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O Witzke

Publications and source records attributed to O Witzke.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1999

Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide).

Alkylating drugs (cyclophosphamide and ifosfamide) have been in clinical use for the treatment of malignant diseases in the past. They are most useful anticancer agents and cyclophosphamide is also widely used for its immunosuppressive properties. However the effect of alkylating drugs on thyroid hormone parameters have not been evaluated so far. Three groups of patients were prospectively evaluated: Group I: 15 patients with Wegener's granulomatosis and 4 patients with severe scleritis received a single dose cyclophosphamide (15 mg/kg bw/day) and 250 mg prednisone i.v. Group II: 9 patients with malignant lymphomas were treated according to the IMVP 16-protocol. Patients received daily ifosfamide 1000 mg/m2 from day 0 to 4 and vepesid from day 0 to 2. Patients did not receive corticosteroids additionally. Group III: 6 patients with a relapse of malignant lymphomas received ifosfamide 1.500 mg/m2/day from day 0 to 4 i.v. and dexamethasone 40 mg/m2 as well as ara-c and etoposid. All patients received mesna to prevent hemorrhagic cystitis and odansetran or metoclopramide as antiemetic drugs. Alkylating drugs were given as a one hour infusion. Thyroid hormone parameters were determined before and on day 1, 2, 3, 4 after drug administration. We observed a significant increase in T4 and fT4 concentrations and a concomitant fall in TSH in either group one day after the administration of alkylating drugs. The effect was most pronounced in group III: T4 increased from 113 +/- 8 nmol/L to 175 +/- 8 (normal: 58-154) and fT4 from 14.0 +/- 0.8 to 24.8 +/- 2.5 pmol/L (normal 10-25). TSH dropped from 1.27 +/- 0.16 to 0.33 +/- 0.07 mU/L (normal 0.3-4). All changes were significant: p < 0.001. Two of the six patients displayed biochemical hyperthyroidism. Also reverse T3 increased significantly. Two days after drug administration a gradual normalization occurred. However, T3, Tg, TBG, Transthyretin and albumin levels did not change throughout the study period. One patient with coexisting hypothyroidism, who received his last thyroxine substitution therapy one day before the administration of cyclophosphamide (as in group I), also demonstrated an increase in T4, fT4 and rT3 and a fall in TSH concentrations. I.v. administrations of cyclophosphamide and ifosfamide induce a transient increase in T4 and fT4 concentrations and a concomitant fall of TSH in the presence of normal Tg, T3 and thyroid binding protein concentrations. These data suggest, that the changes are not due to a release of thyroid hormones from the thyroid itself, but is likewise related to a release of thyroxine from cellular pools such as the liver.

Adult↗
PubMed1999

[Quality of life following transplantation. The impact ofa new immunosuppressive substance].

The improvement of quality of life is one of the major goals in the treatment of patients after renal transplantation. While immunosuppressive therapy is present in almost all of these patients, little is known about the effects of newer immunosuppressive agents. We therefore investigated the impact of tacrolimus on life quality. From November 1997 to January 1998, a questionnaire was handed out which focussed on physical and mental problems as well as sexual capacity and the attitudes towards graft, donor and transplant related side effects. 50 kidney graft recipients treated with tacrolimus were matched to 50 patients with a cyclosporine-based immunosuppression (= controls). Values are given as mean +/- standard deviation. Tacrolimus treated patients had a mean creatinine of 1.8 +/- 0.8 mg/dl, as compared to 1.6 +/- 0.7 mg/dl in controls. The overall status of health was assessed to be good in 82% of the tacrolimus group (controls: 80%). 38% were working full-time (controls: 20%). Only 14% of patients described their physical condition as poor (16% in controls). Sexual function was good in 66% (controls: 74%) and poor in 10% (controls: 12%). Mental function was assessed to be good in 92% (controls: 82%). The majority of patients felt comfortable with their physical, sexual and mental capabilities. This was independent from the immunosuppressive regimen.

Cyclosporine↗
PubMed1999

Induction of tolerance to alloantigen.

The study of transplantation tolerance has been a major area of immunological research since the pioneering work by Medawar and colleagues. It has been classically defined as the absence of an immune response to a specific antigen in the setting of an otherwise normal immune system. The induction of tolerance to alloantigen in the transplantation setting would not only allow better graft survival but would also obviate the need for immunosuppressive therapy. The induction of tolerance is considered by many to be the "holy grail" of organ transplantation but, despite many years of experimental investigation, reliable induction of allograft tolerance has not been achieved in humans. There exists four fundamental mechanisms of T cell tolerance that may be operational in the transplantation setting: deletion, functional anergy, ignorance and regulation/suppression. Several strategies to induce tolerance in transplantation have been employed, but most of these tolerogenic strategies have been investigated in rodents and it remains to be determined whether they can be transferred into large outbred animal models or clinical transplantation.

Animals↗
PubMed1998

Donor resting B cells induce indefinite prolongation of fully allogeneic cardiac grafts when delivered with anti-immunoglobulin-D monoclonal antibody: evidence for tolerogenicity of donor resting B cells in vivo.

BACKGROUND: Resting B (rB) cells have been shown to induce T-cell anergy in vitro and to prolong the survival of skin and cardiac grafts mismatched for minor histocompatibility antigens. However, rB cells were unable to modulate the rejection response when grafts mismatched for major histocompatibility complex antigens were transplanted. We reasoned that donor antigens, which presented via the indirect pathway by recipient antigen-presenting cells, in particular B cells, might influence the ability of rB cells to induce unresponsiveness. To explore this hypothesis, we used an anti-immunoglobulin (Ig)-D monoclonal antibody (mAb) specific for recipient B cells to deplete these cells, thereby decreasing the potential for indirect presentation in vivo. METHODS: CBA mice were pretreated with 1 x 10(7) donor rB or activated B (aB) cells 7 days before transplantation of a C57BL/10 cardiac graft in the absence or presence of anti-IgD mAb. RESULTS: Naive CBA mice rejected C57BL/10 grafts acutely (median survival time [MST]=8 days). Pretreatment with rB cells alone resulted in a modest prolongation of graft survival (MST=11.5 days). In marked contrast, when rB cells were delivered with anti-IgD mAb, indefinite graft prolongation (MST>100 days) was observed in all recipients. Interestingly, aB cells produced only a small prolongation of graft survival when delivered with anti-IgD mAb (MST=15 days). Recipients treated with anti-IgD mAb alone rejected C57BL/10 cardiac allografts acutely (MST=8 days). CONCLUSION: These data suggest that depletion of recipient B cells in vivo can augment the ability of donor rB cells to induce indefinite prolongation of fully allogeneic cardiac grafts. Thus, IgD+ B cells in the recipient may influence the development of unresponsiveness in vivo.

Animals↗
PubMed1998

Comparison between subcutaneous and intravenous interleukin-2 treatment in HIV disease.

OBJECTIVES: Therapy of HIV-infection using intravenous interleukin-2 (IL-2) is known to be effective in terms of increasing CD4-counts but is associated with significant side-effects and hospitalization. However, the combination with protease-inhibitor therapy has not been tested yet. The aim of the present study was to investigate the safety and efficacy of intravenous vs. subcutaneous IL-2 regimes using 9 Mio I.U. of IL-2, in combination with protease-inhibitor therapy. DESIGN: All patients were treated with a combination of two reverse transcriptase inhibitors and a protease-inhibitor prior to IL-2 administration for at least 6 weeks. Ten patients were assigned to the intravenous IL-2 group (group A). 10 to the subcutaneous group (group B). RESULTS: In both treatment groups, CD4 count significantly increased shortly after the end of therapy (group A: 223% over baseline [day 7]; group B: 264% over baseline [day 7]). During the follow-up CD4 counts slowly decreased thereafter but remained above baseline 3 months following IL-2 treatment. The CD8 lymphocytes showed a similar but less pronounced pattern with a maximum at day 7 (group A: 116% over baseline, group B: 158% over baseline) and reached baseline earlier in the follow-up-period. Altogether the CD4/CD8-ratio was elevated through long periods on follow-up. Throughout follow-up, there were no apparent changes in viral load during IL-2 therapy in either groups. IL-2 therapy was administered for a mean time of 4.2+/-0.1 days in the intravenous group and of 4.8+/-0.1 days in the subcutaneous group until therapy was terminated at day 5 or due to side-effects. Only 1/10 patients completed the 5-day course of intravenous therapy in contrast to 6/10 in the subcutaneous group. CONCLUSIONS: Subcutaneous interleukin-2 using 9 Mio IU day(-1) in combination with protease-inhibitors showed equal efficacy as intravenous therapy and was associated with less side-effects.

Adult↗
PubMed1998

Sequential changes of biochemical bone parameters after kidney transplantation.

BACKGROUND: Persistent hyperparathyroidism after renal transplantation (Rtx) has been reported in several studies. However these studies evaluated biochemical bone parameters either only during a short time period (up to 6 months) or for a longer time period, but with long intervals in between. Therefore, we prospectively evaluated biochemical bone parameters of kidney-transplant recipients at short intervals for 2 years after surgery. METHODS: Biochemical bone parameters were prospectively investigated in 129 patients 2, 3, 5, 8, 12, 18 and 24 months after Rtx. All patients received prednisone and cyclosporin A as immunosuppressive therapy, and 75 patients also received azathioprine. None of the patients was treated with calcium, phosphorus, or vitamin D preparations. RESULTS: Serum creatinine levels decreased from 166.8 +/- 5.4 mumol/l to 140.0 +/- 4.9 two years after Rtx; (data are expressed as mean +/- s.e.m.). Serum phosphorus levels increased slightly from 0.9 +/- 0.022 mmol/l to 0.98 +/- 0.025 (12 m), but remained within the lower normal range. We observed a rise in total and albumin adjusted calcium concentrations 3 months after Rtx. 52% of all patients had serum calcium levels above 2.62 mmol/l (upper normal limit in our laboratory) 3 months after renal transplantation with a gradual decrease thereafter. There was no correlation of calcium and PTH levels. We observed a significant rise in biochemical bone parameters from 2 to 5 months after renal transplantation (P < 0.001): alkaline phosphatase (AP) increased from 164.3 +/- 9.4 to 236 +/- 12.7 U/l (normal 50-180), bone specific alkaline phosphatase (BAP) rose from 17.7 +/- 1.36 to 23.2 +/- 1.7 ng/ml (normal:4-20) and osteocalcin (OC) increased from 20.2 +/- 1.5 to 26.7 +/- 1.9 ng/ml (normal 4-12). AP and BAP levels values normalized 12 months after renal transplantation, whereas OC was still above normal throughout the study period. Patients were subdivided into two groups: those with good and those with impaired graft functions. Patients with good graft function had stable serum creatinine levels (< or = 132 mumol/l or < or = 1.5 mg/dl) well below the mean serum creatinine concentration during the study period. The significant changes in AP, BAP, and OC occurred irrespective of renal function. However, patients with impaired graft function (n = 65) had significantly higher PTH-levels (70 pg/ml higher) than patients with good graft function (n = 64), P < 0.01. PTH was positively correlated with serum creatinine (r = 0.81, P < 0.001). Moreover, patients with low 25 (OH) vitamin D levels (n = 63) had significantly higher PTH concentrations (between 40 and 80 pg/ml, P < 0.01) throughout the study period compared to patients (n = 66) with a sufficient 25(OH)D supply irrespective of graft function. There was a negative correlation of 25 (OH)D levels and PTH; (r = -0.49, P < 0.001). 1,25(OH)2D3 (evaluated in 24 patients) levels increased from 46.5 +/- 6.6 to 76.9 +/- 7.6 pg/ml (normal:35-90) at 12 months. CONCLUSION: Hypercalcaemia is a common phenomenon in the early period after kidney transplantation and occurs in the presence of low normal phosphorus levels. It is most probably related to improved PTH action and 1-hydroxylation of vitamin D. The rise in biochemical bone parameters between 3 and 5 months occurs irrespective of graft function and normalization is only achieved 1 year after transplantation. PTH is constantly elevated for up to 2 years after kidney transplantation and is most probably related (a) to impaired graft function and (b) to suboptimal 25 OH vitamin D supply.

Adult↗
PubMed1998

Tacrolimus rescue therapy in patients with rejection and long-term dialysis after kidney transplantation.

Therapy with tacrolimus has been proven effective in patients with steroid-resistant rejection episodes. It was the objective of the present study to evaluate the efficacy of tacrolimus in patients with long-lasting primary or secondary non-function (defined as being on dialysis for at least 28 days) converted for biopsy proven acute rejection and to determine parameters of prognostic value. Eight patients with biopsy proven acute interstitial rejection unsuccessfully treated with steroids were converted from a cyclosporine based immunosuppressive regimen to tacrolimus. Three patients were additionally pretreated with OKT3 without success. The tacrolimus whole blood through level was 7.5 +/- 2.6 ng/ml at one week and 8.1 +/- 3.4 ng/ml at one month after conversion. The follow-up period after conversion to tacrolimus ranged from 12-18 months. In four patients hemodialysis was stopped after 78 +/- 49 days (range 36-145 days). One year thereafter, creatinine was 3.9 +/- 2.7 mg/dl. In conclusion, our observations, although obtained in a small number of patients, offer some hope in this selected group and may encourage further studies in patients with long-term dialysis after renal transplantation.

Adult↗
PubMed1997

Metabolic factors have a major impact on kidney allograft survival.

BACKGROUND: At the present time, late graft loss is the major cause of kidney failure after transplantation. However, the influence of metabolic factors on this process is ill-defined. METHODS: To identify the impact of lipid metabolism, glucose metabolism, and blood pressure and their prognostic value for graft survival, data for all recipients of a kidney allograft with a potential graft survival of >15 years and a minimum graft survival of 1 month were analyzed retrospectively. Recipients of kidney grafts functioning more than 15 years (n=32) were compared with those with a graft function of less than 10 years (n=152, controls) and evaluated in a multivariate analysis. RESULTS: Low levels of serum cholesterol, triglycerides, and glucose, before and after transplantation, were accompanied by a prolonged graft survival. Prognostic factors for early graft failure included serum triglycerides >300 mg/dl, cholesterol >250 mg/dl before transplantation, serum creatinine >4.0 mg/dl 1 month after transplantation, and donor age above 45 or less than 10 years. Additionally, systolic and, particularly, diastolic blood pressure was lower in the group with a prolonged graft function as compared with controls immediately before and after transplantation. In addition, the incidence of primary graft function was lower and the incidence of acute rejection episodes higher in controls. Cold and warm ischemic time, body mass index, recipient age, and gender did not differ significantly. CONCLUSIONS: Our data suggest that metabolic parameters play an important role in the process of late graft loss after kidney transplantation.

Adult↗
PubMed1997

Beta-human choriogonadotropin therapy and HIV-related Kaposi's sarcoma.

Recently, two clinical trials demonstrated an antitumour effect of systemic high-dose beta-hCG therapy and of different regimens of local beta-hCG injections in AIDS-related Kaposi's sarcoma. We report the efficacy and safety of subcutaneous beta-hCG treatment (low-dose (2500-25000 IU/day) or high dose (25000-100000 IU/day)) in eight patients with advanced HIV disease in whom systemic chemotherapy and radiation were contraindicated or had failed. During therapy, serum hCG-concentrations as well as LH and FSH were measured. In the low-dose regimen one partial response was achieved. In the high-dose regimen, one patient maintained his response without further improvement. Three patients had stable disease and four patients disease progression. Serious side effects related to beta-hCG therapy were not observed. In conclusion, systemic beta-hCG-therapy for Kaposi's sarcoma is safe but associated with regression only in a minority of patients with advanced HIV-disease.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Rescue therapy with tacrolimus in simultaneous pancreas/kidney transplantation.

Tacrolimus has been effective both in primary and rescue therapy following steroid and OKT3-resistant acute rejection in liver and kidney transplantation. Due to the effects of tacrolimus on glucose metabolism, there has been concern about its use in simultaneous pancreas/kidney transplantation. We report on the results of six patients (three female, three male, age 35.2 +/- 7.3 years) converted from cyclosporin A to tacrolimus following simultaneous pancreas/kidney transplantation in steroid-resistant acute rejection. Tacrolimus was induced 2.8 +/- 1.7 months (range 1-4.8 months) after transplantation; follow-up was 3-18 months. Following conversion, creatinine levels declined in all patients [3.5 +/- 1.2 mg/dl before conversion, 3.0 +/- 1.9 mg/dl (n = 6) at three months, 1.4 +/- 0.1 mg/ dl at 1 year (n = 3)]. Before conversion, fasting blood glucose levels averaged 154 +/- 33 mg/dl, with three patients receiving insulin. Three months later no patient required insulin, the mean glucose level being 107 +/- 23 mg/dl (n = 6); at 1 year it was 92 +/- 9 mg/dl (n = 3). One patient lost his pancreatic graft after 4 months due to a mycotic aneurysm. We conclude that conversion to tacrolimus is a safe and effective treatment in cases of steroid-resistant rejections following pancreas/ kidney transplantation.

Administration, Oral↗
PubMed1997

A comparison of EMIT and FPIA methods for the detection of cyclosporin A blood levels: does impaired liver function make a difference?

OBJECTIVE: Apparent cyclosporin A (CSA) blood levels, as determined by fluorescence polarization immunoassay (FPIA) and enzyme-multiplied immunoassay technique (EMIT), were compared in CSA-treated patients with various degrees of liver dysfunction. METHODS: FPIA and EMIT were performed in parallel according to test manufacturer instructions in blood from kidney (n = 82), liver (n = 96) and heart transplant (n = 20) patients. RESULTS: The precision of both techniques was greatest in patients with the highest blood levels, and at each blood level greater for the FPIA than for the EMIT. Apparent CSA blood levels, as determined by EMIT, were typically approximately 70% of those determined by FPIA, indicating greater cross-reaction of the antibody in the FPIA with CSA metabolites. However, the ratio of values determined with EMIT and FPIA was very similar in kidney, liver and heart transplant patients. Among liver transplant patients it was also very similar in those without major alterations of hepatic function and in those with impaired excretory (increased bilirubin and gamma GT) or synthetic (i.e., reduced thromboplastin time) function. Extended storage of blood samples for up to 10 days did not affect apparent CSA blood level estimates by EMIT in a clinically relevant manner. CONCLUSIONS: We conclude that the greater specificity of the antibody in the EMIT for the CSA parent compound does not translate into a clinically relevant advantage for CSA monitoring.

Cyclosporine↗
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↗
PubMed1994

Cryoglobulinemia: a complication of infectious disease.

We report on a 23-year-old male patient with general weakness, subfebrile temperatures, and arthralgia. The first symptoms were observed some months after a severe cytomegalovirus mononucleosis-gastroenteritis. High titers of cryoglobulins suggested an autoimmunological process. This case is interesting because of the association between cytomegalovirus infection and cryoglobulinemia. In conclusion, the differential diagnosis of autoimmune disease should be considered in the course of viral infections.

Adult↗