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Biomedical subjects

U Heemann

Publications and source records attributed to U Heemann.

At least 73 records · Page 4Linked to original sources
PubMed1997

Kidneys from normotensive donors lower blood pressure in young transplanted spontaneously hypertensive rats.

Single transplanted kidneys from spontaneously hypertensive rats (SHR) have been shown to elicit hypertension in genetically normotensive recipients. This study was designed to investigate the effects of single transplanted kidneys from genetically normotensive donors [Biobreeding (BB)/Ottawa Karlsburg (OK) rats] on blood pressure in SHR recipients. The following groups were formed: group 1 (n = 11), SHR donors and SHR recipients; group 2 (n = 15), BB/OK donors and SHR recipients; and group 3 (n = 8), BB/OK donors and BB/OK recipients. Recipients received antihypertensive treatment (hydralazine) from weaning until renal transplantation at the age of 9 wk and immunosuppressive treatment (anti-CD4 antibody and cyclosporine A) for 3 wk starting on the day of transplantation. Six weeks after transplantation, intra-arterially measured blood pressure and heart weight-to-body weight ratio were highest in group 1, intermediate in group 2, and lowest in group 3. There were no significant differences with respect to plasma urea and creatinine concentrations among the three groups. These results support the hypothesis that hypertension in renal-transplanted SHR depends in part on the genetic background of the transplanted kidney.

Animals↗
PubMed1996

Retransplantation reverses mononuclear infiltration but not myointimal proliferation in a rat model of chronic cardiac allograft rejection.

Episodes of acute rejection seem to play an important role in the development of chronic allograft failure. Whereas acute rejection appears to be fully reversible, at least at early stages, reversibility of chronic graft alterations is still unclear. Male Fisher F344 rat hearts were heterotopically transplanted into Lewis recipients (n=8/group). Minimal immunosuppression (rapamycin 0.5 mg/kg for 14 days) guaranteed allograft survival during the observation period (group 1). Allografted hearts were retransplanted into syngeneic recipients after 14 days (group 2) and 50 days (group 3) and compared with F344 isografts undergoing retransplantation after 4 days (group 4) and with F344 isografts without a second procedure (group 5). All organs were removed after 100 days and morphologically and immunohistologically assessed. Allografts of group 1 developed concentric myointimal proliferation with dense intramural and perivascular mononuclear infiltration and intravascular thrombosis in 59 +/- 7% of coronary arteries. Retransplantation into syngeneic recipients almost completely abolished mononuclear infiltration, but did not affect the development of myointimal proliferation (groups 2/3: 46 +/- 7%/31 +/- 24%, NS). Isograft retransplantation resulted in a similar incidence of coronary lotions (group 4: 37 +/- 9%, NS), whereas coronary arteries of isografts without a second transplant procedure (group 5) remained normal (0%, P<0.001). In conclusion, syngeneic retransplantation of allografts reverses mononuclear infiltration but not myointimal proliferation. The development of coronary lesions in retransplanted isografts underlines the participation of antigen-independent stimuli in the development of myointimal proliferation. These experiments further support the hypothesis of an interaction of antigen-dependent and antigen-independent factors for the development of coronary myointimal proliferation.

Animals↗
PubMed1996

Mycophenolate mofetil inhibits lymphocyte binding and the upregulation of adhesion molecules in acute rejection of rat kidney allografts.

Mycophenolate mofetil (MMF) interacts with purine metabolism and possibly with the expression of adhesion molecules. In the present study, we analysed the expression of these molecules in transplanted kidney allografts treated with RS LBNF1 kidneys were orthotopically transplanted into Lewis rats and either treated with RS (20 mg/kg/day) or vehicle. Rats were harvested 3, 5 and 7 days following transplantation. For binding studies, fresh-frozen sections of transplanted kidneys were incubated with lymph node lymphocytes (LNL) derived from transplanted rats. Additionally, immunohistology was performed with various monoclonal antibodies. In general, MMF resulted in better preservation of graft structure by 7 days. Cellular infiltration and tubular atrophy were less pronounced. At day 3, macrophages were diminished in MMF-treated animals to a high extent, while the number of T cells was almost identical to that of controls. In addition, the number of cells positive for MHC class II and LFA-1 was reduced in the MMF-treated animals. These findings correlated with the binding results. Three days following engraftment, LNL bound to MMF-treated kidneys to a lesser extent compared to controls. In conclusion, MMF resulted in a markedly reduced leucocytic infiltrate, presumably based on a reduced expression of lymphocytic adhesion molecules and an interaction with macrophages.

Animals↗
PubMed1996

Diltiazem minimizes tubular damage due to FK506-mediated nephrotoxicity following ischemia and reperfusion in rats.

We examined the nephrotoxicity of tacrolimus (FK506) in a model of mild warm ischemia. After clamping of both renal arteries of male Sprague-Dawley rats for 20 min, the animals received tacrolimus (3 mg/kg/day i.p.), vehicle of a combination of tacrolimus (3 mg/kg/day i.p.) and diltiazem (12 mg/kg, orally) or vehicle and diltiazem (12 mg/kg, orally). The excretion of urinary enzymes was determined on a daily basis, creatinine clearance at day 10. Tacrolimus significantly increased NAG (N-acetyl-beta-glucosaminidase) excretion and associated histological damage, finally decreasing creatinine clearance. The toxic potential of tacrolimus was markedly enhanced by ischemia. The additional application of diltiazem reduced NAG excretion and histological damage without affecting creatinine clearance. Thus, the protective effect of diltiazem on tacrolimus-induced nephrotoxicity seems to be at least partially a tubular one.

Acetylglucosaminidase↗
PubMed1996

Experimental and clinical experience with the use of tacrolimus (FK506) in kidney transplantation.

Tacrolimus is a recently developed immunosuppressive agent, based on a mechanism similar to cyclosporin. A broad variety of trials has provided evidence for its efficacy in human liver transplantation. In these trials, the incidence of acute rejection was markedly reduced. The following article reviews recent knowledge regarding clinical and experimental experience with tacrolimus in kidney transplantation. In summary, clinical trials suggested a marked reduction of acute allograft rejections comparable to those observed in liver transplantation. Its efficacy in steroid-resistant rejections is also well documented, while not critically analyzed in a prospective trial. Its effect is independent of the preceding administration of antilymphocyte antibodies. Thus, its use seems warranted even in the presence of steroid-resistant graft rejection, when treatment with antilymphocyte antibodies is contraindicated. Based on preliminary experience with tacrolimus in previous studies of primary immunosuppressive treatment and on the compelling evidence that the drug is effective in rescue therapy, its use as primary immunosuppressive regimen in immunologic high risk patients should now be considered.

Animals↗
PubMed1996

Initial experience with tacrolimus rescue therapy in OKT3 resistant rejection.

Follow-up of 9 renal transplant recipients who were converted from cyclosporin A to tacrolimus (FK506) as recue therapy for intractable rejection is described. All patients initially received a cyclosporin A based immunosuppression. They developed biopsy proven acute rejections 22 +/- 11 days after transplantation which did not resolve by i.v. steroids and subsequent OKT3. Fifty-three +/- 11 days post transplantation the patients were converted from cyclosporin A to tacrolimus. After conversion to tacrolimus 6 patients developed a stabile transplant function. One transplant recipient who initially responded to tacrolimus lost his graft due to a chronic rejection 9 months following conversion. Two patients with never functioning kidneys remained on dialysis despite tacrolimus therapy. After conversion no serious adverse events occurred and only a slightly increased infection rate and hyperglycemia were noted as major side effects of tacrolimus. Tacrolimus rescue therapy was effective in treating acute renal allograft rejection unresponsive to steroids and OKT3. Tacrolimus rescue therapy was not accompanied by a substantial rise in complications. Patients with never functioning kidneys did not seem to benefit from tacrolimus rescue therapy.

Adult↗
PubMed1996

Effects of mycophenolic acid mofetil on acute rejection of kidney allografts in rats.

Mycophenolic acid mofetil (MMF) is an agent which has recently gained a lot of attention. In clinical trials MMF has reduced the rate of acute rejection episodes in human recipients of kidney allografts by inhibiting inosin-monophosphat-dehydrogenasis (IMPDH), an enzyme involved in the purin metabolism and related to the expression of adhesion molecules. The aim of the present study was to analyze the effects of MMF upon the expression of adhesion molecules in transplanted kidney allografts. LBNF1 kidneys were orthotopically transplanted into Lewis rats and either treated with MMF (20 mg/kg/day) or vehicle. Rats were harvested 3, 5 and 7 days following transplantation. Immunohistology was performed with various monoclonal antibodies. In general, MMF resulted in a better preservation of graft structure by 7 days. Cellular infiltration and tubular atrophy were less pronounced. At day 3, macrophages were diminished in MMF-treated animals to a high extent, while the number of T-cells was almost identical as compared to controls. In addition, the number of cells positive for MHC class II and LFA-1 was reduced in the MMF-treated animals. In conclusion, MMF resulted in a markedly reduced leukocyte infiltrate, presumably based on a reduced expression of lymphocytic adhesion molecules and an interaction with macrophages.

Animals↗
PubMed1996

Assessment of chronic rejection in permanent accepted renal allografts in anti-CD4 treated rats.

In rats, transient prophylactic anti-CD4 therapy with the nondepleting mAB RIB5/2 prevents acute rejection of MHC-mismatched allografted kidneys and induces long-lasting unresponsiveness. However, little is known about long-term benefits of this prophylactic anti-CD4 regimen. Here we report experimental results of permanently accepted rat renal allografts after prophylactic anti-CD4 treatment in regard to signs of chronic rejection. Kidneys from Wistar Furth donors were orthotopically grafted into bilateral nephrectomized BDIX recipients under the cover of anti-CD4 treatment (20 mg/kg b.w). Kidney function was serially monitored by measurement of serum creatinine and urine protein excretion. After 100 or 300 days respectively renal allografts were harvested, histologically and immunohistologically assessed and intragraft cytokine gene expression determined. Serum creatinine increased in few allografted rats. 30% of the 300-day-old grafts had an increased proteinuria and higher degrees of glomerular sclerosis. In these grafts cellular infiltration was more pronounced. However, no activated leukocytes (IL-2 receptor positive) were detected. Correspondingly, intragraft gene expression of CD3, IL-10 and IFN gamma was low. The results of our study indicate that a prophylactic anti-CD4 regimen diminishes chronic rejection to a level comparable to isografted or naive mass-reduced or ischemic kidneys. Thus, the signs of chronic rejection observed seem to be mainly caused by alloantigen-independent processes.

Animals↗
PubMed1995

Rapamycin inhibits transplant vasculopathy in long-surviving rat heart allografts.

We have examined the effects of rapamycin (RPM) on transplant vasculopathy in long-surviving F344 rat heart allografts transplanted heterotopically into Lewis recipients. RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and daily throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 (5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combination with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppression with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (group 6) were also examined. F344 isograft recipients treated with RPM (0.5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Grafts of group 1 were removed at 50, 75, 100, 150, and 200 days and infiltrating cell populations and surface molecules were compared with those of the other groups at 100 days. All allografts in treated hosts functioned > 100 days; in contrast, grafts in untreated recipients were rejected acutely by 8 +/- 1 days (MST +/- SD). The incidence of transplant vasculopathy in group 1 increased progressively (MST +/- SD = 10 +/- 2%, 59 +/- 7%, 85 +/- 15%, and 80 +/- 12% at 50, 100, 150, and 200 days, respectively), as manifested by myointimal proliferation with dense mononuclear infiltration (predominantly ED1+ macrophages). Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhesion molecules and cytokines. The incidence of graft disease and extent of cellular infiltration at 100 days was significantly lower in animals receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25 +/- 15%, 22 +/- 11%, and 10 +/- 3%, respectively; P < 0.005). CsA treatment either in combination with RPM or alone (groups 5 and 6) failed to improve transplant vasculopathy, but reduced mononuclear cell infiltration. Isografts (groups 7 and 8) and naive hearts (group 9) developed no structural abnormalities throughout the follow-up period, regardless of RPM treatment. We conclude that the extent of transplant vasculopathy can be reduced markedly in this rat cardiac transplant model with maintenance RPM. Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.

Animals↗
PubMed1995

Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts.

No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344-to-Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low-dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow-up period. Non-RS61443-treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM-1 on endothelium), cytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-allospecific IgG and IgM peaked at 1-2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow-up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow-up period. Proteinuria was virtually absent, and morphological and immunohistological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.

Animals↗