Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shock.

A quantitative sandwich ELISA for E-selectin in the fluid phase (soluble E-selectin, sEs) has been developed that is sensitive to 100 pg/ml. The assay shows no reactivity with either L- or P-selectins. We have used this to determine the fate of E-selectin after cell-surface expression and to test whether levels measured in vivo may represent the state of endothelial activation. E-selectin was first detectable in supernatants of IL-1-stimulated endothelial cells at 24 h, and increased slowly up until 72 h. However, over this time period the total E-selectin detectable in the system (cells plus supernatants) declined dramatically. 125I-surface-labeled endothelial cells cultured for 24 h show an E-selectin of reduced m.w. in the supernatant, indicating that the molecule is shed from the surface. The shed form also appears to be slightly smaller than the intact membrane form as determined from immunoprecipitation and molecular sieving studies. In addition, the cytoplasmic domain of the molecule found in supernatants of activated endothelial cells and in serum is not intact as determined by loss of reactivity with an antipeptide antibody specific for the cytoplasmic domain. We have examined the sera of 71 normal individuals. Without exception, sEs was found in serum in the range of 0.13 to 2.8 ng/ml, suggesting that even in the absence of overt inflammatory processes E-selectin is being synthesized and released into the bloodstream. In addition, bacteremic patients with hypotension, but not those without, showed markedly elevated sEs values. As determined by cell-binding studies, the blood-derived form of E-selectin is biologically active.

[Acquired polycystic degeneration of the kidneys]. / Erworbene polyzystische Degeneration der Nieren.

Kidneys of patients with advanced renal insufficiency undergo polycystic transformation, described as acquired cystic degeneration (ACD). In 118 chronic dialysis patients clinical data were compared with sonographic findings of their 221 cirrhotic kidneys: 74 (63%) patients showed distinctly discernible renal cysts: 19 patients hat one single cyst, nine patients had two to eight cysts, 46 patients had more than eight cysts. Accordingly 39% of patients had ACD. Cystic transformation was of the same degree on both sides and in a few cases so marked that a formal discrimination to congenital cystic disease seemed impossible. Cystic degeneration was not influenced by patient's age, sex or underlying renal disease, but was dependent on the duration of both, renal disease and dialysis treatment. After eight years 71% of dialysis patients had ACD. In coincidence with cystic transformation the size of the kidneys apparently normalized and Hb-concentration rose from 8 to 10 g/dl. Complications were seen in six patients: two severe retroperitoneal bleedings and four hypernephroma were observed. The etiology of cystic transformation and its possible role as precancerosis are discussed.

Folate nephropathy occurring during cytotoxic chemotherapy with high-dose folinic acid and 5-fluorouracil.

High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

[Rapidly progressing glomerulonephritis. Spontaneous course and differential therapy with special reference to the infection-associated form]. / Rasch progrediente Glomerulonephritis. Spontanverlauf und Differentialtherapie unter besonderer Berücksichtigung der Infektions-assoziierten Form.

Since 1971 we observed 31 patients with histologically proven rapidly progressive (crescentic) glomerulonephritis. At the onset of therapy 16 patients presented with end stage renal failure, the others with impaired renal function. 21 patients received combined immunosuppressive therapy, consisting of prednisone, cyclophosphamide and azathioprine. 8 patients were treated with membrane plasmapheresis, additionally. 10 patients received no specific therapy. After 5 years 13 patients were on hemodialysis, 4 had impaired renal function and 10 patients were dead. Two patients died due to the progression of underlying diseases, the others were lost following infectious diseases. There was no additional positive effect in the group treated with membrane plasma separation compared with patients treated only immunosuppressive. Only in 4 patients without specific therapy normalization of renal function occurred. In these patients RPGN appeared after an infectious disease. We conclude that an infectious disease associated RPGN is an own entity of glomerulonephritis that has a very good prognosis and needs only antibiotic therapy.

Intraperitoneal heparin in peritoneal dialysis and its effect on fibrinopeptide A in plasma and dialysate.

In 6 patients on continuous ambulatory peritoneal dialysis we investigated the inhibition of intraperitoneal fibrin formation by heparin. A continuous addition of 500 U of heparin per liter dialysate was used for 52 h. In plasma no heparin activity could be detected, even 52 h after intraperitoneal administration of heparin. The fibrin formation was determined by fibrinopeptide A, a thrombin-induced split product of fibrinogen. In patients under regular continuous ambulatory peritoneal dialysis we determined the fibrinopeptide A concentrations in plasma. The values were comparable with the fibrinopeptide A concentrations measured in disseminated intravascular coagulopathy. They decreased during intraperitoneal administration of heparin from 63.2 +/- 11.8 to 4.9 +/- 1.7 ng/ml. The fibrinopeptide A concentration in the 4-hour intraperitoneal dialysate (155.8 +/- 15.7 ng/ml) decreased after heparin administration to 8.5 +/- 2.0 ng/ml and was always higher than in plasma. We conclude that 500 U heparin per liter dialysate prevents the intraperitoneal fibrin formation. The low antithrombin III concentration (0.44 +/- 0.13 mg/dl) in protein-poor dialysate seems to be sufficient to inhibit the thrombin activity after acceleration by heparin.

Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: a controlled, multi-center study.

In a randomized study of 26 patients with histologically confirmed rapidly progressive crescentic glomerulonephritis, 12 patients were treated with immunosuppressants alone (corticosteroids, cyclophosphamide and azathioprine) while the other 14 patients received not only the identical immunosuppressive treatment but also plasma exchange therapy for four weeks. No statistically significant difference was found between the two groups. After 8 weeks, 73% and 69% of the patients in each respective group showed recompensation of renal function; serum creatinine fell from initially 7.0 and 6.2 mg/dl mean to 2.7 and 2.3 mg/dl mean, and under continued immunosuppression did not rise in the following months. Thus, in non-autoantibody induced rapidly progressive glomerulonephritis, kidney function could be improved substantially by immunosuppressive therapy, but an advantage of supplementary plasma exchange could not be shown.

Serum levels of free non-protein bound clofibrinic acid after single dosing to patients with impaired renal function of various degrees--a multicenter study.

As a basis for establishing dosing guidelines in order to avoid side effects due to overdosage, the concentrations of total and free non-protein bound clofibrinic acid (CA) were determined before and after the administration of a single clofibrate dose (0, 2, 6, 12, 24, 48, 72, 96h) in patients with various degrees of impaired renal function and in a control group (n = 56). The clofibrate doses administered to the five groups were: group 0 = control group without renal impairment: 1,000 mg; group 1 = serum creatinine up to 354 mumol/l: 1,000 mg; group 2a = creatinine levels greater than 354 mumol/l up to levels requiring dialysis: 1,000 mg; group 2b = creatinine levels like 2a, but only 500 mg; group 3 = patients requiring dialysis: 500 mg. In addition, serum albumin, CK, GOT and GPT were controlled. Total CA was determined by gas chromatography, the unbound fraction by equilibrium dialysis. Increasing serum creatinine levels were correlated with a decrease of total CA but with a statistically significant increase in free CA concentrations. The levels of non-protein bound CA of groups 1 and 2a were significantly different from control group 0 (same dosing). In addition, a significantly negative correlation between free CA and serum albumin levels was demonstrated. Determination of free CA as a control parameter of clofibrate therapy in patients with impaired renal function allows clofibrate dosing to be closer related to the individual subject than the determination of total CA only.

[Determination of the metabolic condition in diabetics with renal insufficiency by means of the fructosamine test]. / Beurteilung der Stoffwechsellage niereninsuffizienter Diabetiker mit dem Fructosamin-Test.

We determined HBA1 (microcolumn method) and glycosylated albumin (fructosamine) in 23 healthy subjects, 35 patients with renal insufficiency without diabetes and 14 patients with diabetes mellitus and renal insufficiency. All patients with renal insufficiency required dialysis. All diabetics were of type I and had been compensated on insulin. The HBA1 in the nondiabetic patients with renal insufficiency (9.4 +/- 1.4%) was significantly raised compared to that in the control group with healthy metabolism (7.3 +/- 0.6%). Irrespective of the quality of compensation, the diabetic patients had HBA1 values of more than 11% of average. On the other hand, the concentrations of glycosylated albumin in healthy nondiabetic patients and in diabetic patients with renal insufficiency did not differ (1.3 +/- 0.5 as compared to 1.1 +/- 0.4 mmol/l) and were all in the normal range. Well-adjusted diabetics with renal insufficiency had a fructosamine concentration of 1.9 +/- 0.7 mmol/l (theoretical value for a good compensation 2.0 to 2.8). We conclude that determination of HBA1 in pronounced renal insufficiency does not provide reliable values because carbamylated hemoglobin is also registered and determination of fructosamine (which only indicates the metabolic situation in the last three weeks, however) is to be preferred in this situation.

Urinary enzyme excretion after a single dose of phenacetin and paracetamol (acetaminophen) during antidiuresis and during water diuresis.

2 g phenacetin or paracetamol in a single oral dose were administered to five healthy persons under the conditions of antidiuresis and subsequent water diuresis. Excretion of the brush border enzyme GGT, the cytoplasm enzyme LDH, and the lysosomal enzymes, NAG and GAL, was analysed before, during and after ingestion of the analgesics. Increased excretion of LDH and GGT indicated a similar moderate damage of the tubular epithelia after phenacetin and paracetamol. The state of diuresis appeared to have no influence.

Intraperitoneal fibrin-formation and its inhibition in CAPD.

The intraperitoneal fibrin formation and its inhibition by intraperitoneal heparin (5000 U) was investigated in six patients on CAPD. The intraperitoneal heparin concentration decreased linearily from 1.78 U/ml to 1.13 U/ml during a 4-hour dwell time. The antithrombin III-concentration increased to 0.56 +/- 0.1 mg/dl, reaching 1.87% of normal plasma values. The antithrombin III-portion of total protein was 0.62% in plasma and 0.79% in dialysate. The fibrinopeptide A-concentration, a specific product of thrombin action on fibrinogen was 37.1 +/- 11.8 ng/ml in plasma (normal range: less than 2.5 ng/ml) and 153.4 +/- 16.8 ng/ml in dialysate during regular CAPD. After the addition of 5000 U heparin the fibrinopeptide A-concentration in dialysate decreased to 11.6 +/- 2.6 ng/ml during a 4-hour dwell time. In vitro experiments showed no remarkable inhibition of fibrin formation by heparin without antithrombin III in dialysate. We suggest that the fibrinopeptide A is produced intraperitoneally and the antithrombin III-concentration in dialysate is sufficient to inhibit the fibrin formation after acceleration by heparin.

[Sonography of the neck in hypercalcemic crisis]. / Halssonographie in der hypercalcämischen Krise.

In hypercalcaemic crisis sonographic identification of an enlarged parathyroid permits the indication for parathyroidectomy. This is particularly important as determination of the parathormone concentration to find out the cause of hypercalcaemia takes too long and thus delays diagnosis and therapy. In two patients with symptoms of crisis successful parathyroidectomy was performed solely on the basis of a raised serum calcium concentration and a sonographically proven enlarged parathyroid.

Intraperitoneal heparin in CAPD.

In six patients on CAPD (continuous ambulatory peritoneal dialysis) the systemic effects of intraperitoneally administered heparin (5000 U) were investigated. Using a modification of a plasma heparin determination serial measurements of heparin concentration in dialysate were performed. During a dwell time of 4 hours the intraperitoneal heparin level decreased by 1825 +/- 253 U (mean +/- S.E.M.). Simultaneously the plasma anti-IIa-activity of heparin after 4 hours and the anti-Xa-activity after 2 and 4 hours increased significantly (p less than or equal to 0.05). The maximum of heparin activity after 4 hours was 0.015 +/- 0.001 U/ml and 0.024 +/- 0.003 U/ml, respectively (mean +/- S.E.M.). An increase of activated partial thromboplastin time was not observed. The small increase of heparin activity in plasma is in contrast to reported activities measured after subcutaneous application of this dose of heparin. In CAPD the effect of heparin is largely restricted to the peritoneal cavity.

[A radioimmunoassay for the determination of human myoglobin: lower detection limit, precision and use in control of myoglobinuric kidney failure]. / Radioimmuntest zur Bestimmung von Humanmyoglobin: Untere Nachweisgrenze, Präzision, Verlaufskontrolle beim myoglobinurischen Nierenversagen.

The lower detection limit of a radioimmunoassay for human myoglobin was determined by two "precision from day to day" methods (90% and 3 s methods), and by two "precision in series" methods (95% confidence range and the method of Markowetz & Munz). According to Markowetz & Munz, the lower detection limit (as a measure of sensitivity) is the lowest myoglobin concentration which, in 15-fold assays, shows no binding value in common with that of the next highest concentration, and no activity value in common with that of the reference binding value. On theoretical grounds (precision in series) and from a practical standpoint (determination of the lower detection limit using one sample assay), this method is the most suitable for the determination of the lower detection limit as a measure of sensitivity. It remains to be seen whether this is a valid generalization for other methods.

[Nontraumatic rhabdomyolysis with reversible acute kidney failure following hyperosmolar diabetic coma in a child]. / Atraumatische Rhabdomyolyse mit reversiblem akutem Nierenversagen nach hyperosmolarem diabetischem Koma beim Kind.

A 9 10/12 year year old girl developed severe hyperosmolar diabetic coma, and 5 days later acute renal failure. Extremely elevated levels of myoglobin were measured in serum and urine with a radioimmunoassay kit leading to the diagnosis of atraumatic rhabdomyolysis. Intermittent hemodialysis was performed for 2 weeks. Subsequently myoglobin and creatinine values in serum returned to normal. Psychological disturbances and paresis of the lower extremities subsided 4 resp. 12 weeks after the onset of acute illness.

Decreased number of alpha-adrenergic receptors in platelets of patients on maintenance haemodialysis.

In patients on maintenance haemodialysis the number of platelet alpha 2-adrenergic receptors, as assessed by 3H-yohimbine binding, was significantly lower than that in healthy volunteers. Responses to alpha 1-adrenergic receptor stimulation, determined by increases in systolic blood pressure produced by intravenous injections of phenylephrine, were also diminished in chronic haemodialysis patients. Thus, reduced sympathetic activity often observed during chronic haemodialysis treatment may be due to reduced number and/or sensitivity of alpha 1- and alpha 2-adrenergic receptors.