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Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.

To evaluate whether MRI is usefull in staging renal cell carcinomas with caval thrombus the accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) in staging renal tumors with caval thrombus were preoperatively examined. Tumor staging by CT and MR imaging were correlated with histopathological tumor stadium. In MRI 4 out of 7 thrombi were correctly diagnosed with high accuracy, in CT none. In advanced renal carcinoma MRI with Gadolinium was superior to CT imaging, especially in diagnosing tumor thrombus. Consequently the extent of tumor thrombus may be assessed by MRI which therefore may replace conventional cavography.

Hyperacute graft rejection triggered by the activation of the recipient's complement system represents the major obstacle to successful xenotransplantation. After the binding of preformed antibodies to vascular glycoproteins complement-induced activation and injury of endothelial cells with subsequent thrombosis leads to rapid destruction of foreign tissues. Inhibition of complement activation is therefore considered as a prerequisite for xenograft survival. Recent animal and cell culture experiments suggest that support of the physiological regulation of the complement system appears to be most promising. Besides the application of soluble complement inhibitors (e.g. soluble complement receptor 1, sCR1; C1 inhibitor) the genetic transfer of human membrane-bound complement regulatory proteins (e.g. DAF, CD59) offers new chances to protect the xenograft against the cytolytic complement attack. Results from the authors' experiments shall be included in a short overview to the issue.

To evaluate the accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) in staging renal carcinoma.33 renal carcinomas were preoperatively examined for tumour staging by CT and MR imaging and correlated with histopathological staging. CT imaging was performed at first as a non-contrast scan. Finally incremental images (10 mm) after intravenous contrast injection were obtained. In MR imaging we performed a transversal T1-weighted GE sequence (112/5) with and without GDTPA, a transversal fat-suppressed double-echo sequence (3900/22/90), a coronal T1-weighted GE sequence with and without GDTPA and a coronal T2-weighted TSE sequence (2800/128). In addition, dynamic T1-weighted GE imaging after GDTPA injection as well as TOF angiography in coronal direction were performed. Finally CT and MRI findings were correlated with surgical and histopathological staging results.CT and MRI staging was correct in 27 and 28 of 33 tumours. Sensitivity and specificity for tumour stage T3b to T4 was for MRI and CT 88.9% and 95.8%. With MRI 4 out of 7 thrombi were correctly diagnosed with high accuracy, but via CT none.In early stage renal carcinoma CT and MR imaging yielded similar staging accuracies. In advanced renal carcinoma MRI was superior to CT imaging, especially in diagnosing tumour thrombus. Consequently the extent of tumour thrombus may be assessed by MRI which may therefore replace conventional cavography.

Brain metastases develop as a late manifestation of renal cell cancer (RCC) and pose an increasing challenge to urologists as a result of the more frequent prolonged survival of patients with advanced RCC. Therapeutic options, including surgical resection and radiotherapy, were analyzed retrospectively to assess survival and to identify factors influencing prognosis in a group of 90 patients treated either by brain metastasectomy (n = 64) or radiotherapy (n = 26). The analysis confirmed that the overall median survival was a disappointing 461 days and the 1-year survival rate was 31% for patients treated by surgical resection and 310 days and 15% respectively for patients treated by radiotherapy. However, a subgroup of patients who, benefitted significantly from aggressive treatment of metastases could be defined. The following favorable prognostic factors showed a trend toward improved survival: (1) metachronous appearance of brain metastases more than 1 year after nephrectomy (P0.0001), (2) good patient performance (Karnofsky70) (P0.0002), (3) patient's age under 50 years (P0.05), (4) solitary lesions (P0.05), (5) minimal or no neurological deficit (P0.05), and (6) the absence of/or minimal extracranial metastases (P0.05). No influence of lesion size and localization (infratentorial vs supratentorial) on survival was detected. Surgical treatment of recurrent brain tumors (n = 17) yielded and additional median survival advantage of 8 months as compared to untreated patients (n = 16). Our results suggest that, especially in patients with good prognostic criteria, a radical metastasectomy plus vigorous surgery of local recurrences and, if required, subsequent systemic immuno- or chemoimmunotherapy should be performed. In patients with poor prognosis, stereotactic radiosurgery is recommended for palliation and survival prolongation.

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.

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.

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.

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.

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.

Besides renal cell carcinomas and angiomyolipomas panarteritis nodosa (PAN) is a common underlying disorder for spontaneous perirenal hematomas (SPH). Herein we report on 3 cases with PAN associated kidney ruptures where diagnosis of PAN was not known before in 2 instances. The hematoma was identified by computerized tomography (CT) in all patients, nevertheless CT failed to reveal the underlying disorder in any case. In this situation angiography was extremely valuable visualizing multiple renal microaneurysms that are typical for PAN. Operative exploration and drainage of the hematoma was necessary in two patients because of hemodynamic instability. In one patient bleeding could be controlled after an immediate immunosuppressive therapy with prednisone and cyclophosphamide. Due to the high incidence of PAN associated spontaneous perirenal hematomas angiography should be performed in all cases with unclear SPH after CT evaluation. In our opinion an immediate surgical intervention is only indicated in cases with hemodynamic instability. Otherwise a conservative approach including immediate immunosuppression seems justified. Nephrectomy should be avoided whenever possible.

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.

Although the involvement of complement in hyperacute renal allograft rejection is well established, its possible implication in acute reversible and chronic graft rejection remains uncertain. In recent clinical studies with a total of 83 patients undergoing renal transplantation, plasma levels of complement activation products were elevated 4-7 days before clinical diagnosis of graft rejection. Immunohistochemical analysis of biopsies revealed local complement activation with glomerular deposition of the terminal C5b-9 complex within 1 h after organ reperfusion. Increasing levels of complement activation products, preceding the clinical manifestation of renal graft rejections may be of diagnostic value in recognizing patients at risk.

Renal transplantation has become an established form of therapy for children with endstage renal disease. Evaluation and elimination of potential risk factors, standardization of operative technique and better immunosuppressive regimens improved the outcome in paediatric patients. A shortage or organs means that transplantations cannot always be offered to children for whom it would be the treatment of choice. Kidney donation by living relatives opens up the potential for optimal rehabilitation of patients in the paediatric age group.

New approaches to successful prevention and management of transplant rejection include the use of biological immunosuppressants, such as monoclonal antibodies targeting the CD3 and CD4 molecules on native T cells, the interleukin 2 receptor on activated T cells, monocytes and B cells, and adhesion molecules. Several new drugs have been found to be effective immunosuppressive agents: FK 506, a macrolid antibiotic inhibiting lymphokine gene transcription, lymphokine production and secretion, rapamycin, which blocks effects of lymphokine-induced signal transduction, and RS 61443, brequinar and mizoribine, which inhibit DNA/RNA synthesis and lymphocyte proliferation. Initial experience with these drugs clinical protocols currently in use and already devised for use in the near future to test these and other emerging immunosuppressants are reviewed.

In 45 patients with a vena cava tumor thrombus secondary to renal cell carcinoma we present the diagnostic and operative management and relevant data on the extent of the thrombus (classified into 4 stages), postoperative complications and patient survival. Extensive thrombi of the vena cava were removed surgically in hypothermia and with extracorporeal circulation. The importance of an interdisciplinary approach involving cardiac and urologic surgeons is therefore emphasized. With due consideration for relevant prognostic parameters such as tumor differentiation or spread, we estimated a 5-year survival of 29% for our Heidelberg patients. Neither the extent of the tumor thrombus nor tumor infiltration of the perirenal adipose tissue had any influence on patient survival.

As an adjunct to the monitoring of intracellular high-energy phosphorus metabolites by 31P NMR1 for assessment of renal viability, a study of vasculature of preserved kidneys was performed by Image-Guided Volume Selective 19F MR Spectroscopy. 1H and 19F of the same preserved rat and porcine kidneys were obtained. The technique enabled the analysis of the vessel and tissue properties and opens new possibilities for pretransplant assessment of renal vasculature.

Among 1050 consecutive renal transplants (Rtx) performed in Heidelberg since 1967 we have gained experience with 163 children and adolescents under the age of 16, receiving a Rtx since 1969. 30% of these were terminally renal insufficient due to congenital obstructive uropathy, mainly infravesical obstruction and/or reflux nephropathy. A special diagnostic work-up (flow chart) for evaluating and eliminating potential pre- and posttransplant risk factors consisted of noninvasive screening methods (ultrasonography and uroflow) followed step by step by more invasive imaging procedures (MR, MCU) and finally invasive methods of evaluating upper urinary tract and voiding disorders (complete urodynamic work-up). We emphasize the preservation or rehabilitation of urinary bladder function, eradication of significant UTI and pre-Rtx surgical treatment of otherwise hard to handle nephrogenic hypertension. Unnecessary psychologically and somatically traumatizing pretransplant diagnostic and therapeutic procedures can be avoided in pediatric non-obstructive nephropathy patients.

The interposition of the greater omentum was used for treatment of lymphoceles in combination with peritoneal fenestration and for prevention of urinary fistulas in cases of lower pole renal artery lesions and feared ureteral necrosis as well as for protection of pyeloureterostomics and pyelovesicostomics, secondary to ureteral necrosis postrenal transplantation. Especially the combination of peritoneum fenestration with interposition of the greater omentum proved to be the procedure of choice for treatment of posttransplant lymphoceles. The incidence of lymphoceles following renal transplantation is in the range of 5-15%. Even by meticulous surgical technique--ligature of donor and recipient lymph vessels--they cannot be prevented totally since perioperative anticoagulation plays a significant role. Following unsuccessful repeated punctures for decompression, external drainage, local application of tetracycline or fibrinogen glue, internal marsupialisation to the peritoneal cavity is the established ultimate treatment. Inherent risks and difficulties of this procedure can be reduced, if peritoneal fenestration of the lymphoceles is combined with the interposition of the greater omentum. This technique described in details gave totally satisfactory results in 14 cases.

The prevalence of anti-HCV in patients after kidney transplantation was tested by HCV-Antibody-ELISA (Ortho Diagnostics). In addition, reactive samples were tested by HCV-EIA (Abbott Laboratories), neutralization, anti-HBc (Corzyme, Abbott) and by HBs-Ag (Auszyme, Abbott). 27 of 271 patients (10%) were anti-HCV positive. Receiving more than one kidney graft (TPL) or the transfusion of more than four blood units (BU) increases the risk of HCV infection four times (OR: 4.1; p less than 0.01) or 2.5 times (OR: 2.5; p less than 0.05), respectively, compared with one TPL or less than 4 BU. Receiving more than one kidney graft and transfusion of more than four BU raises the risk of HCV infection 6.8 times. 52% of anti-HCV positive patients were anti-HBc positive, 48% were anti-HBc negative as well as HBs-Ag negative.

The diagnosis and management of 12 patients with spontaneous urinary extravasation due to ureteral calculous obstruction are described. Contrary to the "frank" rupture most cases can be managed without surgical intervention. The presistence of extravasation must be the reason for tumour exclusion. The renal fibrolipomatosis was seen as the possible late result of the extravasation.

The hypertension immediately after open heart surgery for coronary heart disease was chosen to evaluate the suitability of computer-controlled infusion sodium nitroprusside, to improve the circulatory state in heart failure by reducing the impedance to the left ventricular ejection. Sodium nitroprusside produced a prompt reduction of MAP to a preset level and a rise in cardiac index from an average of 2.1 +/- 0.3 to 2.4 +/- 0.4 when infused alone and to 3.1 +/- 0.5 1/min m2 (p less than 0.05, + 48%) after volume was infused to maintain LAP at a constant level to eliminate the effects of preload. The rise in cardiac index was associated with marked decrease in systemic vascular resistance from 2260 +/- 530 to 1415 +/- 280 and 1130 +/- 1130 +/- 270 dyns (p less than 0.005, 63%) respectively. The initial values of SVR correlated well with the fall of SVR (r = 0.78). Our results suggest that systemic vascular resistance is a strong indicator of the vascular responsiveness to vasodilation, the computer-controlled infusion of sodium-nitroprusside being suitable for the "titration" of the high systemic vascular resistance.

Noninvasive investigation of renal metabolic changes is possible with 31P-MR, which is characterized by the determination of amounts of "free" phosphorus metabolites and intracellular pH and the possibility of measuring enzyme kinetics by the 31P-MR magnetization transfer method. 31P-MR has been extensively used to monitor such alterations in response to kidney ischemia, in which the ratios of anorganic phosphate to ATP and phosphomonoesters change drastically. The stages of ultrastructural ischemic renal damage can already be accurately classified with reference to a scale of 31P-MR-spectrum-derived renal function predictors. The recent application of MR high-resolution imaging may allow further improvement of organ viability assessment. The clinical use of combined MR imaging and spectroscopy is an essential and imminent step.

Our experience with the urinary diversion especially the end cutaneous ureterostomy with or without contralateral nephrectomy as the last resort option to control the otherwise intractable life threatening bladder post-irrediation hemorrhage is the subject of this study. Among our patients who have undergone various forms of conservative treatment for severe hemorrhagic cystitis following radiotherapy, 17 had to be treated surgically. Of the 17 who underwent urinary diversion 15 responded favourably and 12 were completely free of bleeding. 3 experienced temporary symptomatic relief. It was the underlying disease however, that determined finally the fate of these patients.