Cinacalcet HCI (Sensipar/Mimpara) is an effective chronic therapy for hemodialysis patients with secondary hyperparathyroidism.

AIMS: This 1-year double-blind, placebo-controlled, multicenter study evaluated the long-term safety and efficacy of cinacalcet for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. METHOD: Patients were randomly assigned in a 1:1 ratio to cinacalcet or control treatment groups. The initial dose of cinacalcet (or matching placebo) was 30 mg. Doses were titrated every 3 or 4 weeks based on the intact parathyroid hormone (iPTH) response and safety profile. Sequential doses included 30, 60, 90, 120 and 180 mg/d. Phosphate binders and vitamin D sterols were adjusted per protocol as needed to control levels of calcium and phosphorus. Efficacy and safety were compared between treatment groups among patients who completed the study (52 total weeks of treatment). Reasons for withdrawal are presented for patients who did not complete the study. RESULTS: A total of 210 patients completed 52 weeks of double-blinded treatment with cinacalcet (n = 99) or placebo (n = 111). Over the last 6 months of the study, a greater proportion of patients in the cinacalcet group than the control group achieved an iPTH level < or = 250 pg/ml (61.6 vs. 9.9%, p < 0.001) or a > or = 30% decrease in iPTH from baseline (81.8 vs. 21.6%, p < 0.001). Mean iPTH levels decreased by -47.8% in the cinacalcet group and increased by +12.9% in the control group. Mean percentage changes in other laboratory values in the cinacalcet and control groups included the following: serum calcium -6.5 vs. +0.9% (p < 0.001), serum phosphorus -3.6 vs. -1.1% (p = 0.465), and Ca x P -9.9 vs. -0.3% (p = 0.006). The most commonly reported adverse events related to study drug by the investigators included nausea (13% cinacalcet, 5% control), investigator-reported hypocalcemia (11% cinacalcet, 1% control), vomiting (9% cinacalcet, 2% control), dyspepsia (5% cinacalcet, 4% control), and diarrhea (5% cinacalcet, 2% control). CONCLUSIONS: Treatment with cinacalcet is a safe and effective therapy for long-term control of secondary hyperparathyroidism. 1-year therapy with cinacalcet was associated with sustained, clinically significant reductions in calcium, Ca x P and iPTH which allowed a greater percentage of patients to achieve NKF-KDOQI target goals for PTH and Ca x P.

Posttransplant hemolytic uremic syndrome in adult retransplanted kidney graft recipients: advantage of FK506 therapy?

BACKGROUND: Posttransplant hemolytic uremic syndrome (pHUS) is a rare but severe disorder that confers a poor prognosis on an allograft due to thrombotic microangiopathy. Immunosuppression with cyclosporine (CsA) is implicated as a significant risk factor for the development of pHUS. In early reports, it was hypothesized that immunosuppression with FK506 (tacrolimus) would avoid the development of pHUS. However, this initially supposed beneficial effect remains controversial, because pHUS associated with tacrolimus therapy has been published in some later case reports. This article aims to further evaluate FK506 with respect to the development and resolution of pHUS. METHODS: We describe the course of seven adult kidney graft recipients with pHUS, treated with FK506 either as initial immunosuppression for retransplantation or after discontinuation of CsA for resolution of pHUS. Work-up for pHUS was initiated when certain clinical features, such as hemolytic anemia, thrombocytopenia, and deterioration of graft function, were found. The diagnosis was confirmed by histologic examination of a renal allograft biopsy specimen (thrombotic microangiopathy). With the onset of pHUS, additional plasma exchange was performed in all patients. RESULTS: Two patients suffered from end-stage renal disease due to primary HUS and had a history of recurrent pHUS in previous renal transplants. In both patients, the attempt to regraft was only made because of the early optimistic reports using FK506. Despite initial FK506 therapy, both recipients developed pHUS again, leading to loss of graft function. Two additional kidney graft recipients with primary renal failure other than HUS also received FK506 as initial immunosuppression. One of them (loss of the first kidney graft due to CsA-induced pHUS) was successfully treated with FK506 for his second renal transplant. The other recipient, a patient in whom de novo pHUS had occurred in the first graft despite initial therapy with FK506, was treated with CsA for his second graft and again developed pHUS. The latter process, however, could be reversed by a switch to steroids and azathioprine. In all three patients regrafted for reasons other than pHUS, development of de novo pHUS was treated by CsA withdrawal and a switch to FK506; this approach was effective in two patients. CONCLUSION: Our results demonstrate that three of seven renal allograft recipients benefited from FK506 therapy for prevention or resolution of pHUS. Treatment or prophylaxis with FK506 can be considered advantageous in some patients with de novo pHUS, but FK506 fails to prevent recurrent pHUS in patients with primary HUS.

Monocyte activation and humoral immune response to endotoxins in patients receiving on-line hemodiafiltration therapy.

With the on-line preparation of substitution fluid, an easy-to-operate and cost-effective alternative to conventional hemodiafiltration (HDF) has been realized. The continuous filtration of dialysis fluid, furthermore, allows high volumes of exchange. Microbial contamination and subsequently endotoxins, however, may be present in dialysis fluid, and thus the microbiological safety has become a pivotal issue. In this clinical study we evaluated the safety of the Fresenius Medical Care on-line HDF system which is based on a two-stage filtration of dialysis fluid with upstream DIASAFE and downstream on-line HDF filter. During the three-month study period we failed to detect germs or endotoxins in the substitution fluid. Augmented plasma interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) concentrations were found neither during the intradialytic period nor when pre-session values at study begin and study end were compared. In addition, changes in the anti-endotoxin core antibody levels and soluble CD14 (sCD14) concentration, or pyrogenic episodes were not observed. On-line HDF with DIASAFE and on-line HDF filter thus represents a safe treatment modality by effectively depleting dialysis fluid of cytokine-inducing substances.

Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease. Austrian Study Group of the Effects of Enalapril Treatment in Proteinuric Renal Disease.

Angiotensin-converting enzyme (ACE) inhibitors are known to reduce blood pressure and proteinuria in a variety of different glomerular diseases. Nonetheless, a marked interindividual difference in the efficacy of these agents exists. The activity of the ACE and therefore of the renin-angiotensin-aldosterone system (RAAS) has been shown to be under genetic influence. Patients with a deletion genotype at the intron 16 of the ACE gene have been shown to exhibit higher activity of plasmatic ACE when compared to patients with the insertion genotype. We therefore studied prospectively the hemodynamic and antiproteinuric effect of a 6-month therapy with enalapril in patients with biopsy-proven proteinuric glomerular diseases and the DD (n = 10) and ID/II (n = 26) genotype. Although patients with the DD genotype received a slightly higher dose of enalapril, blood pressure and proteinuria did not change significantly. However, both were significantly reduced in the II/ID group after 10 weeks and 6 months of therapy. Creatinine clearance decreased steadily in DD patients. In II/ID patients, creatinine clearance was reduced significantly after 10 weeks of therapy but increased again thereafter and the value at 6 months was again comparable to the one obtained in the DD patients. We conclude from our study that the ACE genotype influences the blood pressure-lowering and antiproteinuric effect of enalapril in patients with proteinuric glomerular disease.

[Aerobic and anaerobic capacity of chronic hemodialysis patients under continuous therapy with recombinant human erythropoietin]. / Verhalten der aeroben und anaeroben Leistungsfähigkeit chronischer Hämodialysepatienten unter einer Dauertherapie mit rekombinantem humanem Erythropoietin.

In earlier studies we have shown that partial correction of anemia by recombinant human erythropoietin (r-HuEPO) already after 12 weeks results in a significant increase of exercise capacity in patients on chronic hemodialysis. As causative effect increased oxygen availability with improved oxygen delivery to the tissues was assumed. To elucidate the long-term effects of a partial correction of anemia with r-HuEPO on exercise capacity, oxygen uptake at maximum exercise and at the anaerobic threshold was measured by repetitive spiroergometry. Measurements were done before, 3 months and 6 months after initiation of r-HuEPO therapy. The results are summarized below: (table; see text) Our results show that a long-term improvement of peripheral oxygen availability leads to a further increase of anaerobic threshold in patients on chronic hemodialysis even without a further increase of hemoglobin levels and without exercise training. It appears that elimination of the chronic hypoxic condition results in a restoration of previously diminished mitochondrial enzymes in muscle, particularly for aerobic glycolysis. Besides acute improvement of aerobic and anaerobic exercise capacity, the long-term administration of r-HuEPO with its increased anaerobic threshold enhances the patients' everyday life working capacity.

Working capacity is increased following recombinant human erythropoietin treatment.

To investigate the effect of partial correction of anemia in patients maintained by chronic intermittent hemodialysis on aerobic and anaerobic working capacity, eight patients underwent a bicycle spiro-ergometry before and after treatment with recombinant human erythropoietin (r-HuEPO). the initial mean (+/- SD) hemoglobin value was 5.9 mg/dl +/- 0.61 and increased during treatment to 10.9 +/- 0.59 mg/dl, P less than 0.0001). This partial correction of anemia resulted in a significant increase of both oxygen uptake at the anaerobic threshold and peak peripheral oxygen uptake at subjective exhaustion (P less than 0.01 and P less than 0.0002, respectively). The increase in oxygen uptake corresponded to significant increases in Watts, both at the anaerobic threshold and at maximum workload (P less than 0.02 and P less than 0.0004). These data show that partial correction of renal anemia results in a significant increase of both exercise capacity and maximum work.

[Ethylene oxide-induced antibodies and hypersensitivity reactions in hemodialysis]. / Athylenoxidinduzierte Antikörper und Hypersensitivitätsreaktionen während Hämodialyse.

The presence of antibodies against ethylene oxide, which is used for sterilization of dialyzers, was evaluated in 52 hemodialysis patients (30 male, 22 female). The aim of the prospective study was to evaluate a possible correlation of these antibodies with hypersensitivity reactions during hemodialysis. By means of a radio-allergo-sorbent-test (RAST) only 3.9% (2 patients) were detected to have ethylene oxide antibodies. There was no significant correlation between antibodies on the one hand, and symptoms, eosinophilia and IgE-elevation on the other hand. We could not find ETO-induced hypersensitivity reactions in our study population. Thorough rinsing and sufficient storage time of the dialyzers might be the reasons for these findings.

Acute oliguria associated with chlorprothixene overdosage.

The occurrence of acute reversible oliguria is described in a 23-year-old male after ingestion of 1,500 mg of chlorprothixene in a suicidal attempt. In contrast to earlier reports hypothesizing that the pathophysiology of the renal insufficiency associated with chlorprothixene intoxication may be attributed to direct nephrotoxic effects of the compound or to ischaemia owing to transitory unrecognized shock, a careful diagnostic work-up including renal biopsy, disclosed the presence of acute interstitial nephritis.

[Effectiveness of recombinant human erythropoietin in the treatment of transfusion-dependent anemia in patients on chronic dialysis]. / Wirksamkeit von rekombinantem humanem Erythropoietin in der Behandlung der transfusionsabhängigen Anämie chronischer Dialysepatienten.

Recombinant human erythropoietin (r-HuEPO) has recently become available for clinical trial and has been used for the first time in Austria for the treatment of transfusion dependent patients on chronic haemodialysis. Inclusion criteria into the study were baseline haemoglobin levels of less than or equal to 6 g/dl and transfusion requirements of greater than or equal to 1 unit of blood per month. r-HuEPO (CILAG/AMGEN/ORTHO) was administered intravenously 3 times weekly at the end of dialysis. The initial dose was 100 U/kg body weight at each administration and was increased by 25 U/kg if Hb levels failed to increase by greater than 5% of baseline at intervals of 3 weeks. All 9 patients studied showed an increase in Hb values to the desired value at least greater than or equal to 10 g/dl within 6 to 16 weeks and none of the patients required further blood transfusions. All patients reported subjective improvement of life quality and markedly increased working ability. Apart from minor episodes of bone pain and subfebrile temperatures after r-HuEPO administration no major side effects were noted. These preliminary results show that r-HuEPO (CILAG/AMGEN/ORTHO) is a safe and effective form of therapy for renal anaemia and one which opens new horizons in the management of patients on chronic haemodialysis.

Blood-membrane interaction in hemodialysis leads to increased cytokine production.

Recently much interest has been focused on the role of immunoregulatory cytokines such as interleukin 1 (IL 1) and interleukin 2 (IL 2) during the pathogenesis of immunological as well as inflammatory diseases. Therefore peripheral blood mononuclear cells (PBMC) of eight patients undergoing hemodialysis (HD) were tested for IL 1 and IL 2 production. Before starting HD, cytokine production by PBMC in culture was not altered in comparison to normal healthy controls, however, a significant increase of IL 1 and IL 2 production was observed within the first HD hour which lasted throughout the end of HD. Moreover direct effects of cellulose membranes on PBMC cytokine production as well as serum IL 1 levels have been investigated. Serum IL 1 levels were already elevated before onset of HD and increased further during HD. The discrepancy between PBMC IL 1 production and serum IL 1 levels may be due to the diminished excretion in patients with end-stage renal disease. Since addition of dialysis membrane particles enhanced monocytes to produce more IL 1 as well as lymphocytes to release more IL 2, a direct stimulatory membrane effect is postulated. The increased release of immunoregulatory cytokines may account for some of the pathologic findings observed during hemodialysis.

[Clinical value of endotoxin determination in infection. Comparison of the Limulus amebocyte lysate test with detection of bacterial pathogens]. / Klinische Wertigkeit der Endotoxinbestimmung bei Sepsis. Vergleich des Limulus-Amoebozyten-Lysat-Tests mit bakteriellem Erregernachweis.

To evaluate usefulness of Limulus amoebocyte lysate test and blood culture in the diagnosis of septicemia both tests were performed in 27 intensive care patients. Test results were compared with a clinical sepsis score. Ten (62%) out of 16 patients with clinical diagnosis of septicemia showed a positive endotoxin test and 11 (69%) a positive blood culture. In 14 patients (87%) either endotoxin test or blood culture revealed a positive result. Two out of 11 patients (20%) classified by the sepsis score as non-septic showed positive blood cultures as well as positive endotoxin tests. 4 patients with gram-positive bacteria in the blood cultures showed a positive endotoxin test. Due to lack of sensitivity and specificity the Limulus amoebocyte lysate test is of rather low value in the diagnosis of septicemia. Simultaneous performance of Limulus amoebocyte lysate test and blood culture is able to improve the sensitivity, which then over-rules the one obtained when only blood cultures are performed.

Abnormalities in the hypothalamic-pituitary-adrenocortical axis in patients with chronic renal failure.

The recently described human corticotropin-releasing factor was administered to eight patients with chronic renal failure in order to assess hypothalamic-pituitary-adrenocortical (HPA) function. Acute administration of corticotropin-releasing factor lead to a diminished increase of the basally elevated levels of ACTH and beta-endorphin immunoreactivity in patients on chronic hemodialysis. Basal plasma cortisol concentration was normal in end-stage renal disease; however, considering the corresponding elevated ACTH concentrations, cortisol levels were inadequately low. Thus, the hypothalamus as well as the adrenal gland seems to contribute to the alterations in HPA function observed in patients with chronic renal failure; involvement of the pituitary gland and effects of metabolic alterations cannot be ruled out.

The histopathologic identification of CMV infected cells in biopsies of human renal allografts. An evaluation of 100 transplant biopsies by in situ hybridization.

In order to determine the incidence and significance of CMV infected cells within human renal allograft biopsies 100 transplant biopsies were examined for the presence of CMV DNA within the renal tissue specimens using the in situ hybridization technique. In 41 cases CMV infected cells were predominantly found within proximal tubular epithelial cells, although typical nuclear inclusion ("owl eyes") were absent. In only one case was CMV detected within a few glomerular cells. The presence of CMV infected cells within allograft biopsies does not correlate with active CMV infection of the patients at the time of biopsy. There are no significant differences in the distribution of primary and secondary CMV infections between patients with positive and negative biopsy findings. No significant differences as to the histological alterations between CMV infected and non-infected biopsies could be found. The data give evidence that the renal allograft is more often affected by CMV than is generally appreciated. The in situ hybridization technique may be useful for the fast detection of latently CMV infected cells in renal transplants and thus may influence the choice of therapeutic steps early after transplantation. Furthermore, it may facilitate the diagnosis of interstitial nephritis due to virus infection if typical nuclear inclusions in routinely stained tissue sections are absent.

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.

Radioimmunoassay of atrial natriuretic peptides in human plasma.

The concentration of atrial natriuretic peptide (hANP) in plasma from venous blood of healthy subjects was measured by radioimmunoassay. hANP from 5 mL of EDTA-treated plasma was adsorbed onto Sep-Pak C18 cartridges, which were eluted with methanol/trifluoroacetic acid (5 mL/L), 90/10 by volume. The eluates were concentrated by evaporation under nitrogen and lyophilized. After redissolving the samples in 0.5 mL of sodium phosphate buffer, we incubated 100-microL aliquots with anti-alpha-hANP for 24 h, then added 125I-labeled alpha-hANP tracer; 24 h later, we separated the bound and free fraction by adding an antibody/polyethylene glycol complex as the second antibody. The sensitivity of the assay was 2 pg per tube (B0-3 SEM). In the useful range of B = 15 to 85% of B0, CVs for within-run and between-run precision did not exceed 8 and 12%, respectively. The 50% intercept of the standard curve was at 12 pg per tube. hANP concentrations for 36 healthy adults ranged from 8 to 68 ng/L.

A new algorithm for individual dialysis prescription based on urea kinetics.

Methods for calculating required dialysis time to maintain certain blood urea nitrogen levels predialytically thus far have neglected the influence of ultrafiltration during hemodialysis and of weight changes in the interdialytic period. We therefore have developed a new algorithm for individual dialysis prescription based on urea kinetics which further optimizes accuracy of dialysis prescription by considering these two factors. The accuracy of this new method was proven in a prospective follow-up of 3 patients during some 9 consecutive hemodialysis session. It was found that there was a very close relation between the measured and the predicted values of blood urea nitrogen, the difference being only due to variations in dietary protein intake as the patients were kept on liberal food intake. The new algorithm is easily implemented into a pocket calculator and thus can be used under arbitrary dialysis conditions.

Center-specific variations of thyroid hormone serum levels in hemodialysis patients.

Thyroid hormone (free and total thyroxine, total 3,5,3'- and 3,3'5'-triiodothyronine, thyroxine-binding globulin, thyrotropin) serum concentrations were measured in 107 uremic patients of 4 hemodialysis centers, in order to study the prevalence of hypothyroidism in hemodialysis patients. In accordance with the clinical impression there was no laboratory evidence of thyroid dysfunction. In spite of the fact that all patients had the expected low-T3 syndrome, there were highly significant differences between the mean thyroid hormone concentrations of the 4 different centers. The center with the highest thyroid hormone levels (all normal except for borderline low 3,5,3'-triiodothyronine) also had the lowest urea levels, indicating the relatively best metabolic control. One center had significantly lower hormone levels than the other 3 centers (all hormones except free thyroxine were below normal) with urea levels that did not differ significantly from one of these centers. A retrospective analysis of patients and of the techniques of dialysis of 3 centers excluded factors like heparin or the length of time on dialysis to be the reason for the low values of this center. Finally, only the significantly higher proportion of unsuccessfully transplanted patients and some technical differences (lack of water treatment, regenerated cellulose as dialyser membrane, and low magnesium content in the dialysate) unique for this center remained as possible factors that may speculatively explain the observed low thyroid hormone values.(ABSTRACT TRUNCATED AT 250 WORDS)