Background: In the kidney glucose is freely filtered by the glomerulus and, mainly, reabsorbed by sodium glucose cotransporter 2 (SGLT2) expressed in the early proximal tubule. Human proximal tubule epithelial cells (PTECs) undergo pathological and fibrotic changes seen in diabetic kidney disease (DKD) in response to elevated glucose. We developed a specific in vitro model of DKD using primary human PTECs with exposure to high D-glucose and TGF-β1 and propose a role for SGLT2 inhibition in regulating fibrosis.

Systematic Review and Meta-analysis of COVID-19 and Kidney Transplant Recipients, the South West London Kidney Transplant Network Experience.

Introduction: There is paucity of literature comparing outcomes of kidney transplant patients with COVID-19 to that of dialysis and waitlisted patients. This report describes our data, provides comparative analysis, together with a meta-analysis of published studies, and describes our protocols to restart the transplant program.

Methods: Data were analyzed on kidney transplant, dialysis, and waitlisted patients tested positive for SARS-CoV-2 (nasopharyngeal swab polymerase chain reaction [PCR] test) between March 1, 2020, and June 30, 2020, together with a meta-analysis of 16 studies.

The Characteristics, Dynamics, and the Risk of Death in COVID-19 Positive Dialysis Patients in London, UK.

Background: Patients on dialysis with frequent comorbidities, advanced age, and frailty, who visit treatment facilities frequently, are perhaps more prone to SARS-CoV-2 infection and related death-the risk factors and dynamics of which are unknown. The aim of this study was to investigate the hospital outcomes in patients on dialysis infected with SARS-CoV-2.

Methods: Data on 224 patients on hemodialysis between February 29, 2020 and May 15, 2020 with confirmed SARS-CoV-2 were analyzed for outcomes and potential risk factors for death, using a competing risk-regression model assessed by subdistribution hazards ratio (SHR).

Dilated Cardiomyopathy in an Adult Renal Transplant Recipient: Recovery Upon Tacrolimus to Sirolimus Switch: A Case Report.

The objective of immunosuppressive drugs used in solid organ transplantation is to achieve acceptable rejection rates, minimize infections, and prolong graft and patient survival. Cardiovascular disease is a major cause of death in kidney transplant recipients. The drugs commonly used to prevent rejection (calcineurin inhibitors [CNIs] and steroids) contribute to cardiac disease seen in transplant patients by increasing the risk of hypertension and diabetes.

COVID-19 infection in kidney transplant recipients.

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure.

Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients.

Background: The efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear.

Methods: This retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010-June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone.

Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies.

Background: Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements.

The Regulation of TGFβ1 Induced Fibronectin EDA Exon Alternative Splicing in Human Renal Proximal Tubule Epithelial Cells.

The EDA+ splice variant of fibronectin (Fn) is an early and important component of the extracellular matrix in renal fibrosis. In this work, we investigate cellular mechanisms of EDA+Fn production in human primary proximal tubule epithelial cells (PTECs). TGFβ1-induced EDA+Fn production was assessed by immunocytochemistry, PCR, and Western blotting.

Confusion after starting citalopram in a renal transplant patient.

The UK NICE (National Institute for Clinical Excellence) guidelines on management of depression in adults recommends use of selective serotonin re-uptake inhibitor (SSRI) as a first choice agent. Citalopram, an SSRI antidepressant, is a preferred antidepressant in those patients with concomitant chronic physical health problems. Hyponatraemia because of syndrome of inappropriate antiduretic hormone secrection has been reported with SSRI antidepressants but is usually mild and responds to fluid restriction and cessation of the drug.

Smad mediated regulation of inhibitor of DNA binding 2 and its role in phenotypic maintenance of human renal proximal tubule epithelial cells.

The basic-Helix-Loop-Helix family (bHLH) of transcriptional factors plays a major role in regulating cellular proliferation, differentiation and phenotype maintenance. The downregulation of one of the members of bHLH family protein, inhibitor of DNA binding 2 (Id2) has been shown to induce de-differentiation of epithelial cells. Opposing regulators of epithelial/mesenchymal phenotype in renal proximal tubule epithelial cells (PTEC), TGFβ1 and BMP7 also have counter-regulatory effects in models of renal fibrosis.

Hyperparathyroidism in a renal transplant patient: an unusual cause of resistance to therapy.

A long-term renal transplant patient who was regularly followed up in the transplant clinic with stable renal allograft function was found to have elevated parathyroid hormone (PTH) levels on a biointact PTH assay. The elevated PTH levels were resistant to suppression on increasing doses of 1-alfacalcidol. Detailed history taking and clinical examination revealed the reason for apparent resistance to therapy.

Connective tissue growth factor-(CTGF, CCN2)--a marker, mediator and therapeutic target for renal fibrosis.

Connective tissue growth factor (CTGF, CCN2) is a key mediator of tissue fibrosis. CCN2 plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. In this review, we discuss the biology of CCN2 with a focus on the regulation of CCN2 gene, cellular mechanisms of profibrotic CCN2 effects and the current in vivo and in vitro evidence for the role of CCN2 in the development of renal fibrosis.

Tgf-beta auto-induction and connective tissue growth factor expression in human renal tubule epithelial cells requires N-ras.

Background/aims: Transforming growth factor (TGF) beta is strongly implicated in the progression of renal fibrosis. TGFbeta1 is reported to cause epithelial-mesenchymal transition, inhibition of epithelial cell proliferation, increased apoptosis, auto-induction of TGFbeta production and induction of secondary mediators of tissue fibrosis such as connective tissue growth factor (CTGF, CCN2). The aims of this study were to investigate the role of the Ras/MAP kinase pathway in TGFbeta1 inhibition of proliferation, TGFbeta auto-induction and TGFbeta1-induced CTGF expression in HKC human renal tubule epithelial cells.

The TGFbeta1-induced fibronectin in human renal proximal tubular epithelial cells is p38 MAP kinase dependent and Smad independent.

Background/aim: Transforming growth factor beta 1 (TGFbeta1) is a fibrokine implicated in the progression of renal fibrosis. Following TGFbeta1 receptor activation, a number of signalling pathways are stimulated. This study investigates the role of p38 mitogen-activated protein (MAP) kinase and Smad pathways in the TGFbeta1-induced fibronectin (FN) production.

The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1 responses in human proximal-tubule epithelial cells.

In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFbeta1-Smad (transforming growth factor-beta1-Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial-mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFbeta are critical Smad-dependent events in the development of tubulo-interstitial fibrosis.

TGF-beta1-induced connective tissue growth factor (CCN2) expression in human renal proximal tubule epithelial cells requires Ras/MEK/ERK and Smad signalling.

Background: Connective tissue growth factor (CTGF, CCN2) plays a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and mediating many of the pro-fibrotic effects of transforming growth factor (TGF)-beta. CCN2 induction by TGF-beta in renal proximal tubule epithelial cells (PTECs) is likely to play an important role in the development of tubulointerstitial fibrosis. In this study, we investigated the induction of CCN2 by TGF-beta1 and the possible mechanisms of this induction in human PTECs.

Intradialytic exercise as anabolic therapy in haemodialysis patients -- a pilot study.

Haemodialysis (HD) patients are characterized by muscle wasting and consequently decreased physical functioning and poor outcome. This pilot study investigated if a novel intradialytic exercise programme could increase lean mass via up-regulation of the insulin-like growth factor (IGF) system. Nine HD patients were assessed before (w-12) and after a 3-month control phase (w0), after a three-month intradialytic interval training programme using high intensity cycle exercise (w12), and after a withdrawal of treatment phase (w24).