Abstract Background and Aims Chronic active antibody-mediated rejection (caABMR) causes 40% of long-term graft failure after kidney transplantation (KT). Early treatment is of great importance, however, hard clinical evidence is still lacking. Currently the combination of plasmapheresis (PF), rituximab and intravenous immunoglobulin is used as standard treatment. Tocilizumab (TCZ) is a monoclonal antibody, IL-6 receptor antagonist, and it inhibits the production of donor-specific antibodies (DSA). We hypothesized that tocilizumab administration has an additional effect on graft survival and non-inferior to standard therapy in KT patients with ABMR. Method Retrospective single-center noninferiority case-control study was performed by involving 73 KT patients (43.5 ± 14.3 years, females 31, eGFR 19.5 ± 13.4) with biopsy proven ABMR diagnosed between June 2017 and May 2022. 19 patients received 8 mg/kg intravenous TCZ therapy for 6 months (12 aABMR, 7 caABMR, 38.6 ± 12.8 years, females 6). In the control group (C, n=54, 10 aABMR, 44 caABMR, 45.2 ± 14.5 years, females 25), 20 patients received plasmapheresis treatment, the rest stayed on optimized maintenance therapy (tacrolimus, mycophenolic acid, prednisolone). Baseline demographic data, standard laboratory data, proteinuria and DSA level were also monitored and analyzed. Results Graft loss occurred in 13 cases (6 aABMR, 7 caABMR) in KT on TCZ therapy and 43 (6 aABMR, 37 caABMR) in C group, meaning significantly lower risk of graft loss in the TCZ group (RR 0.69, p=0.036) during the median follow-up of 11.3 (IQR 2.5-23.1) months. In TCZ group, all caABMR patients lost their graft during the observation. In TCZ group, 1 year after the TCZ treatment, DSA (pooled) was lower (7028 (575-17782) versus 1605 (551-16903), p<0.05). Conclusion Early administration of TCZ seems to be noninferior to standard therapy and effective to prevent early graft loss as part of standard therapy in aABMR. Further clinical studies are needed to clarify clinical indications of TCZ and its long-term effects on the course of chronic active ABMR.

BACKGROUND:Prophylactic administration of valganciclovir (VG) is an accepted method for the prevention of cytomegalovirus (CMV) infection after kidney transplantation (KTx). The standard dosage of oral VG is 900 mg/day, adjusted to renal function. There is growing evidence that low-dose 450 mg/day VG might be safe and effective. We compared low-dose vs standard-dose prophylaxis after KTx in a single-center follow-up study. METHODS:Data from 603 renal transplantations at a single center were retrospectively analyzed (2011-2014, 12-month follow-up). Recipients with donor IgG positive-recipient IgG positive (D+/R+), (D+/R-), and (D-/R+) CMV serostatus were routinely treated with 450 mg/day VG for 3 months. Based on the same prophylactic dose, patients could be categorized into two groups according to their postoperative renal function: those receiving standard-dose VG due to a lower estimated glomerular filtration rate (eGFR) (average eGFR<60 mL/min/1.73 m2) and those receiving low-dose VG due to higher eGFR (average eGFR>60 mL/min/1.73 m2). RESULTS:Estimated glomerular filtration rate-based VG serum alterations significantly affected the risk of CMV infection with a higher incidence in higher VG levels (standard-dose: 357 patients, CMV: 33 cases (9.2 %); low-dose: 246 patients, CMV: 10 cases (4.1%). The occurrence of known risk factors: serologic risk distribution and rate of induction therapy were not statistically different between the 2 groups. Treatment of an acute rejection episode influenced the infection rate significantly in the standard-dose group. As a side effect of prophylaxis, leucopenia (<3G/L) was 2.46 times higher in standard-dose vs low-dose group. CONCLUSION:Low-dose VG administration is safe and non-inferior to the standard dose in the prophylaxis of CMV infection after KTx.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current treatments for DKD do not halt renal injury progression, highlighting an urgent need for therapies targeting key disease mechanisms. Our previous studies demonstrated that activating the Sigma-1 receptor (S1R) with fluvoxamine (FLU) protects against acute kidney injury by inhibiting inflammation and ameliorating the effect of hypoxia. Based on these, we hypothesized that FLU might exert a similar protective effect in DKD. Diabetes was induced in male Wistar rats using streptozotocin, followed by a seven-week FLU treatment. Metabolic and renal parameters were assessed along with a histological analysis of glomerular damage and fibrosis. The effects of FLU on inflammation, hypoxia, and fibrosis were tested in human proximal tubular cells and normal rat kidney fibroblasts. FLU improved renal function and reduced glomerular damage and tubulointerstitial fibrosis. It also mitigated inflammation by reducing TLR4, IL6, and NFKB1 expressions and moderated the cellular response to tubular hypoxia. Additionally, FLU suppressed TGF-beta 1-induced fibrotic processes and fibroblast transformation. These findings suggest that S1R activation can slow DKD progression and protect renal function by modulating critical inflammatory, hypoxic, and fibrotic pathways; therefore, it might serve as a promising novel drug target for preventing DKD.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin–angiotensin–aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima–media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Metabolic diseases, particularly diabetes mellitus (DM), are significant global public health concerns. Despite the widespread use of standard-of-care therapies, cardiovascular disease (CVD) remains the leading cause of death among diabetic patients. Early and evidence-based interventions to reduce CVD are urgently needed. Large clinical trials have recently shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) ameliorate adverse cardiorenal outcomes in patients with type 2 DM. These quite unexpected positive results represent a paradigm shift in type 2 DM management, from the sole importance of glycemic control to the simultaneous improvement of cardiovascular outcomes. Moreover, SGLT2i is also found to be cardio- and nephroprotective in non-diabetic patients. Several mechanisms, which may be potentially independent or at least separate from the reduction in blood glucose levels, have already been identified behind the beneficial effect of these drugs. However, there is still much to be understood regarding the exact pathomechanisms. This review provides an overview of the current literature and sheds light on the modes of action of novel antidiabetic drugs, focusing on inflammation, oxidative stress, and fibrosis.

Kidney transplantation is the preferred treatment for patients with end-stage kidney disease. Maintaining organ viability between donation and transplantation, as well as minimizing ischemic injury, are critically important for long-term graft function and survival. Moreover, the increasing shortage of transplantable organs is a considerable problem; thus, optimizing the condition of grafts is a pivotal task. Here, rodent models of kidney transplantation and cold storage were used to demonstrate that supplementation of a preservation solution with Sigma-1 receptor (S1R) agonist fluvoxamine (FLU) reduces cold and warm ischemic injury. Post-transplant kidney function was improved, histological injury was mitigated, and mRNA expression of two tubular injury markers-kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin-was robustly reduced. In addition, renal inflammation was diminished, as shown by reduced leukocyte infiltration and pro-inflammatory cytokine expression. In the cold ischemia model, FLU ameliorated structural injury profoundly after 2 h as well as 24 h. The reduced number of TUNEL-positive and Caspase 3-positive cells suggests the anti-apoptotic effect of FLU. None of these beneficial effects of FLU were observed in S1R(-/-) mice. Of note, organ damage in FLU-treated kidneys after 24 h of cold storage was similar to just 2 h without FLU. These results indicate that S1R agonists can prolong storage time and have great potential in improving organ preservation and in alleviating the problem of organ shortages.

Introduction Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. Methods Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip .) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po .). Results DAPA decreased blood glucose levels (D: 37±2.7 vs . D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. Conclusions These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

Abstract BACKGROUND AND AIMS End-stage renal disease affects nearly 2 million people worldwide. The disease is associated with an irreversible deterioration in renal function and can only be treated by dialysis or kidney transplantation (KTx). KTx is associated with better long-term outcomes and quality of life compared with dialysis, but the shortage of donor organs is a serious and unsolved problem. Graft survival is highly dependent on the extent of cold and warm ischemic injury during Tx. We recently described the renoprotective effects of Sigma-1 receptor (S1R) agonist treatment in IRI. Thus, our aim was to develop a novel preservation solution that, with the addition of S1R agonist compounds, minimizes ischemic damage in order to improve the condition of grafts and so increase the number of organs suitable for Tx. METHOD Kidneys of male Wistar rats were perfused and placed in ice cold (i) custodiol preservation solution; custodiol containing S1R agonists, (ii) fluvoxamine or (iii) SA-4503 for 2 h, then autotransplanted and sacrificed 24 h after reperfusion. Sham-operated rats served as controls. In a second experiment, kidneys of wild-type and S1R knockout mice were perfused and placed in an ice-cold preservation solution containing an original, selective S1R agonist compound (VCC) for 24 h of cold ischemia and tissue samples were collected. Renal function parameters were determined. Renal expression of tubular injury markers (Kim-1, Ngal) and inflammatory cytokines (Il-1α, Il-6, Tnf-α, Mcp-1) were measured. Periodic acid-Schiff staining was performed on kidney tissue sections to evaluate structural changes. CD45 immunostaining was performed on kidney sections to determine the extent of leukocyte infiltration. DNA fragmentation resulted by apoptotic events in the kidney was evaluated by TUNEL-assay. RESULTS S1R agonists mitigated renal functional impairment and tubular dilatation following Tx. Expression of early and sensitive tubular injury markers was markedly less elevated in S1R agonist-treated kidneys. S1R agonists alleviated renal apoptosis as shown on TUNEL-stained kidney sections. Decreased numbers of CD45 + leukocytes and decreased inflammatory cytokine expressions confirmed the anti-inflammatory effect of S1R agonists. The S1R agonist VCC compound mitigated cold ischemic structural kidney damage in wild-type but not in S1R KO mice, which confirms the protective role of the receptor. CONCLUSION The addition of S1R agonists to the preservation solution during Tx improves graft function and alleviates structural damage, thus improving long-term outcomes. S1R agonists reduce graft injury during cold storage, therefore the number of transplantable donor organs can be increased. FUNDING OTKA PD-131 637; FK-124 491; 2020–4.1.1.-TKP2020-6 183 069 269; 2020–4.1.1.-TKP2020-6 183 169 273; KDP-2020/1 019 145.

Patients facing severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infections with comorbidities, especially patients whose immune system is weakened have higher chances to face severe outcomes. One of the main reasons behind the suppression of the immune system is iatrogenic, in patients who have autoimmune diseases and/or had an organ transplant. Although there are studies that are examining immunocompromised and/or transplanted patients with COVID-19 infection, furthermore there is a limited number of studies available which are dealing with COVID-19 in pregnant women; however, it is unique and is worth reporting when these factors are coexisting. In this study, we present the case of a 33-year-old Caucasian pregnant woman, who had a kidney transplant in 2009 and contracted the SARS-CoV-2 virus on the 26th gestational week, in 2021. After her infection, superimposed preeclampsia was diagnosed and due to the worsening flowmetric parameters, she gave birth to a premature male newborn with cesarean section. Our kidney transplant patient’s case highlights how COVID-19 disease can lead to preeclampsia and artificial termination of gestation.

BACKGROUND:Publications from the last decade have increased knowledge regarding long-term risks after kidney donation. We wanted to perform a survey to assess how transplant professionals in Europe inform potential kidney donors regarding long-term risks. The objectives of the survey were to determine how they inform donors and to what extent, and to evaluate the degree of variation.METHODS:All transplant professionals involved in the evaluation process were considered eligible, regardless of the type of profession. The survey was dispatched as a link to a web-based survey. The subjects included questions on demographics, the information policy of the respondent and the use of risk calculators, including the difference of relative and absolute risks and how the respondents themselves understood these risks.RESULTS:The main finding was a large variation in how often different long-term risks were discussed with the potential donors, i.e. from always to never. Eighty percent of respondents stated that they always discuss the risk of end-stage renal disease, while 56% of respondents stated that they always discuss the risk of preeclampsia. Twenty percent of respondents answered correctly regarding the relationship between absolute and relative risks for rare outcomes.CONCLUSIONS:The use of written information and checklists should be encouraged. This may improve standardization regarding the information provided to potential living kidney donors in Europe. There is a need for information and education among European transplant professionals regarding long-term risks after kidney donation and how to interpret and present these risks.

Abstract Background and Aims Diabetic kidney disease (DKD) is a major cause of chronic kidney disease and end stage renal disease, therefore identification of novel therapeutic strategies that reduce the risk of DKD is a research priority. Recent large clinical trials suggest that improved renal outcomes by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects. Enhanced glucose reabsorption in diabetes leads to tubular hypoxia triggering fibrotic response. Hyperglycemia is in strong association with increased protein O-GlcNAcylation, a post-translational modification contributing to renal fibrosis. Considering the proximal tubular involvement in DKD pathogenesis and the key role of SGLT2 in glucose metabolism, here we investigated the effects of SGLT2i on tubular hypoxia and O-GlcNAcylation. Method Diabetes (D) was induced by streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day, po.). Metabolic parameters and renal function were evaluated. Novel urinary biomarkers of extracellular matrix remodeling (Pro-C3, uC3M, tumstatin) and profibrotic growth factors (TGF-β, CTGF, PDGF) were determined. Histological evaluation of glomerular damage (PAS), tubulointerstitial fibrosis (Masson’s trichrome, Picrosirius red) and fibronectin accumulation were performed. The effect of hyperglycemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions for 24 hours. HG cells were treated with 10 µM DAPA. O-GlcNAc, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber (1% O2) for 2 hours. Hypoxic injury was investigated using three different methods (qRT-PCR, Western blot, immunofluorescence analysis). HIF-1α, EPO, VEGFA and profibrotic factors were measured. Results DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p<0.01). In parallel, novel urinary biomarkers of extracellular matrix remodeling, profibrotic growth factor expressions and extensive fibrotic tissue accumulation were reduced in the kidney. DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Moreover, DAPA treatment prevented HIF-1α translocation to the nucleus, thereby confirming abolished HIF-1α activation. EPO, VEGFA and profibrotic factor levels were also increased in hypoxia and DAPA prevented EPO, TGFB and PDGF elevation. Conclusion These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia and fibrosis, a vicious trio, which seem to be targeted by SGLT2i. All these mechanisms are important parts in the puzzle of the complex system behind the protective effect of SGLT2i. OTKA-FK124491-K135398, 2017-1.3.1-VKE-2017-00006, 2020-4.1.1.-TKP2020-6183169273, 2020-4.1.1.-TKP2020-6183069269

Abstract Background and Aims Tacrolimus is an integral part of the immunosuppressive regimen after solid organ transplantation. Due to its narrow therapeutic window, it requires frequent serum trough level (C0) monitoring and dose adjustment. Both over-and under treatment may have harmful effects regarding overall mortality and graft survival due to increased risk of cardiovascular diseases, malignancies, new onset diabetes and rejection. C0 and total daily dose ratio (CD) has recently been suggested as a potential predictor of worse graft outcome in the early period after transplantation, however, long term prospective studies are lacking. We hypothesized the association between lower CD ratio and increased risk of death with functioning graft (DWFG), graft loss (GL) and overall death (D) in our prospective cohort study. Method Our study included 386 prevalent kidney transplant recipients (205(53%) males, median and IQR age of 47.5 (13.2) years, eGFR 53.5 (22.5) ml/min/1.73m2, time since last transplant 51 (26-79) months) out of a total of 993 enrolled between 2006-2007. Sociodemographic, past medical history, clinical and laboratory data were collected and CD was recorded at baseline and 1 year after the enrollment. The associations between CD and CD2 ratios and above mentioned outcomes were examined using survival models.. Results The median and IQR of CD was 2.1(1.4-3.2) at baseline and 2.0 (1.3-3.0) 1 year later (CD2). There was 46 (11.9%) DWFG, 79 (20.5%) GL and 68 (17.6%) D, respectively. After adjustment for important confounders (age, gender, eGFR, Charlson score, dialysis duration, donor age, rejection), neither CD (DWGL: HR 0.56(0.30-1.03) p=0.06; GL: HR 0.82(0.50-1.36) p=0.46; D: HR 0.79(0.48-1.32) p=0.38) nor CD2 (DWGL: HR 1.12(0.54-2.31) p=0.74; GL: HR 0.76(0.61-1.97) p=0.78; D: HR 1.19(0.64-2.20) p=0.59) found to be predictors of the outcomes. Conclusion CD ratio was not associated with increased risk of death with functioning graft, graft loss or overall death in our prevalent kidney transplant recipients.

Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.

Abstract Background and Aims The prevalence of end-stage renal disease (ESRD) has increased ten times higher in the past twenty years, where renal replacement therapy (dialysis or kidney transplantation (KTx)) is the sole life-saving treatment. KTx is the preferred option as it is associated with improved survival and quality of life as well. Delayed graft function (DGF) is one of the main problems affecting long-term kidney survival. Brain-derived neurotrophic factor (BDNF) signalling pathways play pivotal role in mitigating cerebral ischemia/reperfusion injury (IRI), however the relation of BDNF and IRI in KTx is unknown. The aim of our human clinical study was to explore the relationship between serum BDNF concentration, BDNF gene polymorphism and renal graft function after KTx. Method Study characteristics: We enrolled 59 ESRD patients with average age of 54.8±12 years who received KTx. Proportion of male patients was 57%. Average cold ischemic time was 927±310 min, warm ischemic time was 54.5±39 min. DGF occurred in 5 cases. Baseline triple immunosuppression therapy consisted of tacrolimus, mycophenolate or everolimus, and prednisolone. Until now, 44 patients completed the 2 years follow-up. For a comparable control group, we collected blood samples from 79 healthy volunteers with average age of 53.9±16 years and with male gender proportion of 52%. Serum BDNF, creatinine, blood urea nitrogen, haemoglobin, blood glucose level and thrombocyte numbers were measured before KTx and 1 week, 1-, 3-, 6 months, and 1-, 2 years after transplantation, as well as in controls. GFR was estimated based on the CKD-EPI formula. BDNF Val66Met polymorphism was determined by PCR-RFLP. Results There was no difference in genotype or allele distribution between any of the groups, and no correlation could be observed between serum BDNF and different genotypes either. Serum BDNF level was lower in ESRD patients than healthy controls (p=0.03). There was a weak correlation and marginal significance (p=0.056) between eGFR and serum BDNF level in controls, while in KTx recipients this correlation reached higher significance (p=0.01). Above median BDNF values at 1 month after KTx were predictive for better graft function during the 2 observed years. Conclusion Our preliminary human study proposes that BDNF could be a novel biomarker of posttransplant graft function, however further clinical studies with significantly larger population are definitely needed to confirm these results.

Background and aimsIdentification of novel therapeutic strategies that reduce the risk of diabetic kidney disease (DKD) is a research priority. Clinical data suggest that improved renal outcomes by sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects; however, mechanisms are still elusive. Enhanced glucose reabsorption in diabetes leads to tubular hypoxia playing part in fibrogenesis. Hyperglycemia is in strong association with increased protein O‐GlcNAcylation, a post‐translational modification contributing to renal fibrosis. Considering the proximal tubular involvement in DKD pathogenesis and the key role of SGLT2 in glucose metabolism, here we investigated the effects of SGLT2i on tubular hypoxia and O‐GlcNAcylation.MethodsDiabetes (D) was induced by streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day, po.). Metabolic parameters and renal function were evaluated. Novel urinary biomarkers of extracellular matrix remodeling (Pro‐C3, uC3M, tumstatin) and profibrotic growth factors (TGF‐β, CTGF, PDGF) were determined. Histological evaluation of glomerular damage (PAS) and tubulointerstitial fibrosis (Masson’s trichrome, Picrosirius red, fibronectin) were performed. The effect of hyperglycemia was tested in human proximal tubular epithelial cells (HK‐2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions for 24 hours. HG cells were treated with 10 μM DAPA. O‐GlcNAc, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 μM DAPA and were placed in a hypoxic chamber (1% O2) for 2 hours. HIF‐1α, EPO, VEGFA and profibrotic factors were measured. Immunocytochemistry (ICC) staining for HIF‐1α was performed.ResultsDAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p<0.01). Subsequently novel fibrosis biomarkers, profibrotic growth factor expressions and renal fibrotic tissue accumulation were reduced. DAPA minimized hyperglycemia‐induced total protein O‐GlcNAcylation in HK‐2 cells. Hypoxia‐induced HIF‐1α elevation was suspended by DAPA treatment. EPO, VEGFA and profibrotic factor levels were also increased in hypoxia and DAPA prevented EPO and CTGF elevation.ConclusionsThese data highlight the role of ameliorated O‐GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia and fibrosis, a vicious trio that could be targeted by SGLT2i. All these mechanisms are important parts in the puzzle of the complex system behind the protective effect of SGLT2i.Support or Funding InformationOTKA‐FK124491, VKE‐2017‐00006, FIKP, UNKP‐19‐3‐III‐SE‐6, EFOP‐VEKOP‐16‐2017‐0009

Introduction and aimsKidney transplantation (Tx) is associated with better quality of life and reduced costs compared to dialysis, but the shortage in donor organs is a limiting factor. Graft survival is highly dependent on the extent of ischemia/reperfusion injury (IRI) during Tx. We recently described the renoprotective effects of Sigma‐1 receptor (S1R) agonist treatment in renal IRI. Thus, our aim was to develop a preservation solution which minimizes ischemic graft damage in order to improve Tx outcomes and to increase the number of organs suitable for Tx.MethodsKidneys of male Wistar rats were perfused and placed in ice cold (i) Custodiol preservation solution; Custodiol containing S1R agonists (ii) fluvoxamine or (iii) SA‐4503 for 2 hours, then autotransplanted and sacrificed 24 hours after reperfusion. Sham‐operated rats served as controls. In a second experiment kidneys of rats as well as wild‐type and S1R knockout mice were perfused and placed in ice cold Custodiol or Custodiol containing various selective S1R agonists for 2/3/8/24 hours and tissue samples were collected.ResultsS1R agonists mitigated renal functional impairment and tubular dilatation following Tx. Expression of early and sensitive tubular injury markers Kim1 and Ngal were markedly less elevated in S1R agonist‐treated kidneys. S1R agonists alleviated renal apoptosis as shown on TUNEL‐stained kidney sections, decreased apoptotic Bax expression, while increased anti‐apoptotic Bcl2 expression. Reduced number of CD45+ leukocytes and reduced inflammatory cytokine (Mcp1, Il1a, Il6, Tnf) expressions confirmed the anti‐inflammatory effect of S1R agonists. All S1R agonists mitigated cold ischemic structural kidney damage at all time points.ConclusionThe addition of S1R agonists to the preservation solution during Tx improves graft function and alleviates structural damage, thus improving long‐term outcomes. S1R agonists reduce graft injury during cold storage, therefore the number of transplantable donor organs can be increased.Support or Funding InformationGrants: VKE‐2017‐00006; OTKA PD‐131637; FK‐124491; K‐116928; NN‐114607; FIKP; STIA_18_KF

Absztrakt: Az új koronavírus okozta COVID–19-járvány kihívást jelent a szervátültetett betegek ellátását illetően is, ezért lényegesnek tartjuk az ezzel kapcsolatos friss ismeretek megosztását a hazai ellátásban dolgozók számára. Nagyobb esetszámmal májátültetettekről még nincsenek adatok az irodalomban, vesetranszplantáltak esetén azonban a spanyol és a francia adatbázisok 18,6%-os és 13%-os halálozásról számoltak be, ami kissé magasabb az ottani átlagpopulációénál. Tünetmentes esetekben SARS-CoV-2-pozitív PCR-eredmény birtokában nem szükséges a transzplantáltak immunszuppresszív terápiáján változtatni, azonban láz, gastrointestinalis vagy légúti tünetek kialakulását követően a mikofenolsav és mTOR-gátló készítmények elhagyása javasolt, és a kalcineurininhibitorok vérszintjét a legalacsonyabb effektív szintre kell csökkenteni. Tüdőkárosodás észlelését követően vesetranszplantáltak esetében a kalcineurininhibitorokat is le kell állítani, míg a májtranszplantáltak esetében a dózis csökkentése szükséges a fenntartó kortikoszteroid mellett. Ez utóbbi dózisának emelése szükséges hyperinflammatiós szindróma (HIS) kialakulásakor. A HIS terápiás befolyásolására transzplantáltakban is sikerrel lehet alkalmazni az IL1- és IL6-gátló monoklonális antitesteket. Célzott vírusellenes készítmény nem áll rendelkezésre, a legszerencsésebb, ha a beteg bevonható a remdesivir vagy a favipiravir klinikai vizsgálatába. A hidroxiklorokin transzplantáltaknak is adható, bár hatékonysága és biztonságossága kérdésessé vált. A lopinavir/ritonavir kombináció a kalcineurininhibitorokkal fennálló súlyos gyógyszerkölcsönhatás miatt nem adható. A SARS-CoV-2 cytopathiás hatása endotheldiszfunkciót okoz, amely prokoaguláns állapot kialakulásához vezet, emellett megváltozik a renin-angiotenzin-aldoszteron rendszer egyensúlya is. Fontos ezért a betegek kezelése során a thrombosisprofilaxis korai elkezdése alacsony molekulasúlyú heparinnal és alacsony dózisú acetilszalicilsavval. Az angiotenzinkonvertálóenzim-gátló (ACEI) és az angiotenzin-II-receptor-antagonista (ARB) terápiára beállított betegek kezelését a COVID–19 miatt nem szabad abbahagyni. Orv Hetil. 2020; 161(32): 1310–1321.

Transplant InternationalVolume 33, Issue 10 p. 1187-1189 Invited Commentary Is it the time to apply the model of Czech-Austrian kidney paired donation program? Adam Remport, Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary These authors contributed equally.Search for more papers by this authorLaszlo J. Wagner, orcid.org/0000-0001-6806-4076 Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary These authors contributed equally.Search for more papers by this authorMiklos Z. Molnar, Corresponding Author mzmolnar@uthsc.edu orcid.org/0000-0002-9665-330X Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA Division of Transplant Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA Correspondence Miklos Z. Molnar MD, PhD, FEBTM, FERA, FASN, Methodist Transplant Epidemiology Research Group, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Methodist University Hospital, 1211 Union Ave., Memphis, TN 38104, USA. Tel.: 1-901-516-0751; fax: 1-901-516-8994; e-mail: mzmolnar@uthsc.eduSearch for more papers by this author Adam Remport, Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary These authors contributed equally.Search for more papers by this authorLaszlo J. Wagner, orcid.org/0000-0001-6806-4076 Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary These authors contributed equally.Search for more papers by this authorMiklos Z. Molnar, Corresponding Author mzmolnar@uthsc.edu orcid.org/0000-0002-9665-330X Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary James D. Eason Transplant Institute, Methodist University Hospital, Memphis, TN, USA Division of Transplant Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA Correspondence Miklos Z. Molnar MD, PhD, FEBTM, FERA, FASN, Methodist Transplant Epidemiology Research Group, James D. Eason Transplant Institute, University of Tennessee Health Science Center, Methodist University Hospital, 1211 Union Ave., Memphis, TN 38104, USA. Tel.: 1-901-516-0751; fax: 1-901-516-8994; e-mail: mzmolnar@uthsc.eduSearch for more papers by this author First published: 20 June 2020 https://doi.org/10.1111/tri.13678 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume33, Issue10October 2020Pages 1187-1189 RelatedInformation