Complement-ary matching: A definite maybe.
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Complement Activation↗
Biomedical subjects
Duska Dragun
Publications and source records attributed to Duska Dragun.
A systematic approach to managing pregnant dialysis patients--the importance of an intensified haemodiafiltration protocol.
BACKGROUND: Pregnancy is still uncommon in women on maintenance dialysis; and their outcomes is reported to have improved to 40% to 85% live births. Here, we report the successful multidisciplinary management of five consecutive pregnant dialysis patients. METHODS: In our centre, we treated each of five patients with a systematically intensified haemodiafiltration protocol, increased erythropoeitin dosages, a generous administration of water-soluble vitamins and trace elements, and a multidisciplinary clinical management approach with a very low threshold for hospitalization. RESULTS: All patients received haemodiafiltration at least 6 times/week, an average of 28.6+/-6.3 h/week. We achieved a mean weekly Kt/Vdp of 9.6+/-1.4 and urea reduction rates of 54.8+/-29.4%. The mean erythropoeitin dose was increased from 169+/-94 IU/kg/week prior to admission at our centre to 314+/-111 IU/kg/week after the initiation of intensified haemodiafiltration. Haemoglobin levels increased from 8.9+/-1.9 g/dl to 10.7+/-0.5 g/dl. Mean gestational age at delivery was 32.8+/-3.3 weeks and mean birth weight was 1765+/-554 g. The length of hospital stay amounted to 85+/-61 days for the mothers and 26+/-18 days for the newborns, and all were discharged healthy. CONCLUSIONS: These modified management guidelines led to favourable outcomes in all our patients, and may help to guide therapy in other pregnant dialysis patients.
Adult↗
Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.
BACKGROUND: Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients. METHODS: We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not. Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT1) receptor might be involved. RESULTS: Activating IgG antibodies targeting the AT1 receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT1 receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT1-receptor-activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-kappaB. The AT1 antagonist losartan blocked agonistic AT1-receptor antibody-mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model. CONCLUSIONS: A non-HLA, AT1-receptor-mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT1-receptor antibodies or from pharmacologic blockade of AT1 receptors.
Angiotensin II Type 1 Receptor Blockers↗
Differential regulation of smooth muscle markers in human bone marrow-derived mesenchymal stem cells.
OBJECTIVE: To study smooth-muscle differentiation and de-differentiation of human bone marrow-derived mesenchymal stem cells (MSCs), which have been shown to enter the circulation and to contribute to vascular repair and atherosclerosis. DESIGN: Human MSCs from bone marrow were cultured with 20% fetal calf serum (FCS) or with 10% FCS and various concentrations of dimethyl sulfoxide (DMSO). Expression of smooth muscle markers was determined by Western blot analysis and immunofluorescence. For signalling studies, involvement of the mammalian target of rapamycin (mTOR) pathway was tested by treatment with rapamycin. RESULTS: MSCs cultured with 20% FCS acquired a smooth muscle-like appearance and expressed the smooth muscle (sm) markers sm-alpha-actin, desmin, sm-calponin and myosin light chain kinase (MLCK). DMSO induced a spindle-like morphology with marked reduction of stress fibers. As judged by Western blot analysis, treatment with 2.5% DMSO strongly downregulated expression of sm-calponin (-85%), short MLCK (-98%) and sm-alpha-actin expression (-51%). Reduced calponin expression was detected by day 2 of treatment with 0.5-2.5% DMSO. After withdrawal of DMSO, MSCs regained high expression of sm-calponin. Treatment with 6 nmol/l rapamycin partly antagonized the effect of DMSO, indicating the involvement of mTOR in regulation of the smooth muscle phenotype of MSCs. CONCLUSIONS: DMSO strongly downregulates the smooth muscle markers sm-calponin, short MLCK and sm-alpha-actin in human MSCs, indicating a transition from a smooth muscle-like phenotype to an undifferentiated state by an mTOR-dependent mechanism. Regulating the phenotype of human MSCs may be of relevance for novel therapeutic approaches in atherosclerosis and intimal hyperplasia after vascular injury.
Actins↗
Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1)-mediated pathway and vascular oxidative injury in older-age rat renal transplants.
BACKGROUND: Older-age renal allografts are associated with inferior survival; however, the mechanisms are unclear. Reactive oxygen species participate in aging and in chronic vascular disease. We investigated how mediators of oxidative stress may increase allograft susceptibility to vascular injury. METHODS: We employed the low-responder allogeneic F344-to-Lew rat renal transplantation model. We used nonimmunosuppressed young (donors and recipients aged 12 weeks), old (donors and recipients aged 52 weeks), and old-to-young animal (donors aged 52 weeks and recipients aged 12 weeks) combinations. Grafts were transplanted after 2 hours cold preservation in University of Wisconsin solution and harvested 1, 2, 7 and 10 days later. Additionally, old animals receiving continuous 1.5 mg/kg cyclosporine (CyA) immunosuppression were included. Renal allograft pathology was scored according to Banff criteria. We studied intragraft vascular adhesion molecule-1 (VCAM-1), lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), and hypochlorite-modified LDL expression as well as ED-1+ monocytes/macrophages and CD8+ lymphocyte infiltration. Intragraft in situ superoxide anion radical production was determined with dihydroethidium assay on cryosections. RESULTS: During the first 2 posttransplant days, old transplants demonstrated higher functional impairment and increased oxidative stress, while young transplant had higher ED-1+ monocytes/macrophage infiltration and VCAM-1 expression. The degree of VCAM-1 expression and ED-1+ monocytes/macrophage and CD8+ lymphocyte infiltration correlated at later time points directly with the transplant age. VCAM-1 and LOX-1 staining were localized predominantly on the endothelium of arterial vessels, shifting the distribution to vascular smooth muscle layer strongly dependent on donor age and the grade of vascular injury. LOX-1 staining colocalized with hypochlorite-modified epitopes in the media of injured arteries. We measured increased in situ superoxide anion radical production in corresponding areas. Immunosuppression with CyA had no protective effect on vascular injury and LOX-1 expression. CONCLUSION: Induction of LOX-1-related oxidation pathways and increased susceptibility to oxidative stress could play an important role in promoting vascular injury in old renal transplants independent of the recipient age.
Aging↗
FTY720 mediates apoptosis-independent lymphopenia in human renal allograft recipients: different effects on CD62L+ and CCR5+ T lymphocytes.
BACKGROUND: The sphingolipid FTY720 (FTY), a novel immune modulator, induces lymphopenia and prevents allograft rejection. This study was designed to study the effect of FTY on lymphocyte subpopulations and apoptosis in stable renal allograft recipients. METHODS: Stable renal allograft recipients received a single oral dose of 0.25 to 3.5 mg of FTY (n= 13) or placebo (n= 3). Whole blood was drawn immediately before and at 4, 8, 12, 24, 72, and 96 hr after administration. The number of lymphocyte subpopulations, with an emphasis on surface markers involved in lymphocyte migration, was analyzed by flow cytometry. Apoptotic lymphocytes were detected following Annexin V-FITC/PI staining. Lymphocyte mobility was investigated in a modified Boyden chamber. RESULTS: FTY induced a transient lymphopenia by an apoptosis-independent mechanism. In vitro experiments with peripheral blood mononuclear cells (PBMC) confirmed that clinically relevant concentrations of FTY (0.1 microM) increased lymphocyte mobility, whereas only suprapharmacologic concentrations of FTY (10 microM) could induce apoptosis. FTY-treated patients had reversible changes in the composition of peripheral lymphocyte subpopulations. CD62L+ T cells decreased to the greatest extent (-57%). In contrast, CCR5+ T-cell counts declined only marginally (-10%). In vitro, treatment of PBMC with FTY (1 mM-10 microM) did not induce changes in the expression of these surface markers. CONCLUSIONS: The data indicate that FTY mediates apoptosis-independent lymphopenia in human renal allograft recipients. FTY-induced lymphopenia preferentially affects CD62L+ and CCR5- T-lymphocyte subpopulations.
Apoptosis↗
Testosterone concentrations and sirolimus in male renal transplant patients.
Sirolimus damages the testes in animals; however, human data are sparse. We conducted a case-control study to obtain further insight into this issue and compared testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin concentrations in matched renal transplant patients who did or did not receive sirolimus. We found that testosterone values were lower (11.2 +/- 6.3 nmol/L vs. 15.5 +/- 7.7 nmol/L, p < 0.05), in 28 sirolimus-treated patients, compared to 28 non-sirolimus-treated controls. Furthermore, these patients more commonly had testosterone concentrations that were below our reference value for normal men. In contrast, FSH and LH concentrations were higher while prolactin levels were not different. These data are consistent with sirolimus-related testosterone suppression and suggest a need for further studies.
Adult↗
FTY720-induced lymphocyte homing modulates post-transplant preservation/reperfusion injury.
BACKGROUND: A novel immunomodulator, FTY720, modulates lymphocyte migration to injured tissues via enhanced lymphocyte sequestration to secondary lymphoid organs. We tested whether or not single-dose FTY720 (0.5 mg/kg) pretreatment rescues renal grafts from post-transplant preservation/reperfusion injury. METHODS: Rat renal grafts were cold-preserved in University of Wisconsin (UW) solution for 4 hours and then transplanted into syngeneic or allogeneic recipients that received a single dose of FTY720 24 hours before transplantation. Flow cytometry analysis of peripheral blood and lymph nodes was performed to confirm the biologic effect of FTY720. Grafts were harvested after 24 hours. Renal sections were examined histologically and stained for intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), platelet endothelial cellular adhesion molecule-1 (PECAM-1), major histocompatibility complex (MHC) class II, and inflammatory cells. Interleukin-1 (IL-1) production was determined in renal protein extracts. RESULTS: FTY720 pretreatment significantly increased CD3+ T-cell sequestration to lymph nodes in the face of peripheral lymphopenia. Isografts and allografts from the FTY720-treated groups did not develop increased creatinine (0.55 +/- 0.12 in isografts and 0.62 +/- 0.08 mg/dL in allografts), compared with vehicle controls (2.28 +/- 0.20 in isografts and 2.24 +/- 0.18 mg/dL in allografts). Kidneys from FTY720-treated groups also showed lower acute tubular damage scores. Furthermore, FTY720 decreased neutrophil influx, although circulating neutrophils were unchanged. FTY720 also prevented postischemic IL-1 intragraft production not affecting infiltration with recipient ED-1+ macrophages and MHC class II-positive cells. Expression of ICAM-1, VCAM-1, and PECAM did not differ among groups. CONCLUSION: FTY720 ameliorated morphologic and functional consequences of post-transplant reperfusion injury. Thus, FTY720-induced peripheral T-cell absence may influence intragraft IL-1 production and neutrophil infiltration, despite proadhesive endothelial properties. FTY720 may broaden the utility in renal transplantation as a pretreatment strategy against preservation/reperfusion injury.
Animals↗
Reports of large immunosuppression trials in kidney transplantation: room for improvement.
The reporting quality of publications of clinical trials can affect the quality of clinical decision-making. We systematically assessed the quality of publications of large multicenter trials evaluating immunosuppressive regimens in de novo kidney transplantation. Study quality, reporting quality and accessibility of the results of 63 publications were assessed independently by three blinded investigators using an instrument combining the Jadad scale with a list of reporting quality items. Study quality was rated with an average of only 2.3 (range 1-5) on the Jadad scale. Unblinded studies were reported in 68.3% of publications and follow-up longer than 12 months was reported for only 13 out of 50 studies. The reviewed publications fulfilled an average of 69.1% of the reporting quality criteria. Fifty-four percent of publications did not report both treated and biopsy-proven rejections. Whether reported graft survival was censored for death could not be determined for 27% of publications. Only a few publications gave confidence intervals (CIs) or stated whether additional analyses were pre-specified. Even the largest trials of immunosuppression in kidney transplantation show considerable quality deficits in their design and publication. Additional efforts are required of investigators, editors and sponsors to achieve maximum study and reporting quality.
Clinical Trials as Topic↗
Review of the immunosuppressant enteric-coated mycophenolate sodium.
Enteric-coated mycophenolate sodium (EC-MPS; myfortic, Novartis Pharma AG) is an advanced formulation delivering mycophenolic acid (MPA). EC-MPS was designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until reaching the small intestine. At a dose of 720 mg, EC-MPS exhibits equivalent MPA exposure (area under the concentration curve [AUC]) and maximal MPA concentration (C(max)) to mycophenolate mofetil (MMF; CellCept, Roche AG) 1000 mg. The time to maximal MPA concentration (T(max)) for EC-MPS is delayed relative to that for MMF, consistent with a functioning enteric coating. EC-MPS 720 mg b.i.d. has demonstrated therapeutic equivalence to MMF 1000 mg b.i.d. in renal transplant patients. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients. Furthermore, studies have confirmed that maintenance patients can be safely converted from MMF to EC-MPS with no compromise of efficacy or safety. EC-MPS therefore presents physicians and patients with a valid alternative MPA therapy with a comparable efficacy and safety profile to MMF.
Clinical Trials as Topic↗
Successful pregnancies in dialysis patients including those suffering from cystinosis and familial Mediterranean fever.
For women on maintenance dialysis, pregnancy is still uncommon. The outcome of such pregnancies has improved in recent case series. Here, we report in detail the treatment of five successful pregnancies in dialysis patients from our centre. The present case series also includes the first successful pregnancy of a dialysis patient with underlying familial Mediterranean fever, and of a dialysis patient with cystinosis. We treated all patients with an intensified hemodiafiltration protocol, increased erythropoietin dosages, a generous application of water-soluble vitamins and trace elements in addition to a multidisciplinary clinical management approach with a very low threshold for hospital admission. Specifically, we report treatment of arterial hypertension with respect to changes in dry weight and pharmacological therapy. Mean gestational age at delivery was 32.8+/-3.3 weeks and mean birth weight was 1,765+/-554 g. All mothers and newborns were discharged healthy and in good condition. These modified management guidelines have led to a favourable outcome in all our patients including two patients with familial Mediterranean fever and with cystinosis, and may help to guide therapy in other pregnant dialysis patients.
Adult↗