[Salvage therapy with anti-IL-2 receptor antibodies in high-risk kidney transplant patients].
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Adult↗
Biomedical subjects
G Staehler
Publications and source records attributed to G Staehler.
Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection.
In a prospective study of 80 patients, we investigated the association of acute kidney graft rejection with pretransplant T helper/suppressor activity, B-cell responses, and in vitro cytokine secretion. Patients' CD4+ or CD8+ T cells were cocultured with control B cells and pokeweed mitogen for 6 days. SAC I was used for T cell- and monocyte-independent B-cell stimulation and pokeweed mitogen was used for T cell-dependent B-cell stimulation. B-cell differentiation was assessed in a reverse hemolytic plaque assay. Cytokine responses of T cells (interleukin [IL]-2, IL-10, gamma-interferon) and B cells/monocytes (IL-6, IL-8, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor) were determined in culture supernatants using ELISA. Subsets of CD4+ T cells, CD8+ T cells, and B cells were assessed by flow cytometry. None of 12 patients with pretransplant CD4 helper defects (CD4 helper activity < 10%) had acute rejection episodes, in contrast to 32 of 68 (47%) patients with normal pretransplant CD4 helper function (P = 0.001). Patients with pretransplant CD4 helper defects also had better 1-year graft function than patients without CD4 helper defects (serum creatinine 1.2 +/- 0.1 mg/dl and 1.7 +/- 0.1 mg/dl, respectively, P < 0.05). Pretransplant IL-10 responses were significantly associated with the occurrence of acute rejection episodes (P = 0.001) and impaired 1-year graft function (P < 0.001). All 14 patients with low pretransplant IL-10 responses (< 100 pg/ml) had 1-year serum creatinine values of < 1.5 mg/dl. Pretransplant B-cell defects and B cell/monocyte-derived cytokine secretion were not related to the incidence of graft rejection or infectious complications. Pretransplant CD8 suppressor-effector (CD11b+), cell counts were significantly associated with the occurrence of infections (P < 0.05). These results show that pretransplant CD4 helper defects and low IL-10 responses predict a low risk of graft rejection, whereas Th1 (IL-2, gamma-interferon) and B-cell/monocyte responses are not of predictive value.
Acute Disease↗
Protective effect of autoantibodies against the hinge region of human IgG in kidney graft recipients.
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Amino Acid Sequence↗
Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas.
To define the possible role of the VHL gene in the development of sporadic renal cell carcinomas, 91 different parenchymal tumours of the kidney have been investigated for mutation of the VHL gene by single strand conformation polymorphism (SSCP) and/or heteroduplex (HD) techniques. Chromosome 3p deletion was detected in 98 per cent of non-papillary renal cell carcinomas and in 25 per cent of chromophobe renal cell carcinomas. In 22 of the 43 non-papillary renal cell carcinomas, abnormally migrating DNA bands were detected by SSCP and/or HD analysis. No mobility shift was seen in any of the 23 chromophobe renal cell carcinomas. In addition, 15 papillary renal cell tumours and ten renal oncocytomas, which are characterized by genetic changes other than loss of chromosome 3p sequences, were analysed for mutation of the VHL gene. None of these tumours showed abnormal migration patterns. The results indicate that mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinoma.
Base Sequence↗
[Effect of complement modulation with the soluble complement receptor sCR1 on survival and function of kidney xenotransplant. An experimental study with a new guinea pig to rate transplant model].
In this study a modified experimental kidney xenograft model was developed, which reproduced, in a reliable way, the course of hyperacute rejection. In this model guinea-pig kidneys were transplanted to rats using end-to-side anastomoses with recipient aorta and vena cava, respectively, and ureter drainage for diuresis monitoring. The aim of this study was to investigate the protective effects of complement modulation by soluble complement receptor 1 (sCR1) on the xenografts. Twenty-four xenotransplantations were performed and recipients randomized for treatment either by 3 ml saline or 50 mg/kg sCR1 as a 3-ml bolus. It was found that sCR1 was highly efficient in delaying hyperacute rejection from 10.5 +/- 2.1 min in the control group to at least 2 h in the therapy group and in prolongation of graft function. The complement activity was significantly reduced in the sCR1-treated rats, even at the time of rejection, as a result of complement modulation in this group of xenograft recipients. Xenografts from saline-treated animals showed necroses, interstitial haemorrhages and platelet aggregates occluding the vessels as soon as 10 min after the reperfusion started. No such changes could be seen even after 120 min in the xenografted kidneys of sCR1-treated rats. Also C3 deposits in the glomeruli and interstitium were markedly reduced.
Animals↗
Absorption of vitamin B12 administered to continent ileal reservoirs for urinary diversion.
Urinary diversion through intestinal segments is a widely used method after radical cystectomy. During the last few years, new methods of bladder substitution, continent ileal neobladders, were developed. We used the method described by Hautmann et al. in 1986. 70 cm of ileum is used to form a reservoir. The ureters are implanted into the reservoir, which is then anastomosed to the urethral stump. A known problem when intestine is used for urinary diversion is the absorption of urinary solutes leading to metabolic disturbances. Therefore, the absorption of vitamin B12, instilled into the neobladders of 20 patients, was measured and related to the postoperative interval. The results show a high absorption rate 2 weeks postoperatively that is reduced quickly and significantly (p < 0.001) within the first 10 months (from more than 30 to below 5%). One year to 23 months after the operation, some neobladders absorbed no vitamin B12 at all, whereas others still absorbed significantly but only small quantities. These results may probably be attributed to the loss of villous structure as well as atrophy of the epithelial surface.
Absorption↗
Aetiology, diagnosis and management of spontaneous perirenal haematomas.
This study focuses on the diagnostic and therapeutic challenge posed by spontaneous perirenal haematomas (SPHs). The medical records of 18 patients with SPHs seen in the past 8 years were reviewed with respect to aetiology, diagnosis and therapeutic management. SPH was secondary to angiomyolipoma (n = 4), polycystic kidneys (n =4), panarteritis nodosa (n = 3), renal cell carcinomas (RCCs, n = 2), glomerulonephritis, pyelonephritis, Morbus Wegener and cortical adenoma (one each). One case remained unclear. With appropriate imaging techniques (computed tomography and angiography) the underlying disorder was detected in 72%; in 4 cases the diagnosis was revealed by exploration and biopsy. Surgery was necessary in 16 patients. The cause of bleeding can be revealed by appropriate imaging in most cases. When imaging procedures fail to reveal the cause of SPH, exploration and biopsy are mandatory to exclude RCC. If the cause of SPH remains unclear even after exploration, patient monitoring by CT is justified.
Adenoma↗
[Effect of HLA compatibility on the transplanted kidney in relation to recipient age].
Donor-recipient histocompatibility, as evaluated by the HLA matching results, plays an important role in the outcome of renal transplants, although much controversy surrounds the benefit of kidney allocation based on HLA typing. In this report HLA matching and survival data on 1,342 transplants performed at the University of California at San Francisco between 1984 and 1992 and treated uniformly by quadruple immunosuppression were analyzed in relation to the recipient's age. With respect to the influence of the increasing number of mismatches from 0 to 6, the analysis revealed decreasing 3-year graft survival rates as follows: 85.4%; 87.3%; 71.3%; 78.2%; 75.8%; 70.9% and 67.5%. Whereas the impact of cold ischemia time and histocompatibility was equally important during the 3-year postoperative period, the essential positive influence of good HLA matching on the long-term graft survival was demonstrated. The children aged between 5 and 18 years were identified as a high-risk group by the analysis, HLA-A incompatibility being attributed to poor graft survival in this age group. With respect to the effect of HLA-A histoincompatibility, the data provide evidence that HLA-A matching results seem to play an important role in graft survival in children, whereas transplants well matched in terms of HLA-B did well in adult recipients. No age difference in the impact of HLA-DR could be detected. In conclusion, HLA matching is still essential. It seems that there are differences in the impact of HLA loci in relation to the recipient's age.
Adolescent↗
[Traditional and future criteria for progression in renal cell carcinoma. Molecular biology and clinical aspects].
In addition to the commonly used pathologic staging systems such as the TNM classification, the grading and demographic features have been reported to affect survival following surgical extirpation of renal cell carcinoma (RCC). These features, especially the pathologic stage, are well established as prognostic factors. However, several cellular and molecular variables, although potentially important in the ultimate outcome, are not taken into consideration by these criteria. Thus patients with different prognoses may be classified as belonging to the same stages. Attempts are now made to use cytogenetic and molecular findings to predict long-term survival of RCC patients. Chromosome 16 q and 14 q aberrations may play an important role in the future by identifying the high-risk groups of patients with papillary and nonpapillary RCC, resp. In nonpapillary RCC, mutations of the von Hippel-Lindau gene have been implicated as the initial step of carcinogenesis. However, the subsequent steps remain to be elucidated and the search for genetic markers associated with tumor progression is under way. The distinction between patients with high and low risk of progression will become increasingly important as more effective adjuvant therapies are available.
Carcinoma, Renal Cell↗
[Improved organ survival in transplantation of pediatric kidneys by optimizing donor-recipient size relation].
The risk for renal allograft failure in pediatric renal transplantation (donor age below 3 years) is still high, although it has been reduced by the use of potent immunosuppressive therapies. In this study we report on experience with 80 kidneys of donors below 3 years of age (PD) transplanted at the University of California at San Francisco Hospital in accordance with the policy of minimizing donor-recipient size differences. The graft survival rates were comparable with the results for adult donors, 18-50 years of age (AD, n = 891): at 1 year PD 74.1% vs AD 85.5%, at 2 years PD 70.5% vs AD 80.2%, at 3 years PD 63.5% vs AD 76%; there were no significant differences. The policy of minimizing donor-recipient size differences seems to improve graft survival rates, avoiding the tendency for hyperfiltration phenomena and possibly being responsible for this salutary effect. We conclude that the use of pediatric donor kidneys can yield excellent long-term results independent of primary disease if the donor-recipient size difference is minimized and a potent immunosuppressive regimen is employed.
Adolescent↗
[Repetitive immuno-embolization of inoperative liver metastases of renal cell carcinoma. Method characterization and preliminary results].
Interleukin 2 (IL2)-based immunotherapy is effective in a subgroup of patients with metastatic renal cancer, but cure from liver metastases is very rare and even the selection of patients to be treated is very much limited by the toxicity of IL2. To reduce this toxicity and to augment the efficacy of intrahepatic IL2 application, a protocol of combined rIL2 (3 mg/day) and Lipiodol (2-5 ml/day according to tumour size), via a catheter inserted percutaneously into the hepatic artery, was implemented. As an adverse reaction, moderate fever (WHO) grade I and II was noted. A partial remission was seen in one patient and stable disease in four patients over a period of 2-6 years (median 32.2 month). It seems that immuno-embolisation of otherwise intractable liver metastases of renal cancer is well tolerated and its efficacy may be augmented by optimisation of the therapeutic protocol.
Adult↗
Terminal deletion of chromosome 3p sequences in nonpapillary renal cell carcinomas: a breakpoint cluster between loci D3S1285 and D3S1603.
Deletion of chromosome 3p13-pter sequences is a specific genetic change in nonpapillary renal cell carcinomas (RCC). The VHL gene, a putative tumor suppressor gene, has already been cloned from the 3p25-26 chromosomal region. Conflicting cytogenetic and RFLP studies, however, suggest multiple interstitial deletions and additional tumor suppressor genes at chromosome 3p. To investigate the loss of DNA sequences on chromosome 3p in nonpapillary RCCs, we analyzed 41 paired normal and tumor DNAs obtained from short-term cultures of pure tumor cells with 12 polymorphic microsatellite markers covering the 3p11.2-p25 region. Deletion mapping provided evidence for terminal deletion with the most distal breakpoint between D3S1300 and D3S1285 loci, which is the site of breakpoint in familial 3;8 translocation predisposing to nonpapillary RCC. All breakpoints, including those occurring in familial translocation 3;6, were clustered in a more than 20-cM-large region between loci D3S1285 and D3S1603. Interestingly, 7 of the 28 cases with 3p deletion showed a recurrent breakpoint between D3S1603 and D3S1595, which cover about 1 cM genetic distance. The results suggest that a tumor suppressor gene, in addition to the VHL gene, might be localized somewhere on chromosome 3p distal to the familial 3;8 translocation, or it might be at the breakpoint cluster. Alternatively, the breakpoint serves as a mechanism to lose distal DNA sequences.
Carcinoma, Renal Cell↗
Matrix protein synthesis by glomerular mesangial cells in culture: effects of transforming growth factor beta (TGF beta) and platelet-derived growth factor (PDGF) on fibronectin and collagen type IV mRNA.
The pathogenesis of glomerular scarring is multifactional; recent evidence suggests that transforming growth factor beta (TGF beta), a pleiotropic cicatricial mediator, may promote mesangial sclerosis by enhancing the production of extracellular matrix proteins. We studied the effect of TGF beta 1 and TFG beta 2 on collagen type IV and fibronectin (FN) synthesis in human glomerular mesangial cells in culture (GMC). Two hours after addition of TGF beta, an up to twofold increase in abundance of collagen type IV mRNA was found, which further increased up to fivefold within 24 h. Addition of cycloheximide did not inhibit the TGF beta effect, but caused by itself an up to twofold increase in the abundance of collagen type IV mRNA after 2 h. Together with collagen mRNA, the mRNA for FN and for platelet-derived growth factor (PDGF) was also enhanced. PDGF was found to enhance abundance of the collagen type IV and fibronectin mRNA in GMC. A neutralizing antibody to PDGF or a PDGF-antisense oligonucleotide partly inhibited the TGF beta-induced increase of collagen type IV mRNA, suggesting that TGF beta can affect the collagen type IV synthesis not only directly but also indirectly via the synthesis of PDGF.
Base Sequence↗
The influence of thymectomy on germ-cells of the testis in mice.
We performed thymectomy on the immature and mature male mice and made a quantitative assay of various germ cells of the seminiferous epithelium in the testis with Image Analyser System 35 days following thymectomy. The results indicated that as compared with the control group, all germ cells of the spermatogenesis lineage decreased in the immature group and in the mature group after thymectomy. The present study showed that thymus and its hormone stimulated not only the mitotic division, but also the meiotic division of germ cells during spermatogenesis, suggesting that thymus-sexual axis may play an important role in the process of spermatogenesis in the testis.
Animals↗
Laser-induced fluorescence diagnosis and photodynamic therapy of human renal cell carcinoma.
Photodynamic therapy (PDT) has recently attracted much attention, especially among urologists, because it appears to be a selective form of cancer treatment which causes minimal damage to normal surrounding tissues. In this study we made use of a new class of photosensitizers for the laser-induced fluorescence diagnosis (LIFD) and photodynamic therapy of human renal cell carcinoma xenotransplanted into nude mice. The purpose of this study was to evaluate the recently developed photosensitizing drug THOPP-MPEG for its efficacy as photosensitizer for LIFD and PDT of renal cell carcinoma. THOPP-MPEG was injected intraperitoneally (0.5 micrograms/g body weight) into the mice 6-8 days after tumor transplantation. On the 18th day after transplantation, the tumors reached a diameter of 3-4 mm. Seven days after administration of the drug the tumor-bearing kidney was irradiated percutaneously with a total light dose of 2 x 60 J/cm2 and a power density in the irradiated area of less than 150 mW/cm2. A continuous-beam argon-pumped dye laser (656 nm) was used. After excitation with laser light (488-514 nm), the vital tumor clusters and the surrounding tissues invaded with tumor cells showed intense red coloration by laser-induced fluorescence. Subsequent to the light exposure (656 nm), a heavy tumor necrosis of up to 3-5 mm resulted. No THOPP-MPEG phototoxicity in normal surrounding tissue at a dose of up to 100 mg/kg body weight was seen. We believe the future role of PDT in the management of tumors of the kidney to be adjuvant within the concept of conservative kidney-preserving surgery.
Animals↗
Pretransplant IgA-anti-hinge and IgA-anti-Fab autoantibody activity is associated with good kidney graft survival.
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Amino Acid Sequence↗
Transurethral incision of the prostate following renal transplantation.
Urinary retention in male patients after renal transplantation may cause serious complications in terms of graft function and even patient survival. Only few data concerning the management and outcome of these patients are reported in the literature. Therefore, we retrospectively analyzed the outcome of patients who underwent transurethral incision of the prostate immediately after renal transplantation. Between 1990 and 1993, we performed 259 renal transplantations and 15 patients had symptoms of urinary retention postoperatively. These patients underwent a midline transurethral incision of the prostate from the bladder neck to the verumontanum. Median peak flow preoperatively was 7 ml. per second (range 0 to 11.4) and median residual urine volume was 100 ml. (range 30 to 500). Median prostate volume was 28 ml. (range 12 to 45). After transurethral incision of the prostate a significant improvement (p < 0.001) in peak flow rates (19.6 ml. per second, range 8 to 49) as well as a significant decrease in residual urine volumes (40 ml., range 20 to 80) could be achieved. After a median followup of 19 months the effect was still present.
Adult↗
[Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization].
Interleukin 2 (IL2) production is known to bypass T-helper-cell function in the generation of an antitumour response. The present analysis was designed to assess the effects of application of renal cancer vaccine with and without IL2 on delayed-type hypersensitivity (DTH) skin responses to the vaccine itself and tumour cell challenge. The renal cancer vaccine consisted of Newcastle disease virus (NDV)-infected autologous irradiated tumour cells and topical application of low-dose rIL2 (75,000 Cetus units). As a result, the coadministration of a supplement of rIL2 proved to be important for augmentation of DTH responsiveness to tumour cell challenge. Patients with aneuploid tumours vaccinated without rIL2 developed an anergy to the vaccine throughout vaccination. This effect could be reversed by the topical coapplication of this cytokine. While the treatment of renal cancer patients with IL2-based immunotherapy regimens appears to be effective in advanced renal cell carcinoma the IL2-supplemented vaccines should be tested to assess their benefit in the situation of "minimal disease" after surgery especially in high-risk patients with aneuploid tumours.
Aneuploidy↗