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Biomedical subjects

Uwe Heemann

Publications and source records attributed to Uwe Heemann.

36 records · Page 2Linked to original sources
PubMed2003

New model for simultaneous heart and kidney transplantation in mice.

In clinical settings, combined heart and kidney transplantation results in a lower incidence of cardiac graft and renal graft rejection as compared to isolated heart and kidney transplantation. To study the phenomenon in an experimental setting, we developed a model of combined heart and kidney transplantation in mice. According to our technique, we kept the patch of the infrarenal aorta and inferior vena cava (IVC) as long as possible during the donor's kidney explantation, and then, after finishing the kidney implantation with conventional techniques, we anastomosed the innominate artery and pulmonary artery of the heart graft to the patch of the infrarenal aorta and IVC of the renal graft, respectively, instead of the recipient's aorta and IVC. With the use of our method, combined heart and kidney transplantation in mice can be performed to get enough suture room for the second graft, to avoid prolonging the occlusion time of the recipient's circulation, and to profoundly decrease postoperative complications such as paraplegia and mortality. Of the 14 recipients with combined heart-kidney isografting, 10 have been successful (71.4%), surviving over 100 days with normal function of both grafts, and with lack of change in histological appearance. This suggests that the technique is feasible and reliable.

Animals↗
PubMed2003

Aspects of quality of life through end-stage renal disease.

This study was conducted to explore differentiated aspects of quality of life (QoL) throughout the course of end-stage renal disease (ESRD) with special regard to kidney transplantation (KTX). In detail two questions were addressed: (1) does social support change over time? and (2) is psychological distress a predictor of generic and disease-specific QoL? Two groups of ESRD-patients were investigated twice with different psychodiagnostic inventories. At t0 the Brief Symptom Inventory (BSI) and a validated German Social Support Questionnaire were administered. At t1 social support as well as generic and disease-specific QoL were investigated (SF-36, End-Stage Renal Disease Symptom Checklist-Transplantation Module [ESRD-SCL]). Group A consisted of 80 patients treated by dialysis while on the waiting list for transplantation when investigated at t0 and was followed after successful transplantation at t1. Group B consisted of 222 patients investigated twice after successful KTX. Groups A and B did not differ with respect to clinical data and comorbidity, except for stronger immunosuppression in transplanted patients of group A. Group A demonstrated a statistically significant (5% explanation of variance) increased satisfaction with social support after KTX, whereas group B reported a decrease. The psychological distress at t0 predicted QoL at t1 in both groups (2-13% explanation of variance of SF-36, ESRD-SCL-scores). High psychological distress on dialysis and after KTX is a predictor for low long-term QoL.

Adult↗
PubMed2003

ATP protects, by way of receptor-mediated mechanisms, against hypoxia-induced injury in renal proximal tubules.

We examined the effect of ATP on hypoxia-induced injury in freshly isolated rat renal proximal tubules and compared it with the effects of stable ATP analogues and ATP degradation products. Extracellular ATP significantly reduced hypoxia-induced structural cell damage (lactate dehydrogenase release). P(2)-receptor agonistic ATP analogues, including 2'-methylthio-ATP (2-Me-S-ATP), were also protective. In contrast, the P(1)-agonistic degradation products AMP and adenosine were not protective. Hypoxia-induced functional cell damage (loss of cellular potassium) was not changed by ATP or 2-Me-S-ATP. We therefore conclude that the protective property of ATP is not based on an effect of the degradation products or on a direct effect on cellular energy metabolism. The data indicate that the protective effect of ATP is mediated by P(2) receptors.

Adenosine↗
PubMed2003

Tumours after kidney transplantation.

PURPOSE OF REVIEW: With the improved long-term outcome of renal allograft recipients, malignant tumours or cardiovascular disease become increasingly important. Malignant tumours develop in 15-20% of graft recipients after 10 years, and thus contribute substantially to the morbidity and mortality of these patients. In contrast to the general population, skin tumours and lymphoproliferative disorders are the most frequent malignancies in transplant recipients. Malignancies can develop in three ways: de-novo occurrence in the recipient; recurrent malignancy in the recipient; or transmission of malignancy from the donor. RECENT FINDINGS: The immunosuppressive strategies after renal transplantation differ with respect to the development of malignancies, with cell-depleting antibodies being the highest risk, whereas newer immunosuppressants such as rapamycin could possess anti-tumour potential. The relationship of chronic viral infections to skin tumours and lymphoproliferative diseases has become clearer during recent years. Concomitantly, experience in the management of such diseases has grown. Furthermore, as older donors are accepted, awareness of the possibility of transferring malignancies from the donor to the recipient must increase. SUMMARY: Malignancies are a major contributor to morbidity and mortality among kidney transplant recipients as such diseases gain importance with longer graft survival. Immunosuppression and chronic viral infections in combination with the transmission of malignant cells from the donor or recurrent malignancies contribute to the increased incidence of cancer. In kidney transplant recipients, screening before and after transplantation and an individualized choice of immunosuppression are thus mandatory.

Humans↗
PubMed2003

Primary failure of arteriovenous fistulae in auto-immune disease.

BACKGROUND/AIM: Chronic haemodialysis depends on an arteriovenous fistula. Primary failure of vascular access is a common problem which is mainly related to thrombosis. As ambulatory surgery is common, it is mandatory to identify patients with a high thrombophilic risk to allow better prevention (anticoagulation) and direct re-intervention after thrombosis. The purpose of this study was to determine thrombophilic risk factors for primary access failure in order to identify patients at risk before the operation. METHODS: We performed a retrospective study on 62 chronic haemodialysis patients who received permanent vascular access. We evaluated established risk factors for chronic access failure as well as the number of earlier shunt operations in these patients. RESULTS: The patients predominantly suffered from auto-immune diseases. The frequency of a successful first vascular access was above average (92.5%). We identified four major risk factors for primary access failure: number of previous vascular access thromboses (p < 0.01; R = 0.96), pre-existing thrombophilic risk factors (p < 0.01), pre-operative fibrinogen (p < 0.02), and vasculitis (p < 0.01). CONCLUSIONS: We identified four risk factors which allowed an individual risk evaluation. Among the factors investigated, the activity of the auto-immune disease was the most striking. Our data suggest not to perform a vascular access during an active period of vasculitis.

Adolescent↗
PubMed2002

Fumaric acid esters are potent immunosuppressants: inhibition of acute and chronic rejection in rat kidney transplantation models by methyl hydrogen fumarate.

The effectiveness and safety of fumaric acid esters (FAEs) for the treatment of psoriasis has been demonstrated. Their mode of action, however, is poorly understood. To determine the immunomodulatory potential of calcium methyl hydrogen fumarate (CaMHF) in transplant models, we tested the compound in rat transplantation models of acute rejection (AR) and chronic rejection (CR). Orthotopic kidney transplantation was combined with contralateral nephrectomy using the strain combinations WF to BDIX (AR) and F344 to LEW (CR). Recipients were treated orally prophylactically (day -28 to day +28, AR and CR model) or therapeutically (day +30 to day +60, CR model). CaMHF significantly prolonged the time to onset of AR in the WF/BDIX model. The half-lives of the grafts were 14 days in the CaMHF group, 7 days in the placebo-treated control group and 9 days in the untreated control group ( P<0.01). Three of ten CaMHF-treated rats showed permanent graft acceptance (defined as survival for >100 days) resulting in a mean survival time of >42.3+/-41.0 ( P<0.01) in comparison with >28.3+/-38.3 days in the placebo-treated group and 9.4+/-2.6 days in the untreated control group. In the F344/LEW model of chronic graft injury, only prophylactic CaMHF treatment significantly inhibited the development of CR ( P=0.001; mean survival times >28.4+/-2.0 weeks, >23.9+/-6.0 weeks and >21.1+/-5.4 weeks in the prophylactic CaMHF, therapeutic CaMHF, and placebo group, respectively). By 30 weeks six of ten prophylactically treated animals were still alive, but only three of nine and one of ten were alive in the therapeutically treated and placebo-treated groups, respectively ( P<0.05). These findings indicate that CaMHF treatment effectively inhibits AR and CR, and demonstrates marked in vivo immunomodulatory efficacy. Thus, FAEs should be considered as drugs showing considerable immunosuppressive efficacy. This might have implications with regard to safety issues (e.g. immune monitoring) and novel potentially suitable indications (e.g. transplantation and other immune diseases).

Acute Disease↗
PubMed2002

The involvement of activated T cells and growth-factor production in the early and late phase of chronic kidney allograft nephropathy in rats.

T cells are thought to play a regulatory role in chronic allograft nephropathy (CAN). Thus, we investigated whether lymphocyte inhibition influences CAN. Fisher rat (F-344) kidneys were transplanted orthotopically into Lewis rats. Animals received cyclosporin A (1.5 mg/kg per day, s.c.) for 10 days and were treated daily with either cyclosporin A (1.5 mg/kg), tacrolimus (0.16 mg/kg), or a vehicle thereafter ( n=15 per group). Kidneys were harvested at 16 or 24 weeks. Interleukin-2 (IL-2) and interleukin-2 receptor beta (IL-2Rbeta) mRNA synthesis were intense at 16 weeks and decreased thereafter. Unsurprisingly, both cyclosporin A and tacrolimus significantly inhibited IL-2 and IL-2Rbeta at both time points. Proteinuria increased more rapidly in controls than in treated animals. Morphologically, over 40% of glomeruli were sclerosed by 16 weeks in controls, and ED-1+ macrophages and CD5+ T cells infiltrated the graft. IL-2 mRNA synthesis paralleled the number of infiltrating cells. Inhibition of T-cell proliferation significantly reduced glomerulosclerosis and leukocyte infiltration at both time points. Transforming growth factor (TGF)-beta(1) and platelet-derived growth factor (PDGF) synthesis were highly upregulated in controls at 16 weeks, the time of peak infiltration. At 24 weeks, as cellular infiltration was replaced by scar formation, TGF-beta(1) mRNA returned to normal, while PDGF did not. Inhibition of T cells prevented the upregulation of TGF-beta(1) at both time points; however, PDGF was suppressed only at week 16. These results indicate a beneficial effect of continuous suppression of T cells in CAN. T cells are probably more important in the early, inflammatory phase.

Animals↗
PubMed2002

Intrasplenic transplantation of syngenic hepatocytes modified by IFN-gamma gene ameliorates hepatic fibrosis in rats.

Transplanted hepatocytes are ideal carriers for exogenous genes in liver gene therapy. The present study investigated the anti-fibrogenic effects of intrasplenically transplanted hepatocytes modified with interferon gamma (IFN-gamma) gene on cirrhotic rats. Hepatocytes isolated from normal Sprague-Dawley (SD) rats were transfected with an adenoviral vector encoding human IFN-gamma gene (AdCMVhIFN-gamma) and transplanted into the spleens of syngenic recipients with ongoing liver fibrosis induced by carbon tetrachloride (CCl(4)). Histology was assessed, and liver hydroxyproline was detected. Additionally, serum procollagen type III (PIIINP) levels and hepatic collagenase activity were measured to determine hepatic collagen synthesis and degradation. Transplantation with AdCMVhIFN-gamma transfected hepatocytes ameliorated the histological outcome of liver fibrosis by reducing liver collagen content and decreasing hepatic hydroxyproline. Additionally, IFN-gamma transfected hepatocytes reduced serum PIIINP levels and increased hepatic collagenase activity. Our data suggest that transplantation of IFN-gamma transfected hepatocytes may reduce the pace of liver fibrosis by inhibiting the synthesis and enhancing the degradation of hepatic collagen.

Adenoviridae↗
PubMed2002

Opposite effects of testosterone and estrogens on chronic allograft nephropathy.

In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of chronic allograft nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on chronic allograft nephropathy.

Animals↗
PubMed2002

Quality of life in kidney recipients: comparison of tacrolimus and cyclosporine-microemulsion.

Treatment of end-stage renal disease (ESRD) is evaluated by survival, quality of life (QOL) and cost-effectiveness. Little is known about the influence of immunosuppressive agents on global and disease-specific QOL in kidney recipients. In winter 1997/98 (t0) as well as in winter 1998/99 (t1), all kidney recipients of our University were asked to participate in a QOL study. The psychodiagnostic approach combined a global QOL-measure (SF-36 Health Survey) and a disease-specific questionnaire (ESRD-SCL, Nephron 1999). Inclusion criteria for the final analysis were (a) participation in both surveys and (b) eligibility after the matching procedure: patients with tacrolimus-based immunosuppressive regimen were matched to patients with cyclosporin-microemulsion (CsA-ME)-based immunosuppressive-regimen as to age, gender and duration of graft function. Group data were compared by performing a two-variate ('immunosuppression', 'time') analysis of variance. Both groups consisted of 63 patients. Analysis of QOL revealed statistically significant advantages for the tacrolimus treated patients concerning global (SF-36 'Physical Component Summary') as well as disease-specific QOL (ESRD-SCLTM 'Global Severity Index'; both p < 0.05). In detail, these results were due to statistically significant better QOL in tacrolimus treated patients as to the SF-36 subscales 'Physical Functioning' and 'General Health' (p < 0.05) and the ESRD-SCL subscales 'Limited Physical Capacity' (p < 0.05), 'Cardial and Renal Dysfunction' (p < 0.01) and 'Increased Growth of Gum and Hair' (p < 0.001). The factor 'time' did not contribute statistically significant to explanation of variance. In terms of QOL in kidney recipients, tacrolimus is superior to CsA-ME. Tacrolimus improves disease-specific QOL and also shows slight advantages concerning global QOL compared with CsA-ME. To record differentiated aspects of QOL in kidney recipients, the diagnostic approach should include a global QOL measure completed by a sensitive disease-specific instrument.

Adult↗
PubMed2002

Early application of Met-RANTES ameliorates chronic allograft nephropathy.

BACKGROUND: Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration. METHODS: Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. RESULTS: Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B). CONCLUSIONS: Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Animals↗
PubMed2002

Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.

Patients with liver cirrhosis and a superimposed acute injury with progressive hyperbilirubinemia have a high mortality. A prospective, controlled study was performed to test whether hyperbilirubinemia, 30-day survival, and encephalopathy would be improved by extracorporeal albumin dialysis (ECAD). Twenty-four patients were studied; 23 patients had cirrhosis; 1 had a prolonged cholestatic drug reaction and was excluded from per protocol (PP) analysis. Patients had a plasma bilirubin greater than 20 mg/dL and had not responded to prior standard medical therapy (SMT). Patients were randomized to receive SMT with ECAD or without (control). ECAD was performed with an extracorporeal device that dialyzes blood in a hollow fiber dialyzer (MW cutoff < 60 kd) against 15% albumin. Albumin-bound molecules transfer to dialysate albumin that is regenerated continuously by passage through a charcoal and anion exchange column and a conventional dialyzer. ECAD was associated with improved 30-day survival (PP, 11 of 12 ECAD, 6 of 11 controls; log rank P <.05). Plasma bile acids and bilirubin decreased on average by 43% and 29%, respectively, in the ECAD group after 1 week of treatment, but not in the control group. Renal dysfunction and hepatic encephalopathy improved in the ECAD group, but worsened significantly in the control group. ECAD was safe, with adverse events being rare and identical in both groups. In conclusion, ECAD appears to be effective and safe for the short-term treatment of patients with cirrhosis and superimposed acute injury associated with progressive hyperbilirubinemia and may be useful for increasing survival in such patients awaiting liver transplantation.

Adult↗
PubMed2002

[Quality of life in patients before and after kidney transplantation].

The presented study was carried out to differentially assess the quality of life (QOL) of two patient groups with end-stage renal disease (ESRD) with regard to the replacement therapy (dialysis vs. transplantation) and healthy controls. Successfully transplanted patients (n = 149) and patients treated by dialysis (n = 149) on the waiting list for transplantation at the Transplant Center Essen, Germany were enrolled. Additionally, 149 healthy controls were enrolled by an accumulative process starting from employees of the University Hospital Essen. Members of these three groups were strictly matched by age and gender. Medical data were gained from the patient record, QOL was measured by a global inventory, the Munich Quality of Life Dimension List (MLDL), and two specific inventories, the Brief Symptom Inventory (BSI) and the Questionnaire for Social Support - Short Form (K-22). Transplanted patients and healthy controls reported similar QOL, which was significantly higher than in dialysis patients (p < 0.0001). This was particularly true for the physical and the psychological status, but not for the social situation. Both patient groups reported similar social support, which was significantly lower than in controls (p < 0.006). Both ESRD groups described higher satisfaction with social support than the healthy controls (p < 0.0001). Successful kidney transplantation not only improved distinct aspects of QOL, but even put the patients on par with healthy controls regarding physical, psychological and functional QOL. Lower social support and higher satisfaction with social support in both patient groups should be evaluated further. From a clinical viewpoint, the improvement of QOL due to transplantation is impressive, but more attention should be paid to the interpersonal relations of ESRD patients. International multicenter longitudinal studies to investigate QOL in ESRD patients under different treatment modalities are emphasized.

Activities of Daily Living↗
PubMed2002

Behavioral conditioning of immunosuppression is possible in humans.

Behavioral conditioned immunosuppression has been described in rodents as the most impressive demonstration of brain-to-immune system interaction. To analyze whether behavioral conditioned immunosuppression is possible in humans, healthy subjects in this double-blind, placebo-controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporin A as an unconditioned stimulus paired with a distinctively flavored drink (conditioned stimulus) each 12 h. In the next week, re-exposure to the conditioned stimulus (drink), but now paired with placebo capsules, induced a suppression of immune functions as analyzed by the IL-2 and IFN-gamma mRNA expression, intracellular production, and in vitro release of IL-2 and IFN-gamma, as well as lymphocyte proliferation. These data demonstrate for the first time that immunosuppression can be behaviorally conditioned in humans.

Adult↗
PubMed2002

Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin.

BACKGROUND: Postischemic organ dysfunction is influenced by gender and sexual steroids. METHODS: To compare the susceptibility of the kidney to postischemic failure between sexes, the left vascular pedicle was clamped for 50 minutes in anesthetized male and female Wistar rats. Survival rate, renal and systemic hemodynamics and renal prepro-endothelin (pp-ET) mRNA expression were measured. RESULTS: Eight percent of males as compared to 75% of females survived for more than 7 days. Previous orchidectomy of mature rats or sexual immaturity improved the rate of 7 day survival to 67% and 58%, respectively, as compared to intact males (P < 0.05). Estradiol treatment of mature male animals also resulted in a significantly better survival. Ovariectomy, sexual immaturity or testosterone treatment had no impact on the course of renal failure in females. The early postischemic recovery of renal blood flow was delayed due to a dramatic increase in renal vascular resistance in male versus female rats. The expression of pp-ET gene in the kidneys was increased at 5 minutes following reperfusion and was significantly higher 2 hours after ischemia in males, but not in females. Pretreatment with the endothelin A receptor antagonist LU 135252 provided indistinguishable survival rates in intact male and female rats after warm renal ischemia. CONCLUSION: Female rats enjoy relative protection against postischemic renal failure. Furthermore, in intact males the effects of androgens upon ischemic kidney damage seem to be mediated by endothelin-induced vascular changes.

Animals↗
PubMed2001

Recipient age and weight affect chronic renal allograft rejection in rats.

Nephron doses and immune responses change with age. Therefore, age is a potential risk factor for graft survival after kidney transplantation. The aim of this study was to determine whether age-related differences are of importance for long-term outcomes after renal transplantation. Kidneys from Fisher 344 rats were orthotopically transplanted into nephrectomized Lewis rats. Kidneys were transplanted using donors and recipients of three age levels, i.e., young (8 wk of age), adult (16 wk of age), and old (40 wk of age). Rats were killed 24 wk after transplantation, and functional, morphologic, and molecular evaluations were performed. Recipient age, rather than donor age, determined graft survival rates. No significant correlation was observed between donor kidney weight on the day of transplantation and morphologic results. Advanced recipient age was associated with reduced creatinine clearance, more severe histologic injuries, including extended glomerular sclerosis, interstitial fibrosis, and vascular lesions, more pronounced cellular infiltration, and greater expression of transforming growth factor-beta and platelet-derived growth factor A and B chains. Although no significant correlation between donor age or kidney weight on the day of transplantation and morphologic results was observed, there was a significant correlation between recipient body weight on the day of transplantation and allograft injury. It is concluded that recipient age and weight affect chronic renal rejection. Renal allografts may benefit from young recipient age but may deteriorate in old recipients, suggesting effects of recipient functional demand on long-term outcomes.

Aging↗
PubMedDate not supplied

Prolonged catheter survival in intermittent hemodialysis using a less thrombogenic micropatterned polymer modification.

Adequate vascular access is a major prerequisite for hemodialysis treatment. Catheter related complications, in particular thrombus formation, are frequent, difficult to handle, and cost intensive. We investigated whether a new surface modified catheter containing a microdomain structure is beneficial for catheter survival. Surface thrombogenicity of standard double lumen catheters (STD-DC) and surface modified film-coated domain structured double lumen catheters (FCDS-DC) consisting of a novel reactive polyurethane copolymer coating was assessed by measurement of thrombinantithrombin (TAT) III complex in vitro. Furthermore, in a randomized observational study with 20 patients on hemodialysis, we analyzed catheter survival of either STD-DC (GamCath GDK 11 French, length 12.5 or 15 cm) or FCDS-DC (GamCath Dolphin GDK 11 French, length 12.5 or 15 cm). Catheter care protocol was identical, and dialysis treatment parameters were kept constant in both groups. In vitro measured surface thrombogenicity was reduced in the modified catheter compared with standard catheter. The clinical investigation revealed that both number of days before catheter removal according to clinical requirements and number of treatments per catheter were significantly higher with the modified catheter as compared with the standard catheter (14.5 vs. 10.3 days; 7 vs. 4 treatments; p < 0.03, Fisher-Yates test). Micropatterned surface coating with a polyurethane polymer significantly increased catheter survival and the number of treatments per catheter.

Acute Kidney Injury↗