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Papers by Jan Bruijn

Molecular Human Reproduction, 2015

Microchimerism is the occurrence of small populations of cells with a different genetic backgroun... more Microchimerism is the occurrence of small populations of cells with a different genetic background within an individual. Tissue microchimerism is considered to be primarily pregnancy-derived and is often studied relative to female-dominant autoimmune diseases, pregnancy complications, malignancies, response to injury, and transplantation outcomes. A particular distribution pattern of chimeric cells across various organs was recently described in a model of murine pregnancies. Our aim was to determine the frequency and distribution of tissue microchimerism across organs during and after pregnancy in humans. We performed in situ hybridization of the Y chromosome on paraffin-embedded autopsy samples of kidneys, livers, spleens, lungs, hearts and brains that were collected from 26 women who died while pregnant or within 1 month after delivery of a son. Frequencies of chimeric cells in various tissues were compared with those of a control group of non-pregnant women who had delivered sons. Tissue microchimerism occurred significantly more frequently in the lungs, spleens, livers, kidneys and hearts of pregnant women compared with non-pregnant women (all P , 0.01). We showed that some of the chimeric cells were CD3+ or CD34+. After correction for cell density, the lung was most chimeric (470 Y chromosome-positive nuclei per million nuclei scored), followed by the spleen (208 Y+/ 10 6 nuclei), liver (192 Y+/10 6 nuclei), kidney (135 Y+/10 6 nuclei), brain (85 Y+/10 6 nuclei) and heart (40 Y+/10 6 nuclei). Data from this unique study group of women who died while pregnant or shortly after delivery provide information about the number and physiologic distribution of chimeric cells in organs of pregnant women. We demonstrate that during pregnancy, a boost of chimeric cells is observed in women, with a distribution across organs, that parallels findings in mouse models.

Arthritis & Rheumatology, 2015

Objective In this study, we investigate the incidence of malignancies in patients diagnosed with ... more Objective In this study, we investigate the incidence of malignancies in patients diagnosed with ANCA-associated vasculitis (AAV) between 1991 and 2013, covering a mean follow-up period of 10 years. Additionally, we examine the effect of immunosuppressive therapy on the malignancy risk in these patients. Methods We included patients with histopathologically-proven AAV, diagnosed between 1991 and 2013 at a large university hospital. Malignancy incidence was assessed with the Dutch National Pathology Database. We used the Netherlands Cancer Registry incidence rates for comparing the malignancy incidence in our AAV cohort to that of the general Dutch population. Results Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean follow-up of 9.7 years. The gender-, age-, and calendar year-adjusted malignancy risk was 2.21-fold (95% CI: 1.64-2.92) higher than that of the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio: 4.23, 95% CI: 2.76-6.19). The incidences of other reported malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide therapy. Interestingly, malignancy risk was not increased in patients that received cyclophosphamide for less than 1 year. Conclusion Patients with AAV have a higher risk of malignancies than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies - specifically bladder and haematological malignancies - has decreased in patients with AAV. This finding reflects ongoing efforts to reduce cyclophosphamide exposure by developing new therapy regimens. This article is protected by copyright. All rights reserved.

Journal of the American Society of Nephrology : JASN, Jan 7, 2015

Over 10 years have passed since the latest revision of the histopathologic classification of lupu... more Over 10 years have passed since the latest revision of the histopathologic classification of lupus nephritis. This revision was a significant improvement compared with the previous version, mainly because of clearer and more concise definitions and the elimination of mixed subclasses. Despite these improvements, there are still some difficulties in the classification for lupus nephritis, many of which are in the definitions provided. In this review, we focus on the difficulties surrounding the evaluation of classes III and IV lesions, particularly the definitions of endocapillary and extracapillary proliferation, the use of the terms endocapillary proliferation and hypercellularity, the clinical relevance of segmental and global subdivision in class IV, and the value of distinguishing lesions that indicate activity and chronicity. Vascular and tubulointerstitial lesions are also discussed. Furthermore, we give an overview of the history of the classification to provide background on...

Arthritis and Rheumatism, 2006

Background Systemic lupus erythematosus ,(SLE) is an ,immune-mediated ,disease that particularly ... more Background 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 Tcells in offspring. In humans, pregnancy-induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

In the early 1990s, an international working group of experienced renal pathologists, the Renal H... more In the early 1990s, an international working group of experienced renal pathologists, the Renal Histology group, set up a scoring system for biopsies with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This scoring system subdivided glomerular, interstitial and vascular lesions and served as a tool for the evaluation of all renal biopsies from studies of the European Vasculitis Study Group (EUVAS). Histopathological studies gave new insights into the prediction of renal outcome in patients with ANCA-associated glomerulonephritis. Percentage of normal glomeruli and a selected number of interstitial parameters were reliable predictors of long-term follow-up glomerular filtration rate in all studies. Out of these results, a histopathological classification distinguishing focal, crescentic, mixed and sclerotic classes of ANCA-associated glomerulonephritis was developed. Until today, 13 studies have validated this classification system. Future studies will...

Journal of the American Society of Nephrology : JASN, Jan 8, 2015

Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can o... more Complement activation has a major role in thrombotic microangiopathy (TMA), a disorder that can occur in a variety of clinical conditions. Promising results of recent trials with terminal complement-inhibiting drugs call for biomarkers identifying patients who might benefit from this treatment. The primary aim of this study was to determine the prevalence and localization of complement factor C4d in kidneys of patients with TMA. The secondary aims were to determine which complement pathways lead to C4d deposition and to determine whether complement activation results in deposition of the terminal complement complex. We examined 42 renal sections with histologically confirmed TMA obtained from a heterogeneous patient group. Deposits of C4d, mannose-binding lectin, C1q, IgM, and C5b-9 were scored in the glomeruli, peritubular capillaries, and arterioles. Notably, C4d deposits were present in 88.1% of TMA cases, and the various clinical conditions had distinct staining patterns within ...

Rheumatology (Oxford, England), Jan 22, 2014

We investigated whether ENT involvement is associated with renal biopsy findings and renal functi... more We investigated whether ENT involvement is associated with renal biopsy findings and renal function in patients with ANCA-associated vasculitis (AAV). Newly diagnosed AAV patients derived from three international, multicentre trials were included. To investigate an association between ENT involvement and estimated glomerular filtration rate (eGFR) at diagnosis and 5-year follow-up, we performed multivariable regression analyses including clinical and histopathological parameters. To investigate whether our findings are specific to ENT involvement, we performed comparable analyses between eGFR and other early disease manifestations (arthralgia/arthritis, cutaneous and lung involvement). One hundred and eighty-five of the 414 patients had ENT involvement. The mean presenting eGFR of patients with and without ENT involvement was 39.16 and 23.88 ml/min/1.73 m(2), respectively (P < 0.001). Mean eGFR increased by 6.76 ml/min/1.73 m(2) with each added ENT symptom (P = 0.007). Patients w...

Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2014

Preeclampsia is characterized by hypertension and proteinuria, and increased shedding of podocyte... more Preeclampsia is characterized by hypertension and proteinuria, and increased shedding of podocytes into the urine is a common finding. This finding raises the question of whether preeclamptic nephropathy involves podocyte damage. This study examined podocyte-related changes in a unique sample of renal tissues obtained from women who died of preeclampsia. All patients with preeclampsia who died in The Netherlands since 1990 and had available autopsy tissue were identified using a nationwide database of the Dutch Pathology Registry (PALGA). This resulted in a cohort of 11 women who died from preeclampsia. Three control groups were also identified during the same time period, and consisted of normotensive women who died during pregnancy (n=25), and nonpregnant controls either with (n=14) or without (n=13) chronic hypertension. Glomerular lesions, including podocyte numbers, podocyte proliferation, and parietal cell activation, were measured. Patients with preeclampsia had prominent cha...

The Journal of laboratory and clinical medicine, 1997

The purpose of this article is to review a set of recently obtained data concerning matrix and ma... more The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competi...

Transplantation, 2006

Endothelial chimerism in transplanted organs is a fascinating phenomenon, indicative of a mechani... more 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, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;contamination&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; 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.

Transplantation, 1996

Histological and immunohistochemical analyses were made of biopsy specimens from 50 consecutive p... more Histological and immunohistochemical analyses were made of biopsy specimens from 50 consecutive patients who experienced putative graft rejection. The mean age of the patients was 44.5 years (range, 17-69 years) and 26 were men. There were 67 evaluable allograft specimens, which were grouped according to the histological diagnosis: group 1, acute tubulointerstitial rejection (n = 42); group 2, acute vascular rejection (n = 18); and group 3, diffuse thrombosis (n = 7). Over a follow-up period of 21-57 months, the mean number of rejection episodes was 1.7, 2.8, and 3.3 in groups 1, 2, and 3, respectively. Allograft loss occurred in 7 out of 30, 10 out of 16, and 4 out of 4 patients in groups 1, 2, and 3, respectively. The following histological parameters differed significantly (P < 0.05) among the groups: interstitial edema, congestion of peritubular capillaries, glomerular thrombosis, and glomerular ischemia (group 3 > group 2 > group 1). Interstitial bleeding was seen more often in group 2 and 3 tissues than in group 1 specimens (P < 0.01). Immunohistochemical analyses showed that vascular rejection was associated with WT14 staining for monocytes and macrophages around the tubuli and with interstitial deposition of complement factor 3. With regard to serology, positive anti-endothelial cell antibody-dependent cellular cytotoxicity was associated with vascular rejection and thrombosis of the graft in all patients tested, and with graft loss in 75%. Pre-existent positive anti-IgG immunofluorescence on peritubular capillaries in pretransplant biopsy specimens incubated with patient serum was found in only 3 of the 50 patients, but was associated with graft loss in 2 of the 3. Cytomegalovirus infection was associated with a higher percentage of graft loss. There were significant intergroup differences in panel reactive antibodies before transplantation (P < 0.001), with higher titers in groups 2 and 3. The findings in relation to interstitial rejection are compatible with cellular rejection, while the data on vascular rejection support a humorally mediated pathogenesis.

Transplantation, Jan 27, 2003

Acute rejection is a major complication after renal transplantation and the most important risk f... more Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term outcome and compared the risk profiles of early versus late ARE. A cohort of 654 patients who underwent cadaveric renal transplants (1983-1997) that functioned for more than 6 months was studied. In 384 of 654 transplant recipients, one or more treated AREs were documented; the last ARE occurred in 297 of 384 transplant recipients within 3 months and in 87 of 384 after 3 months. Applying multivariate logistic regression analysis, we compared the predictor variables of the two groups with transplants without AREs. Ten-year graft survival rates censored for causes of graft loss other than chronic rejection were 94%, 86%, and 45% for patients without ARE, with early ARE, and with late ARE, respectively. Delayed graft function, odds ratio (OR) 2.37 (1.55-3.62...

Clinical journal of the American Society of Nephrology : CJASN, Jan 7, 2015

To treat lupus nephritis effectively, proper identification of the histologic class is essential.... more To treat lupus nephritis effectively, proper identification of the histologic class is essential. Although the classification system for lupus nephritis is nearly 40 years old, remarkably few studies have investigated interobserver agreement. Interobserver agreement among nephropathologists was studied, particularly with respect to the recognition of class III/IV lupus nephritis lesions, and possible causes of disagreement were determined. A link to a survey containing pictures of 30 glomeruli was provided to all 360 members of the Renal Pathology Society; 34 responses were received from 12 countries (a response rate of 9.4%). The nephropathologist was asked whether glomerular lesions were present that would categorize the biopsy as class III/IV. If so, additional parameters were scored. To determine the interobserver agreement among the participants, κ or intraclass correlation values were calculated. The intraclass correlation or κ-value was also calculated for two separate levels...

Transplantation, 2002

ABSTRACT Background. A case-control study was performed to investigate whether mRNA levels of tra... more ABSTRACT Background. A case-control study was performed to investigate whether mRNA levels of transforming growth factor-beta (TGF-beta) and various extracellular matrix molecules in renal transplant biopsy specimens, taken during acute rejection episodes within 6 months of transplantation, discriminate between patients who show deterioration of graft function and develop chronic rejection (CR+ group), and those who do not develop chronic rejection (CR- group). Methods. Patients in both the CR+ group (n=10) and the CR- group (n=18) had at least one biopsy-proven acute rejection episode within the first 6 months after transplantation. The two groups were similar with respect to donor-, recipient-, and transplantation-related clinical variables. Histologic changes (Banff classification) and the timing of the acute rejection episodes in the biopsies studied did not differ between groups. Renal cortical mRNA levels of TGF-beta(1), collagen alpha1(IV), collagen alpha1 (I), decorin, and the household gene glyceraldehyde-3-phosphate dehydrogenase in biopsy specimens taken during acute rejection episodes were quantified by real-time polymerase chain reaction. Results. The mean TGF-beta mRNA level in the CR+ group was 3.4 times higher than that in the CR+ group (P<0.04). The mean collagen IV, collagen I, and decorin mRNA levels in the CR- group were 4.2 times (P<0.05), 5.1 times (not significant), and 3.2 times (P<0.05) higher, respectively, than those in the CR+ group. The mean TGF-beta to decorin mRNA ratios between the two patient groups did not differ significantly. Conclusions. In summary, high mRNA levels for TGF-beta, collagen IV, and decorin, but not histopathologic changes, in biopsies taken during acute rejection episodes early after kidney transplantation are associated with absence of chronic rejection. We hypothesize that TGF-beta might have beneficial effects during acute rejection through its known antiinflammatory actions or as an inducer of tissue repair.

Transplantation, 1997

Graft rejection is one of the major causes of graft loss after pancreas transplantation. Pancreat... more Graft rejection is one of the major causes of graft loss after pancreas transplantation. Pancreatitis-associated protein (PAP) is synthesized by the pancreas due to pancreatic inflammation and has shown to be a good serum marker for injury of the pancreas. It may also be potentially useful in the early recognition of rejection and may thus improve pancreas survival. We retrospectively evaluated PAP as an early serum marker of pancreas graft rejection in a cross-sectional study in which immunohistochemical analysis of pancreas biopsies was undertaken using antibodies against PAP. PAP concentrations were also measured in sera of blood donors and in patients with renal failure, renal replacement therapy, kidney transplantation alone, and simultaneous pancreas-kidney transplantation. All patients had elevated PAP serum levels compared with blood donors (median PAP: 22 ng/ml, range: 5-75 ng/ml; P<0.0001). Patients on renal replacement therapy had higher values than patients with renal failure (median: 420 ng/ml and 150 ng/ml, respectively). There was a strong inverse correlation between PAP levels and creatinine clearance (P<0.001). PAP values in simultaneous pancreas-kidney transplantation patients with histological rejection were significantly higher than values in those who were clinically stable (median: 925 ng/ml and 322 ng/ml, respectively; P=0.006). Rejection was significantly associated with PAP staining of acinar cell surface. There was also a significant correlation between surface positivity of staining and serum PAP levels (P=0.008). No positive PAP staining was observed in concurrently collected biopsies of renal allografts undergoing rejection. Serum PAP levels appear to strongly correlate with creatinine clearance measurements. In patients with a pancreas-kidney transplantation, PAP may prove to be a useful biological and histological marker of pancreatic graft rejection.

Transplant International, 1997

Abstract To examine the incidence Key words Pancreas of interstitial and vascular rejection in pa... more Abstract To examine the incidence Key words Pancreas of interstitial and vascular rejection in pancreas allografts and its impact on graft survival, we studied 36 percutaneous pancreas biopsies and 10 pancreas transplantectomy specimens from 32 patients who had undergone simultaneous pancreas-kidney transplantation. Interstitial rejection (IR) was predominantly found in the biopsies, while vascular rejection (VR) was most prominent in the transplantectomies. Pancreas graft survival was significantly decreased for pancreas grafts that had suffered from vascular rejection when compared to those with only interstitial rejection. Potential rejection markers, i. e., serum amylase, glucose, creatinine, and urinary amylase, did not correlate with histological signs of rejection, although increased levels of serum amylase were, in all but one case, associated with rejection.We conclude that a percutaneous pancreas biopsy remains the most reliable method to determine pancreas rejection, and that by distinguishing between IR and VR, a pancreas biopsy may provide important diagnostic as well as prognostic information.

Journal of Laboratory and Clinical Medicine, 1997

We report the results of a meta-analysis of 349 patients with Wegener's granulomatosis (W... more We report the results of a meta-analysis of 349 patients with Wegener's granulomatosis (WG) that were described in the literature from 1979 onward. We describe the patients in terms of diagnosis (granulomas present or absent in biopsy samples from various organs, results of the anti-neutrophil cytoplasmic antibody [ANCA) test) and of the clinical impact of renal involvement. Furthermore, we report the incidence of histopathologic lesions that were found in 134 renal biopsy samples. Before and after the development of the ANCA test, the percentage of patients in whom WG was diagnosed with histologically proven granulomas is the same. However, after 1987 the diagnosis of the group without granulomas is frequently supported by a positive ANCA test result. For the entire group we found that patients without renal involvement (N = 82) were reported to have lower erythrocyte sedimentation rate (ESR), lower white blood cell count (WBC), less anemia, less hypertension, less occurrence of joint symptoms, and less multi-organ involvement than patients with renal involvement (N = 267). The most frequently reported lesion in the renal biopsy samples was extracapillary proliferation (70%), followed by fibrinoid necrosis of the glomerular tuft (54%). Renal granulomas were reported in only 7 biopsy samples.

Journal of Laboratory and Clinical Medicine, 2001

Abbreviations: GvHD = graft-versus-host disease; ICAM-1 = intercellular adhesion molecule 1; IgG ... more Abbreviations: GvHD = graft-versus-host disease; ICAM-1 = intercellular adhesion molecule 1; IgG = immunoglobulin G; IgM = immunoglobulin M; IL = interleukin; MHC = major histocompatibility complex; mRNA = messenger RNA; PDGF = platelet-derived growth factor; RANTES = regulated upon activation normal T cells expressed and secreted; SLE = systemic lupus erythematosus; TGF-β = transforming growth factor β; TNF-α = tumor necrosis factor α; TXA = thromboxane From the