Biomedical subjects

Yvo W J Sijpkens

Publications and source records attributed to Yvo W J Sijpkens.

10 recordsLinked to original sources

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↗

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

Chronic renal allograft rejection: pathophysiologic considerations.

Chronic rejection is currently the most prevalent cause of renal transplant failure. Clinically, chronic rejection presents by chronic transplant dysfunction, characterized by a slow loss of function, often in combination with proteinuria and hypertension. The histopathology is not specific in most cases but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified such as young recipient age, black race, presensitization, histoincompatability, and acute rejection episodes, especially vascular rejection episodes and rejections that occur late after transplantation. Chronic rejection develops in grafts that undergo intermittent or persistent damage from cellular and humoral responses resulting from indirect recognition of alloantigens. Progression factors such as advanced donor age, renal dysfunction, hypertension, proteinuria, hyperlipidemia, and smoking accelerate deterioration of renal function. At the tissue level, senescence conditioned by ischemia/reperfusion (I/R) may contribute to the development of chronic allograft nephropathy (CAN). The most effective option to prevent renal failure from chronic rejection is to avoid graft injury from both immune and nonimmune mechanism together with nonnephrotoxic maintenance immunosuppression.

Chronic Disease↗

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

Antibody response against the glomerular basement membrane protein agrin in patients with transplant glomerulopathy.

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.

Agrin↗

PubMed2004

The pathobiology of chronic allograft nephropathy: immune-mediated damage and accelerated aging.

Chronic allograft nephropathy includes chronic calcineurin nephrotoxicity, recurrent and de novo glomerulonephritis and a group of disorders with graft dysfunction of unknown etiology designated chronic rejection. Review of risk factors of the latter category show that the chronic rejection lesions emerge in organs that have undergone injury. Despite the relevance of nonalloantigen-dependent progression factors in the tissue injury, alloantigen-dependent factors predominate in the pathogenesis. Lately, B cell responses have received increasing interest in transplant rejection and include responses against both major histocompatibility complex (MHC) and tissue-specific antigens, mainly on the endothelium and in the glomeruli. These humoral responses are thought to be involved in the development of vascular and glomerular lesions. Furthermore, at the tissue level, markers of senescence are found in the tubular epithelium contributing to the lesions of tubular atrophy and interstitial fibrosis.

Aging↗

PubMed2003

Early versus late acute rejection episodes in renal transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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), and major histocompatibility complex (MHC) class II incompatibility, OR 2.28 (1.62-3.20) per human leukocyte antigen (HLA)-DR mismatch, were independent risk factors for early ARE. In contrast, recipient age, OR 0.75 (0.61-0.93) per 10-year increase, donor age, OR 1.28 (1.07-1.53) per 10-year increase, female donor gender, OR 1.74 (1.03-2.94), and MHC class I incompatibility, OR 1.35 (1.07-1.72) per mismatch of cross reactive groups, were associated with late ARE. CONCLUSIONS: Late ARE has a detrimental impact on long-term graft survival and is associated with MHC class I incompatibility, whereas early ARE is correlated with HLA-DR mismatches and has a better prognosis. These data are consistent with the role of direct and indirect allorecognition in the pathophysiology of early and late ARE, respectively.

Acute Disease↗

PubMed2003

Predicting kidney graft failure using time-dependent renal function covariates.

Chronic rejection and recurrent disease are the major causes of late graft failure in renal transplantation. To assess outcome, most researchers use Cox proportional hazard analysis with time-fixed covariates. We developed a model adding time-dependent renal function covariates to improve the prediction of late graft failure. We studied 692 kidney transplants at the Leiden University Medical Center that had functioned for at least 6 months. Graft failure from chronic rejection or recurrent disease occurred in 106 patients. The reciprocal of last recorded serum creatinine (RC), the ratio of RC and RC at 6 months (RC6), and the time elapsed since last observation (TEL) were used as time-dependent covariates. Cadaveric donor transplantation, a lower RC, and a lower ratio of RC/RC6 were independently associated with graft failure. The impact of the last recorded RC was dependent on its value, TEL, and the time since transplantation. Validation of the model confirmed much higher failure predictions in those with subsequent graft failure compared with nonfailures. This study illustrates that the prediction of late graft failure could be improved significantly by using time-dependent renal function covariates.

Adult↗

PubMed2003

Chronic rejection with or without transplant vasculopathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is defined and graded in the Banff '97 scheme by the severity of interstitial fibrosis and tubular atrophy. It has been denoted that chronic rejection can be diagnosed if the typical vascular lesions are seen, consisting of fibrointimal thickening. We observed several patients who developed CAN without vascular changes or signs of cyclosporine toxicity. Therefore, we assessed the risk factor profiles of CAN with and without transplant vasculopathy. METHODS: A cohort of 654 cadaveric renal transplants performed between 1983 and 1997 that functioned for more than 6 months was studied. Fifty-four transplants had CAN defined by a significant decline in renal function together with interstitial fibrosis and tubular atrophy without signs of cyclosporine nephrotoxicity or recurrent disease. Using the Banff chronic vascular (CV) score, 23 of 54 cases (43%) had a chronic vasculopathy score of 0 or 1 whereas 31 cases (57%) had a CV score of 2 or 3. Applying multivariate logistic regression, predictor variables of the two groups were compared with 231 transplants with a stable function for at least 5 yr. RESULTS: Graft histology was obtained at a mean of 2.4 and 2.9 yr after transplantation in the group with or without vasculopathy, respectively. Acute rejection episodes (AREs) after 3 months post-transplantation were the strongest risk factor for both forms of CAN, odds ratio (OR) 14.7 (6.0-36.0). CAN with vasculopathy was also associated with transplants performed in the 1980s, OR 4.95 (1.65-14.9) and with creatinine clearance at 6 months, OR 0.58 (0.44-0.75) per 10 mL/min increase. In contrast, young recipient age, OR 0.69 (0.47-0.99) per 10-yr increase, and the presence of panel reactive antibodies at the time of transplantation, OR 1.26 (1.08-1.47) per 10% increase, were independent risk factors for CAN without vasculopathy. CONCLUSIONS: After exclusion of cyclosporine toxicity or recurrent disease CAN occurred without moderate or severe transplant vasculopathy in 43% of the cases. The correlation with young recipient age, sensitization and late ARE suggest an immune pathogenesis, consistent with chronic rejection.

Acute Disease↗

PubMed2002

High transforming growth factor-beta and extracellular matrix mRNA response in renal allografts during early acute rejection is associated with absence of chronic rejection.

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-beta1, 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.

Acute Disease↗