Experimental and Clinical Endocrinology & Diabetes, 1998
The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the developme... more The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the development of diabetic microvascular lesions is well established. On the other hand, little is known on its impact on diabetic macrovascular disease, which is still the major cause of death in diabetes, including patients after PKT. In order to evaluate the influence of PKT on the cardiovascular risk profile, we performed a cross-sectional study on 55 patients. Special attention was given to the hemorheological parameters fibrinogen and plasma viscosity, two important cardiovascular risk factors, which so far have found no attention in the field of PKT research. The patients were subdivided into three groups according to their graft function: group 1-26 patients after successful PKT (no insulin dependency, serum creatinine <2 mg%), group 2-23 patients after PKT and rejection of the pancreas graft (insulin dependency, serum creatinine <2 mg%), group 3-6 patients after PKT with pancreas rejection and renal insufficiency (insulin dependency, serum creatinine >2 mg%, no dialysis). There was a high prevalence of arterial hypertension after PKT (group 1: 65%, group 2: 70%, group 3: 100%). Serum lipids were in the normal range as long as renal function was intact. In renal insufficiency, however, LDL-cholesterol and triglycerides were significantly elevated (p < 0.05). Fibrinogen was significantly raised after PKT (p < 0.001), as was plasma viscosity when the pancreas graft was rejected (p < 0.02). There was a tendency towards elevated fibrinogen levels with decreasing graft function. In conclusion, a number of cardiovascular risk factors were identified in patients after PKT, predominantly arterial hypertension and impaired hemorheology, with elevated fibrinogen levels and plasma viscosity. There is a further enhancement with decreasing graft function.
The history of solid organ transplantation is, from an immunotherapeutic standpoint, divided in t... more The history of solid organ transplantation is, from an immunotherapeutic standpoint, divided in the era before and after the introduction of cyclosporine to the clinic. The introduction of cyclosporine to the clinic in 1978 is looked upon as a turning point in transplantation. The immediate success of the new drug was based on the reduction of early graft rejection and the substantial improvement of 1-year graft survival. With growing experience in the use of this new compound, together with the ability to measure drug levels in serum, allograft rejection and organ survival could be improved even further. Because of the clinical results, cyclosporine became the gold standard in immunosuppressive therapy after organ transplantation. Even after 20 years, as more and more new immunosuppressants emerge, the clinical evaluation of a new drug is frequently compared versus a cyclosporine-based regimen. Today, cyclosporine is probably one of the best investigated drugs in the field of organ transplantation. Beside the undoubted benefits of cyclosporine, experimental and clinical studies have also revealed some unwanted effects, such as nephrotoxocity and an increased risk in development of malignant tumors. Here, we review the experience at our institution with transplant recipients receiving cyclosporine as the main immunosuppressant over the past 20 years.
In a multicentre trial conducted in eight European centres, 232 recipients of cadaveric renal all... more In a multicentre trial conducted in eight European centres, 232 recipients of cadaveric renal allografts were randomly allocated to receive either cyclosporin A (CyA, 117 patients) or azathioprine and steroids (control, 115 patients) for immunosuppression. After a follow-up period of up to eleven months, graft survival probability estimates are 73% in the CyA group and 53% in the control group. Two deaths have occurred in the CyA group and seven in the control group. 82% of the CyA group with functioning grafts are receiving CyA alone, 17% have been changed to azathioprine and steroids and one patient is receiving prednisolone in addition to CyA; 27% have never received steroids. At six months post-transplant renal function is similar in patients receiving CyA and in those receiving azathioprine and steroids. On the basis of these preliminary results CyA appears to be more effective than conventional immunosuppression and avoids the necessity of longterm steroid therapy. In einer multizentrischen Studie mit acht beteiligten Zentren wurden 232 Empfänger von Leichennieren-Transplantaten nach dem Zufallsprinzip einer Behandlung mit Cyclosporin A (CyA-Gruppe: 117 Patienten) bzw. mit Azathioprin und Steroiden (Kontrollgruppe: 115 Patienten) zugewiesen. Nach einer Beobachtungsperiode zwischen 2 Wochen und 11 Monaten betrug die geschätzte Überlebenswahrscheinlichkeit der Transplantate 73% in der CyA- und 53% in der Kontrollgruppe. Während der Therapie gab es zwei Todesfälle in der CyA- gegenüber sieben in der Kontrollgruppe. 82% der CyA-Patienten mit funktionsfähigen Transplantaten erhielten CyA allein, 17% wurden auf die herkömmliche Therapie umgestellt, und ein Patient erhielt Prednisolon zusätzlich zu CyA. Steroide haben nie 27% erhalten. Die Nierenfunktion 6 Monate nach der Transplantation war in der CyA-Gruppe ähnlich wie in der Azathioprin- und Steroid-Gruppe. Nach diesen vorläufigen Ergebnissen scheint CyA wirkungsvoller als die konventionelle Immunsuppression zu sein, wobei Langzeit-Steroid-Therapie vermieden werden kann.
In vier mit hochdosiertem ALG (0,15–0,2 ml/kg KG täglich) intravenös behandelten Patientengruppen... more In vier mit hochdosiertem ALG (0,15–0,2 ml/kg KG täglich) intravenös behandelten Patientengruppen wurde mit der passiven Hämagglutination, der Hammelerythrocytenagglutination und der Agargelpräcipitation die Antikörperbildung gegen Pferdeprotein untersucht. Bei jeder Gruppe wurde ein anderes Therapieschema angewendet. Alleinige ALG-Gabe sowie die Applikation von ALG mit Corticosteroiden verhindern nicht die Antikörperproduktion gegen ALG und haben hyperergische Reaktionen zur Folge. Zusätzliche Verabreichung von Azathioprin senkt die Antikörperbildung gegen ALG und damit auch die Unverträglichkeitserscheinungen. Die Kombination von ALG, Corticosteroiden, Azathioprin mit der Drainage des Ductus thoracicus und dem Versuch einer vorherigen Toleranzinduktion gegenüber Pferde-IgG führten in den bisher behandelten Fällen zur komplikationslosen Verträglichkeit von ALG. Antikörper gegen Pferdegammaglobulin konnten bis zu 5 Wochen von Behandlungsbeginn an nicht nachgewiesen werden. Je nach angewandtem Behandlungsschema ändert sich das Verhalten der Immunglobuline. Ein Immunglobulinanstieg korrreliert in allen Fällen mit der Höhe der gegen ALG gebildeten Antikörpertiter. The production of antibodies against horse protein in patients treated with ALG intravenously in high doses (0.15–0.2 ml/kg/b.w. daily) was investigated using the passive hemagglutination test, the sheep cell agglutination test and the gel diffusion test. 4 groups of patients were divided according to their individual schedules of treatment. ALG application alone as well as the combined therapy with ALG and steroids did not prevent the production of antibodies against ALG. In such cases the incidence of allergic reactions could be observed. Simultaneous administration of ALG, steroids and azathioprine decreases remarkably the antibody formation against ALG and reduces the incidence of foreign serum reactions. Recently a more effective schedule of treatment was developed which consists of 1) the application of ALG, steroids and azathioprine, 2) the performance of a thoracic duct drainage, 3) the attempt to induce immunological tolerance to horse IgG before ALG application. Using these methods we could not find any antibodies against horse protein over a period of 5 weeks. These patients tolerated ALG without any sign of allergic reactions. The level of immunoglobulins depended on the schedule of treatment which had been performed. The increase of immunoglobulins shows a good correlation with the titer of antibodies against ALG.
Fifty-eight patients with long-standing type 1 (insulin-dependent) diabetes were studied prospect... more Fifty-eight patients with long-standing type 1 (insulin-dependent) diabetes were studied prospectively after combined pancreas and kidney transplantation for a mean observation period of 47.9 months (range 17–116 months). Thirty-three per cent of these patients (19/58) developed carpal tunnel syndrome after a mean interval of 1.7 years (range 3 months–5 years). This rate is about twice that in type 1 diabetic patients. The manifestation of carpal tunnel syndrome was not significantly associated with worsening of diabetic polyneuropathy or with deterioration of kidney or pancreas function. In all but one patient symptoms improved without surgical intervention. This study suggests that patients after combined pancreas and kidney transplantation have an increased risk of carpal tunnel syndrome for which the etiology and pathophysiology are unknown. In most patients no surgical intervention is necessary.
Diabetic vascular lesions and peripheral autonomic neuropathy are both closely linked to long-ter... more Diabetic vascular lesions and peripheral autonomic neuropathy are both closely linked to long-term metabolic control of diabetes. Transcutaneous oxygen tension (P tcO2) measurements were made to elucidate whether autonomic neuropathy disturbs the cutaneous microciculatory blood flow, and whether long-term glucose normalization ameliorates such impairment. Twenty-eight type 1 (insulin-dependent) diabetic patients in whom clinically significant macroangiopathy had been excluded by angiography were studied, subdivided into group An=14; before simultaneous pancreas/kidney transplantation (SPKT); mean age 35 years, range 22–51 years; mean duration of diabetes 24 years, (range 15–32) years and group B (n=14; mean 31 months, range 2–101 months, after successful SPKT; mean age 35 years, range 19–56 years; mean duration of diabetes 22 years, range 14–29 years). On addition there was a group (group C) of age-and sex-matched healthy control subjects (n=14; mean age 35 years, range 23–62 years).P tcO2 measurements included basal recordings at 44°C on the leg and the foot, functional recordings at 44°C after arterial occlusion of the limb for 4 min, measurements during breathing 5 l oxygen per minute and finally while standing up (stand up dP 50/dt). All subjects underwent extensive cardiac autonomic testing. In this cross-sectional study the recordings of basal values and of the functional parameters after arterial occlusion and during breathing oxygen did not differ significantly between groups A, B and C. The stand-up dP 50/dt values were not significantly different between groups A and B (0.43±0.02 vs 0.47±0.03 mmHg/s, mean ± SEM); but A+B values were significantly higher than in C (0.22±0.01 mmHg/s;P<0.001). These values were correlated significantly with all parameters of cardiac autonomic neuropathy (r range−0.56 to −0.88;P<0.001). It may be concluded that normalization of blood glucose by pancreatic transplantation is not able to ameliorate peripheral microcirculation, but that measurement of transcutaneous oxygen tension is a possible new technique for quantifying alterations in the venoarteriolar reflex in peripheral diabetic autonomic neuropathy that lead to disturbed peripheral microcirculation in diabetic patients.
Es werden experimentelle Untersuchungen zur Steigerung der Spezifität und Verbesserung der Verträ... more Es werden experimentelle Untersuchungen zur Steigerung der Spezifität und Verbesserung der Verträglichkeit von heterologen Antilymphocytenseren (ALS) geschildert. 1. In Analogie zur Verhütung der Rhesussensibilisierung durch Antikörper konnte die Entstehung unerwünschter Hämagglutinine bei der Herstellung von ALS durch passive Zufuhr entsprechender Antikörper gegen Erythrocyten gehemmt werden. Dieses Modellsystem läßt sich vermutlich auch auf die Unterdrückung anderer unerwünschter Antikörper übertragen. 2. Ein Zustand der immunologischen Toleranz gegenüber IgG vom Pferd konnte in erwachsenen Hunden durch wiederholte Injektionen von ultrazentrifugiertem IgG erzeugt werden. Dieses Vorgehen könnte einen Weg darstellen, Überempfindlichkeitsreaktionen bei längerer Anwendung von ALS bzw. von Gammaglobulinfraktionen zu vermeiden. Experiments have been carried out to increase the specificity of ALS and to improve the toleration of antilymphocyteserum (ALS) treatment. 1. During immunization of rabbits with dog lymphocytes it was possible to suppress the production of hemagglutinins against dog erythrocytes by simultaneous injection of rabbit - anti - dog - erythrocyteserum. This is in accordance with the prevention of Rhesus-sensitization by means of antibodies. 2. A state of immunological tolerance in adult dogs against normal IgG from horse was obtained by repeated injections of small doses of ultracentrifuged IgG. The experiments strengthen the opinion, that induction of an immunological tolerance against foreign protein is possible also in men. This method might be helpful in avoiding hypersensitive reactions in patients to be treated with ALS-γ-Globulins.
Abstract: Despite encouraging and improving results, organ transplantation is still hampered by a... more Abstract: Despite encouraging and improving results, organ transplantation is still hampered by a shortage of organs, chronic transplant loss, and a changed patient population. Liberal inclusion criteria for dialysis and/or renal transplantation and the increasing unwillingness to donate organs in some countries has led to a growing imbalance between the numbers of transplantations performed and patients on waiting lists. Until now, poorly understood chronic transplant dysfunction is responsible for a still unchanged graft loss of approximately 5% per year. The patient population has changed to include more multimorbidity and an increasing number of risk factors (age, diabetes mellitus, former [failed] transplantations, or preexisting cardiovascular diseases). The recommendation for or against dialysis or transplantation has become increasingly difficult for the responsible physician. Newly developed immunosuppressant drugs, an increasing consideration regarding living organ donation, or xenotransplantation in the future may solve this dilemma. New reflections and considerations about the ethical background of transplantation medicine are necessary.
The efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens were com... more The efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens were compared in a prospectively defined subgroup of kidney transplant recipients from the European, open, multicentre, 2 : 1 randomised, parallel group study. Patients were stratified as high risk for immunological events if they had a panel-reactive antibodies grade greater than 80 % and/or a previous transplant functional for less than 1 year. The primary efficacy variables evaluated were the incidence of acute rejection, steroid usage and patient and graft survival. Safety was assessed based on adverse events and laboratory evaluations. At 1 year, the tacrolimus group (n = 22) had a lower incidence of biopsy-proven acute rejection (31.8 %) and a higher graft survival (86.0 %) than the 11 patients in the cyclosporine group (54.5 % and 72.0 %, respectively). The frequencies of adverse events were similar between the two groups. The tacrolimus regimen appears more beneficial for high risk patients than cyclosporine.
Prolonged cold ischemia time and the generation of free oxygen radicals during reperfusion are ri... more Prolonged cold ischemia time and the generation of free oxygen radicals during reperfusion are risk factors for allograft arteriosclerosis. Growth factors are the main pro-proliferative mediators of smooth muscle cells in classical and in allograft arteriosclerosis. Superoxide dismutase is an enzyme that catalyzes the dismutation of superoxide anions into hydrogen peroxide. This study was designed to investigate which smooth muscle cell growth factor contribute to the formation of arteriosclerosis in syngenic vascular grafts with prolonged ischemia time, and whether perioperative intravenous administration of recombinant human superoxide dismutase (rh-SOD) prevents arteriosclerosis in these grafts. DA aortas were transplanted into DA recipients. One group of transplants was made with a short ex vivo ischemia time (15 min), while the other group transplant grafts was stored for 24 hr in cold saline. In addition to morphometric quantitation of the histological alterations, RNA isolated from grafts with short cold ischemia time in a semiquantitative polymerase chain reaction specific for various known smooth muscle cell growth factors. Syngeneic grafts with prolonged cold ischemia time showed severe intimal thickening and prominent medical necrosis, which were not seen in control groups. Approximately 3-fold levels of insulin-like growth factor-1 were found in ischemic syngeneic grafts compared with non-ischemic syngenic grafts, whereas epidermal growth factor levels were slightly lower. No changes in other growth factor mRNAs were found. Perioperative treatment with rh-SOD did not have significant effect on the extent of intimal thickening nor on the intensity of medial necrosis in grafts with prolonged ischemia time, and administration of rh-SOD did not change the expression level of insulin-like growth factor-1 in the grafts, either.
Experimental and Clinical Endocrinology & Diabetes, 1998
The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the developme... more The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the development of diabetic microvascular lesions is well established. On the other hand, little is known on its impact on diabetic macrovascular disease, which is still the major cause of death in diabetes, including patients after PKT. In order to evaluate the influence of PKT on the cardiovascular risk profile, we performed a cross-sectional study on 55 patients. Special attention was given to the hemorheological parameters fibrinogen and plasma viscosity, two important cardiovascular risk factors, which so far have found no attention in the field of PKT research. The patients were subdivided into three groups according to their graft function: group 1-26 patients after successful PKT (no insulin dependency, serum creatinine &lt;2 mg%), group 2-23 patients after PKT and rejection of the pancreas graft (insulin dependency, serum creatinine &lt;2 mg%), group 3-6 patients after PKT with pancreas rejection and renal insufficiency (insulin dependency, serum creatinine &gt;2 mg%, no dialysis). There was a high prevalence of arterial hypertension after PKT (group 1: 65%, group 2: 70%, group 3: 100%). Serum lipids were in the normal range as long as renal function was intact. In renal insufficiency, however, LDL-cholesterol and triglycerides were significantly elevated (p &lt; 0.05). Fibrinogen was significantly raised after PKT (p &lt; 0.001), as was plasma viscosity when the pancreas graft was rejected (p &lt; 0.02). There was a tendency towards elevated fibrinogen levels with decreasing graft function. In conclusion, a number of cardiovascular risk factors were identified in patients after PKT, predominantly arterial hypertension and impaired hemorheology, with elevated fibrinogen levels and plasma viscosity. There is a further enhancement with decreasing graft function.
The history of solid organ transplantation is, from an immunotherapeutic standpoint, divided in t... more The history of solid organ transplantation is, from an immunotherapeutic standpoint, divided in the era before and after the introduction of cyclosporine to the clinic. The introduction of cyclosporine to the clinic in 1978 is looked upon as a turning point in transplantation. The immediate success of the new drug was based on the reduction of early graft rejection and the substantial improvement of 1-year graft survival. With growing experience in the use of this new compound, together with the ability to measure drug levels in serum, allograft rejection and organ survival could be improved even further. Because of the clinical results, cyclosporine became the gold standard in immunosuppressive therapy after organ transplantation. Even after 20 years, as more and more new immunosuppressants emerge, the clinical evaluation of a new drug is frequently compared versus a cyclosporine-based regimen. Today, cyclosporine is probably one of the best investigated drugs in the field of organ transplantation. Beside the undoubted benefits of cyclosporine, experimental and clinical studies have also revealed some unwanted effects, such as nephrotoxocity and an increased risk in development of malignant tumors. Here, we review the experience at our institution with transplant recipients receiving cyclosporine as the main immunosuppressant over the past 20 years.
In a multicentre trial conducted in eight European centres, 232 recipients of cadaveric renal all... more In a multicentre trial conducted in eight European centres, 232 recipients of cadaveric renal allografts were randomly allocated to receive either cyclosporin A (CyA, 117 patients) or azathioprine and steroids (control, 115 patients) for immunosuppression. After a follow-up period of up to eleven months, graft survival probability estimates are 73% in the CyA group and 53% in the control group. Two deaths have occurred in the CyA group and seven in the control group. 82% of the CyA group with functioning grafts are receiving CyA alone, 17% have been changed to azathioprine and steroids and one patient is receiving prednisolone in addition to CyA; 27% have never received steroids. At six months post-transplant renal function is similar in patients receiving CyA and in those receiving azathioprine and steroids. On the basis of these preliminary results CyA appears to be more effective than conventional immunosuppression and avoids the necessity of longterm steroid therapy. In einer multizentrischen Studie mit acht beteiligten Zentren wurden 232 Empfänger von Leichennieren-Transplantaten nach dem Zufallsprinzip einer Behandlung mit Cyclosporin A (CyA-Gruppe: 117 Patienten) bzw. mit Azathioprin und Steroiden (Kontrollgruppe: 115 Patienten) zugewiesen. Nach einer Beobachtungsperiode zwischen 2 Wochen und 11 Monaten betrug die geschätzte Überlebenswahrscheinlichkeit der Transplantate 73% in der CyA- und 53% in der Kontrollgruppe. Während der Therapie gab es zwei Todesfälle in der CyA- gegenüber sieben in der Kontrollgruppe. 82% der CyA-Patienten mit funktionsfähigen Transplantaten erhielten CyA allein, 17% wurden auf die herkömmliche Therapie umgestellt, und ein Patient erhielt Prednisolon zusätzlich zu CyA. Steroide haben nie 27% erhalten. Die Nierenfunktion 6 Monate nach der Transplantation war in der CyA-Gruppe ähnlich wie in der Azathioprin- und Steroid-Gruppe. Nach diesen vorläufigen Ergebnissen scheint CyA wirkungsvoller als die konventionelle Immunsuppression zu sein, wobei Langzeit-Steroid-Therapie vermieden werden kann.
In vier mit hochdosiertem ALG (0,15–0,2 ml/kg KG täglich) intravenös behandelten Patientengruppen... more In vier mit hochdosiertem ALG (0,15–0,2 ml/kg KG täglich) intravenös behandelten Patientengruppen wurde mit der passiven Hämagglutination, der Hammelerythrocytenagglutination und der Agargelpräcipitation die Antikörperbildung gegen Pferdeprotein untersucht. Bei jeder Gruppe wurde ein anderes Therapieschema angewendet. Alleinige ALG-Gabe sowie die Applikation von ALG mit Corticosteroiden verhindern nicht die Antikörperproduktion gegen ALG und haben hyperergische Reaktionen zur Folge. Zusätzliche Verabreichung von Azathioprin senkt die Antikörperbildung gegen ALG und damit auch die Unverträglichkeitserscheinungen. Die Kombination von ALG, Corticosteroiden, Azathioprin mit der Drainage des Ductus thoracicus und dem Versuch einer vorherigen Toleranzinduktion gegenüber Pferde-IgG führten in den bisher behandelten Fällen zur komplikationslosen Verträglichkeit von ALG. Antikörper gegen Pferdegammaglobulin konnten bis zu 5 Wochen von Behandlungsbeginn an nicht nachgewiesen werden. Je nach angewandtem Behandlungsschema ändert sich das Verhalten der Immunglobuline. Ein Immunglobulinanstieg korrreliert in allen Fällen mit der Höhe der gegen ALG gebildeten Antikörpertiter. The production of antibodies against horse protein in patients treated with ALG intravenously in high doses (0.15–0.2 ml/kg/b.w. daily) was investigated using the passive hemagglutination test, the sheep cell agglutination test and the gel diffusion test. 4 groups of patients were divided according to their individual schedules of treatment. ALG application alone as well as the combined therapy with ALG and steroids did not prevent the production of antibodies against ALG. In such cases the incidence of allergic reactions could be observed. Simultaneous administration of ALG, steroids and azathioprine decreases remarkably the antibody formation against ALG and reduces the incidence of foreign serum reactions. Recently a more effective schedule of treatment was developed which consists of 1) the application of ALG, steroids and azathioprine, 2) the performance of a thoracic duct drainage, 3) the attempt to induce immunological tolerance to horse IgG before ALG application. Using these methods we could not find any antibodies against horse protein over a period of 5 weeks. These patients tolerated ALG without any sign of allergic reactions. The level of immunoglobulins depended on the schedule of treatment which had been performed. The increase of immunoglobulins shows a good correlation with the titer of antibodies against ALG.
Fifty-eight patients with long-standing type 1 (insulin-dependent) diabetes were studied prospect... more Fifty-eight patients with long-standing type 1 (insulin-dependent) diabetes were studied prospectively after combined pancreas and kidney transplantation for a mean observation period of 47.9 months (range 17–116 months). Thirty-three per cent of these patients (19/58) developed carpal tunnel syndrome after a mean interval of 1.7 years (range 3 months–5 years). This rate is about twice that in type 1 diabetic patients. The manifestation of carpal tunnel syndrome was not significantly associated with worsening of diabetic polyneuropathy or with deterioration of kidney or pancreas function. In all but one patient symptoms improved without surgical intervention. This study suggests that patients after combined pancreas and kidney transplantation have an increased risk of carpal tunnel syndrome for which the etiology and pathophysiology are unknown. In most patients no surgical intervention is necessary.
Diabetic vascular lesions and peripheral autonomic neuropathy are both closely linked to long-ter... more Diabetic vascular lesions and peripheral autonomic neuropathy are both closely linked to long-term metabolic control of diabetes. Transcutaneous oxygen tension (P tcO2) measurements were made to elucidate whether autonomic neuropathy disturbs the cutaneous microciculatory blood flow, and whether long-term glucose normalization ameliorates such impairment. Twenty-eight type 1 (insulin-dependent) diabetic patients in whom clinically significant macroangiopathy had been excluded by angiography were studied, subdivided into group An=14; before simultaneous pancreas/kidney transplantation (SPKT); mean age 35 years, range 22–51 years; mean duration of diabetes 24 years, (range 15–32) years and group B (n=14; mean 31 months, range 2–101 months, after successful SPKT; mean age 35 years, range 19–56 years; mean duration of diabetes 22 years, range 14–29 years). On addition there was a group (group C) of age-and sex-matched healthy control subjects (n=14; mean age 35 years, range 23–62 years).P tcO2 measurements included basal recordings at 44°C on the leg and the foot, functional recordings at 44°C after arterial occlusion of the limb for 4 min, measurements during breathing 5 l oxygen per minute and finally while standing up (stand up dP 50/dt). All subjects underwent extensive cardiac autonomic testing. In this cross-sectional study the recordings of basal values and of the functional parameters after arterial occlusion and during breathing oxygen did not differ significantly between groups A, B and C. The stand-up dP 50/dt values were not significantly different between groups A and B (0.43±0.02 vs 0.47±0.03 mmHg/s, mean ± SEM); but A+B values were significantly higher than in C (0.22±0.01 mmHg/s;P<0.001). These values were correlated significantly with all parameters of cardiac autonomic neuropathy (r range−0.56 to −0.88;P<0.001). It may be concluded that normalization of blood glucose by pancreatic transplantation is not able to ameliorate peripheral microcirculation, but that measurement of transcutaneous oxygen tension is a possible new technique for quantifying alterations in the venoarteriolar reflex in peripheral diabetic autonomic neuropathy that lead to disturbed peripheral microcirculation in diabetic patients.
Es werden experimentelle Untersuchungen zur Steigerung der Spezifität und Verbesserung der Verträ... more Es werden experimentelle Untersuchungen zur Steigerung der Spezifität und Verbesserung der Verträglichkeit von heterologen Antilymphocytenseren (ALS) geschildert. 1. In Analogie zur Verhütung der Rhesussensibilisierung durch Antikörper konnte die Entstehung unerwünschter Hämagglutinine bei der Herstellung von ALS durch passive Zufuhr entsprechender Antikörper gegen Erythrocyten gehemmt werden. Dieses Modellsystem läßt sich vermutlich auch auf die Unterdrückung anderer unerwünschter Antikörper übertragen. 2. Ein Zustand der immunologischen Toleranz gegenüber IgG vom Pferd konnte in erwachsenen Hunden durch wiederholte Injektionen von ultrazentrifugiertem IgG erzeugt werden. Dieses Vorgehen könnte einen Weg darstellen, Überempfindlichkeitsreaktionen bei längerer Anwendung von ALS bzw. von Gammaglobulinfraktionen zu vermeiden. Experiments have been carried out to increase the specificity of ALS and to improve the toleration of antilymphocyteserum (ALS) treatment. 1. During immunization of rabbits with dog lymphocytes it was possible to suppress the production of hemagglutinins against dog erythrocytes by simultaneous injection of rabbit - anti - dog - erythrocyteserum. This is in accordance with the prevention of Rhesus-sensitization by means of antibodies. 2. A state of immunological tolerance in adult dogs against normal IgG from horse was obtained by repeated injections of small doses of ultracentrifuged IgG. The experiments strengthen the opinion, that induction of an immunological tolerance against foreign protein is possible also in men. This method might be helpful in avoiding hypersensitive reactions in patients to be treated with ALS-γ-Globulins.
Abstract: Despite encouraging and improving results, organ transplantation is still hampered by a... more Abstract: Despite encouraging and improving results, organ transplantation is still hampered by a shortage of organs, chronic transplant loss, and a changed patient population. Liberal inclusion criteria for dialysis and/or renal transplantation and the increasing unwillingness to donate organs in some countries has led to a growing imbalance between the numbers of transplantations performed and patients on waiting lists. Until now, poorly understood chronic transplant dysfunction is responsible for a still unchanged graft loss of approximately 5% per year. The patient population has changed to include more multimorbidity and an increasing number of risk factors (age, diabetes mellitus, former [failed] transplantations, or preexisting cardiovascular diseases). The recommendation for or against dialysis or transplantation has become increasingly difficult for the responsible physician. Newly developed immunosuppressant drugs, an increasing consideration regarding living organ donation, or xenotransplantation in the future may solve this dilemma. New reflections and considerations about the ethical background of transplantation medicine are necessary.
The efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens were com... more The efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens were compared in a prospectively defined subgroup of kidney transplant recipients from the European, open, multicentre, 2 : 1 randomised, parallel group study. Patients were stratified as high risk for immunological events if they had a panel-reactive antibodies grade greater than 80 % and/or a previous transplant functional for less than 1 year. The primary efficacy variables evaluated were the incidence of acute rejection, steroid usage and patient and graft survival. Safety was assessed based on adverse events and laboratory evaluations. At 1 year, the tacrolimus group (n = 22) had a lower incidence of biopsy-proven acute rejection (31.8 %) and a higher graft survival (86.0 %) than the 11 patients in the cyclosporine group (54.5 % and 72.0 %, respectively). The frequencies of adverse events were similar between the two groups. The tacrolimus regimen appears more beneficial for high risk patients than cyclosporine.
Prolonged cold ischemia time and the generation of free oxygen radicals during reperfusion are ri... more Prolonged cold ischemia time and the generation of free oxygen radicals during reperfusion are risk factors for allograft arteriosclerosis. Growth factors are the main pro-proliferative mediators of smooth muscle cells in classical and in allograft arteriosclerosis. Superoxide dismutase is an enzyme that catalyzes the dismutation of superoxide anions into hydrogen peroxide. This study was designed to investigate which smooth muscle cell growth factor contribute to the formation of arteriosclerosis in syngenic vascular grafts with prolonged ischemia time, and whether perioperative intravenous administration of recombinant human superoxide dismutase (rh-SOD) prevents arteriosclerosis in these grafts. DA aortas were transplanted into DA recipients. One group of transplants was made with a short ex vivo ischemia time (15 min), while the other group transplant grafts was stored for 24 hr in cold saline. In addition to morphometric quantitation of the histological alterations, RNA isolated from grafts with short cold ischemia time in a semiquantitative polymerase chain reaction specific for various known smooth muscle cell growth factors. Syngeneic grafts with prolonged cold ischemia time showed severe intimal thickening and prominent medical necrosis, which were not seen in control groups. Approximately 3-fold levels of insulin-like growth factor-1 were found in ischemic syngeneic grafts compared with non-ischemic syngenic grafts, whereas epidermal growth factor levels were slightly lower. No changes in other growth factor mRNAs were found. Perioperative treatment with rh-SOD did not have significant effect on the extent of intimal thickening nor on the intensity of medial necrosis in grafts with prolonged ischemia time, and administration of rh-SOD did not change the expression level of insulin-like growth factor-1 in the grafts, either.
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