Cognitive-behavioral and dietary weight loss intervention in adult kidney transplant recipients with overweight and obesity: Results of a pilot RCT study (Adi-KTx).

The obesity epidemic and its health consequences have not spared the population of kidney transplant (KTx) candidates and recipients. In addition, KTx recipients are susceptible to weight gain after transplantation. Overweight and obesity after KTx are strongly associated with adverse outcomes. Therefore, we designed a randomized controlled, mono-center study to specifically test the effectiveness of a primarily cognitive-behavioral approach supplemented by nutritional counseling for weight reduction following KTx as the intervention group (IG) in comparison to a brief self-guided intervention as control group (CG). The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00017226). Fifty-six KTx patients with a BMI from 27 to 40 kg/m2 were included in this study and randomized to the IG or CG. Main outcome was the number of participants achieving a 5% weight loss during the treatment phase. Additionally, participants were assessed 6 and 12 months after the end of the 6-month treatment phase. Participants significantly lost weight without group differences. 32.0% (n = 8) of the patients in the IG and 16.7% (n = 4) of the patients in the CG achieved a weight loss of 5% or more. Weight loss was largely maintained during follow-up. Retention and acceptance rate in the IG was high, with 25 (out of 28) patients completing all 12 sessions and one patient completing 11 sessions. Short-term, cognitive-behaviorally oriented weight loss treatment seems to be feasible and acceptable for patients after KTx who suffer from overweight or obesity. This clinical trial was ongoing at the onset of the COVID-19 pandemic which might have influenced study conduct and results. Clinical Trial Registration: https://clinicaltrials.gov/ DRKS-ID: DRKS00017226.

Renal cell carcinoma in kidney transplant recipients: descriptive analysis and overview of a major German transplant center.

Aim: Elevated risk of malignancy-related death after renal transplantation is reported and renal malignancy was ranked as the third most frequent site of malignancy-related death. However, there is a lack of data characterizing renal cell carcinoma associated with end-stage renal disease and kidney transplantation. Patients & methods: We retrospectively identified 5250 patients who underwent kidney transplantation at the Hannover Medical School since 1970. Results: 124 patients with renal cell carcinoma (incidence 2.36%) were identified. Among all patients, metastatic recurrence was noted in 4.8%. In multivariate analysis, tumor stage and hemoglobin were identified as independent prognostic markers of OS, while tumor grading was predictive for disease recurrence. Conclusion: Apart from showing the prognostic value of tumor staging and hemoglobin, our data suggest that a risk adapted approach for early transplantation is feasible.

Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia In Vivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro.

BACKGROUND: Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. METHODS: Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. RESULTS: Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. CONCLUSIONS: Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine.

STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival.

OBJECTIVE: Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model. METHODS: Wistar-Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 micromol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation. RESULTS: As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6+/-0.5 days to 7.8+/-1.3 days and 7.4+/-0.5 days, respectively (mean+/-S.D., p<0.01, n=5 in each group). Immunohistochemical examination on days 1, 3 and 6 revealed a marked reduction of infiltrating leukocytes (AP-1 dODN: 85%, STAT-1 dODN: 50%), namely T-cells, in the dODN-perfused grafts at day 3 post transplantation. In addition, as demonstrated by immunohistochemical analysis, endothelial expression of ICAM-1 and VCAM-1 was found to be markedly reduced in dODN-treated grafts. CONCLUSION: Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.

Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure.

BACKGROUND: The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis. METHODS AND RESULTS: Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 microg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P<0.05), although hematocrit levels were similar in both groups. Darbepoetin treatment ameliorated endothelial damage; attenuated the composite tissue injury score (saline 1.9+/-0.4; darbepoetin 0.4+/-0.2; P<0.001), which included vascular sclerosis, glomerulosclerosis, and tubulointerstitial damage; and preserved renal function. We found persistent activation of the pro-survival Akt signaling pathway in endothelial and epithelial glomerular cells in darbepoetin-treated animals, accompanied by a significant reduction of apoptotic cell death in renal tissue. CONCLUSIONS: Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.

Glucose-induced TGF-beta1 and TGF-beta receptor-1 expression in vascular smooth muscle cells is mediated by protein kinase C-alpha.

Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-beta1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC-alpha in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-beta1 and its receptors (TGF-beta-R1 and -R2) are mediated by activation of this PKC isoform. TGF-beta1 and TGF-beta-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC-alpha was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-beta1 and TGF-beta-R1 expression but not TGF-beta-R2 expression. PKC inhibitors and specific PKC-alpha downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-beta, -epsilon, and -zeta had no influence. PKC-alpha overexpression increased TGF-beta1 and TGF-beta-R1 expression but not TGF-beta-R2 expression. PKC-alpha microinjection into individual VSMCs also increased TGF-beta1 and TGF-beta-R immunofluorescence. Last, VSMCs from PKC-alpha-deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-beta1 and TGF-beta-R1 expression is mediated by PKC-alpha. Our findings suggest an autocrine feedback mechanism and a possible role for PKC-alpha in diabetic vascular disease.