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Jan A Bruijn

Publications and source records attributed to Jan A Bruijn.

At least 19 recordsLinked to original sources
PubMed2006

Endothelial chimerism in transplantation: Looking for needles in a haystack.

Endothelial chimerism in transplanted organs is a fascinating phenomenon, indicative of a mechanism by which progenitor recipient cells replace the donor endothelium. It has been hypothesized that this replacement could lead to a decrease in alloreactivity and thus would positively influence graft outcome. However, recent studies have shown that the amount of recipient-derived endothelial cells found in donor organs is relatively small. What effect on graft survival can we expect from this low number of chimeric cells? There are several hypotheses that address this question, but distinguishing the true effect of donor endothelial replacement on outcome from other factors affecting graft survival is difficult. Furthermore, "contamination" of chimeric cells from sources other than the recipient would have to be excluded before the effect of donor endothelial replacement by recipient cells can be accurately assessed. Pregnancies and blood transfusions are the other sources that may induce chimerism. Most of the techniques currently used to detect chimeric cells in donor organs are not specific enough to distinguish chimeric cells that may have been present in the graft before transplantation and recipient-derived chimeric cells that replace the endothelium after transplantation. Also, the sensitivity of these techniques may be questioned: do we really detect all chimeric cells that are present? This review will elaborate on these questions and discuss future perspectives of research into chimerism.

Chimerism↗
PubMed2006

Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement.

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 micromol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR0) and 12 mo after diagnosis (GFR12), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR0 were age (r = -0.40, P = 0.04), arteriosclerosis (r = -0.53, P = 0.01), segmental crescents (r = 0.35, P = 0.07), and eosinophilic infiltrate (r = -0.41, P = 0.04). Prognostic indicators for GFR12 were age (r = -0.32, P = 0.01), normal glomeruli (r = 0.24, P = 0.04), tubular atrophy (r = -0.28, P = 0.02), intraepithelial infiltrate (r = -0.26, P = 0.03), and GFR0 (r = 0.29, P = 0.01). Fibrous crescents (r = 0.22, P = 0.03) were predictive of dialysis at entry. Normal glomeruli (r = -0.30, P = 0.01) and treatment arm (r = -0.28, P = 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r = -0.36, P = 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

Anti-Inflammatory Agents↗
PubMed2006

Molecular comparison of calcineurin inhibitor-induced fibrogenic responses in protocol renal transplant biopsies.

The calcineurin inhibitor cyclosporine (CsA) induces a fibrogenic response that may lead to scarring of the renal allograft. This study investigated whether tacrolimus, a novel calcineurin inhibitor, exerts fibrogenic effects to a similar extent. Sixty patients were enrolled in a randomized study: 29 received CsA, and 31 received tacrolimus. Patients were subjected to tailored exposure-controlled calcineurin inhibitor regimens. Protocol biopsies were obtained at the time of transplantation and 6 and 12 mo after transplantation. Cortical TGF-beta and collagens alpha1(I) and alpha1(III) mRNA steady-state levels were determined with real-time PCR. The extent of protein deposition of TGF-beta, alpha-smooth muscle actin, and interstitial collagens in the renal cortex was quantified with computer-assisted image analysis. The extent of interstitial collagen deposition measured with Sirius red and the accumulation of alpha-smooth muscle actin and TGF-beta protein after 6 and 12 mo were similar for both immunosuppressive regimens. mRNA levels of TGF-beta and collagens alpha1(I) and alpha1(III) were not significantly different in the treatment groups either. It is concluded that the fibrogenic response in renal allografts is similar in patients who receive CsA-based regimens and patients who receive tacrolimus-based regimens.

Adult↗
PubMed2006

Chimerism occurs twice as often in lupus nephritis as in normal kidneys.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an immune-mediated disease that particularly affects the kidneys, causing lupus nephritis. In experimental mouse models, lupus nephritis can be mimicked by inducing a chimeric state through the injection of parental T cells in offspring. In humans, pregnancy-induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is likely that only certain chimeric cells have pathogenic potential. In this study, we investigated whether the distribution of chimeric cells is different in the kidneys of women with SLE from that in normal kidneys, and we examined the phenotype of chimeric cells in women with SLE. METHODS: The presence of chimeric cells was investigated by in situ hybridization targeting the Y chromosome in 57 renal biopsy samples from 49 women with lupus nephritis. Fifty-one kidney autopsy specimens without histomorphologic lesions served as controls. Double-staining for the Y chromosome in combination with CD3 and CD34 markers was performed in 5 kidney specimens with lupus nephritis to identify the phenotype of the chimeric cells. RESULTS: Y chromosome-positive cells were found in 27 of 49 patients with lupus nephritis and in 13 of 51 normal controls (P < 0.01). Both CD3+ and CD34+ chimeric cells were identified in lupus nephritis kidney specimens. CONCLUSION: Chimeric cells are present significantly more often in kidneys with lupus nephritis than in normal kidneys, and some of these chimeric cells are T cells. This finding is interesting in light of experimental models demonstrating that lupus nephritis is initiated by chimeric T cells.

Adult↗
PubMed2006

Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans.

Islet transplantation is associated with a high rate of early graft failure caused by early immune attack and poor functionality of islets. Apoptosis of islet cells appears soon after islet isolation and primarily involves the beta-cell. The purpose of this study was to determine the effect of ligation to extracellular matrix (ECM) proteins on survival of the islets of Langerhans following islet isolation. Islets that had been cultured for 24 h on collagen type I showed an islet survival of 59.7 +/- 8.7%, while islets that had been cultured on collagen type IV and laminin showed an islet survival of 88.6 +/- 10.3 and 94.3 +/- 5.6%, respectively. Islets that had been pretreated with anti-beta1 antibodies and argenin-glycin-aspartic acid (RGD) peptides showed a decrease in the level of apoptosis by a factor of 2.5 and 3.1, respectively, and an increase of phospho-Akt Ser 473 activity by a factor of 3.1 and 2.9, respectively, compared with untreated islets. When detached from their natural ECM surrounding in the pancreas, islet cells undergo apoptosis, unless islets are cultured on collagen IV or laminin or treated with anti-beta1 integrin antibodies or RGD peptides to mimic ECM ligation. These results indicate that inhibition of anoikis may offer opportunities to improve function and viability of islet cells.

Animals↗
PubMed2006

Imipramine is effective in preventing relapse in electroconvulsive therapy-responsive depressed inpatients with prior pharmacotherapy treatment failure: a randomized, placebo-controlled trial.

OBJECTIVE: To compare the efficacy of imipramine versus placebo in preventing relapse after successful electroconvulsive therapy (ECT) in depressive inpatients with pharmacotherapy treatment failure prior to ECT. METHOD: During a 6-month period, the incidence of relapse was assessed. Two centers, both inpatient units for treatment of depressed patients, participated in this trial. Patients with DSM-IV-diagnosed major depressive disorder resistant to an anti-depressant and subsequent lithium addition and/or a monoamine oxidase inhibitor were included. Patients were randomly assigned to double-blind treatment with imipramine with adequate plasma levels (N=12) or placebo (N=15) after successful ECT. The mean imipramine dosage was 209 mg/day (standard deviation: 91.7, range: 75-325 mg/day). The main outcome measure was relapse defined as at least "moderately worse" compared with baseline score on the Clinical Global Impressions-Improvement scale. Treatments were compared with survival analysis using the Cox proportional hazards model, including psychotic features and the score on the Hamilton Rating Scale for Depression (HAM-D) at baseline as prespecified covariables. Patients were enrolled in the study from April 1997 to July 2001. RESULTS: In the placebo group, 80% (12/15) of the patients relapsed compared with 18% (2/11) in the imipramine group. The Cox regression analysis showed a significant reduction in the risk of relapse of 85.6% with imipramine compared to placebo (p=.007; 95% confidence interval [CI]=24.6% to 97.2%) adjusted for the covariables. There was an 18% increase in the relapse rate (p=.032; 95% CI=2% to 36%) per unit increase in HAM-D score before the start of the trial; psychotic features had no significant effect (p=.794). CONCLUSIONS: Depressed patients with pharmacotherapy treatment failure may benefit from the prophylactic effect of the same class of drug during maintenance therapy after response to ECT.

Adult↗
PubMed2006

Outcome of a 4-step treatment algorithm for depressed inpatients.

OBJECTIVE: The aim of this study was to examine the efficacy and the feasibility of a 4-step treatment algorithm for inpatients with major depressive disorder. METHOD: Depressed inpatients, meeting DSM-IV criteria for major depressive disorder, were enrolled in the algorithm that consisted of sequential treatment steps (washout period, anti-depressant monotherapy, lithium addition, treatment with a nonselective monoamine oxidase inhibitor, electroconvulsive therapy). Definition of nonresponse and progression through the steps of the algorithm was dependent on the score on the 17-item Hamilton Rating Scale for Depression (HAM-D) at predefined evaluation times. Patients were admitted from April 1997 through July 2001. RESULTS: Of the 203 patients studied, 149 were treated according to the full algorithm, and 54 patients were immediately entered into step 3. Of the 203 patients, 165 (81%) achieved response (> or = 50% reduction in HAM-D score) and 101 (50%) remitted (final HAM-D score < or = 7). Of the 149 patients treated according to the full algorithm, 129 (87%) responded and 89 (60%) remitted. Twenty-four patients (16%) dropped out from the algorithm. CONCLUSION: Although response with antidepressant monotherapy was less than 50%, successive treatment according to the 4-step algorithm was very effective in a sample of depressed inpatients. The adherence to the algorithm was good as shown by a low dropout rate. This study emphasizes the importance of persisting with standardized antidepressant treatment in patients who are initially nonresponders to the first antidepressant. By the end of the study, more than 80% of the patients responded and 50% achieved full remission.

Adult↗
PubMed2005

Expression of surfactant protein-C, S100A8, S100A9, and B cell markers in renal allografts: investigation of the prognostic value.

The intent of this study was to identify genes of which expression during acute rejection is associated with progression to chronic allograft nephropathy using gene expression profiling. Ten patients who had graft loss through chronic allograft nephropathy (progression [PR] group) and 18 patients who had stable graft function over time (nonprogression [NP] group) were studied. Rejection severity and extent of infiltrating leukocytes in acute rejection biopsies were similar for both groups. Microarray analysis and real-time PCR validation showed that surfactant protein-C (SP-C), S100 calcium-binding protein A8 (S100A8), S100A9, and beta-globin levels distinguished the two groups. Relationship between expression of B cell markers and prognosis was also examined. Location in the graft of the protein and mRNA expression of candidate genes was investigated. The prognostic value of mRNA transcripts was tested in an independent cohort of 43 rejection biopsies. mRNA and protein expression of S100A8 and S100A9 in infiltrating cells was significantly higher in the NP group compared with the PR group. Expression of SP-C was four-fold higher in the PR group and was detected in glomeruli. No association between B cell clusters and outcome was found. In the second group of acute rejection biopsies, SP-C mRNA levels predicted renal function course beyond 6 mo in multivariate analysis. Relatively high expression of S100A8 and S100A9 during acute rejection is associated with a favorable prognosis, and high SP-C expression is associated with an unfavorable prognosis. Messenger RNA transcripts complement the biopsy in the prediction of graft function deterioration.

Adolescent↗
PubMed2005

Imipramine dose in relation to therapeutic plasma level: are clinical trials using imipramine as a positive control flawed?

RATIONALE: Imipramine has often been used as positive control in studies investigating the efficacy of new antidepressants. Imipramine-controlled studies in general employ a fixed-dose design. It is unclear how many patients would achieve effective plasma levels with such a design. OBJECTIVES: The objectives of this study were to assess the range of doses necessary to attain a therapeutic plasma level in the imipramine arms of two double-blind, fixed-plasma-level studies and to compare them with doses administered in efficacy studies with imipramine as a positive control. METHOD: During two double-blind studies, imipramine doses were adjusted to a predefined fixed plasma level. Here we report an analysis of the range of doses necessary to attain that level in the imipramine arms of the studies. We also computed the cumulative percentage of patients with therapeutic plasma levels (> or = 200 ng/ml) at various imipramine doses in order to compare them with doses administered in efficacy studies with imipramine as a positive control. RESULTS: Target plasma levels were attained with a mean daily dose of 248 mg, with a dose range of 50-450 mg. We calculated a possible increase in efficacy of imipramine of about 20% if doses had been adjusted to therapeutic plasma levels in clinical trials using it as a positive control. CONCLUSIONS: The absence of significant differences in efficacy between selective serotonin re-uptake inhibitors (SSRIs) and imipramine in these trials is at least in part due to improper dosing of the latter; imipramine with therapeutic drug monitoring may be more effective than SSRIs.

Adult↗
PubMed2005

RGD peptides confer survival to hepatocytes via the beta1-integrin-ILK-pAkt pathway.

BACKGROUND/AIMS: Allogeneic cell transplantation is characterized by a lack of sustained survival of the transplanted cells in the recipient. Activation of the appropriate integrin-linked signaling pathways in cells can promote cell survival. The purpose of this study was to determine how presence or absence of anti-beta1 integrin chain antibodies or RGD peptides affects the survival of hepatocytes. METHODS: Hepatocytes of BN rats were isolated. Hepatocyte survival was tested after the hepatocytes had been cultured in the presence of anti-beta1 integrin antibodies or RGD peptides. Hepatocytes that had been given a different treatment were stained for caspase 3 (apoptosis marker) and phospho-Akt Ser 473 (survival marker) and were measured for their integrin-linked kinase (ILK) activity. RESULTS: Ligation of integrins using antibodies against the beta1 integrin chain or RGD peptides protected isolated hepatocytes from apoptosis and resulted in an increased ILK activity and persistent phosphorylation of protein kinase B/Akt at serine 473. CONCLUSIONS: Integrin activation in isolated hepatocytes contributes to the activation of ILK, phosphorylation of Akt on serine residue 473, and inhibition of apoptosis. Integrin signaling through the ILK-phospho Akt pathway protects isolated hepatocytes from apoptosis. This notion may potentially be applied to render the transplantation of hepatocytes more effective.

Animals↗
PubMed2005

Endothelial cell chimerism occurs more often and earlier in female than in male recipients of kidney transplants.

BACKGROUND: Endothelial chimerism occurs in renal transplants, but factors involved in its development and its impact on outcome, are unknown. Most studies on chimerism are restricted to gender-mismatched combinations of female donor organs into male recipients. By using blood group antigen mismatches to detect chimeric cells, we circumvented this restriction. We determined which factors predispose for the development of endothelial chimerism, and how it influences graft survival. METHODS: We studied 85 renal transplant biopsies of 24 patients with either blood group A or B, who received a blood group O kidney. Biopsies were scored according to BANFF '97. Blood group antigens were stained by immunohistochemistry. Semiquantitative scoring was performed by four independent observers. RESULTS: Endothelial chimerism was found in 27/85 biopsies from 16/24 patients. All female recipients, but only half of the male recipients, had endothelial chimerism in their grafts (P < 0.025). In female recipients, endothelial chimerism occurred significantly earlier than in male recipients (P < 0.02). The presence of endothelial chimerism was not associated with: rejection, outcome, original renal disease, previous transplantations, age, warm/cold ischemia time, pretransplantation blood urea levels, or erythropoietin therapy. CONCLUSION: We are the first to report that endothelial chimerism occurs significantly more often in female than in male recipients of renal transplants. Endothelial chimerism had no influence on graft outcome. We hypothesize that hormonal factors may influence the development of endothelial chimerism, in parallel with differences in endothelial function between males and females in cardiovascular disease.

Adult↗
PubMed2005

Chimerism in kidneys, livers and hearts of normal women: implications for transplantation studies.

Tissue chimerism was recently described in transplanted organs from female donors into male recipients, by demonstration of the Y-chromosome in tissue-derived cells. It was claimed that these Y-chromosome positive cells were recipient derived. To find out whether the chimeric cells, derived from pregnancies of sons or blood transfusions, could have been present in the solid organs before transplantation, we performed the following study. In situ hybridization for the Y-chromosome was performed on the normal organs (51 kidneys, 51 livers, 69 hearts) from 75 women of the normal population, whose child and blood transfusion status were known. Chimeric cells were found in 13 kidneys, 10 livers and 4 hearts, of 23 women. There was no relation between the child status or the blood transfusion history with the presence of Y-chromosome positive cells. We have for the first time demonstrated that male cells are present in normal kidneys, livers and hearts. Theoretically, these organs could have been used for the transplantation. Therefore, our findings demonstrate that the chimeric cells thus far described in transplantation studies, are not necessarily donor derived, and could have been present in the organs before the transplantation.

Adult↗
PubMed2004

Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats.

Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F2 population derived from SS and SHR (n = 230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared with SHR. Both SHRSP and SS developed severe glomerulosclerosis, whereas microangiopathy, tubulointerstitial fibrosis, and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, whereas RNO19 plays a significant role during both low- and high-salt conditions. Some F2 animals demonstrated severe microangiopathy and tubulointerstitial injury, which exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, whereas no linkage to glomerular damage was found. Further analyses at these loci indicated that the severity of renal injury was attributable to the SHR allele. Our data suggest that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.

Albuminuria↗
PubMed2004

Calcium levels as a risk factor for delayed graft function.

BACKGROUND: Delayed graft function (DGF) occurs in up to 50% of renal transplants. Hypercalcemia and hyperparathyroidism are associated with impaired renal function. Little is known on the effects of serum calcium levels on DGF. This issue was addressed in the current study. METHODS: Patients receiving a cadaveric renal transplant between 1986 and 1996 were studied. Data on calcium metabolism and histologic characteristics of nephrocalcinosis, acute tubular necrosis (ATN), and acute rejection in biopsies taken within the first week were related to the occurrence of DGF. RESULTS: The incidence of DGF in a cohort of 585 cadaveric transplants was 31%. DGF correlated independently with serum calcium levels (odds ratio [OR] 1.14 [95% confidence interval (CI) 1.04-1.26] per 0.1 mmol/L). The use of calcium channel blockers before transplantation protected against DGF (OR 0.5 [95% CI 0.29- 0.87]). In this selected group, we found an association with histologic signs of ATN and DGF. However, most of the biopsies also had features of acute rejection or nephrocalcinosis. Nephrocalcinosis was found in 12 of 71 biopsies and was not associated with serum calcium levels or the occurrence of DGF. CONCLUSIONS: In this study, serum calcium levels were independently associated with DGF. This could not be explained by the presence of microscopic nephrocalcinosis. Therefore, DGF is attributed to high intracellular calcium levels. Because calcium supplementation and vitamin D analogues are commonly used in dialysis practice, hypercalcemia influences long-term graft outcome by its effect on DGF. The pretransplant use of calcium channel blockers has a protective effect on the occurrence of DGF.

Adult↗
PubMed2004

Alternatively spliced isoforms of fibronectin in immune-mediated glomerulosclerosis: the role of TGFbeta and IL-4.

Fibronectin (FN) is the main extracellular matrix component in glomerulosclerotic lesions. There are different FN isoforms that result from alternative splicing at the EDA and EDB regions of FN mRNA. Increased inclusion of EDA and EDB, which can be elicited by TGFbeta, may be conducive to the development of glomerulosclerosis (GS). TGFbeta and IL-4 have previously been shown to play a role in the development of GS. In this study, the mRNA splicing patterns for EDA+ and EDB+ fibronectin were investigated in vivo in various experimental sclerotic glomerulopathies, in vitro in rat mesangial cells (MC) that were stimulated by TGFbeta or transfected with IL-4, and in human kidney biopsies with GS from patients with various kidney diseases. Analysis of glomerular FN mRNA demonstrated inclusion of both ED regions in rats with anti-Thy1 nephritis or chronic serum sickness and in mice with anti-GBM glomerulonephritis. Inclusion of both the EDA and EDB regions was associated with glomerular TGFbeta expression. In contrast, in mice with Th2-mediated graft-versus-host disease, a model for lupus nephritis, the FN transcripts included neither the EDA nor the EDB region, and renal TGFbeta expression was absent. Compared to normal MCs in culture, MCs transfected with IL-4 produced lower amounts of FN and demonstrated less EDA inclusion, while MC that had been treated with TGFbeta showed increased production of FN and more EDA inclusion. Renal biopsies from patients with renal diseases, except those taken from patients with lupus nephritis, showed higher TGFbeta levels, higher FN levels, and more EDA inclusion than controls. TGFbeta may be a key player in the development of GS by inducing local FN production and alternative splicing of FN mRNA. In lupus glomerulonephritis, in which the involvement of TGFbeta in GS is less prominent, Th2 cytokines such as IL-4 probably account for increased intrarenal collagen synthesis and subsequent FN accumulation from the circulation. In conclusion, neither alternative FN splicing, nor a high transcription level of TGFbeta, appears to be a general prerequisite for the development of GS.

Alternative Splicing↗