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B Watschinger

Publications and source records attributed to B Watschinger.

At least 37 records · Page 2Linked to original sources
PubMed1998

Decreased urinary apolipoprotein (a) excretion in patients with impaired renal function.

BACKGROUND: Plasma lipoprotein (a) [Lp(a)] levels are elevated in patients with kidney disease and are strongly associated with premature cardiovascular disease and stroke. METHODS: As the kidney is suggested to play an important role in apolipoprotein (a) [apo(a)] catabolism and as apo(a) fragments appear in urine, we determined plasma Lp(a) levels and urinary apo(a) excretion in relation to kidney function in a large cohort of renal patients. A total of 368 renal patients with normal or different degrees of impaired renal function and 163 healthy control subjects matched for age and sex were investigated. Plasma Lp(a) and urinary apo(a) were analysed immunochemically. RESULTS: Renal patients were found to have significantly elevated total cholesterol and low-density lipoprotein (LDL)-C values but lower high-density lipoprotein (HDL)-C values than control subjects. Plasma Lp(a) values were significantly higher only in patients with creatinine clearance < 70 mL min-1. There was a significant correlation between urinary apo(a) and plasma Lp(a) in patients and control subjects. Urinary apo(a) excretion was significantly lower in patients than in control subjects and showed no correlation with urinary protein excretion. CONCLUSION: Although it is unlikely that impaired renal excretion of apo(a) fragments largely contributes to increased plasma Lp(a) levels in patients suffering from impaired kidney function, these data suggest that urinary apo(a) excretion is significantly decreased in renal patients and that this might contribute to increased plasma Lp(a) levels in this patient group.

Aged↗
PubMed1998

Smoking as a risk factor for end-stage renal failure in men with primary renal disease.

BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.

Adult↗
PubMed1997

The start of clinical nephrology in Austria and developments in the treatment of patients with end stage renal disease over the last decades.

Over the last 50 years nephrology has seen milestone achievements in basic sciences as well as in clinical medicine. This article describes the start of clinical nephrology in Austria in the 1950's and the significant changes over the last decades. With 625 patients/pmp Austria has worldwide one of the highest numbers of patients treated for endstage renal disease. In 1995, 5020 patients were alive on replacement therapy, equally distributed between transplanted and dialyzed patients. An overview over the developments that led to Austria's prominent role in the treatment of end stage renal disease is given.

Austria↗
PubMed1997

Hypothyroidism.

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Adult↗
PubMed1997

Urinary excretion of apo(a) in patients after kidney transplantation.

BACKGROUND: Increased plasma Lipoprotein (a) (Lp(a)) levels are strongly associated with premature cardiovascular disease and stroke. The kidney is purported to play an important role in apo(a) catabolism. Therefore we investigated plasma Lp(a) levels in relation to kidney function and urinary apo(a) excretion. METHODS: One hundred and sixteen kidney transplant patients with normal or impaired renal function and 109 age- and sex-matched healthy controls were investigated. Plasma Lp(a) and urinary apo(a) levels were determined immunochemically and all other parameters were determined by routine laboratory methods. RESULTS: Transplant recipients were found to have significantly elevated total cholesterol and LDL-C values, but equal HDL-C values compared to controls. Plasma Lp(a) values were higher and urinary apo(a) excretion was lower in transplant recipients compared to controls, independent of renal function. When the patient group was subdivided into 'normal' and 'impaired creatinine clearance', only the latter group secreted less apo(a) than normal controls. CONCLUSION: These data suggest that urinary apo(a) excretion is reduced in transplant recipients with impaired excretory graft function, which may contribute to the elevation of plasma Lp(a) levels in these patients.

Aged↗
PubMed1996

The effects of nondepleting CD4 targeted therapy in presensitized rat recipients of cardiac allografts.

The immunosuppressive effects of RIB-5/2, a nondepleting anti-rat CD4 monoclonal antibody (mAb), were analyzed in a well-defined model of accelerated cardiac allograft rejection. (LEW x BN)F1 hearts are rejected within 24 hours in LEW hosts presensitized with BN skin grafts at day -7. Treatment with RIB-5/2 mAb (3.5 mg/day i.v.) at days -7 and -1, prolonged cardiac allograft survival to the median of >62 days. The long-term recipients rejected acutely third-party (Wistar-Furth) test skin grafts, without an adverse effect on the survival of the original cardiac transplants. Lymphocytes harvested from mAb-treated hosts significantly decreased proliferative responses of donor cells in mixed leukocyte reaction. The cell activation and cytokine elaboration patterns were evaluated at the mRNA and protein levels by competitive template reverse transcriptase polymerase chain reaction and immunohistochemistry, respectively. Cardiac allografts in CD4 mAb-treated rats at 24 hours displayed reduced CD3, CD25, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-2, interferon (IFN)-gamma, and IL-10 mRNA levels as compared to those in rejecting grafts. Equal amounts of IL-4 mRNA were detected throughout in both animal groups; the expression of IL-10 mRNA increased progressively in the treated hosts. In contrast, IFN-gamma was consistently depressed after mAb therapy. The mRNA levels coding for CD3, CD25, tumor necrosis factor-alpha, IL-1-beta, and IL-2 genes were comparable in long-surviving and rejecting allografts. The staining for IL-2R, IL-2, and IFN-gamma was diminished, whereas the staining for IL-4 was either unaffected or enhanced in well-functioning grafts in RIB-5/2 mAb-treated hosts. The untreated recipients elicited strong circulating IgM allo-Ab response, which peaked around the time of cardiac rejection and then switched to IgG allo-Ab 4-7 days after heart transplantation. Treatment with RIB-5/2 mAb decreased IgM and prevented the switch into the IgG allo-Ab response. In conclusion, the ability of RIB-5/2 mAb treatment to combat accelerated rejection and to produce long-term graft acceptance is unprecedented in our experience in this model. These data provide new insights into the complexities of the cellular and humoral responsiveness, contributing to the the induction of donor-specific unresponsiveness in sensitized hosts. This study, along with our previous reports, indicate that an immune deviation in which intragraft Th1-type cytokines (primarily IFN-gamma) are diminished and Th2-type cytokines (IL-4 and IL-10) are maintained represents the common effector mechanism of CD4 mAb regimens in recipients of vascularized organ allografts.

Animals↗
PubMed1996

Endothelin in organ transplantation.

Solid organ allografts are often compromised by ischemia, acute rejection episodes associated with hemodynamic changes, and chronic rejection typically characterized by the development of obliterative vasculopathy, and in the case of the kidney, and glomerulosclerosis. Recent in vivo data indicate that endothelin (ET) production is locally upregulated in rejecting allografts, and that, in addition to endothelial cells, ET is also produced by graft-infiltrating mononuclear cells (monocytes/macrophages). In vitro data also indicate that ET production is regulated, at least in part, by certain T cell-and monocyte/macrophage-derived cytokines, which are abundant in rejecting allografts. These data and the findings of elevated plasma levels of ET after transplantation (in particular during rejection processes), the effects of immunosuppressive drugs (cyclosporine and tacrolimus in particular) on ET production, and the profound vasoconstrictive and mitogenic properties of this peptide suggest that endothelin may be involved in the initiation and propagation of posttransplantation complications; including systemic hypertension, acute allograft dysfunction, and perhaps most importantly, chronic allograft dysfunction. These observations provide the rational to use ET receptor antagonists to formally address the potential role of ET in these processes, and to develop therapeutic strategies that ameliorate or possibly prevent these complications.

Cytokines↗
PubMed1995

The alloantibody network following intrathymic immunomodulation of sensitized rat recipients of cardiac allografts.

An intrathymic injection of allogeneic spleen cells (2 x 10(7)) prevents accelerated (< 36 hr) rejection in sensitized LEW rats, and prolongs the survival of LBNF1 cardiac allografts to about 11 days. This effect is donor-specific, x-irradiation-sensitive and thymus-dependent, and it does not require adjunctive immunosuppressive therapy. We have recently shown that following intrathymic allo-Ag injection, host cell proliferative responses in lymphoid organs are markedly depressed as compared with untreated sensitized recipients. Little is known about how intrathymic immunomodulation may affect host humoral alloreactivity. In this work, we studied the dynamic interplay between the humoral responses, both in the circulation and at the graft site of sensitized hosts. Intrathymic allo-Ag exposure triggered a profound change in the utilization pattern of alloreactive IgM, IgG, and IgG subclasses compared with recipients receiving syngeneic cells. Administration of allo-Ag into the thymus at the time of sensitization resulted in an earlier and significantly increased systemic production of IgM, as shown by flow cytometry. Subsequently, isotype switching to IgG occurred prematurely and resulted in elevated levels of IgG1 and IgG2a. Indeed, the addition of such allo-Ab enriched serum suppressed the MLR assay in a dose-dependent manner. The binding of Ig to cardiac allografts was analyzed in eluates by flow cytometry, and by immunohistochemical staining at day 1 after transplantation. Intragraft IgM and IgG levels were consistently higher in well-functioning grafts following administration of allo-Ag, as compared with controls. IgG deposits at the graft site consisted predominantly of IgG1 and IgG2a, while significant amounts of IgG2b could only be detected in control hosts undergoing accelerated graft rejection. These data document that intrathymic injection of donor-specific allo-Ag in sensitized recipients leads to profound alterations of the host humoral alloresponses, and that such elevated allo-Ab levels interfere with the Ag reactivity or alloresponsive effector cells in vitro. These results support the notion that the pattern of allo-Ab utilization is indicative of the functional status of the alloimmune response in the transplant recipient.

Animals↗
PubMed1995

The indirect pathway of allorecognition. The occurrence of self-restricted T cell recognition of allo-MHC peptides early in acute renal allograft rejection and its inhibition by conventional immunosuppression.

There is evidence that T cells can "directly" recognize intact allo-MHC molecules on the surface of allogeneic stimulator or target cells, and/or "indirectly" recognize processed allo-MHC peptides presented by self antigen-presenting cells (APCs). We and others have recently demonstrated that in vivo-primed rat CD4+ T cells recognize and proliferate to specific polymorphic amino acid sequences when presented as MHC allopeptides by self APCs. Studies on the mechanisms of indirect T cell recognition of alloantigen are now reported. First, we studied the immunogenicity of 4 synthetic polymorphic class II MHC allopeptides representing full-length sequences of the hypervariable domains of RT1.Du beta (DR or I-E-like) in several responder strains: LEW (RT1(l)), ACI (RT1a), BUF (RT1b), BN (RT1n), and control syngeneic WF (RT1u) strains. Immunogenicity of the individual 25mer allopeptides varied in the different responder strains, indicating that self-restricted T cell recognition of allo-MHC peptides is determined not only by polymorphisms, but also by the responder MHC genotype. Self-restricted CD4+ T cell recognition of processed allo-MHC peptides has been shown to occur during acute skin and cardiac allograft rejection, and there is evidence that this pathway may play an important role in initiating and amplifying the immune response to allografts. T cells from LEW animals primed in vivo by WF (RT1u) vascularized renal allografts were capable of proliferating to the RT1.Du beta peptides as early as 3 days postengraftment, when presented by self APCs. We then tested the effects of various immunosuppressive drugs on self-restricted primed T cell proliferative response to an immunogenic MHC allopeptide in vitro. Methylprednisolone, cyclosporine, and FK506 inhibited the proliferative response of RT1.Du beta 2-primed LEW T cells in a dose-dependent fashion. In addition, a single injection of cyclosporine (25 mg/kg i.m.) to LEW recipients of WF renal allografts on the day of transplantation completely abolished the proliferative response of in vivo-primed T cells to RT1.Du beta 2, indicating the susceptibility of the indirect pathway of allorecognition to conventional immunosuppressive drugs.

Amino Acid Sequence↗
PubMed1995

Up-regulation of endothelin-1 mRNA and peptide expression in rat cardiac allografts with rejection and arteriosclerosis.

Acute and chronic rejection are frequent and significant complications of cardiac transplantation, and graft arteriosclerosis is the leading cause of death beyond the first year after transplant. Levels of endothelin-1 (ET-1) are elevated in plasma of patients with cardiac allografts and those with symptomatic vascular atherosclerosis, but little is known about the role of ET-1 in these processes. This study examined intragraft ET-1 expression in rat cardiac models of acute rejection and chronic rejection associated with graft arteriosclerosis. Corrected ET-1 gene transcript levels were measured with a [32P]dCTP reverse transcription polymerase chain reaction assay normalized with glyceraldehyde-3-phosphate dehydrogenase, and the gene product was evaluated by immunohistology with a monospecific anti-ET-1 antibody at different time points after transplant. ET-1 mRNA levels were significantly increased in acutely rejected (Wistar-Furth rat cardiac allografts transplanted into Lewis rat recipients) and chronically rejected (Lewis allografts transplanted into F344 recipients) vascularized cardiac allografts as compared with isograft controls. In acutely rejected allografts, peak expression occurred on day 5 after transplant. In chronically rejected allografts, the increase in ET-1 mRNA was sustained on days 7, 28, and 75. In both acutely and chronically rejected allografts, ET-1 mRNA upregulation was not seen in host spleens or paired host hearts. Immunohistological analysis confirmed that the bulk of ET-1 peptide expression was localized to mononuclear cells that diffusely infiltrated the graft interstitium (acute rejection and early chronic rejection) and accumulated within the neointima of chronically rejecting hearts with arteriosclerosis. These observations, taken together with in vitro data showing that ET-1 production is stimulated by certain cytokines, indicate that the allogeneic stimulus within rejecting vascularized cardiac allografts, presumably cytokine mediated, leads to significant intragraft up-regulation of ET-1 mRNA and peptide expression. The local up-regulation of this vasoactive and mitogenic peptide within acutely and chronically rejected cardiac allografts suggests that ET-1 may be involved in the development of graft arteriosclerosis.

Animals↗
PubMed1995

How T cells recognize alloantigen: evidence for two pathways of allorecognition.

During allograft rejection, both allorecognition pathways seem to be effective. The direct pathway, where T-cell receptors directly recognize intact allo-MHC with or without bound peptides on the surface of target cells, accounts for most of the cytotoxic T cell function. The indirect pathway in contrast, where T-cell receptors recognize MHC allopeptides after processing and presentation by self APCs, may lead to the activation of T helper cells which secrete cytokines and provide the necessary signals for the growth and maturation of effector cytotoxic T lymphocytes and B cells leading to allograft rejection. The role of the indirect pathway is supported by the findings that mouse skin transplants from a class II deficient donor can be rejected involving CD4+ self-restricted T-cell recognition of donor antigen. In addition, rats primed by class I MHC peptides do reject skin grafts as well as renal allografts in an accelerated fashion. Studies showing that synthetic class II peptides can also be used to tolerize animals for a subsequent renal transplant further underline the importance of this self restricted recognition of allo-MHC. More studies are needed to better define the contribution of this self-restricted T cell recognition of processed allo-MHC to the rejection process in particular in regard to its suggested role in chronic allograft failure as well as to its susceptibility to therapeutic regimens in organ transplant recipients.

Animals↗
PubMed1994

Intrathymic injection of donor-specific X-irradiation-sensitive spleen cells abrogates accelerated rejection of cardiac allografts in sensitized rats.

LBNF1 cardiac allografts are rejected within 36 hr in Lewis (LEW) rats sensitized with Brown Norway (BN) skin grafts (acute rejection = 7.5 days). We analyzed the effects of intrathymic versus intravenous alloantigen challenge upon graft survival in this well-defined accelerated rejection model. Intrathymic injection of LBNF1 spleen cells (2 x 10(7)) at the time of skin transplantation (day -7) abrogated < 36 hr rejection, and prolonged the survival of cardiac allografts to about 11 days. This striking effect did not require concomitant immunosuppression, and was donor specific, as the transfer of syngeneic (LEW) or third-party (Wistar-Furth) splenocytes was ineffective. X-irradiation of donor spleen cells before inoculation restored accelerated rejection, whereas thymectomy at day -6 or 0 (the day of heart transplant) significantly shortened graft survival. In contrast, although intravenous administration of the same number of donor cells into sensitized recipients prolonged cardiac allograft survival to about 9 days, the effect was x-irradiation resistant and was never influenced by thymectomy. Radioactive tracer studies have revealed distinct trafficking patterns for the transferred cells, with those given intrathymically retained mostly in the thymus, and sequestered into host spleen and lymph nodes. Instead, intravenously injected splenocytes did not accumulate in the thymus, but were eventually trapped in the liver. Moreover, intrathymic immunomodulation has switched off cellular, rather than humoral, events at the graft site, and markedly depressed cell proliferative responses in host lymphoid organs, as analyzed by immunohistology and mixed lymphocyte response (MLR)* assay, respectively. In contrast, intravenous therapy did not have any significant effect on early intragraft cellular infiltration, including considerable neutrophil infiltration, and did not affect lymph node cell proliferation in vitro. These data document the importance of the thymus as a potential target organ for modulation of alloreactivity in vivo, and reinforce the role of distinct "central" and "peripheral" host immune mechanisms contributing to immunological unresponsiveness following organ transplantation.

Animals↗