Psychological conflicts between relatives during the long-term course after successful living organ donation.

The German transplantation law prefers living organ donation between close relatives and spouses, which is assumed to guarantee unequivocal altruistic motivation. Since 2001, 68 recipient-donor-pairs, who aspired to have a renal or liver transplantation, underwent a systematic psychosomatic evaluation. Meanwhile, 43 transplantations were performed including 34 renal and 9 liver cases. Seventeen recipient-donor-pairs were readministered evaluations by the department of psychosomatic medicine after 1 to 6 years after transplantation for long-term follow-up. In 10 cases of medically successful transplantation, we identified severe conflicts between donor, recipient, and next-of-kin. Major conflicts are presented by case vignettes regarding deterioration of a previously conflicted marriage, noncompliance of the recipient due to a marital stalemate, and family conflict revolving around refusal to donate. Based on these findings, concise assessments of donor-recipient-pairs are recommended regardless of family relationships. Particular attention must be paid to signs of conflict both before and after transplantation.

[Fabry's disease, glomerulonephritis with crescentic and granulomatous interstitial nephritis. Case of one family]. / Morbus Fabry, Glomerulonephritis mit Halbmondbildung und granulomatöse interstitielle NephritisBericht über eine Familie.

A 26-year-old female patient was admitted to the hospital because of fever of unknown origin and renal failure. Diagnosis of Fabry's disease, extracapillary proliferative (crescentic) glomerulonephritis and granulomatous interstitial nephritis was made by histological, immunohistochemical and electron microscopical diagnosis in a kidney biopsy and confirmed by further investigations. Years ago the brother of the patient had a kidney biopsy diagnosed as metabolic disease. The re-evaluation of this biopsy confirmed Fabry's disease while in this patient an association with tubulointerstitial nephritis occurred. To our knowledge this is the first family with two members having Fabry's disease combined with further kidney diseases.

[Mitomycin-induced hemolytic-uremic syndrome]. / Mitomycininduziertes hämolytisch-urämisches Syndrom.

HISTORY AND CLINICAL FINDINGS: A 58-year-old patient suffered from rapidly progressing renal insufficiency and 11 kg weight-loss three months after adjuvant treatment of a carcinoma of the lower bowel (G 2 T 3 N 1 M 0 ) with mitomycine C. At the point of hospitalisation the patient was anuric while suffering from pulmonary oedema, hemolytic anemia and thrombocytopenia. INVESTIGATIONS: Computed tomography and bronchial endoscopy showed pulmonary haemorrhage. Recurrence of carcinoma or metastases were excluded. Renal biopsy revealed mesangiolysis and concentric intimaproliferation (onion skinning). Beside haemolytic anaemia and fragmentocytes toxic damage of the bone marrow was found. TREATMENT AND COURSE: After one week treatment in the intensive care unit because of respiratory insufficiency recovery was observed under plasma separation and high dose corticosteroid therapy. Disease activity involved renal failure, bone marrow insufficiency, microangiopathic anaemia thrombopenia and pulmonary haemorrhage. CONCLUSION: Lung involvement in the course of haemolytic uremic syndrome is rare and carries a high lethality. The case illustrates the need of detailed diagnostic for correct treatment of haemolytic uremic syndrome. If chemotherapy is required in patients with pre-existing or intercurrent renal failure dose adaptation is necessary to avoid dose-dependent toxicity of mitomycine C.

Fibroblasts enhance the invasive capacity of melanoma cells in vitro.

In previous experiments we have shown an enhanced expression of matrix metalloproteinase-1 (MMP-1) in fibroblasts obtained from the border of invasive melanoma in comparison to fibroblasts more distant from the tumour. In the study reported here we sought to determine whether melanoma-derived soluble factors are responsible for the stimulation of MMP-1 expression in fibroblasts. By real-time PCR and enzyme-linked immunosorbent assays, we demonstrated that the stimulation of fibroblasts with melanoma cell conditioned medium led to an increased expression of MMP-1 mRNA as well as MMP-1 protein, whereas melanoma cells themselves did not produce detectable amounts of MMP-1 protein. Basic fibroblast growth factor (bFGF) was detected as an important factor responsible for the enhanced expression of MMP-1 by fibroblasts after stimulation with melanoma cell conditioned medium. In a three-dimensional in vitro invasion assay, we demonstrated that fibroblasts are essential for melanoma cell invasion into a collagen I matrix. These findings support the hypothesis that stromal fibroblasts assist the invasion of melanoma cells through the extracellular matrix by producing elevated amounts of proteolytic enzymes after interaction with soluble factors (e.g. bFGF).

The pharmacokinetics of cerivastatin in patients on chronic hemodialysis.

OBJECTIVE: The single-dose and steady-state pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin and its two major metabolites, M-1 and M-23, were evaluated in patients with renal failure on chronic hemodialysis. METHODS: After having given their informed consent, 12 end-stage renal disease patients (5 female/7 male; 18 to 63 years) received a single-dose of 0.2 mg cerivastatin sodium followed by a 4-hour dialysis session for pharmacokinetic profiling. Two to four weeks later, all patients received 0.2 mg once-daily as maintenance treatment for a period of 7 days during which PK profiling was carried out on Days 1 and 7/8, both being dialysis-free days. Plasma concentrations of parent drug and active metabolites were measured by HPLC with fluorescence detection. In addition, assessment of lipid parameters, safety and tolerability, and a complete clinical chemistry program were included in the study procedures. RESULTS: Cerivastatin was well-tolerated and no serious adverse events were observed. In spite of the short treatment period, treatment responses with respect to total cholesterol, LDL cholesterol and triglycerides lowering were observed. Mean cerivastatin and metabolite concentrations and thus systemic exposure were slightly higher (up to 50%) in patients on chronic dialysis compared to previous studies carried out in healthy subjects. The unbound fraction of cerivastatin ranged from 0.6 - 1.5% in these patients (normal range: 0.5 - 0.9%). The half-lives of both parent drug (approximately 3 h) and metabolites remained unaffected and, most notably, no accumulation occurred under repeated dosing. In addition, cerivastatin clearance was not increased by concurrent dialysis as would be predicted from the high plasma protein-binding (> 99%), and there were no significant differences in cerivastatin exposure between the dialysis period and the dialysis-free profile days. CONCLUSION: Cerivastatin can be safely administered in the usual dosages to patients with end-stage renal disease on chronic hemodialysis. Based on the observed moderate increase in cerivastatin mean exposure, patients should be started at the lower end of the recommended dosing range and subsequent titration should be performed with caution.

Proteinase-3 mRNA expressed by glomerular epithelial cells correlates with crescent formation in Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG) is characterized by systemic vasculitis with crescentic glomerulonephritis (CGN) and circulating autoantibodies directed against neutrophil cytoplasmic antigens (ANCA). Proteinase 3 (PR-3), a neutral serine proteinase in neutrophils implicated in the growth control of myeloid cells, has been identified as the target antigen for ANCA in WG. Since the kidneys are frequently involved in WG, we studied the in situ expression of PR-3 by renal parenchymal cells. METHODS: We assessed the expression of PR-3 in kidney biopsies of 15 patients with WG by immunohistochemistry (IHC) and in situ hybridization (ISH). Normal kidney tissue served as the control. RESULTS: We detected PR-3 mRNA and PR-3 protein in distal tubular epithelial cells (TECs) and glomerular epithelial cells (GECs) in normal kidney tissue and in CGN. Furthermore, a strong glomerular PR-3mRNA expression restricted to the site of cellular crescents was detected in patients with WG. The analysis of 144 glomeruli with cellular or sclerotic crescents revealed a positive correlation of glomerular PR-3mRNA expression with the percentage of cellular crescents per glomerulus. The capability of human TECs and GECs to synthesize PR-3 was confirmed by Northern blot and ISH on cultured cells. CONCLUSION: These data provide evidence that nonhematopoetic renal parenchymal cells express PR-3 and that glomerular expression of PR-3 is associated with crescent formation in WG. Our findings suggest that renal parenchymal cells may directly be involved in the pathogenesis of CGN in WG.

Reduced secretion of proinflammatory cytokines of monosodium urate crystal-stimulated monocytes in chronic renal failure: an explanation for infrequent gout episodes in chronic renal failure patients?

BACKGROUND: In gouty arthritis, monosodium urate (MSU) crystals interact with monocytes and neutrophils to produce inflammatory reactions associated with acute synovitis. In patients with end-stage renal disease (ESRD), gouty arthritis is a rare condition despite often severe hyperuricaemia. We wondered whether differences in the secretion of proinflammatory cytokines by MSU crystal-stimulated monocytes might be one explanation for the low incidence of gouty arthritis in patients with ESRD compared with healthy controls. METHODS: Thirteen patients with ESRD on intermittent haemodialysis treatment, six patients with chronic renal failure not yet on dialysis, and 15 age- and sex-matched healthy controls were examined. Monocytes, purified from peripheral blood mononuclear cells (PBMC) by immunomagnetic bead separation, were incubated for 18 h in the presence of MSU crystals, Escherichia coli lipopolysaccharide (LPS) or medium alone. The supernatants were studied for the presence of interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) using cytokine-specific enzyme-linked immunosorbent assays. RESULTS: Monocytes from patients with ESRD produced significantly lower amounts of IL-1beta, IL-6 and TNF-alpha after stimulation with MSU crystals or LPS than did monocytes from healthy subjects. Cytokine production was not significantly different between ESRD patients on haemodialysis and chronic renal failure patients not yet on dialysis. Artificial MSU crystals were stronger stimuli than tophus-derived 'natural' MSU crystals. CONCLUSION: We demonstrate that monocyte-associated immunosuppression in ESRD leads to reduced secretion of proinflammatory cytokines in response to stimuli such as MSU crystals. This may be one of the factors preventing many ESRD patients from the manifestation of acute gout despite often severe hyperuricaemia.

Fibroblasts surrounding melanoma express elevated levels of matrix metalloproteinase-1 (MMP-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro.

Tumour growth and metastasis involve the degradation of extracellular matrix components by matrix degrading enzymes produced by tumour cells and stromal fibroblasts. In this study, fibroblasts were obtained from biopsies on the border (TB) and 1 cm distant from the melanoma (TD) and cultured separately. Similar studies were performed with fibroblasts surrounding melanocytic nevi as control. The expression of matrix metalloproteinase-1 (MMP-1) mRNA and tissue matrix metalloproteinase inhibitor 1 (TIMP-1) were studied by Northern blot analysis. The activation antigen intercellular adhesion molecule-1 (ICAM-1) in TB-and TD-fibroblasts was investigated by flow cytometry. In melanoma, TB-fibroblasts showed an increased expression of MMP-1 mRNA mainly in fibroblasts obtained from tumours with extended invasive growth demonstrated by Clark level whereas the expression of the major specific inhibitor TIMP-1 was unaltered. In contrast, fibroblasts surrounding benign melanocytic nevi did not express elevated levels of MMP-1. The upregulation of MMP-1 in TB-fibroblasts compared to TD-fibroblasts was maintained during cultivation. Furthermore, MMP-1 mRNA expression and MMP-1 total protein amount in normal fibroblasts were increased by melanoma cell conditioned medium. We demonstrated an increased expression of ICAM-1 in TB-fibroblasts compared to TD-fibroblasts in vitro depending on the amount of inflammatory infiltrate in situ. The differences of ICAM expression disappeared during continued cell culture. These results support the idea that fibroblasts surrounding melanoma are activated and are possibly involved in the degradation of matrix proteins surrounding the tumour.

The use of computer-assisted video image analysis for the quantification of CD8+ T lymphocytes producing tumor necrosis factor alpha spots in response to peptide antigens.

Enzyme-linked immunospot (ELISPOT) analysis is a sensitive technique for the detection and quantification of single T lymphocytes forming cytokine spots after antigen contact in vitro. Herein computer-assisted video image analysis (CVIA) was applied to automatically determine the number and size of tumor necrosis factor alpha (TNF-alpha) spots formed by single blood-derived CD8+ T cells after contact with peptide-loaded target cells. With CVIA and TNF-alpha ELISPOT analysis we quantified CD8+ T cells responsive to HLA-A2.1-binding tyrosinase and influenza matrix peptides in healthy donors. We followed the course of the virus-specific T cell response in two HLA-A2-positive patients with reactivation of latent cytomegalovirus (CMV) infection during immunosuppressive therapy. The test proved sufficiently sensitive to detect in the blood of both patients a temporary expansion of CD8+ T lymphocytes reactive with a known immunogenic HLA-A2.1-binding peptide from glycoprotein B of CMV. Reactivity to peptide antigens was not only reflected by numeric increases of spot formation, but also by the appearance of larger spot areas, presumably formed by strongly peptide-reactive CD8+ T cells. We conclude that the combined use of the TNF-alpha ELISPOT assay and CVIA allows reliable monitoring of the T cell responsiveness to peptide antigens in peripheral blood.

[Prospective observational study of surgical therapy of renal hyperparathyroidism]. / Prospektive Beobachtungsstudie zur operativen Therapie des renalen Hyperparathyreoidismus.

A prospective long-term follow-up study in patients who had had surgical therapy for renal hyperparathyroidism was launched to investigate the results of surgical treatment and to evaluate possible correlations between preoperative laboratory values and the course of symptoms. From August 1987 to December 1995, 79 patients underwent surgery for renal hyperparathyroidism. It was the first neck exploration for 72 patients. Total parathyroidectomy with autotransplantation to a forearm was our preferred procedure (n = 67). The postoperative course of all patients is know. We carried out one to nine reexaminations (median 4) in 74 of 79 patients. The follow-up period ranged from 1 month to 5 years with a median of 18 months. After the operation transient hypocalcaemia occurred in 84.4% of patients. Postoperative hypocalcaemia correlated negatively with the preoperative levels of alkaline phosphatase and intact parathyroid hormone. Within the first month after surgery 60% of the preoperatively affected patients completely recovered from pruritus, whereas the skeletal syndrome took longer to disappear. One year after surgery 75% of the patients with pruritus and 79% of those with skeletal syndrome had became asymptomatic. After total parathyroidectomy with autotransplantation, patients with preoperatively elevated concentrations of alkaline phosphatase (> 200 U/I) experienced faster relief from joint pain than patients with preoperatively normal concentrations (P = 0.0297). To date 4.5% of the patients developed recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation. Morbidity of surgery for renal hyperparathyroidism is influenced by patients' risk factors. Postoperative hypocalcaemia correlates negatively with the grade of renal osteopathy at the time of operation. Preoperative concentrations of alkaline phosphatase influence the rapidity of the relief from joint pain.

[Surgical management of dysfunctions of dialysis fistulas]. / Operatives Management bei Funktionsstörungen von Dialysefisteln.

Due to the superficial position of shunt vessels we do not use complicated equipment or diagnostic procedures in the morphological assessment of shunt insufficiency or shunt occlusion. Preoperatively, we merely conduct a clinical examination including inspection, pulse, palpation of the shunt veins and arteries with and without venous congestion, and shunt auscultation. Subsequently, we reoperate the shunt under local anesthesia, at which time the anastomosis is usually checked and repositioned. From January 1995 to May 1996, 539 shunt operations were performed in 371 patients, whereby 263 of these were reoperations. The reoperations were performed due to shunt occlusion (n = 144), shunt stenoses (n = 60), shunt aneurysms (n = 17), steal syndrome (n = 3), and rare complications such as hematoma, shunt infection, seroma, and other disturbances (n = 6) (32 patients were treated in other clinics after reoperation or the functional disturbance of the shunt was not recorded). Angiography was only conducted if the clinical examination did not provide enough information about the shunt problems, and so, preoperatively, only six angiographic examinations were conducted (stenosis, n = 3; aneurysm, n = 1; steal syndrome, n = 2). All reoperations, with only few exceptions (PTFE shunt), were conducted under local anesthesia. At reoperation, 184 new proximal shunts were made, 14 thrombectomies conducted, seven PTFE fistulas made, 13 shunts positioned on the opposite side, five shunts ligated, and eight various other operations performed (32 patients were given further treatment elsewhere or no treatment records were available). If during reoperation flow disturbances were suspected (arterial stenosis) or the blood was flowing towards center (proximal venous stenosis) angiography was performed intraoperatively to assess the condition of the vessels. The 4% rate of early occlusion using this procedure was very low. Only 21 patients had to have more than two reoperations. After 2 years 65% of the reoperated AV fistulas were still functional. Without further diagnostic procedures, we performed immediate, outpatient reoperation under local anesthesia, preferably positioning new proximal shunts so that dialysis could be conducted immediately using the existing dialysis shunt. Only if there were particularly complex functional shunt disturbances (steal syndrome, proximal venous flow disturbance, or arterial stenosis) did we employ other diagnostic procedures (angiography, DSA). With this approach the functional shunt disturbances could be eliminated quickly and effectively, which also minimized the cost and stress for the patient.