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Biomedical subjects

U Heemann

Publications and source records attributed to U Heemann.

At least 19 recordsLinked to original sources
PubMed2001

A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.

BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Adult↗
PubMed2001

Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer.

Expression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell-cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues (n = 8). In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion.

Adenocarcinoma↗
PubMed2001

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Adrenal Cortex Hormones↗
PubMed2001

Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis.

Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.

Animals↗
PubMed2001

Contribution of androgens to chronic allograft nephropathy is mediated by dihydrotestosterone.

BACKGROUND: Donor and recipient gender influence long-term allograft outcome after kidney transplantation. Sex hormones are likely to contribute to these gender-related differences. The present study investigated the role of androgens and their inhibition on the development of chronic allograft nephropathy. METHODS: Male or female Fisher (F344) kidneys were orthotopically transplanted into intact male Lewis recipients. Animals were treated either with testosterone, the antiandrogen flutamide, the 5alpha-reductase inhibitor finasteride, or vehicle. Twenty weeks after transplantation animals were harvested for histology, immunohistology, and molecular analysis. RESULTS: Testosterone treatment resulted in an increased proteinuria as well as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononuclear cell infiltration that paralleled enhanced intragraft mRNA levels of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride reduced glomerulosclerosis as well as the inflammatory cell infiltration associated with decreased TGF-beta, PDGF-A, and -B chain mRNA expression. No gender-related donor differences were noted between the groups. CONCLUSIONS: Our data suggest that dihydrotestosterone mediates the adverse effects of androgens on chronic allograft nephropathy. The inhibition of androgens improves long-term allograft outcome after kidney transplantation.

Androgen Antagonists↗
PubMed2001

Impact of febrile infections on the long-term function of kidney allografts.

PURPOSE: We prospectively determined the impact of febrile infectious disease on long-term renal graft function compared with a matched control group. MATERIALS AND METHODS: Included in our study were 39 patients who presented with episodes of febrile infection with body temperature greater than 38C on 2 consecutive occasions, necessitating hospitalization. In addition, 39 controls without febrile infection requiring hospitalization within 2 months were chosen from the complete data pool of all renal transplant recipients followed at our transplant clinic using the matched pair technique. Renal function was estimated by serum creatinine and calculated creatinine clearance. RESULTS: Of the 39 patients with infection 15 had urinary tract infection and 24 had other, mostly bacterial infection, including pneumonia/severe bronchitis in 12, oral/dental infection in 2, gastroenteritis in 2, shunt sepsis in 1, herpes zoster in 1, cytomegalovirus in 1 and other in 5. Mean estimated creatinine clearance plus or minus standard deviation was similar in the infection and control groups at the beginning of the study (51 +/- 22 and 51 +/- 23 ml. per minute, respectively). During the infectious episode mean creatinine clearance significantly decreased to 38 +/- 17 ml. per minute in the infection group. After infection resolved creatinine clearance returned to an almost baseline mean value of 50 +/- 23 ml. per minute. However, after 2 years of followup there was a significant difference in mean creatinine clearance in the infection group versus controls (45 +/- 25 versus 52 +/- 25 ml. per minute, p = 0.022). CONCLUSIONS: To our knowledge we have shown for the first time in a prospective controlled study that febrile infectious episodes correlate with poor long-term renal graft function.

Adult↗
PubMed2000

Cyclosporine A and azathioprine are equipotent in chronic kidney allograft rejection.

Chronic rejection is the major cause of graft loss after kidney transplantation. Various immunosuppressive protocols have been used to ameliorate this process. We investigated whether cyclosporin A- (CyA) or azathioprine- (Aza) based immunosuppression is better able to slow the progression of chronic rejection. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats. Recipients received CyA (1.5 mg/kg/day, s.c.) for 10 days, and were treated from day 11 with either CyA (1.5 mg/kg)+pred (0.15 mg/kg) (C+P),Aza (2 mg/kg)+pred (A+P), vehicle+pred (P), or vehicle alone (controls) (n = 8/group). Proteinuria was regularly assessed and grafts were harvested for morphological, immunohistological, and molecular biological analysis at week 24. By week 12 proteinuria had increased to significant levels. At week 24, proteinuria was significantly lower and creatinine clearance was significantly higher in C+P and A+P, than in P or controls. Morphological analysis supported these functional results: at week 24, glomerulopathy, tubular atrophy and intimal proliferation (as assessed according to the BANFF score) were less pronounced in C+P and A+P, as compared with P or controls. These morphological parameters were accompanied by a reduced infiltration of ED-1+ macrophages and CD-5+ T lymphocytes. In P or controls the synthesis of IL-2Ralpha mRNA was markedly elevated at this time. In parallel to the reduced cellular infiltration, IL-2Ralpha mRNA expression was markedly inhibited, both, in C+P and A+P. There were no significant differences between C+P and A+P regarding the parameters studied. In conclusion, both C+P and A+P reduced the infiltration of activated T lymphocytes, and the pace of chronic kidney allograft rejection. The outcome of C+P and A+P based therapy did not differ significantly.

Animals↗
PubMed2000

SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts.

BACKGROUND: Chronic rejection remains the most frequent cause of renal graft loss over the long term. However, effective treatment of this process is not yet available. SDZ-RAD (40-O-[2-hydroxyethyl]-rapamycin) is a new, orally active rapamycin derivative with potent immunosuppressive activity. We have examined the effects of SDZ-RAD in a well-established model of chronic renal allograft rejection in rats. METHODS: Kidneys of Fisher (F334) rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. To suppress an initial episode of acute rejection, rats were briefly treated with low doses of cyclosporine for the first 10 days. Thereafter they received either SDZ-RAD (0.5 mg/kg(day) or vehicle. At 24 weeks, functional evaluations were performed, kidneys were harvested, and histological, immunohistological, and reverse transcription-polymerase chain reaction evaluations were performed. RESULTS: Animals treated with SDZ-RAD developed lower proteinuria and less glomerulosclerosis as compared with controls. Additionally SDZ-RAD reduced the infiltration of macrophages and lymphocytes and the expression of intercellular adhesion molecule-1, laminin, and fibronectin. Furthermore, we observed a reduced expression of growth factor mRNA (transforming growth factor-beta and platelet-derived growth factor-AA) in these animals. CONCLUSION: Our results demonstrated that SDZ-RAD effectively ameliorates chronic renal allograft rejection in rats, probably mediated by suppression of growth factors.

Animals↗
PubMed2000

Conversion from cyclosporine A to tacrolimus after kidney transplantation due to hyperlipidemia.

As more than 90% of renal grafts retain their function 1 year after renal transplantation, side effects of immunosuppressive therapy gain more and more importance. In a randomised prospective study, we investigated the effects of conversion from cyclosporine A to tacrolimus due to hyperlipidemia in recipients of renal allografts. Fifty-seven patients with stable graft function treated with cyclosporine were randomly assigned to conversion to tacrolimus or continuation of their current therapy and followed for 1 year. Twenty-seven patients were switched and 30 patients remained on cyclosporine A. Cholesterol levels decreased significantly in the tacrolimus group as compared to controls in the intent to treat analysis. When only those patients were evaluated who received cyclosporine or tacrolimus during the whole study, statistical significance was even more pronounced. Triglyceride levels decreased in the tacrolimus group, whereas they increased in controls. Creatinine levels remained stable and no acute rejection was observed. A switch to tacrolimus is a safe alternative in cases of hyperlipidemia after renal transplantation.

Adult↗
PubMed2000

Cystatin C--an accurate marker of glomerular filtration rate after renal transplantation?

The performance of serum cystatin C as a screening marker of reduced creatinine clearance in renal transplantation was evaluated and compared to serum creatinine. In addition we studied whether cystatin C accurately reflects creatinine clearance over the entire range of transplant function. Serum cystatin C, serum creatinine, and creatinine clearance were measured in 110 adult renal transplant recipients. Cystatin C detected reduced creatinine clearance with the high sensitivity of 95%. Serum cystatin C and serum creatinine did not differ regarding 90 and 95% sensitivity, derived from the receiver-operating characteristics plot. We demonstrated a strong correlation and linear association between 1/cystatin C and creatinine clearance over the entire range of transplant function, equivalent to that of 1/creatinine. In summary, serum cystatin C accurately reflects creatinine clearance over the entire range of transplant function and is as efficacious as serum creatinine to detect reduced creatinine clearance in renal transplant recipients.

Adult↗
PubMed2000

Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury : possible connection to an interleukin-6-dependent pathway.

In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal doses of endotoxin or LPS. In this study we tested the effects of LPS pretreatment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days -4 and -3. The right kidney was removed, and the vessels of the left kidney were clamped for 30 or 45 minutes on day 0. Creatinine levels and survival of animals were monitored. To test the involvement of cytokines, additional animals were harvested before ("time 0") and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and reverse transcriptase-polymerase chain reaction analysis (including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, inducible nitric oxide synthase (iNOS), and interferon (IFN)-gamma messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died within 48 +/- 18 hours, after 45 minutes of ischemia. All different doses of LPS protected the animals from lethal renal ischemia/reperfusion injury. Starting at similar levels, serum creatinine increased significantly in controls but not in LPS-pretreated animals over time. As early as 2 hours after reperfusion, tubular cell damage was significantly more pronounced in controls than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocytic infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay revealed significantly more apoptotic cells in controls compared with LPS-pretreated animals. IL-1, IFN-gamma, and iNOS mRNA expression did not differ between the groups throughout the time points examined. However, the expression of TNF-alpha mRNA was significantly increased at 2 hours and IL-6 mRNA was significantly down-regulated before ischemia and shortly after reperfusion in the LPS-pretreated kidneys. Therefore, we found that sublethal doses of LPS induced cross-tolerance to renal ischemia/reperfusion injury. Our data suggest that increased TNF-alpha and reduced IL-6 mRNA expression might be responsible. However, more studies are needed to decipher the exact mechanism.

Animals↗
PubMed2000

Male gender predisposes to development of endotoxic shock in the rat.

OBJECTIVE: After intravenous (i.v.) injection of lipopolysaccharide (LPS) macrophages release nitric oxide (NO) due to the expression of the inducible NO synthase (iNOS). After LPS NO is abundantly produced also in the cardiovascular system and may contribute to the development of hypotension and shock. Since the immune response, the synthesis of NO and the regulation of blood pressure (BP) differ between males and females, in the present study the effect of LPS on BP, renal function, the plasma and urinary concentration of the metabolites of NO as well as the splenic and aortic expression of the iNOS gene were compared between male and female rats. METHODS: BP and renal function were measured in anesthetized rats following the i.v. injection of LPS (E. coli, 4 mg/kg). The NO2- and NO3- (metabolites of NO=NOx) concentration was measured by the Griess reaction. The iNOS gene expression was studied by RT-PCR. RESULTS: Four hours after LPS, BP of males (n=9) was reduced by 63+/-12 mmHg versus 10+/-4 in females (n=7, P<0.005). Aminoguanidine, a selective inhibitor of iNOS, prevented the reduction of BP in males. The plasma concentration of NOx (P(NOx)), microM) was lower in hypotensive males (128+/-20) than in normotensive females (235+/-29, P<0.005). Males also exhibited lower urinary NOx excretion (U(NOx)V) after LPS (P<0.001 vs. females). Prior castration of males provided protection against hypotension (fall of BP: -4+/-4 mmHg, n=6, P<0.02 versus males) and resulted in higher P(NOx) as well as U(NOx)V (both P<0.001 versus males and not different from females). Prior ovariectomy (n=5) had no influence on the hemodynamic and NOx response to LPS. Male rats displayed enhanced aortic iNOS/beta-actin ratio relative to females after LPS (n=3 in each group, P<0.05). CONCLUSIONS: (1) Male gender may sensitize to LPS-induced shock and (2) sensitivity of males to endotoxin is associated with an attenuated, not exaggerated total rate of NO synthesis.

Animals↗
PubMed2000

The Whitaker test, a useful tool in renal grafts?

OBJECTIVES: To evaluate the Whitaker test, a pressure flow examination, for its prognostic value in dilated renal transplants because urologic complications, such as ureteral stenosis, are significant problems after kidney transplantation. METHODS: Twenty-five patients with obstruction of the renal transplant and subsequent percutaneous nephrostomy were evaluated with a urodynamic pressure flow test (Whitaker test) in combination with antegrade pyeloureterography. The results of the Whitaker test were related to the serum creatinine values. RESULTS: The Whitaker test demonstrated normal pressure flow (less than 15 cm H(2)O) in 7 patients, pressure flow between 15 and 25 cm H(2)O in 10, and pathologic results (greater than 25 cm H(2)O) in 8 patients. After percutaneous nephrostomy, the serum creatinine level decreased in 22 of 25 patients, although the urodynamic pressure flow revealed a significant obstruction (Whitaker test greater than 25 cm H(2)O) in only 8 patients. The sensitivity of the Whitaker test to indicate the relevance of post-renal transplant stenosis in comparison to the declining serum creatinine level after successful percutaneous nephrostomy was 79%; the specificity was 50%. CONCLUSIONS: The results of our study indicate that a decreasing creatinine level in correlation with radiologic results is the leading finding in dilation of transplanted kidneys without rejection. The Whitaker test, as a pressure flow examination, provided no additional information.

Adolescent↗