Helmut Graf

Decreased serum interleukin 1 activity and monocyte interleukin 1 production in patients with fatal sepsis.

The role of interleukin 1 (IL 1) in 16 patients with sepsis and 16 normal controls was investigated. Thymocyte costimulation was used to assay in vitro IL 1 levels produced by adherent cells in the peripheral blood, and in vivo IL 1 levels in the serum. Adherent cells (i.e., monocytes) from nonsurviving septic patients produced significantly less IL 1 activity than cells from healthy controls or surviving patients, either spontaneously or by silica stimulation. In contrast, in vitro IL 2 production by T lymphocytes was not altered in septic patients. Serum IL 1 activity was determined using serum fractions from high-pressure liquid chromatographic gel filtration. Suppressor factors in healthy subjects as well as septic patients usually eluted at molecular weights above 50 kilodaltons, while IL 1-like activity was normally present between 35 and 1 kilodaltons. Sera of nonsurviving septic patients contained significantly less IL 1 compared to that of controls or surviving patients. Thus, decreased serum IL 1 levels and diminished monocyte production of IL 1 appear to be negative prognostic indicators, possibly reflecting a breakdown of mononuclear phagocytes.

Beta-2-microglobulin in hemodialysis patients: effects of different dialyzers and different dialysis procedures

beta 2-Microglobulin (beta 2m) has been identified as the major constituent of dialysis-related amyloid. Although there is no clear correlation between absolute beta 2m levels and amyloidosis-related symptoms, elevated serum levels are thought to be the basis for tissue deposition of beta 2m. Besides diminished renal excretion and insufficient removal during hemodialysis, a dialysis-related induction of beta 2m production is discussed as the major cause of elevated serum beta 2m levels. In order to evaluate the influence of hemodialysis membranes and the hemodialysis procedure on beta 2m levels we determined serum beta 2m levels in patients on chronic intermittent hemodialysis. Polymethylmethacrylate 2.0 m2, cuprophane and cellulose acetate dialyzers led to increasing beta 2m levels during dialysis, which was in excess of what could be accounted for by hemoconcentration. The polymethylmethacrylate 1.6 m2 dialyzer did not result in a significant rise of beta 2m levels during dialysis. This indicates that production of beta 2m is not only dependent on the membrane material but also on the surface area of the dialyzer. The use of polysulfone and hemophane low-flux dialyzers did not induce an increase in beta 2m levels during dialysis but a significant clearance of beta 2m was not demonstrable either. Volume-controlled dialysis with high-flux membranes (polysulfone 0.65 m2 and polysulfone 1.25 m2) lowered beta 2m; clearance values, however, were significantly higher when these dialyzers were used in a hemodiafiltration procedure. We conclude from our study that some dialysis membranes appear to induce beta 2m production, whereas others do not.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and Safety of Recombinant Human Erythropoietin in Predialysis Patients

Experience with erythropoietin in the treatment of anemia in predialysis patients is limited. A practical treatment regimen which minimized the number of outpatient visits was investigated. The Austrian multicenter study included 123 patients. At baseline, the treatment protocol mandated once weekly the administration of 10,000 U recombinant human erythropoietin (r-HuEPO) subcutaneously. The follow-up period was 3 months, and dose adjustments were made at monthly intervals. At baseline, the mean values for creatinine were 6.2 ± 0.2 mg/dl, and for hemoglobin (Hb) 9.0 g/dl. During 3 months of therapy, mean Hb increased to 10.8 g/dl and creatinine to 6.6 mg/dl. The initial r-HuEPO weekly dose was 10,000 U. The mean dose after 3 months was 9,000 ± 4,000 U. There was no significant alteration of the slope of the reciprocal creatinine curve or of blood pressure values. No side effects occurred during the 3-month treatment period. In conclusion, the results of this multicenter trial demonstrate that using a simple once-weekly subcutaneous treatment regime, r-HuEPO can be administered safely and effectively in predialysis patients.

Effects of dichloroacetate on exercise performance in healthy volunteers

Dichloroacetate (DCA), a stimulator of the pyruvate dehydrogenase complex, decreases lactate levels and peripheral resistance and increases cardiac output. This study was performed to examine the effects of DCA on exercise performance in humans. Eight healthy male volunteers (age 20–28 years) were tested by bicycle spiro-ergometry using a microprocessor-controlled gas analysis system after infusion of DCA (50 mg/kg body weight) or saline. Prior infusion of DCA significantly reduced the increase of lactate levels during exercise when compared with infusion of saline (1.40±0.21 vs 2.10±0.09 mmol·l−1 at 50% of the expected maximal working capacity, P<0.05; 8.53±0.45 vs 9.92±0.59 mmol·l−1 at maximal working capacity, P<0.05). Oxygen uptake increased significantly after DCA when compared with saline from 7.5±0.4 vs 7.4±0.5 to 27.2±1.5 vs 23.7±1.7 (P<0.05) at anaerobic threshold and to 35.6±1.7 vs 30.5±1.0 ml · kg−1 min−1 (P<0.05) at maximal exercise capacity. Following DCA infusion the workload at which the anaerobic threshold was reached was significantly higher (160±7 vs 120±5 W, P<0.05) and the maximal working capacity was significantly increased (230±9 vs 209±8 W, P<0.05). In summary, DCA reduced the increase of lactate levels during exercise and increased oxygen uptake at the anaerobic threshold and at maximal working capacity, which was significantly increased. These results warrant further studies on a potential therapeutic application of DCA in patients with reduced exercise capacity.

Effect of Recombinant Human Erythropoietin on Anterior Pituitary Function in Patients on Chronic Hemodialysis

In 7 patients with end stage renal failure, anterior pituitary function was tested by simultaneous application of maximally effective doses of the hypothalamic releasing peptides, corticotropin-releasing hormone, growth hormone-releasing hormone, thyrotropin-releasing hormone and gonadotropin-releasing hormone, and compared to 8 normal controls. In addition to the pituitary hormones, plasma cortisol, thyroxine and testosterone concentrations were measured. To test for possible effects of treatment with recombinant human erythropoietin (rhu-EPO), all patients with chronic renal failure were studied again after partial correction of anemia by treatment with erythropoietin. Before initiation of rhu-EPO treatment, plasma concentrations of follicle-stimulating hormone were significantly elevated and the thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone blunted when compared to normal controls. Treatment with rhu-EPO induced a significant increase in plasma ACTH and follicle-stimulating hormone concentrations. All other pituitary functions remained unchanged. Thus, the general improvement in well-being, working capacity and sexual activity cannot be attributed to hormonal changes.

Pharmacokinetics of enteric-coated mycophenolate sodium: comparative study in patients with autoimmune disease and renal allograft

Background: Recently, mycophenolic acid drugs have gained interest in the treatment of autoimmune diseases. However, only limited pharmacokinetic data are available on enteric-coated mycophenolate sodium in non-transplant indications. Objective: This study compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium in patients with autoimmune disease and renal transplant recipients. Methods: Twelve autoimmune disease patients (mainly with antineutrophil cytoplasmic antibody-associated vasculitis) and 11 stable renal transplant patients, all of whom had been on enteric-coated mycophenolate sodium for ≥ 10 weeks, received an oral dose of enteric-coated mycophenolate sodium of 720 mg under fasting conditions. Blood samples for the determination of mycophenolic acid in the plasma were collected over 24 h. Results. Overall, no significant difference was found between both groups for their 0 – 12 h and 0 – 24 h areas under the concentration–time curve, Cmax, Tmax, C0 h, C12 h and C24 h, although the mean Cmax was numerically higher by 39% in the autoimmune disease patients (autoimmune disease 27.3 ± 17.4 mg/l and renal transplant 19.6 ± 15.7 mg/l). Patients on concomitant ciclosporin tended to have a lower mycophenolic acid exposure than patients on a non-ciclosporin regimen. The intersubject variabilities in the mycophenolic acid pharmacokinetics were high in both patient populations (around 40% for the area under the curve values). Both groups exhibited a weak and non-significant correlation between their mycophenolic acid trough (C12 h) levels and mycophenolic acid 0 – 12 h area under the curve (autoimmune disease r = 0.482 and renal transplant r = 0.138), whereas in the autoimmune disease group the mean C1.5 h and C2 h concentrations provided a satisfactory association with the 0 – 12 h area under the curve (for both r > 0.7 and p < 0.001). Conclusion: These data suggest that mycophenolic acid exposure (in terms of the area under the curve) from enteric-coated mycophenolate sodium is comparable in autoimmune disease and renal transplant patients. The mycophenolic acid trough levels did not reflect the systemic exposure to mycophenolic acid adequately; a limited sampling strategy for estimating mycophenolic acid exposure in autoimmune disease patients should include times around C1.5 h and/or C2 h reflecting Tmax if further studies confirm its usefulness.

Glucose metabolism and insulin sensitivity in patients on chronic hemodialysis

In order to evaluate the potential role of parathyroid hormone on glucose metabolism in patients on chronic hemodialysis hyperglycemic clamp studies were performed in 7 parathyroidectomized and 11 nonparathyroidectomized patients on chronic hemodialysis and in healthy controls. There were no significant differences in the peripheral glucose uptake of the 3 groups. The beta cell response to hyperglycemia during the early phase as well as during the steady state was almost identical in controls and in nonparathyroidectomized uremics, whereas in the parathyroidectomized group a markedly enhanced insulin secretion was found. Calculated tissue sensitivity to insulin therefore was equal in controls and in nonparathyroidectomized uremics, whereas patients after parathyroidectomy had peripheral insulin resistance. Our results demonstrate that patients on chronic hemodialysis apparently have normal peripheral glucose uptake. The subgroup of patients who have undergone parathyroidectomy, however, show an enhanced insulin response to hyperglycemia suggesting peripheral insulin resistance. We conclude that longstanding and severe secondary hyperparathyroidism--the usual cause for parathyroidectomy in these patients--results in irreversible insulin resistance with a compensatory increase of insulin secretion.

Non-phenacetin analgesics and analgesic nephropathy Clinical assessment of high users from a case-control study [ ] *

BACKGROUND A recent large-scale case-control study on analgesic nephropathy (SAN) [1] found no increased risk of end-stage renal disease (ESRD) in users of combined or single formulations of phenacetin-free analgesics. In a subgroup of 22 high users, however, a dose-dependent increased risk was found, which raised the question if these patients presented or not with analgesic nephropathy (AN). METHODS The individual questionnaires of this subgroup of high users were reviewed, and the total lifetime intake of different types of analgesics was calculated. For evidence of AN, the following data were considered: (1) the amount and type of analgesics consumed, (2) the cause of ESRD, as diagnosed by the nephrologist in charge of the patient and (3) renal imaging and other relevant laboratory data. RESULTS This group of ESRD patients consumed on average 7.8 kg of antipyretic analgesics (range 30.8-2.7 kg) over an average of 21.5 years (range 35-6 years). Single analgesics were exclusively used by 12 patients (54.5%) and combined analgesics by 5 patients (22.7%), while 5 patients used both. None of the patients was diagnosed as having AN, and a review of the questionnaires did not disclose evidence suggestive of AN. The possibility that, irrespective of AN, the analgesic (ab)use contributed to the progression of existing renal diseases cannot be answered in the absence of well-defined criteria. The data supporting the existence of such an analgesic-associated nephropathy (AAN) are, however, not consistent and most likely due to confounding by indication. CONCLUSION In a group of ESRD patients with high use of non-phenacetin analgesics, no evidence of AN was found. There is no evidence that (ab)use of analgesics or NSAIDs other than phenacetin leads to a pathologically or clinically defined renal disease that could be named AN or AAN.

Hemodynamic Effects of Partial Correction of Chronic Anemia by Recombinant Human Erythropoietin in Patients on Dialysis

Eighteen patients on chronic hemodialysis with renal anemia were treated with recombinant human erythropoietin (r-HuEPO). Hemodynamic parameters in the resting state were determined before and after successful treatment. Posttreatment cardiac index was decreased (3.3 v 2.8 L/min/m2), whereas diastolic blood pressure (72 v 79 mm Hg) and calculated peripheral resistance (2,230 v 2,860 dyne.cm.s-5) were increased significantly when compared with the pretreatment period. We conclude from our study that the increase of blood pressure as seen in patients on dialysis, who are effectively treated with r-HuEPO, is due to an increase in peripheral resistance. This increase overrules the decrease of cardiac index and might well be a result of peripheral vasoconstriction due to improved oxygen availability.

Glucose Intolerance and Hemoglobin A, in Chronic Renal Insufficiency

Glycosylated hemoglobin A (HbA1), a proposed indicator of the integrated plasma glucose concentration over a long period of time, was investigated in patients with various degrees of renal