Immunosuppressive therapy and hepatitis C virus infection: the clinical course of liver disease.

In a retrospective long-term follow-up study the clinical course of liver disease was examined in renal allograft recipients with hepatitis C virus (HCV) infection and negative hepatitis B surface antigen under immunosuppressive therapy. We compared 42 anti-HCV antibody (anti-HCV) positive patients (study group) to 213 anti-HCV negative patients (control group). All patients received immunosuppressive therapy. Measurements were made of the following: aminotransferases, bilirubin, albumin, gammaglobulins, ascites, spleen diameter, HCV RNA, and anti-HCV antibody. We found all but four anti-HCV positive patients to be HCV RNA positive prior to transplantation. There were no differences in overall mortality or mortality secondary to liver disease or sepsis. Normal liver enzymes were found in 13 (31%) anti-HCV positive and in 137 (64%) anti-HCV negative patients during the whole mean observation period of 65 months (range 10-215). Aminotransferase activity decreased in anti-HCV positive and negative patients during the observation period. Liver function with regard to synthesis and excretion was normal in anti-HCV negative and anti-HCV positive patients. No signs of portal hypertension were observed in the anti-HCV positive group. Neither the different immunosuppressive regimens nor the antirejection therapy led to differences between anti-HCV positive and negative groups with respect to liver function and did not alter the clinical course. We conclude that HCV infection in patients under immunosuppressive therapy causes only a mild liver disease, as determined by clinicochemical and clinical parameters, and that mortality rate is not increased.

Beta-adrenergic, angiotensin II, and bradykinin receptors enhance neurotransmission in human kidney.

The aim of this study was to investigate angiotensin II (Ang II) receptor-, bradykinin receptor-, and beta-adrenergic receptor-mediated modulation of norepinephrine release from human renal sympathetic nerves and to characterize the respective receptor subtypes involved. Human cortical kidney slices were incubated with [3H]norepinephrine, placed in superfusion chambers between two platinum electrodes, and superfused with Krebs-Henseleit solution. The sympathetic nerves were stimulated electrically at 2.5 Hz for 1 minute, and the stimulation-induced outflow of radioactivity was taken as an index of endogenous norepinephrine release. Ang II and its precursor Ang I (both 0.01 to 1 mumol/L) enhanced stimulation-induced outflow of radioactivity in a concentration-dependent manner, with EC50 values of 0.03 and 0.05 mumol/L, respectively. The enhancement by Ang I but not that by Ang II was inhibited by the angiotensin-converting enzyme inhibitor captopril (3 mumol/L). The concentration-response curves of Ang I and Ang II were shifted to the right by EXP 3174 (0.01 mumol), the in vitro active form of the Ang II type 1 receptor antagonist losartan, with affinity estimates of 8.72 and 9.30, respectively. A higher concentration of EXP 3174 (0.1 mumol/L) abolished the facilitatory effects of Ang I and Ang II. The Ang II type 2 receptor antagonist PD 123319 (10 mumol/L) did not alter the facilitation by Ang II. In the absence of other drugs, bradykinin (0.01 to 1 mumol/L) failed to modulate stimulation-induced outflow of radioactivity but in the presence of captopril (3 mumol/L) enhanced it in a concentration-dependent manner, with an EC50 of 0.1 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation.

Kidney transplant recipients are exposed to multiple factors that lead to osteoporosis after kidney transplantation. Recent short-term longitudinal studies revealed a strong decline of bone mineral density (BMD) within 1 year after transplantation. The long-term course of BMD after transplantation is still unknown. Therefore, we performed a cross-sectional study to determine BMD in 190 renal graft recipients (mean age 44 years, range 20-71 years) by dual-energy x-ray absorptiometry at various time intervals up to 20 years after transplantation (range 0-237 months). Mean BMD of graft recipients was lower than BMD values of an age- and sex-matched European reference collective at every time of measurement after renal transplantation (P < 0.01). Lowest mean BMD values were measured 12-24 months after transplantation. No loss of BMD occurred after the second posttransplant year beyond the normal age- and sex-dependent decline of BMD. Mean daily prednisone dosage was significantly higher within the first 2 posttransplant years compared with the later posttransplant period (13.1 +/- 6.2 vs. 6.7 +/- 3.4 mg/day). Other drugs or metabolic causes, including daily dosage of CsA, AZA, parathormone level, and graft function, did not show additional important differences before and after the second posttransplant year. Interpreting the results of a cross-sectional study in light of a time-dependent process, we suggest that the preexisting low BMD of kidney transplant recipients at the time of transplantation is further strongly reduced within the initial 2 posttransplant years, probably due mainly to the effect of prednisone therapy. After that time, when prednisone dosage is below a threshold of 7.5 mg/day, only a moderate, normal loss of BMD is apparent, even in patients up to 20 years after transplantation.

Bone fracture and osteodensitometry with dual energy X-ray absorptiometry in kidney transplant recipients.

Kidney transplant recipients have multiple factors leading to osteoporosis. The purpose of this study was to determine the fracture rate after kidney transplantation and the significance of osteodensitometry with dual energy x-ray absorptiometry (DXA) in identifying the risk patients. Bone mineral density (BMD) was measured with DXA in 100 graft recipients (mean interval 63 +/- 53 months after transplantation) and correlated with the incidence of fractures. Fracture rate of peripheral bones increased from 0.009 before transplantation and 0.012 on hemodialysis to 0.032 fractures per patient and year after transplantation. Seventeen fractures of peripheral bones occurred in 11% of the patients within a mean of 103 +/- 59 months after transplantation. Three additional patients had fractures of the lumbar spine. Patients with fractures were characterized by low or low-normal BMD (0.93 +/- 0.23 versus 1.04 +/- 0.17 g/cm2 at lumbar spine), a frequent history of parathyroidectomy (21% versus 6%), and a longer transplant interval (103 +/- 59 versus 57 +/- 49 months). Fractures occurred in patients with low and normal BMD. DXA at the femoral neck proved to be of no value to define patients at risk of fractures. DXA at the lumbar spine also proved to be of limited value for this question. Therefore, alternatively, more sensitive methods of BMD and of bone architecture measurements are necessary for identifying the kidney transplant recipients at risk of fracture.

Treatment of osteopenia and osteoporosis after kidney transplantation.

BACKGROUND: Osteopenia and osteoporosis are frequent complications after kidney transplantation. Data for the treatment of low bone mass after kidney transplantation are not available. METHODS: To test the efficacy of antiresorptive treatment, 46 patients with osteopenia or osteoporosis after kidney transplantation (bone mineral density < or =1.5 SD below normal) were randomly assigned to three groups cyclically treated as follows: group 1 with daily oral clodronate (800 mg) and group 2 with daily intranasal calcitonin (200 IU) for 2 weeks every 3 months. These two groups were compared with a control group (group 3). Every patient was supplemented with 500 mg of calcium per day. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at the lumbar spine and femoral neck before and after the 12-month treatment period. RESULTS: BMD at the lumbar spine was increased by 4.6% in the clodronate group (n=15, P=0.005), by 3.2% in the calcitonin group (n=16, P=0.034), and by 1.8% in the control group (n=15, P=0.265). However, the differences in BMD changes among the groups were not statistically significant. During therapy, serum calcium decreased slightly in all groups by 4.6%; however, parathyroid hormone values increased significantly in the treatment groups by 116%. Therapy was well tolerated without impact on graft function. CONCLUSIONS: Cyclical therapy with clodronate or calcitonin appears to induce a gain in BMD at the lumbar spine in patients with low bone mass after kidney transplantation. This treatment had no adverse impact on graft function but may aggravate preexisting secondary hyperparathyroidism.

Vasoconstrictor responses to the P2x-purinoceptor agonist beta, gamma-methylene-L-ATP in human cutaneous and renal blood vessels.

1. Strips of human saphenous veins and of human renal arteries and veins were superfused with Krebs-Henseleit solution at 37 degrees C. Constrictor responses were elicited by exogenous noradrenaline and the P2x-purinoceptor-selective agonist, beta, gamma-methylene-L-ATP. 2. In human saphenous veins, beta, gamma-methylene-L-ATP (0.3-30 microM; EC50 2.2 microM) induced marked constrictor responses. The maximal response to beta, gamma-methylene-L-ATP was similar to the maximal response to noradrenaline. The P2-purinoceptor antagonist suramin (30 microM) shifted the concentration-response curve of beta, gamma-methylene-L-ATP to the right (apparent pKB value 4.8); suramin (100 microM) markedly inhibited the responses to beta, gamma-methylene-L-ATP. The preferential P2x-purinoceptor antagonist, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 3 microM) slightly reduced the response to beta, gamma-methylene-L-ATP. At a ten times higher concentration (30 microM), PPADS almost abolished the responses to beta, gamma-methylene-L-ATP. PPADS (30 microM), in contrast, caused no significant change in the concentration-response curve of noradrenaline. 3. In extrarenal and intrarenal arteries, EC50 values and maximal responses to noradrenaline were similar when compared with responses to noradrenaline in saphenous veins. Noradrenaline also constricted extrarenal veins. However, in contrast to the results obtained on saphenous veins, beta, gamma-methylene-L-ATP caused almost no constrictor responses in extrarenal veins and arteries and only moderate responses in intrarenal arteries. 4. The results demonstrate marked differences in responsiveness of human blood vessels to the selective P2x-purinoceptor agonist, beta, gamma-methylene-L-ATP, suggesting tissue differences in the occurrence or operation of P2x-purinoceptors in human vascular tissues. Moreover, the results indicate that PPADS blocks P2x-purinoceptors in human isolated blood vessels as previously demonstrated in animal blood vessels.

Renal functional reserve in elderly patients.

The concept of renal functional reserve (RFR) is used in the evaluation of renal function in health and disease. RFR is defined as the difference between glomerular filtration rate (GFR) at rest and the maximum GFR for example under stimulation by an amino acid infusion or a protein rich meal. GFR decreases normally with age by about 1 ml/min per year. The purpose of this study was to establish the effect of the GFR decrease with age on absolute and relative values of RFR. We investigated 12 hospitalized patients 60 to 85 years of age (mean 74 +/- 2.0 SEM) recovering from nonrenal disease. On two consecutive days, inulin and paraaminohippuric acid (PAH) clearance was performed over a period of 4 hours. On day A patients received 1 liter of a 5% glucose solution i.v. On day B an equal volume of an amino acid solution (2 mg/kg/min) was given. In these elderly patients baseline GFR without stimulation measured 73.2 +/- 7.9 ml/min per 1.73 m2 and stimulated GFR was 99.1 +/- 8.5 ml/min, a 35.3% increase (p < 0.025). Thus, renal functional reserve measured 25.9 +/- 8.7 ml/min. PAH clearance increased from 329.0 +/- 41.9 ml/min per 1.73 m2 to 438.8 +/- 50.3 ml/min (p < 0.025). These data confirm that baseline GFR is lower in the elderly compared to young adults. However, renal functional reserve is well maintained in elderly human subjects. This suggests that glomerulosclerosis of aging may not be the only explanation for the low baseline GFR in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

Bicarbonate-based dialysis solution preserves granulocyte functions.

OBJECTIVE: Intraperitoneal phagocytes play an important role in local defense in preventing continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study therefore investigates the effect of the conventional lactate-based dialysis solution-pH 5.2 (LBDS-pH 5.2) and a bicarbonate-based dialysis solution (BBDS) on various cell functions. DESIGN: We studied C5a-induced actin polymerization (AP) as a measure of the cytoskeletal alteration, phagocytosis of zymosan particles, and chemotaxis in neutrophils incubated in either LBDS-pH 5.2, LBDS-pH 7.4, or BBDS-pH 7.4, comparing the data with cells treated with phosphate-buffered saline-pH 7.4 (PBS-pH 7.4) as a control. SUBJECTS: Polymorphonuclear neutrophils (PMNs) were isolated from the blood of healthy donors and incubated with dialysis solution prior to the experiment. RESULTS: C5a-induced AP was dramatically inhibited in PMNs incubated in LBDS-pH 5.2, paralleled by a complete inhibition of phagocytosis and C5a-induced chemotaxis. In comparison, BBDS improved AP to values above the control and also nearly normalized phagocytosis. Chemotaxis markedly improved in cells treated with the low glucose-containing BBDS (Bic 20), containing high glucose concentrations (Bic 30). CONCLUSION: In comparison with conventional lactate-based dialysis solution-pH 5.2, bicarbonate-based dialysis solution at low osmolality better preserves neutrophil functions that involve the cytoskeleton.

Persistent inhibition of neutrophil function by glucose based dialysis solutions.

Local defense mechanisms play an important role in prevention of peritonitis, a major complication of continuous ambulatory peritoneal dialysis (CAPD) therapy. The authors have shown that hypertonic, lactate containing glucose based dialysis solutions (GBDS) used in CAPD lead to an immediate and complete pH-dependent inhibition of actin polymerization and phagocytosis in polymorphonuclear neutrophils (PMN) in vitro. Earlier studies have shown that the pH of the fluid equilibrates from 5.2 to approximately 6.4 during the first 30 min of intraperitoneal dwell time. Thus, the authors designed the current study to determine whether the inhibition of cytoskeletal function and intracellular acidosis induced by acidic solutions are reversed by this pH adjustment. To this end, actin polymerization, phagocytosis, and intracellular pH were studied in PMN isolated from healthy human donors during a 10 min incubation in commercially available GBDS at pH 5.2 and again after pH adjustment to 6.4. Actin polymerization was assessed by measuring F-actin content using NBD phallacidin staining and fluorescence activated cell scanner analysis. Phagocytosis was assessed using zymosan particles, and intracellular pH was monitored by spectrofluorometry. The impairment of cytoskeletal alterations in cells exposed to GBDS at pH 5.2 was persistent and not fully reversed by adjusting the pH. Likewise, phagocytosis remained markedly inhibited and intracellular pH did not rise after adjustment of pH. Thus, the results demonstrate a persistent cytotoxic effect of CAPD solutions on human phagocytes. The authors think that CAPD solutions must be modified to provide a more physiologic pH environment for proper phagocyte function.

Inhibition of C5a-induced actin polymerization, chemotaxis, and phagocytosis of human polymorphonuclear neutrophils incubated in a glucose-based dialysis solution.

Chemotaxis and phagocytosis are important functions of phagocytic cells, which are closely related to cytoskeletal reorganization. These functions may be abnormal in phagocytes of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). In order to examine whether these abnormalities result from treatment, we studied actin polymerization (AP), as an index of cytoskeletal alterations, chemotaxis, and phagocytosis in polymorphonuclear neutrophils (PMNs) of healthy subjects. Polymorphonuclear neutrophils were exposed to either a hepes buffer or a glucose-based dialysis solution (GBDS) of different pH's (5.2, 7.4) and different glucose concentrations (1.36%, 2.27%, 3.86%). After incubation for 0, 5, or 20 minutes, cells were activated with 10 nmol/L C5a-complement. AP was measured as filamentous (F) actin content by NBD phallacidin staining and FACS analysis. Chemotaxis of PMNs was measured in Boyden chambers. In addition, phagocytosis of zymosan particles was assessed. Prior exposure to GBDS pH 5.2 of each glucose concentration immediately and completely inhibited AP in response to 10 nmol/L C5a-complement, reduced chemotaxis (> 95%), and completely inhibited phagocytosis. The inhibition was pH-dependent, since GBDS pH 7.4 caused less inhibition of these functions. We conclude that glucose-based dialysis solutions are cytotoxic towards neutrophils and completely inhibit their ability to display responses requiring cytoskeletal reorganization.

[Unilateral blindness in neurosyphilis]. / Einseitige Erblindung bei Neurolues.

A 55 year-old patient developed loss of vision in his right eye over a period of a few weeks with the clinical finding of uveitis and papillaedema. Subsequently, also the left eye was affected by a marked deterioration of vision. The neurological findings were normal. The laboratory findings showed a marked elevation of the ESR (> 100 mm within the first hour) and protein electrophoreses showed changes suggestive of chronic inflammation. Analysis of the cerebrospinal fluid revealed a lymphocytic meningitis with 180/3 cells; the positive serological and liquor findings for TPHA and FTA led to the definite diagnosis of neurosyphilis. Treatment intravenously with 3 x 4 million units penicillin G daily for a fortnight proved curative. Vision of the left eye recovered fully, but the ophthalmological changes in the right eye were irreversible. This case shows that even today the differential diagnosis of syphilis must be considered with loss of vision of doubtful aetiology and uveitis.

Neutrophil dysfunction in end-stage renal failure: reduced response to priming by C5a.

We studied the effect of C5a pretreatment on phosphatidyl-inositol-4,5-bisphosphate (PIP2) hydrolysis and on the increase in peak and resting cytosolic calcium levels induced by C5a (0.1 and 10 nM) and/or N-formyl hexapeptide (FLPEP; 10 nM) in neutrophils isolated from patients with end-stage renal failure (ESRF) and those from healthy controls. We also investigated superoxide anion production under the same conditions using the fluorescent para-hydroxyphenylacetic acid assay. The hydrolysis of PIP2 induced by C5a or FLPEP alone was similar in neutrophils from patients with ESRF and in control cells. Likewise, pretreatment of patients' neutrophils with C5a prior to FLPEP did not affect hydrolysis or the increase in cytosolic calcium concentration as shown previously for control neutrophils. Resting calcium levels in both ESRF and control neutrophils, however, were significantly increased after priming with low C5a concentrations. After priming with low C5a, prior to FLPEP, there was also a significant increase in superoxide production. This increase was significantly lower in cells from uremic patients than in those from healthy controls. Our data suggest that priming-induced superoxide production in neutrophils is reduced in patients with ESRF.

Mediators of complement-independent granulocyte activation during haemodialysis: role of calcium, prostaglandins and leukotrienes.

Granulocyte activation during haemodialysis using cuprophane membrane is mediated by complement-derived anaphylatoxins C3a and C5a. However, neutrophil degranulation induced by modified cellulosic membranes or synthetic membranes does not correlate with C3a or C5a concentrations. Incubation and recirculation experiments were performed to find out which messengers trigger neutrophil degranulation during blood contact with different membrane materials. During in vitro haemodialysis for 2 hours, PMMA and cuprophane induced pronounced degranulation of neutrophils. With PMMA this was associated with increased thromboxane B2 but low C3a levels, while with cuprophane membrane, marked complement activation but only little thromboxane B2 release was observed. Indomethacin (10 microM) nullified all thromboxane B2 response but could not influence elastase release, indicating that cyclo-oxygenase products are not involved in neutrophil degranulation under these conditions. During incubation of blood with dialysis membranes, inhibition of lipoxygenase by esculetin or of phospholipase A2 by hydrocortisone also had no effect on neutrophil degranulation. One messenger involved in granulocyte activation might be free cytosolic calcium. Application of different calcium channel blockers (verapamil, diltiazem, or nitrendipine) did not influence neutrophil degranulation in incubation experiments, in PMMA or cuprophane membranes. In contrast, chelation of plasmatic calcium by sodium citrate or EDTA blunted elastase release induced by these membranes. This study indicates that calcium is a key mediator required for neutrophil degranulation in complement-activating and non-complement-activating dialysis membranes, while activation of the prostaglandin or leukotriene cascade are not required.

Biocompatibility of four plasmapheresis membranes in patients treated for hypercholesterolemia.

Membrane plasma separation uses artificial polymers which might interact with blood components during treatment. In 7 patients treated for familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation (HELP), we studied 4 different synthetic plasma separation materials. The effect of membranes made from polyethylene, polymethylmethacrylate (PMMA), polypropylene and polysulfone on complement activation (C3a), granulocyte elastase release and granulocyte count were measured repeatedly during the treatment. Polyethylene and PMMA induced high levels of plasma elastase and marked granulocytopenia after 60 min of treatment, much later than during hemodialysis, where granulocyte nadir is known to occur already after 15 min. Polysulfone and polypropylene did not change granulocyte counts and caused only modest levels of elastase during plasmapheresis. Complement activation was present in all 4 membranes but with polyethylene, very high concentrations of C3a were detected. These data indicate that irritation of immune system components as granulocytes or the complement system do occur during plasmapheresis to different degrees depending on the membrane material used. Reinfusion of plasma after processing increases the amount of plasmatic activation products infused into the patient. This was the case, although the plasma processing procedure itself did not add activation products to the plasma. Activation patterns during plasma separation differ from those known to occur during hemodialysis despite use of the same polymer. Immunocompromised patients treated with plasmapheresis may react differently than these otherwise healthy subjects with familial hypercholesterolemia.

Effect of nifedipine and captopril on glomerular hyperfiltration in normotensive man.

Glomerular hyperfiltration and hypertension induced by extensive loss of renal parenchyma are suspected to accelerate progression of renal failure. Amino acid infusion or protein ingestion also modify renal hemodynamics and increase glomerular filtration rate (GFR). This phenomenon was used to study the influence of two commonly used antihypertensive agents, captopril and nifedipine, on renal hemodynamics at rest and during glomerular hyperfiltration. Thirteen healthy volunteers were studied on three separate days (days A, B, and C) in random sequence: inulin and p-amino hippurate (PAH) clearance were measured first under glucose infusion and afterwards under stimulation by amino acid infusion (0.35 mmol/kg/min; 4 mg/kg/min). Day A served as a control, where no medication was given. On day B, 10 mg nifedipine, and on day C, 25 mg captopril, were administered orally before study. Without premedication (= day A, control) GFR increased from 108.0 +/- 6.9 mL/min (SEM) to 131.7 +/- 7.0 mL/min (P less than 0.05). On day B (nifedipine), GFR before stimulation by amino acids was already elevated to 121.8 +/- 4.2 mL/min (P less than 0.05 compared with day A) and increased to 132.6 +/- 6.3 mL/min with infusion of amino acids, thus to the same range as on day A without medication. On day C, after captopril, GFR did not increase with infusion of amino acids (from 112.5 +/- 7.2 to 117.3 +/- 6.3 mL/min). Our results indicate the calcium channel antagonist nifedipine and the angiotensin-converting enzyme (ACE) inhibitor captopril differ in their effect on intrarenal hemodynamic parameters. Nifedipine induces hyperfiltration at rest and allows maximal hyperfiltration to develop under amino acid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

C5a reduces formyl peptide-induced actin polymerization and phosphatidylinositol(3,4,5)trisphosphate formation, but not phosphatidylinositol (4,5) bisphosphate hydrolysis and superoxide production, in human neutrophils.

We investigated phospholipid signal transduction, calcium flux, O2- anion production and actin polymerization after stimulation with the C fragment and chemoattractant, C5a, and then determined how C5a pretreatment affected subsequent responses to formyl peptide in human neutrophils. We have previously demonstrated that the novel lipids, phosphatidylinositol trisphosphate (PIP3) and phosphatidylinositol(3,4)P2 (PI(3,4)P2), rise transiently in neutrophils after activation with formyl peptide. Furthermore, the rise in PIP3 parallels actin polymerization. In this study, neutrophils activated with C5a exhibited two distinct G protein-dependent signal pathways involving different phosphoinositides: 1) [32P]PI(4,5)P2 hydrolysis and [32P]PA production, and 2) the transient formation of D-3-phosphorylated phosphoinositides, [32P]PIP3 and [32P]PI(3,4)P2. When neutrophils were preincubated with C5a for 5 min before stimulation with formyl peptide, [32P]PI(4,5)P2 hydrolysis was unchanged, and [32P]PA production and O2- formation were slightly enhanced compared with controls stimulated with formyl peptide in the absence of C5a. In contrast, [32P]PIP3 production, right angle light scatter, and actin polymerization were all reduced 35 to 40%. Therefore, these data support the hypothesis that PIP3 plays a role in chemotaxis but not superoxide formation.

Rebound of plasma vancomycin levels after haemodialysis with highly permeable membranes.

Vancomycin is usually given only once a week to haemodialysis (HD) patients. If highly permeable dialysis membranes are used, however, high clearance values have been reported, so the aim of the study was to determine whether high clearance of vancomycin resulted in sufficient drug elimination to induce subtherapeutic plasma levels after one week. In 18 chronic HD patients, treated with polysulfone dialyzers (1.2 m2), the pharmacokinetics of vancomycin were studied after administration of 1 g. Concentrations were determined by fluorescence polarisation immunoassay. At a blood flow of 219 ml.min-1, HD clearance of vancomycin was 62.3 ml.min-1. Immediately after dialysis plasma concentrations were 38% lower than predialysis levels. However, marked rebound in the vancomycin level was observed 5 h later, resulting in plasma levels only 16% lower than prior to dialysis. 3 HD treatments in 1 week removed about one third of the initial dose. After one week 15 of 18 patients still had a therapeutic plasma level (greater than 4 micrograms.ml-1). In conclusion, polysulfone membranes show high clearance of vancomycin. However, transfer of drug from blood to dialysate appears to be faster than from tissues to blood. Because of a marked rebound in plasma level after treatment, therapeutic drug concentrations will still be present in most patients after one week.

Dopamine DA2-receptor activation inhibits noradrenaline release in human kidney slices.

Dopamine receptor modulation of noradrenaline release from renal sympathetic nerves was investigated. Human kidney slices were incubated with 3H-noradrenaline, placed into superfusion chambers between two platinum electrodes and field-stimulated at 5 Hz. The slices accumulated radioactivity. Pretreatment of the kidney slices with 6-hydroxy-dopamine (1.2 mM) prior to the 3H-noradrenaline incubation reduced the accumulation of radioactivity. The stimulation induced (S-I) outflow of radioactivity was mainly composed of intact 3H-noradrenaline. The sodium channel blocker tetrodotoxin (1 microM), 6-hydroxy-dopamine pretreatment and omission of calcium from the superfusion solution abolished S-I outflow of radioactivity. The DA1-receptor agonist fenoldopam (SKF 82526; 0.01 and 0.1 microM) did not alter but fenoldopam (1 microM) increased S-I outflow of radioactivity. However, in the presence of either the non-selective alpha-adrenoceptor antagonist phentolamine (1 microM) or the selective alpha 2-adrenoceptor antagonist idazoxan (1 microM) fenoldopam (1 microM) had no effect. The DA2-receptor agonist quinpirole (LY 171555; 1 microM) inhibited S-I outflow of radioactivity, an effect blocked by the selective DA2-receptor antagonists S(-)-sulpiride (10 microM) and domperidone (0.3 microM) but unaltered either by the DA1-receptor antagonist SCH 23390 (1 microM) or by phentolamine (1 microM). The alpha 2-adrenoceptor agonist UK 14304 (0.1 microM) inhibited S-I outflow of radioactivity, and this effect was blocked by phentolamine (1 microM) and idazoxan (1 microM) but unaltered by S(-)-sulpiride (10 microM). Phentolamine and idazoxan, in contrast to S(-)-sulpiride, domperidone and SCH 23390, enhanced S-I outflow of radioactivity by themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients.

BACKGROUND: Bone loss is an important problem in renal transplant recipients immediately after surgery. No data are available about the bone loss beyond the first post-transplantation year. METHODS: In a longitudinal, uncontrolled observational study bone mineral density (BMD) was measured by dual X-ray absorptiometry in 115 renal graft recipients starting at different times after transplantation (0-20 years after transplantation) with a follow-up time of 12 months. RESULTS: A total of 56 patients showed a reduction of BMD during the observation period. Bone loss depended on the time after transplantation. Mean reduction of BMD at lumbar spine was 7 +/- 10%, 1 +/- 9% during the first and second postoperative year. Beyond the third year bone mineral density did not change or even increased slightly (0 +/- 4% during 3-5th year, 1 +/- 6% during 6-10th year and 2 +/- 4% during 11-20th year after transplantation). Decrease of BMD correlated with a higher mean daily prednisone dosage (P < 0.001), a higher cumulative prednisone dose (P < 0.01), a more frequent and more steroid-resistant rejection (P < 0.001) and a higher initial parathyroid hormone level (P < 0.001). Patients with 25-OH-cholecalciferol therapy (P < 0.05) or more physical activity (P < 0.05) had a smaller bone loss. CONCLUSIONS: Reduction of BMD after transplantation is highest within the first post-transplant year. The effects of acute graft rejection, prednisone dosage and initial parathyroid hormone level are predominant among the multiple factors associated with pronounced bone loss.

Trabecular bone architecture in female renal allograft recipients--assessed by computed tomography.

BACKGROUND: Osteopenia with decreased bone mineral density (BMD) is a frequent finding in renal allograft recipients. Data concerning the bone architecture in these patients do not exist, however. METHODS: We compared the bone architecture of 33 randomly assigned women (age 49 +/- 12 years), who had received renal allografts 5.6 +/- 5.3 years before the investigation, with 74 women (age 50 +/- 14 years) who were admitted for osteodensitometry. All patients underwent single-energy computed tomography (SEQCT) and a midvertebral high-resolution tomography with computer-assisted analysis of the trabecular vertebral body architecture. RESULTS: Progressive alteration of bone architecture was associated with increasing vertebral height loss of the vertebral body. Height reduction of a vertebral body of more than 15% was associated with a significantly lower BMD (-2.3 +/- 0.8 versus -1.1 +/- 1.1 standard deviations below normal BMD), a lower trabecular bone area (13 +/- 8% versus 42 +/- 22%) and a lower trabecular diameter (1.4 +/- 0.5 mm versus 2.2 +/- 0.8 mm) compared to recipients without height reduction. In comparison to a matched group of patients with similarly reduced BMD (1.1 +/- 1.2 versus 1.2 +/- 1.1 SD below normal BMD), renal allograft recipients showed a lower number of trabecular plates (5.6 +/- 3.1 versus 7.0 +/- 3.7) and a smaller intertrabecular surface (54 +/- 116 mm versus 75 +/- 138 mm). CONCLUSIONS: Alterations of bone architecture in renal allograft recipients were associated with progressive vertebral height loss. Despite similar bone mineral density, differences of bone architecture could be observed between renal allograft recipients and patients with osteoporosis.