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1.
Transpl Immunol ; 75: 101714, 2022 12.
Article in English | MEDLINE | ID: mdl-36108808

ABSTRACT

Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163+ macrophages have a decreased risk (OR = 0.021, P = 0.008) for ACR in the first 6 months after transplantation. In pre-transplant biopsies of a comparable DCD cohort, with >80% DGF, presence of donor CD163+ macrophages showed no effect on ACR risk. Therefore, leukocyte infiltrate present during the inflammatory response at the time of DGF may contain anti-inflammatory macrophages that exert a protective effect against ACR development.


Subject(s)
Kidney Transplantation , Humans , Kidney Transplantation/adverse effects , Delayed Graft Function , Graft Survival , Graft Rejection/etiology , Tissue Donors , Kidney , Risk Factors , Macrophages , Retrospective Studies
2.
Neth J Med ; 75(6): 225-234, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28741581

ABSTRACT

BACKGROUND: More older patients with end-stage renal disease (ESRD) are starting dialysis. Elderly patients often prefer treatments that focus on quality of life rather than primarily extending life and a substantial group of elderly dialysis patients might regret their decision to start dialysis. Healthcare provider and patient-related factors may be involved. Our objective was to measure the percentage of patients in the Netherlands who regretted their decision to start dialysis. METHODS: Cross-sectional Dutch national survey of dialysis patients. A short questionnaire about age, satisfaction with pre-dialysis education, present treatment, dialysis initiation, regret about decision to start dialysis and key figures in decision-making was developed. RESULTS: A total of 1371 questionnaires were returned for analysis from 28 dialysis units. Of the patients 7.4% regretted their decision to start dialysis, 50.5% reported the nephrologist's opinion to be crucial in decision-making and these patients experienced more regret than those who made the decision themselves (odds ratio, OR: 1.81). When family influenced decision-making more regret was experienced compared with those who decided themselves (OR: 2.73). Older age was associated with less regret (p = 0.02) and higher treatment satisfaction (p < 0.001); 52.8% of participants described dialysis initiation as being sudden. CONCLUSION: The majority of patients did not regret their decision to start dialysis. Older patients were more satisfied with their treatment and felt less regret. The nephrologist's and the family's opinion were directional in decision-making on ESRD treatment options and were associated with more regret, especially in younger patients.


Subject(s)
Emotions , Kidney Failure, Chronic/psychology , Patient Satisfaction/statistics & numerical data , Renal Dialysis/psychology , Adult , Age Factors , Aged , Aged, 80 and over , Cross-Sectional Studies , Decision Making , Female , Humans , Kidney Failure, Chronic/therapy , Male , Middle Aged , Netherlands , Physician-Patient Relations , Quality of Life , Surveys and Questionnaires
3.
Am J Transplant ; 17(1): 161-172, 2017 01.
Article in English | MEDLINE | ID: mdl-27251361

ABSTRACT

Kidney transplant donors are not currently implicated in predicting BK polyomavirus (BKPyV) infection in kidney transplant recipients. It has been postulated, however, that BKPyV infection originates from the kidney allograft. Because BKPyV seroreactivity correlates with BKPyV replication and thus might mirror the infectious load, we investigated whether BKPyV seroreactivity of the donor predicts viremia and BKPyV-associated nephropathy (BKPyVAN) in the recipient. In a retrospective cohort of 407 living kidney donor-recipient pairs, pretransplantation donor and recipient sera were tested for BKPyV IgG levels and correlated with the occurrence of recipient BKPyV viremia and BKPyVAN within 1 year after transplantation. Donor BKPyV IgG level was strongly associated with BKPyV viremia and BKPyVAN (p < 0.001), whereas recipient BKPyV seroreactivity showed a nonsignificant inverse trend. Pairing of high-BKPyV-seroreactive donors with low-seroreactive recipients resulted in a 10-fold increased risk of BKPyV viremia (hazard ratio 10.1, 95% CI 3.5-29.0, p < 0.001). In multivariate analysis, donor BKPyV seroreactivity was the strongest pretransplantation factor associated with viremia (p < 0.001) and BKPyVAN (p = 0.007). The proportional relationship between donor BKPyV seroreactivity and recipient infection suggests that donor BKPyV seroreactivity reflects the infectious load of the kidney allograft and calls for the use of pretransplantation BKPyV serological testing of (potential) donors and recipients.


Subject(s)
BK Virus/pathogenicity , Kidney Diseases/diagnosis , Kidney Transplantation/adverse effects , Polyomavirus Infections/immunology , Tumor Virus Infections/immunology , Viremia/diagnosis , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Kidney Diseases/etiology , Kidney Function Tests , Living Donors , Male , Middle Aged , Netherlands/epidemiology , Polyomavirus Infections/blood , Polyomavirus Infections/virology , Prognosis , Retrospective Studies , Risk Factors , Transplant Recipients , Tumor Virus Infections/blood , Tumor Virus Infections/virology , Viremia/etiology
5.
Am J Transplant ; 16(5): 1441-55, 2016 05.
Article in English | MEDLINE | ID: mdl-26607974

ABSTRACT

Acute rejection is a risk factor for inferior long-term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is less clear. Expression of S100 calcium-binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium-binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid-derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cell-mediated acute rejection.


Subject(s)
Calgranulin A/metabolism , Calgranulin B/metabolism , Graft Rejection/etiology , Graft Survival/immunology , Kidney Transplantation/adverse effects , Myeloid-Derived Suppressor Cells/immunology , T-Lymphocytes/immunology , Adult , Biomarkers/metabolism , Calgranulin A/immunology , Calgranulin B/immunology , Case-Control Studies , Cohort Studies , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/metabolism , Graft Rejection/pathology , Humans , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/surgery , Kidney Function Tests , Male , Middle Aged , Prognosis , Risk Factors
6.
Am J Transplant ; 15(4): 1081-90, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25716422

ABSTRACT

Because microvascular disease is one of the most important drivers of diabetic complications, early monitoring of microvascular integrity may be of clinical value. By assessing profiles of circulating microRNAs (miRNAs), known regulators of microvascular pathophysiology, in healthy controls and diabetic nephropathy (DN) patients before and after simultaneous pancreas-kidney transplantation (SPK), we aimed to identify differentially expressed miRNAs that associate with microvascular impairment. Following a pilot study, we selected 13 candidate miRNAs and determined their circulating levels in DN (n = 21), SPK-patients (n = 37), healthy controls (n = 19), type 1 diabetes mellitus patients (n = 15) and DN patients with a kidney transplant (n = 15). For validation of selected miRNAs, 14 DN patients were studied longitudinally up to 12 months after SPK. We demonstrated a direct association of miR-25, -27a, -126, -130b, -132, -152, -181a, -223, -320, -326, -340, -574-3p and -660 with DN. Of those, miR-25, -27a, -130b, -132, -152, -320, -326, -340, -574-3p and -660 normalized after SPK. Importantly, circulating levels of some of these miRNAs tightly associate with microvascular impairment as they relate to aberrant capillary tortuosity, angiopoietin-2/angiopoietin-1 ratios, circulating levels of soluble-thrombomodulin and insulin-like growth factor. Taken together, circulating miRNA profiles associate with DN and systemic microvascular damage, and might serve to identify individuals at risk of experiencing microvascular complications, as well as give insight into underlying pathologies.


Subject(s)
Diabetic Nephropathies/blood , Kidney Transplantation , MicroRNAs/blood , Pancreas Transplantation , Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult
7.
Am J Transplant ; 14(4): 936-42, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24712331

ABSTRACT

Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody-mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas-kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft <1 year after transplantation. AMR was diagnosed based on donor-specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred >1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss <1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts <1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.


Subject(s)
Graft Rejection/diagnosis , Isoantibodies/blood , Kidney Transplantation/adverse effects , Pancreas Transplantation/adverse effects , Pancreatic Diseases/complications , Postoperative Complications/diagnosis , Thrombosis/physiopathology , Adult , Allografts , Case-Control Studies , Complement C4b/immunology , Female , Follow-Up Studies , Graft Rejection/etiology , Graft Rejection/mortality , Humans , Immunity, Cellular/immunology , Isoantibodies/immunology , Male , Middle Aged , Pancreatic Diseases/surgery , Peptide Fragments/immunology , Postoperative Complications/etiology , Postoperative Complications/mortality , Prognosis , Retrospective Studies , Risk Factors , Survival Rate , Tissue Donors
8.
Am J Transplant ; 13(8): 2106-18, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23763497

ABSTRACT

Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (p < 0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC = 0.88, p < 0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (p = 0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that nonresponse to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor.


Subject(s)
Drug Resistance/genetics , Graft Rejection/metabolism , Kidney Failure, Chronic/therapy , Kidney Transplantation/adverse effects , Metallothionein/genetics , Methylprednisolone/adverse effects , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , Biomarkers/metabolism , Case-Control Studies , Chromosomes, Human, Y , Cohort Studies , Female , Gene Expression Profiling , Graft Rejection/pathology , Humans , Immunoenzyme Techniques , In Situ Hybridization , Kidney Failure, Chronic/genetics , Male , Metallothionein/metabolism , Methylprednisolone/administration & dosage , Middle Aged , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
9.
Am J Transplant ; 13(5): 1272-81, 2013 May.
Article in English | MEDLINE | ID: mdl-23433125

ABSTRACT

Simultaneous pancreas-kidney transplantation (SPK) is an advanced treatment option for type 1 diabetes mellitus (DM) patients with microvascular disease including nephropathy. Sidestreamdarkfield (SDF) imaging has emerged as a noninvasive tool to visualize the human microcirculation. This study assessed the effect of SPK in diabetic nephropathy (DN) patients on microvascular alterations using SDF and correlated this with markers for endothelial dysfunction. Microvascular morphology was visualized using SDF of the oral mucosa in DN (n = 26) and SPK patients (n = 38), healthy controls (n = 20), DM1 patients (n = 15, DM ≥ 40 mL/min) and DN patients with a kidney transplant (KTx, n = 15). Furthermore, 21 DN patients were studied longitudinally up to 12 months after SPK. Circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and soluble thrombomodulin (sTM) were measured using ELISA. Capillary tortuosity in the DN (1.83 ± 0.42) and DM ≥ 40 mL/min (1.55 ± 0.1) group was increased and showed reversal after SPK (1.31 ± 0.3, p < 0.001), but not after KTx (1.64 ± 0.1). sTM levels were increased in DN patients and reduced in SPK and KTx recipients (p < 0.05), while the Ang-2/Ang-1 ratio was normalized after SPK and not after KTx alone (from 0.16 ± 0.04 to 0.08 ± 0.02, p < 0.05). Interestingly, in the longitudinal study, reversal of capillary tortuosity and decrease in Ang-2/Ang-1 ratio and sTM was observed within 12 months after SPK. SPK is effective in reversing the systemic microvascular structural abnormalities in DN patients in the first year after transplantation.


Subject(s)
Diabetes Mellitus, Type 1/complications , Diabetic Nephropathies/etiology , Kidney Transplantation , Microcirculation , Pancreas Transplantation , Adult , Cross-Sectional Studies , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/pathology , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/surgery , Female , Follow-Up Studies , Humans , Kidney/physiopathology , Kidney/surgery , Male , Middle Aged , Postoperative Period , Time Factors , Treatment Outcome
10.
Am J Transplant ; 12(7): 1793-800, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22429395

ABSTRACT

Eryhropoiesis-stimulating agents have demonstrated tissue-protective effects in experimental models of ischemia-reperfusion injury. PROTECT was a 12-month, randomized, double-blind, placebo-controlled, single center study with high-dose recombinant human erythropoietin-ß (Epoetin) in 92 donation after cardiac death (DCD) kidney transplant recipients. Patients were randomized to receive an intravenous bolus of Epoetin (3.3 × 10(4) international unit (IU); n = 45) or placebo (saline 0.9% solution; n = 47) on 3 consecutive days, starting 3-4 h before the transplantation and 24 h and 48 h after reperfusion. The immunosuppressive regimen included an anti-CD25 antibody, steroids, mycophenolate mofetil and delayed introduction of cyclosporine. Primary end point was a composite of the incidence of primary nonfunction and delayed graft function, either defined by spontaneous functional recovery or need for dialysis in the first week. Secondary objectives included duration of delayed function, renal function and proteinuria up to 1 year and thrombotic adverse events. Results showed no differences in the incidence or duration of delayed graft function and/or primary nonfunction (Epoetin 77.8 vs. placebo 78.7%, p = 1.00). Epoetin treatment significantly increased the risk of thrombotic events at 1 month and 1 year (Epoetin 24.4% vs. placebo 6.4%, p = 0.02).


Subject(s)
Death , Erythropoietin/administration & dosage , Kidney Transplantation , Tissue Donors , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Placebos
11.
Acta Gastroenterol Belg ; 73(3): 406-8, 2010.
Article in English | MEDLINE | ID: mdl-21086949

ABSTRACT

Arteriovenous malformations are common causes of lower gastrointestinal bleeding in the elderly. Among them, angiodysplasia is one subtype that appears on endoscopy as red, flat superficial lesions, and sometimes slightly elevated. Colonic angiodysplasia is very rarely seen as a polypoid lesion. The present case describes a bleeding large polypoid colonic angiodysplasia in a 60-year-old man. It was removed endoscopically using a PolyLoop ligature device without complications.


Subject(s)
Angiodysplasia/surgery , Colonic Diseases/surgery , Colonoscopy , Gastrointestinal Hemorrhage/etiology , Angiodysplasia/pathology , Gastrointestinal Hemorrhage/surgery , Humans , Male , Middle Aged
12.
Kidney Int ; 73(12): 1426-33, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18354379

ABSTRACT

Treatment of patients with IgA nephropathy (IgAN) depends on a reliable assessment of disease progression based on measurements of glomerular filtration rate (GFR), proteinuria, hypertension, and tubulointerstitial changes. We sought to determine whether progression could be predicted from analysis of glomerular and tubulointerstitial inflammation in biopsies taken at an early stage of IgAN. We retrospectively analyzed biopsies from 50 patients, relating the subsequent clinical course to infiltration with B- and T-lymphocytes, granule membrane protein of 17 kDa (GMP-17) positive cytotoxic T cells, macrophages, fibroblasts, and tubulointerstitial expression of human leukocyte antigen-D related (HLA-DR). At biopsy, 19 patients had decreased GFR while 13 of 31 patients with normal GFR and progressive IgAN differed significantly from 18 non-progressors in the level of proteinuria and in the severity of scores for mesangial proliferation, tubular atrophy, interstitial fibrosis, and interstitial infiltrates. On multivariate regression analysis these differences disappeared; however, associations with GMP-17-positive cytotoxic T-lymphocytes in intact renal tubules and of B-lymphocytes in the interstitium remained significant. Our study may have identified a marker of disease progression in early stages of IgAN.


Subject(s)
Glomerulonephritis, IGA/pathology , Kidney Tubules/pathology , Membrane Proteins/analysis , T-Lymphocytes, Cytotoxic/immunology , Biomarkers/analysis , Disease Progression , Female , Glomerular Filtration Rate , Glomerulonephritis, IGA/immunology , Glomerulonephritis, IGA/physiopathology , HLA-DR Antigens/analysis , Humans , Kidney Tubules/immunology , Kidney Tubules/physiopathology , Male , Prognosis , Regression Analysis , Retrospective Studies
13.
J Physiol Paris ; 96(3-4): 183-92, 2002.
Article in English | MEDLINE | ID: mdl-12445895

ABSTRACT

In the adult cat, axons running through the corpus callosum interconnect the border between the visual cortical areas 17 and 18 (A17 and A18) of both hemispheres. This specific pattern emerges during postnatal development, under normal viewing conditions (NR), from the elimination of initially exuberant callosal projections. In contrast, if the postnatal visual experience is monocular from birth (MD), juvenile callosal projections are stabilised throughout A17 and A18. The present study aimed at using such a model in vivo to find indications of a contribution of glial cells in the shaping of projections in the developing CNS through interactions with neurones, both in normal and pathological conditions. As a first stage, the distribution and the morphology of microglial cells and astrocytes were investigated from 2 weeks to adulthood. Microglial cells, stained with isolectin-B4, were clustered in the white matter below A17 and A18. Until one month, these clustered cells displayed an ameboid morphology in NR group, while they were more ramified in MD animals. Their phenotype thus depends on the postnatal visual experience, which indicates that microglial cells may interact with axons of visual neurones. It also suggests that they may differentially contribute to the elimination and the stabilisation of juvenile exuberant callosal fibres in NR and MD animals respectively. Beyond one month, microglial cells were very ramified in both experimental groups. Astrocytes were labelled with a GFAP-antibody. The distributions of connexins 43 (Cx43) and 30 (Cx30), the main proteic components of gap junction channels in astrocytes, were also investigated using specific antibodies. Both in NR and MD groups, until 1 month, GFAP-positive astrocytes and Cx43 were mainly localised within the subcortical white matter. Then GFAP, Cx43 and Cx30 stainings progressively appeared within the cortex, throughout A17 and A18 but with a differential laminar expression according to the age. Thus, the distributions of both astrocytes and connexins changed with age; however, the monocular occlusion had no visible effect. This suggests that astrocytes may contribute to the postnatal development of neuronal projections to the primary visual cortex, including visual callosal projections.


Subject(s)
Astrocytes/physiology , Corpus Callosum/cytology , Microglia/physiology , Visual Cortex/cytology , Animals , Corpus Callosum/embryology , Visual Cortex/embryology , Visual Pathways/cytology , Visual Pathways/embryology
15.
Clin Nephrol ; 55(2): 149-55, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11269679

ABSTRACT

BACKGROUND: In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of 150 microg/l. We performed a retrospective cohort study to assess cyclosporine toxicity following this switch and to identify risk factors for nephrotoxicity. PATIENTS AND METHODS: Of 212 patients with a stable graft function pre-conversion clinical parameters at 1 and 12 months post-conversion were compared with those at time of conversion. Cyclosporine nephrotoxicity was defined as a significant decline of the reciprocal of the serum creatinine concentration over time post-conversion in the absence of other obvious causes for declining graft function. Risk factors of cyclosporine nephrotoxicity were assessed using logistic regression analysis. RESULTS: The mean cyclosporine trough level rose from 87 microg/l at the time of conversion to 139 microg/l at 12 months post-conversion whereas the daily drug dose increased over the same period from 233 mg to 252 mg. Mean serum creatinine increased by 10% from 135 to 148 micromol/l (p < 0.001). Cyclosporine nephrotoxicity was present in 42 patients (20%). Cyclosporine dose and trough level did not predict nephrotoxicity but beta-blockers (OR 0.35, 95% CI 0.17-0.72) and calcium channel blockers (OR 0.35, 95% CI 0.19-0.82) reduced the risk of nephrotoxicity, independent from an effect on blood pressure. CONCLUSION: 20% of stable renal transplant patients experienced chronic cyclosporine nephrotoxicity after conversion from a once-daily Sandimmune regimen to a twice-daily Neoral regimen with dose adjustments to a trough level of 150 microg/l. beta-blockers and calcium channel blockers reduced the risk of nephrotoxicity.


Subject(s)
Cyclosporine/adverse effects , Immunosuppressive Agents/adverse effects , Kidney Diseases/chemically induced , Kidney Transplantation , Adrenergic beta-Antagonists/administration & dosage , Calcium Channel Blockers/administration & dosage , Creatinine/blood , Cyclosporine/administration & dosage , Cyclosporine/pharmacokinetics , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacokinetics , Logistic Models , Male , Middle Aged , Retrospective Studies , Risk Factors
17.
J Neurosci ; 21(6): 2028-38, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11245686

ABSTRACT

The postnatal development of rat microglia is marked by an important increase in the number of microglial cells and the growth of their ramified processes. We studied the role of thyroid hormone in microglial development. The distribution and morphology of microglial cells stained with isolectin B4 or monoclonal antibody ED1 were analyzed in cortical and subcortical forebrain regions of developing rats rendered hypothyroid by prenatal and postnatal treatment with methyl-thiouracil. Microglial processes were markedly less abundant in hypothyroid pups than in age-matched normal animals, from postnatal day 4 up to the end of the third postnatal week of life. A delay in process extension and a decrease in the density of microglial cell bodies, as shown by cell counts in the developing cingulate cortex of normal and hypothyroid animals, were responsible for these differences. Conversely, neonatal rat hyperthyroidism, induced by daily injections of 3,5,3'-triiodothyronine (T3), accelerated the extension of microglial processes and increased the density of cortical microglial cell bodies above physiological levels during the first postnatal week of life. Reverse transcription-PCR and immunological analyses indicated that cultured cortical ameboid microglial cells expressed the alpha1 and beta1 isoforms of nuclear thyroid hormone receptors. Consistent with the trophic and morphogenetic effects of thyroid hormone observed in situ, T3 favored the survival of cultured purified microglial cells and the growth of their processes. These results demonstrate that thyroid hormone promotes the growth and morphological differentiation of microglia during development.


Subject(s)
Microglia/metabolism , Thyroid Hormones/metabolism , Animals , Brain/cytology , Brain/drug effects , Brain/growth & development , Cell Count , Cell Division/drug effects , Cell Survival/drug effects , Cells, Cultured , Female , Hyperthyroidism/chemically induced , Hyperthyroidism/metabolism , Hypothyroidism/chemically induced , Hypothyroidism/metabolism , Iodine/deficiency , Methylthiouracil/pharmacology , Microglia/cytology , Microglia/drug effects , Pregnancy , Prenatal Exposure Delayed Effects , Rats , Rats, Wistar , Receptors, Thyroid Hormone/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Thyroid Hormones/pharmacology , Triiodothyronine/metabolism , Triiodothyronine/pharmacology
18.
Eur J Neurosci ; 12(12): 4589-93, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11122374

ABSTRACT

Neuronal cultures derived from developing rat cerebral cortex were used to investigate the influence of glutamate receptors on the neuronal production of transforming growth factor-beta2 (TGFbeta2), a multifunctional cytokine that modulates neuronal and glial growth. Long-term exposure (48 h) of cortical neurons to selective antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors markedly increased TGFbeta2 levels in the culture medium. Conversely, treatment with NMDA or kainate reduced TGFbeta2 to levels below those in untreated cultures. The effect of kainate did not require NMDA receptor activity. Neuronal depolarization with K+ also reduced TGFbeta2 levels by opening voltage-gated L-type Ca2+ channels. Semi-quantitative RT-PCR measurements of neuronal TGFbeta2 mRNA showed that NMDA or AMPA/kainate receptor stimulation reduced TGFbeta2 mRNA levels. These results demonstrate that tonic activation of glutamate-gated cation channels downregulates neuronal expression of the TGFbeta2 gene and provide evidence for a novel mechanism whereby excitatory amino acids could influence the development of glial and neuronal lineages.


Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Neurons/physiology , Receptors, Glutamate/physiology , Transforming Growth Factor beta/physiology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/physiology , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/physiology , Dizocilpine Maleate/pharmacology , Embryo, Mammalian , Excitatory Amino Acid Antagonists/pharmacology , N-Methylaspartate/pharmacology , Neurons/drug effects , Potassium/pharmacology , Rats , Rats, Wistar , Receptors, Glutamate/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta/genetics , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
19.
Kidney Int ; 58(2): 859-66, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10916111

ABSTRACT

BACKGROUND: In renal transplantation, the impact of delayed graft function (DGF) on prognosis is controversial. We analyzed the risk factors of DGF and its impact on graft function and prognosis. METHODS: Seven hundred thirty-four cadaveric renal transplants performed between 1983 and 1997 were analyzed. DGF was diagnosed when serum creatinine levels increased, remained unchanged, or decreased less than 10% per day in three consecutive days in the first week after transplantation. Creatinine clearances of more or less than 50 or 30 mL/min at one year were used as cut-off points for optimal and suboptimal graft function, respectively. The logistic regression model was used to identify independent risk factor related to DGF and renal function one year after transplantation. The Cox regression model was used to examine the influence of DGF on long-term graft survival. RESULTS: Multivariate analysis revealed the following risk factors for DGF: recipient pretransplantation mean arterial blood pressure of less than 100 mm Hg (OR = 2.08, 95% CI, 1.43 to 3.03), female donor to male recipient combination (OR = 1.55, 95% CI, 1.02 to 2.35), donor age of more than 50 years (OR = 2.21, 95% CI, 1.49 to 3.26), cold ischemia time of more than 28 hours (OR = 1.78, 95% CI, 1.19 to 2.63), and peak panel reactive antibodies of more than 50% (OR = 1.7, 95% CI, 1.15 to 2.55). The incidence of DGF was one of the independent risk factors for suboptimal graft function at one year (OR = 1.68, 95% CI, 1.14 to 2.48), together with donor age of more than 50 years (OR = 2.39, 95% CI, 1.61 to 3.57), female donor gender (OR = 1.99, 95% CI, 1.42 to 2.78), the occurrence of acute rejection episodes (OR = 2.66, 95% CI, 1.87 to 3.78), peak panel-reactive antibodies of more than 50% (OR = 1.67, 95% CI, 1.15 to 2.47), and sharing of 1 to 3 versus 4 to 8 cross-reactive antigens groups (OR = 1.65, 95% CI, 1.09 to 2. 49). Moreover, DGF was one of the two independent risk factors for acute rejection episodes, but it had no independent effect on graft survival. CONCLUSION: Several risk factors for DGF were identified, of which a low recipient pretransplant mean arterial blood pressure, the transplantation of kidneys from female donors to male recipients, and a prolonged cold ischemia time are potentially avoidable. Although DGF is one of the several risk factors of acute rejection and suboptimal function at one year, it is not independently associated with an increased rate of graft loss.


Subject(s)
Graft Rejection/epidemiology , Graft Survival/physiology , Kidney Failure, Chronic/surgery , Kidney Transplantation , Kidney/physiology , Acute Disease , Adult , Cadaver , Female , Follow-Up Studies , Graft Rejection/diagnosis , Graft Rejection/physiopathology , HLA-DR Antigens/analysis , Humans , Kidney/blood supply , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Reperfusion Injury/physiopathology , Retrospective Studies , Risk Factors
20.
Kidney Int ; 56(5): 1920-7, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10571803

ABSTRACT

BACKGROUND: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching. METHODS: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis. RESULTS: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94). CONCLUSION: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.


Subject(s)
Graft Survival , Histocompatibility Antigens Class I/immunology , Histocompatibility Testing , Kidney Transplantation , Adult , Aged , Cross Reactions , Female , Graft Rejection , Humans , Male , Middle Aged , Multivariate Analysis , Regression Analysis , Risk Factors
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