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.

Dissection of the internal carotid artery after chiropractic manipulation of the neck.

A 29-year-old woman died from a right hemispheric infarction caused by dissection and subsequent thrombosis of the internal carotid artery after chiropractic manipulations of the neck. Pathologic study of several arteries of muscular and elastic type revealed a mediolytic arteriopathy with widespread mucoid degeneration and cystic transformation of the vessel wall caused by segmental degeneration of smooth muscle cells of the tunica media. We hypothesize that mediolytic arteriopathy was a predisposing factor for the dissection of the internal carotid artery after chiropractic manipulations in our patient.

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.

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).

Laboratory control of minimal heparinization during haemodialysis in patients with a risk of haemorrhage.

For patients undergoing dialysis with a high risk of haemorrhage there is no standardized procedure for anticoagulation during extracorporeal circulation. Minimal heparinization with a dose equivalent to half that used for chronic haemodialysis was employed in 49 patients (125 haemodialyses) performed after operative interventions (83.3%), after haemorrhagic events (5.2%) and after invasive investigations (11.5%). Using a biocompatible membrane and a low molecular weight heparin (bolus dose 500-1300 U; continuous infusion 100-400 U) it was possible to complete haemodialysis in 74 cases (Group 0) without clots appearing in the venous bubble trap of the tubing system. In 30 cases (Group 1) only small clots were detected at the end of haemodialysis, and in 13 cases (Group 2) larger clots (exceeding a diameter of 1 cm) were found. In eight cases (Group 3) partial or complete clot formation occurred in the tubing. No haemorrhagic complications were observed. Anti-Xa activity, thrombin-antithrombin III complex (TAT) and D-dimer were determined before haemodialysis, 2 h after the start of haemodialysis and on completion of the procedure. The anti-Xa activities ranged between < 0.2 and 0.56 U/ml. In contrast, at 2 h there were significant differences (P < 0.05) in the TAT concentrations between Group 0 and the other groups, as well as between Group 1 and Group 2 and 3. Significant differences (P < 0.05) in D-dimer levels occurred only at the end of haemodialysis. Minimal heparinization in haemodialysis is a practicable alternative in patients with a high risk of haemorrhage and extended coagulation monitoring is helpful in adjusting heparin dosage.

Antibodies to cytoskeletal components in patients undergoing long-term hemodialysis detected by a sensitive enzyme-linked immunosorbent assay (ELISA).

To date only a few contradictory reports concerning the incidence of autoantibodies in patients undergoing long-term hemodialysis exist. The aim of the present study was to investigate the sera drawn from 45 patients with chronic renal failure, 39 of them on chronic hemodialysis (duration 1-17 years). Serum samples were tested for 15 autoantibodies, no antinuclear antibodies or antibodies to extractable nuclear antigens could be detected; all sera were also negative for antibodies to dsDNA, mitochondria, gastric parietal cells and smooth muscle. In contrast a high incidence of antibodies to cytoskeletal components could be demonstrated using a sensitive enzyme-linked immunosorbent assay that employed purified antigens. Antibodies of IgG-type (IgM-type shown in brackets) were detected against cytokeratin in 51.3% (15.4%), actin in 17.9% (5.1%), desmin in 28.2% (17.9%), vimentin in 15.4% (5.1%) and tropomyosin in 12.8% (5.1%) of the sera of patients on chronic hemodialysis. No association with diagnosis, duration of hemodialysis, age or interdialytic changes of body weight and antibody titers could be found. In a control group of 82 healthy blood donors no antibodies were detected. Positive correlations of incidence of antibodies to actin, desmin, vimentin and keratin suggests polyclonal activation of immune system in patients with chronic renal failure undergoing long-term hemodialysis. The mechanism is unknown.

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.

[Dialysis-associated amyloid osteopathy--the radiological aspects]. / Dialyseassoziierte Amyloidosteopathie--radiologische Aspekte.

Amongst the complications of dialysis, amyloid osteopathy is getting increasingly significant. It is due to deposition of beta 2-microglobulin. To determine the incidence and time of development of this complication, the skeletal radiographs of 185 patients undergoing dialysis, some for up to ten years, were analysed retrospectively. In about 10% of patients, the presence of beta 2-microglobulin osteopathy may be expected. The radiological features, sites of predilection and differential diagnosis of amyloid osteopathy and of other skeletal changes due to dialysis are discussed.

[Local fibrinolysis in renal artery occlusion]. / Die lokale Fibrinolyse bei Nierenarterienverschlüssen.

The indications and technique of local fibrinolysis therapy of acute renal artery occlusions are discussed in relation to four patients. Because of the short period for which ischaemia is tolerated by the kidney, the result of treatment depends largely on the time interval between occlusion and the beginning of treatment. Partial perfusion of the renal artery was obtained in three patients. Since the "ischaemia time" of the kidneys had been exceeded, it was not possible to obtain complete restitution of renal function in any of these patients.

[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.

[Diagnosis of dysfunctions of replanted parathyroid gland tissue by bilateral analysis of intact parathyroid hormones in cubital vein blood. A prospective study]. / Diagnostik von Dysfunktionen replantierten Nebenschilddrüsengewebes durch seitengetrennte Analyse des intakten Parathormons im Kubitalvenenblut. Eine prospektive Untersuchung.

AIM: In a prospective long-term follow-up study after operative therapy of hyperparathyroidism the value of bilateral determination of parathyroid hormone levels in cubital venous blood after total parathyroidectomy/autologous parathyroid gland reimplantation (musculus brachioradialis) for diagnosis of dysfunctioning grafted tissue is evaluated. PATIENTS AND MATERIAL: From August, 1, 1987 to March, 31, 1994 68 of 243 patients operated on for hyperparathyroidism underwent total parathyroidectomy. Autologous reimplantation of parathyroid gland was carried out simultaneously in 64 patients. Twice delayed reimplantation of cryopreserved tissue was carried out, and there was no reimplantation in two patients up to this day. Three patients were operated on for hyperfunctioning parathyroid autograft after former total parathyroidectomy/reimplantation. RESULTS: During follow-up 5 patients developed dysfunction of (reimplanted) parathyroid gland. Because of low or unprovable levels of intact parathormone the gradients of intact parathyroid hormone between grafted and nongrafted forearm were about 1:1 in postoperative hypoparathyroidism as well as in hypofunction of parathyroid gland. After successful replantation of cryopreserved parathyroid tissue gradients of intact parathyroid hormone increased (> 1:10). In hyperfunction of grafted parathyroid tissue hormone gradients were high (> 1:20 to 1:45,3) because of excessive high levels of intact parathormone in the cubital vein of the graft bearing arm. Successful reduction of parathyroid graft was followed by decrease of parathyroid hormone gradients. CONCLUSION: Regular follow-up of intact parathormone gradients together with intact parathyroid hormone levels and serumcalcium analysis allow the determination of parathyroid graft function. Also differentiation between graft dependent hyperparathyroidism and hyperfunctioning parathyroid tissue in the neck or mediastinum seems to be possible by bilateral determination of intact parathormone. Normal values or a normal range for intact parathyroid hormone gradients can not yet be defined.

[Hypertension in pregnancy--dietary aspects]. / Hypertonie in der Schwangerschaft--Diätetische Aspekte.

Dietary recommendations about prophylaxis and treatment of hypertension in pregnancy are manifold and controversial. Only a few studies of evidence are published till now. Recommendations may be derivable from physiology and pathophysiology of hypertension in pregnancy. A normal protein intake of 70-80 g is to be recommendable, neither protein restriction nor increased protein supply. Protein restriction may be sensible only for blocking a progression of a chronic renal insufficiency. The value of caloric restriction is not secured, but an increasing body fat is not recommendable. Neither restriction nor increased supply of sodium can generally be recommended. The same is valit with respect to liquid supply, which is to be restricted in cases with hyponatriemy and hypoosmolality. Substitution of potassium and magnesium is not necessary, of linoleic acid and water-soluble vitamins not sufficiently verified. The efficacy of calcium substitution on hypertension in pregnancy has to evaluated by further studies.

Acanthocyturia--a characteristic marker for glomerular bleeding.

Erythrocyte morphology by phase contrast microscopic examination (PCM) of the urine is widely employed in distinguishing glomerular from nonglomerular bleeding. The proposed percentages of dysmorphic red cells are significant for glomerular bleeding in the range of 10 to 80% in the literature, because there is no clear cut definition of "dysmorphism." In the present study midstream urine samples of 351 patients with hematuria (greater than 8 erythrocytes/microliters) and of 33 healthy controls were examined. The various dysmorphic red cells were analyzed by PCM according to a detailed hematological classification. Most of the dysmorphic red cells, such as echinocytes, anulocytes, ghost cells, schizocytes, stomatocytes, codocytes and knizocytes, occurred in glomerular or nonglomerular disease as well, and proved to be uncharacteristic for glomerular bleeding. In contrast, a unique red cell deformity, a ringform with vesicle-shaped protrusions (acanthocyte) closely correlated to glomerular disease. In biopsy proven glomerulonephritis acanthocytes comprised 12.4% of all excreted red cells, whereas in nonglomerular diseases or in healthy subjects acanthocytes were seen very rarely (less than 2%) or not at all. Acanthocyturia greater than or equal to 5% (of excreted red cells) was seen in 75 out of 143 patients with proven glomerulonephritis (sensitivity 52%) and in four out of 187 patients with nonglomerular disease (specificity 98%). To improve the diagnostic value of erythrocyte morphology the diagnostic workup should focus on acanthocyturia, which is also indicative in very low erythrocyte counts.

[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 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.

[Minimal heparinization in dialysis patients with increased risk of bleeding]. / Minimalheparinisierung bei Dialysepatienten mit erhöhter Blutungsgefährdung.

In 78 patients (47 men, 31 women; mean age 53 [22-78] years) 174 dialyses were undertaken within one week of a bleeding episode or a diagnostic or therapeutic procedure which may cause bleeding. Minimal anticoagulation with low molecular weight heparin (LMWH) was the aim, using a biocompatible dialyser. During the dialysis coagulation was controlled by global tests (Quick value/international normalized ratio [INR], partial thromboplastin time, thrombin time, antifactor Xa activity), by molecular markers of clotting activity (thrombin-antithrombin III complex [TAT], D-dimers), as well as measurement of elastase (elastase-alpha 1-protein inhibitor complex). The LMWH dosage averaged 932 units as an initial bolus and 234 units/h as a continuous infusion. In the group of chronic dialysis patients (n = 72) this meant (standard heparin units = 2/3 LMWH units) a reduction to 45 +/- 11% from the previously used routine heparin dosage for a 4-hour dialysis. All dialyses were completed without bleeding complications. Considerable clotting formation in the extracorporeal circulation occurred in 11 dialyses (6.3%). TAT, D-dimer and elastase values proved to be suitable for determining individual clotting activity and for reducing anticoagulation to the minimum.

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.

[Diagnosis of restrictive cardiomyopathy in the hypereosinophilia syndrome by 2-dimensional echocardiography]. / Diagnose der restriktiven Kardiomyopathie beim Hypereosinophilen Syndrom durch die zweidimensionale Echokardiographie.

The cardiac manifestation of the hypereosinophilic syndrome was diagnosed by means of echocardiography in a 36-year-old man. The following two-dimensional echocardiographic characteristics indicated a restrictive cardiomyopathy in this patient: Enlargement of the left atrium. Thrombotic obliteration of the left ventricle from the apex up to the subvalvular region. Embedding of the chordae tendineae and papillary muscles by the thrombotic mass. Normal left ventricular ejection fraction. The echocardiographic findings were verified by autopsy.