Factors related to the development of CMV-specific CD8+ T cell response in CMV-seropositive solid organ transplant candidates.

This cross-sectional study analyzes factors associated with the development of CMV-specific CD8+ response, measured by IFNg production after cytomegalovirus (CMV) peptide stimulation, in CMV-seropositive solid organ transplantation candidates. A total of 114 candidates were enrolled, of whom 22.8% (26/114) were nonreactive (IFNγ < 0.2 IU/mL). Multivariate logistic regression analysis showed that age, HLA alleles and organ to be transplanted were associated with developing CMV-specific CD8+ immunity (reactive; IFNγ ≥ 0.2 IU/mL). The probability of being reactive was higher in candidates over 50 than in those under 50 (OR 6.33, 95%CI 1.93-20.74). Candidates with HLA-A1 and/or HLA-A2 alleles had a higher probability of being reactive than those with non-HLA-A1/non-HLA-A2 alleles (OR 10.97, 95%CI 3.36-35.83). Renal candidates had a higher probability of being reactive than lung (adjusted OR 8.85, 95%CI 2.24-34.92) and liver candidates (OR 4.87, 95%CI 1.12-21.19). The AUC of this model was 0.84 (p < 0.001). Positive and negative predictive values were 84.8% and 76.9%, respectively. In renal candidates longer dialysis was associated with an increased frequency of reactive individuals (p = 0.040). Therefore, although the assessment of CMV-specific CD8+ response is recommended in all R+ candidates, it is essential in those with a lower probability of being reactive, such as non-renal candidates, candidates under 50 or those with non-HLA-A1/non-HLA-A2 alleles.

Compliance with mineral metabolism targets in haemodialysis patients: moving backwards?

BACKGROUND: To standardize therapy and improve the clinical outcome for chronic haemodialysis (HD) patients, guidelines have been developed for mineral metabolism management. We evaluated compliance with different mineral metabolism guidelines. METHODS: 2,951 chronic HD patients from 61 dialysis centres in Spain were studied. Mineral metabolism management data from a 1-year period were analysed according to KDOQI, KDIGO, and Spanish guidelines. RESULTS: Only 1% (KDOQI), 6% (KDIGO) and 11% (Spanish guidelines) of patients continuously achieved total calcium (Ca), phosphate (P) and parathyroid hormone (PTH) target-range values during the year with higher percentages if we considered the 1-year average. The yearly Ca, P and iPTH average accomplished Spanish guidelines with different percentage among centres: CA 62-100%, P 59-91%, PTH 61-89%, and 28-77% considering all three targets together. The KDIGO guidelines recommend similar percentages except for P (33-77%). No differences were found related to eKt/V, online haemodiafiltration/HD, weight, body mass index, or dialysis vintage. They were only related to age, blood flow, effective treatment time, and dialysate calcium but without relevant clinical differences. Patients outside the target ranges generated significantly higher treatment costs. CONCLUSIONS: Compliance with mineral metabolism targets in HD patients was poor and showed a wide variation between treatment centres.

[Acetate-free on-line PHF: how to improve hyperacetatemia and haemodynamic tolerance]. / PHF on-line sin acetato: cómo mejorar la hiperacetatemia y la tolerancia hemodinámica.

SUMMARY BACKGROUND: The small quantity of acetate present in the dialysis fluid exposes patient's blood to an acetate concentration 30-40 times the physiological levels. This amount is even greater in hemodiafiltration on-line. Our purpose was to evaluate the clinical-analytical effects using three different dialysis techniques in the same patient. METHODS: 35 patients on hemodialysis were included. All patients were treated with conventional bicarbonate dialysate for 3 months, after randomization were switched to first be treated with PHF online with standard bicarbonate dialysate for 6 months and then switched to PHF on-line acetate-free dialysate for the other 6 months or to invert the two last periods. Blood samples were drawn monthly throughout the study and clinical data were obtained. RESULTS: Postdialysis blood acetate levels were higher in patients treated with conventional bicarbonate dialysate with respect to the period of PHF with free-acetate dialysate. Moreover, the percentage of patients with postdialysis blood acetate levels in the pathologic range was higher in patients treated with conventional bicarbonate dialysate respect to PHF on-line acetate-free dialysate period (61% vs. 30%). Serum concentrations of chloride postdialysis were higher and serum concentrations of bicarbonate pre and posthemodialysis were lower in the PHF free-acetate period. The incidence of hypotensive episodes was significantly lower in the PHF on-line with conventional dialysate. CONCLUSIONS: PHF on-line with free-acetate dialysate allows that most of patients finished hemodialysis with blood acetate levels in the physiologic ranges. PHF on-line is a predilutional hemodiafiltration treatment with better tolerance than hemodialysis with standard bicarbonate dialysate.

Sleep disorders are underdiagnosed in patients on maintenance hemodialysis.

BACKGROUND: Sleep apnea-hypopnea syndrome (SAHS) is a cardiovascular risk factor. The aim of this study was to evaluate sleep disorders using polysomnography on a non-selected population of patients on maintenance hemodialysis. METHODS: Overnight polysomnography was performed on 32 hemodialysis patients (24 men/8 women, 54 +/- 16 years), and on 19 healthy subjects of similar age, sex and body mass index who were used as controls. RESULTS: In hemodialysis patients, the most frequent sleep disorder was SAHS in 44% (14/32), followed by insomnia in 41% (13/32). Compared to healthy controls, patients on hemodialysis showed less slow-wave sleep and rapid eye movement sleep (23 vs. 36%, p = 0.001), less sleep efficiency (71 vs. 87%, p = 0.0079) and a higher periodic limb movement index (39.7 vs. 9.1; p = 0.003). An increase in apnea-hypopnea index (18.9 vs. 4.3; p = 0.007) and dips in the SaO(2) (> or =4%) per hour of sleep (22.6 vs. 6.4; p = 0.021) were also significantly greater in hemodialysis patients than controls. 72% of the cases of SAHS were diagnosed solely by means of polysomnography. CONCLUSIONS: The patients on hemodialysis showed poor sleep quality with a significant increase in the apnea-hypopnea index and in the number of dips in SaO(2). SAHS was underdiagnosed in a large percentage of the hemodialysis patients.

C-reactive protein and low albumin are predictors of morbidity and cardiovascular events in chronic kidney disease (CKD) 3-5 patients.

BACKGROUND: Overall and cardiovascular mortality are significantly higher in hemodialysis patients with elevated C-reactive protein (CRP). The aim of this study was to determine whether CRP is a marker of overall and cardiovascular morbidity in chronic kidney disease (CKD) 3-5 patients. METHODS: 90 chronic kidney disease 3-5 patients were prospectively followed during a period of 24 months. Cardiovascular events were defined as episodes of myocardial infarction, stroke, angina pectoris and/or peripheral vascular disease. Morbidity was analyzed in terms of both the need for hospital admission (> 48 h) and total number of days of hospitalization during the follow-up period. CRP was stratified into tertiles of low (< 8 mg/l), medium (8-10.5 mg/l) and high (> 10.5 mg/l). The use of some drugs such as ACE inhibitor and ARAII were also recorded. RESULTS: During the follow-up period, 23 patients (25%) required hospital admission. New cardiovascular events were observed in 20 patients (22%), 10 patients died during the follow-up. Adjusted Cox regression analysis revealed that CRP and serum albumin significantly predicted the risk of cardiovascular events. Similarly, high CRP, low serum albumin and low hemoglobin levels predicted morbidity as measured by the number of hospitalizations. Hemoglobin and albumin levels were lower in patients with high CRP (> or = 10.5 mg/l, highest tertile) as compared with low CRP levels (< or = 8 mg/l, lowest tertile). Patients receiving treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor Type 1 antagonist (ARA-II) had significantly lower levels of CRP than those who were not under such treatment (n = 46, CRP = 8.7 (5.1-29.8) vs n = 44, CRP = 10.4 (6.1-37.2), p < 0.05) (Figure 1). CONCLUSIONS: Our results show that CRP and low albumin, markers of inflammation, predict cardiovascular events and morbidity in CKD 3-5 patients before initiation of chronic hemodialysis.

Anemia associated with pegylated interferon-alpha2a and alpha2b therapy in hemodialysis patients.

AIMS: Anemia is a well-known side effect of interferon therapy since interferons are potent inhibitors of erythropoiesis. The aim of this study was to compare the anemia associated with pegylated interferon (PEG-IFN) (alpha2a versus alpha2b therapy in hemodialysis patients (HD) with chronic hepatitis C. METHODS: In order to study the anemia, doses of erythropoietic growth factors (EGF), hemoglobin (Hb) and erythropoietin resistance index (ERI) were compared at baseline and after PEG-IFN-alpha2a or alpha2b therapy in 16 HD patients with chronic C hepatitis. Pharmacokinetic studies were performed in 4 of those treated with PEG-IFN-alpha2b and 2 patients treated with PEG-IFN-alpha2a. Secondary end-points were viral response and serious adverse events. RESULTS: At 4-6 months after the beginning of therapy, both PEG-IFN-alpha induced a significant increment in the erythropoietin resistance index. This increment was significantly higher in patients treated with PEG-IFN-alpha2a when compared with alpha2b (45 vs 9.9, p = 0.012). The pharmacokinetics of PEG-IFN-alpha2a and alpha2b in HD patients were different, the C(max), C(min) and the area under the serum concentration time curve, were all higher in patients treated with PEG-IFN-alpha2a compared with PEG-INF-alpha2b. Discontinuation of therapy occurred in 2 (28.5%) of the 7 patients in the PEG-IFN-alpha2a group and in 4 (44%) of the 9 patients in the PEG-IFN-alpha2b group. Three (42%) subjects in the alpha2a group and 5 (55%) in the alpha2b group had a response at the end of the 48 weeks of therapy. In 4 (44.4%) of the 9 patients treated with alpha2b the viral response was sustained. CONCLUSIONS: In summary, patients treated with PEG-IFN-alpha2a have a major inhibitory effect on erythropoiesis. This could be explained by the different pharmacokinetic properties of PEG-IFN-alpha2a and alpha2b. Further studies are needed to clarify how these findings influence the efficacy, safety and cost-effectiveness of the PEG-IFN-alpha2.

Antibody-mediated pure red-cell aplasia (PRCA): the Spanish experience.

BACKGROUND: The incidence of antibody (Ab)-mediated pure red-cell aplasia (PRCA) in patients with chronic kidney disease (CKD) has increased between 1998 and 2002. After initially responding to treatment with recombinant human erythropoietic agents for CKD-associated anemia, patients became treatment-refractory and severely anemic. Although most PRCA cases have occurred in Europe, the varying epidemiologies among individual countries have not been well characterized. METHODS: We investigated Ab-mediated PRCA in 12 Spanish patients treated with epoetin alfa alone or prior to treatment with epoetin beta (n=1) or darbepoetin alfa (n=1). Serum Abs against epoetin alfa were detected by radioimmunoprecipitation (RIP) assay or bioassay. Following diagnosis of PRCA, erythropoietic treatment was stopped and patients received immunosuppressive therapy alone (n=11) or in combination with renal transplant (n=1). RESULTS: Treatments were administered for 16 months (average) before diagnosis of PRCA in bone marrow aspirates (n=8) or biopsies (n=4). At diagnosis, patients had an average of 0.68% blood reticulocytes and blood hemoglobin (Hb) level of 7.13 g/dL. Eight patients had anti-epoetin Abs detected by RIP, and 5 had neutralizing Abs measured in the bioassay. As of December 2003, 4 patients had died, 3 had no recovery, and 5 had recovered from anemia (blood Hb level, 9.9 g/dL). All 5 recovering patients received corticosteroid therapy alone, and 1 received a renal transplant as well as corticosteroids. CONCLUSIONS: Sudden onset of treatment-refractory anemia in CKD patients suggests a course of treatment cessation followed by diagnostic procedures for Ab-mediated PRCA, and immunosuppressive therapy. This study may serve as a model for a centralized global PRCA registry.

Effect of a low calcium dialysate on parathyroid hormone secretion in diabetic patients on maintenance hemodialysis.

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty-three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126+/-20 vs. II, 108+/-19 pg/ml) and maximal (I, 269 pg/ml+/-40 pg/ml vs. II, 342 pg/ml+/-65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98+/-18 vs. II, 200+/-34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml+/-37 pg/ml vs. II, 529 pg/ml+/-115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12-month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0, 6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = -0.59; p < 0.001) and the basal PTH (r = -0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady-state PTH level is largely determined by the prevailing serum calcium concentration.

Evidence for both abnormal set point of PTH stimulation by calcium and adaptation to serum calcium in hemodialysis patients with hyperparathyroidism.

In vitro studies of parathyroid glands removed from dialysis patients with secondary hyperparathyroidism and hypercalcemia have demonstrated the presence of an increased set point of parathyroid hormone (PTH) stimulation by calcium (set point [PTHstim]), suggesting an intrinsic abnormality of the hyperplastic parathyroid cell. However, clinical studies on dialysis patients have not observed a correlation between the set point (PTHstim) and the magnitude of hyperparathyroidism. In the present study, 58 hemodialysis patients with moderate to severe hyperparathyroidism (mean PTH 780 +/- 377 pg/ml) were evaluated both before and after calcitriol treatment to establish the relationship among PTH, serum calcium, and the set point (PTHstim) and to determine whether changes in the serum calcium, as induced by calcitriol treatment, modified these relationships. Calcitriol treatment decreased serum PTH levels and increased the serum calcium and the setpoint (PTHstim); however, the increase in serum calcium was greater than the increase in the setpoint (PTHstim). Before treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium was r = 0.82, p < 0.001, and between the set point (PTHstim) and PTH was r = 0.39, p = 0.002. After treatment with calcitriol, the correlation between the set point (PTHstim) and the serum calcium remained significant (r = 0.70, p < 0.001), but the correlation between the set point (PTHstim) and PTH was no longer significant (r = 0.09); moreover, a significant correlation was present between the change in the set point (PTHstim) and the change in serum calcium that resulted from calcitriol treatment (r = 0.73, p < 0.001). The correlation between the residual values (deviation from the regression line) of the set point (PTHstim), derived from the correlation between PTH and the set point (PTHstim), and serum calcium was r = 0.77, p < 0.001 before calcitriol and r = 0.72, p < 0.001 after calcitriol. In conclusion, the set point (PTHstim) increased after a sustained increase in the serum calcium, suggesting an adaptation of the set point to the existing serum calcium; the increase in serum calcium resulting from calcitriol treatment was greater than the increase in the set point (PTHstim); the set point (PTHstim) was greater in hemodialysis patients with higher serum PTH levels; and the correlation between PTH and the set point (PTHstim) may be obscured because the serum calcium directly modifies the set point (PTHstim).

Effect of calcitriol and age on recovery from hypocalcemia in hemodialysis patients.

Calcitriol is used to treat hyperparathyroidism in hemodialysis patients. Calcitriol treatment, either through a reduction in parathyroid hormone (PTH) levels or direct effect on bone, decreases the osteoblast and osteoclast surface and bone formation rate. Our study of 13 hemodialysis patients was designed to evaluate whether calcitriol treatment changed the rate of spontaneous recovery from hypocalcemia induced by a low-calcium dialysis. Calcitriol treatment decreased basal PTH levels from 614 +/- 84 to 327 +/- 102 pg/mL (P < 0.001) and maximal PTH levels from 1,282 +/- 157 to 789 +/- 161 pg/mL (P < 0.001), but the rate of serum ionized calcium recovery from hypocalcemia did not change. When the 13 patients were separated based on the median age of 64 years, the predialysis serum ionized calcium level was less in the younger (group I, 44 +/- 6 years; n = 6) than older (group II, 68 +/- 1 years; n = 7) patients (1.05 +/- 0.03 v 1.22 +/- 0.03 mmol/L, respectively; P < 0.01) despite similar basal (group I, 595 +/- 122 pg/mL v group II, 629 +/- 96 pg/mL) and maximal (group I, 1,114 +/- 299 pg/mL v group II, 1,425 +/- 141 pg/mL) PTH levels. Before calcitriol treatment, the rate of serum ionized calcium recovery from induced hypocalcemia was greater (P < 0.05) for similar PTH levels in the older than younger patients. After calcitriol treatment, despite a similar reduction in PTH levels, the rate of calcium recovery increased (P < 0.05) in the younger patients but did not change in the older patients. We also observed that toward the end of the low-calcium hemodialysis, PTH values decreased even though serum ionized calcium level continued to decline when the rate of calcium reduction slowed. In addition, hysteresis, defined as a lower PTH value during the recovery from hypocalcemia than during the induction of hypocalcemia for the same serum calcium concentration, was present during the spontaneous recovery from hypocalcemia. In conclusion, in the hemodialysis patient: (1) age appeared to affect the bone response to PTH and calcitriol treatment, (2) the PTH response to hypocalcemia was affected by a deceleration in the rate of calcium decrease, and (3) hysteresis of the PTH response to hypocalcemia occurred during the spontaneous recovery from hypocalcemia.

Evaluation of the Losartan in Hemodialysis (ELHE) Study.

Angiotensin converting enzyme inhibitors (ACEIs) have been shown to be effective in the treatment of dialysis patients with high blood pressure, however, they also have been associated with anaphylactoid reactions at the start of dialysis, when they have been used concomitantly with AN69 membranes. A multicenter, open six-month study was designed to test the tolerability and efficacy of losartan as antihypertensive in patients under hemodialysis (HD), with particular emphasis on the appearance of anaphylactoid reactions. HD patients with systolic blood pressure (SBP) levels > or = 140 and/or diastolic blood pressure (DBP) > or = 90 mm Hg, previously nontreated, treated but uncontrolled, or treated with a poor tolerability, were included. The study performed three controls: baseline, at month 3, and at study completion. DBP and SBP levels were measured on the six HD sessions previous to the three visits in addition to biochemical and hematology measurements. Four hundred and six patients were included. The mean age was 55 years, 42% were women, and 23.6% of the patients were dialyzed with AN69 membranes. There was a significant reduction in pre- and postdialysis SBP and DBP at three and six months. Fifteen patients discontinued the study due to adverse reactions related to losartan, and in seven of them the adverse reaction was hypotension. Only two patients have reported a possible anaphylactoid reaction on treatment with AN69, in one of them the HD session had to be stopped and losartan was discontinued. On the contrary, nine patients with a history of previous anaphylactoid reaction, with ACEIs and AN69, have not shown this complication with losartan and AN69. We conclude that losartan is a well tolerated antihypertensive by HD patients, with a very low incidence of adverse reactions, and a lower prevalence of anaphylactoid reactions than those detected with ACEIs and AN69.

Fibrinolytic activity during hemodialysis: a biocompatibility-related phenomenon.

According to recent reports, fibrinolytic activity may be enhanced during hemodialysis. The aim of this work was to study the fibrinolytic activity in uremic patients, and to evaluate the effect of membrane biocompatibility on the fibrinolytic system during hemodialysis. Tissue plasminogen activator (t-PA), t-PA antigen, plasminogen activator-inhibitor (PAI), plasminogen (PL) and alpha-2-antiplasmin (AP) were measured in 10 uremic patients on maintenance hemodialysis treated sequentially with Cuprophane and polyacrylonitrile (AN69) membranes. Blood samples were obtained before and at 15, 60 and 120 minutes after the initiation of dialysis. Blood was also collected from 20 healthy individuals who served as controls. During cuprophane dialysis, t-PA increased significantly at 60 minutes (14.8 vs. 8.4 IU/ml, P < 0.05) and at 120 minutes (13.8 P < 0.01). This was accompanied by an increase in t-PA antigen, which was significant at 15 (5.1 vs. 13.1 ng/ml), 60 (15.2) and 120 (9.6) minutes (P < 0.05) of dialysis. However, during AN69 dialysis t-PA and t-PA antigen plasma levels remained stable. No significant changes were observed in PL, AP or PAI during hemodialysis with either membrane. In conclusion, hemodialysis enhances fibrinolytic activity, which is likely the result of t-PA Ag release. Therefore, this phenomenon seems to be closely related to dialysis membrane biocompatibility.

Cardiovascular response to hemodialysis: the effects of uremia and dialysate buffer.

Cardiovascular instability continues to be one of the primary clinical problems in hemodialysis. Acetate buffer in dialysate is one of the factors that may induce hypotension. Since uremia may have a direct effect on the regulation of the cardiovascular system, the present study was designed to investigate the separate effects of uremia and acetate hemodialysis on blood pressure in anesthesized dogs, as well as the hemodynamic parameters determined by invasive cardiovascular monitoring. Animals were separated into four groups: (1) group I, hemodialysis with acetate in controls; (2) group II, hemodialysis with acetate in uremic dogs; (3) group III, hemodialysis with bicarbonate in controls; and (4) group IV, hemodialysis with bicarbonate in uremic dogs. Acute uremia was induced by bilateral ureteral ligation and a 90-minute hemodialysis (acetate or bicarbonate) procedure was performed 72 hours later. The results obtained in this study show that, compared with dogs with normal renal function, acute uremia resulted in an elevation in mean arterial pressure (MAP; 178 +/- 13 vs. 115 +/- 23 mm Hg, P < 0.01), which was associated with an increase in cardiac index (CI) and left ventricular stroke work index (LVSWI). In these dogs, the pulmonary capillary wedge pressure (PCWP; preload) and the systemic vascular resistance index (SVRI; afterload) were not different than controls. In uremic dogs, hemodialysis with acetate, but not with bicarbonate, decreased the MAP to values similar to controls. The decrease in MAP induced by acetate hemodialysis in uremic dogs was associated with a decrease in SVRI and PCWP. These results suggest that in dogs with acute uremia, acetate hemodialysis (HD) decreases myocardial contractility that was previously increased by a direct effect of uremia. In controls, acetate produced a moderate decrease in MAP that was the result of a mild decrease in CI and SVR. Since PCWP was not significantly decreased after acetate HD, the decrease in CI can be attributed to a mild decrease in myocardial performance. In conclusion, this study in dogs suggests that uremia enhances myocardial contractility directly. Acetate hemodialysis reduces this elevated myocardial contractility to normal values.

The effect of membrane permeability on ESRD: design of a prospective randomised multicentre trial.

The different permeability of high-flux and low-flux dialysis membranes results in different removal capacity, particularly for uremic toxins of middle and large molecular weight. High-flux dialysers have been evaluated in clinical and epidemiological studies for their effect on mortality, morbidity, dialysis-related amyloidosis, nutritional status, response to erythropoietin treatment, dialysis tolerance and the preservation of residual renal function. Many of these studies, however, lack a prospective design and randomised treatment allocation, or have too few patients and too short a follow-up. Therefore, this clinical trial was designed to prospectively investigate the long-term effect of membrane permeability on clinical outcome in a larger number of patients. The primary objective is to compare the effect of membrane permeability on mortality of patients on bicarbonate hemodialysis and treated with a minimum dialysis dose. Patients included in the study should have been on hemodialysis for no longer than one month and have serum albumin 4 g/dl or lower. Patients will be randomised to either the experimental or the control group. During the four-week run-in period the treatment parameters will be established in order to achieve the required dialysis dose. During the maintenance period of three to five years regular visits are scheduled to record clinical and laboratory parameters, to measure Kt/V and to adapt the treatment parameters. Altogether a minimum of 660 patients should be enrolled within a two-year recruitment period.

High ALT levels predict viremia in anti-HCV-positive HD patients if a modified normal range of ALT is applied.

AIMS: Some studies have reported that ALT determination is of little value in the study of chronic hepatitis C in hemodialysis (HD) patients. This could be due to the fact that ALT values are lower in HD patients than in healthy individuals; ALT in HCV infection follows a fluctuating pattern and the HCV viremia may be intermittent. The aim of this study was to establish the reference ALT values in a large group of hepatitis-free HD patients, and to determine their role in predicting viremia in anti-HCV-positive HD patients. METHODS: Four subject groups were studied: group I, patients with normal renal function (n = 88); group II, hepatitis-free HD patients (n = 218); group III, non-viremic anti-HCV+ HD patients (n = 9); and group IV, viremic anti-HCV+ HD patients (n = 24). The ALT used for calculation purposes was the mean value of the twelve previous months for each individual patient. PCR screening for HCV-RNA was performed at least twice for anti-HCV+ patients; these were deemed viremic (HCV-RNA+) if at least one screening was positive, and non-viremic (HCV-RNA) if all PCR results were negative. RESULTS: Mean ALT in group II was lower than in subjects with normal renal function (15.6 +/- 12 vs. 22.7 +/- 18 IU/l, p < 0.05). No significant differences were observed between group III and group II (17.7 +/- 6 vs. 15.6 +/- 6 IU/l, ns). ALT levels in group IV patients were higher than those of groups II and III (38.5 +/- 39 IU/l, p < 0.05). The upper limit (mean + 2 SD and 95th percentile) for ALT in hepatitis-free HD patients was 27 IU/l. Sensitivity of a mean ALT value > or = 27 IU/l in the diagnosis of HCV viremia was 50%, and specificity was 100%. The positive predictive value of this test in the diagnosis of hepatitis C viremia was 100%. CONCLUSIONS: ALT values are lower in HD patients and a high ALT level can constitute an excellent tool in predicting viremia in anti-HCV-positive HD patients once other causes of liver disease have been excluded.

Natural history of acute HCV infection in hemodialysis patients.

AIMS: Chronic liver disease develops in the majority of non-uremic patients with hepatitis C virus (HCV) infection. The aim of this study was to analyze the evolution towards chronic hepatopathy in 19 cases of acute hepatitis C observed in hemodialysis patients from 1990 to 2001. METHODS: A prospective follow-up study on HCV infection was conducted in 3 HD units from April 1990 to June 2001 to study clinical outcomes after acute hepatitis C. A total of 781 patients were tested monthly for alanine aminotransferase and anti-HCV in serum. In this period, 19 patients suffered from acute hepatitis C. Evolution to chronic liver disease in the follow-up was evaluated by means of biochemical (increased ALT) and virological criteria (HCV-RNA+). The transmission mechanism, the apparition of anti-HCV, clinical manifestations and mortality were also investigated. RESULTS: In 15 (78.9%) of the 19 patients, the viremia remained positive (chronic viremia) and 11 patients (57.8%) evolved to chronic liver disease (chronic viremia and high transaminase levels) with a median follow-up of 3 years (range 1 - 6). Five of them who underwent liver biopsies had histologic signs of chronic active hepatitis. One of them (5.2%) evolved to liver cirrhosis in the follow-up. In 4 out of 19 patients (21%) the HCV infection resolved. Although 7 (36.8%) of them died in the follow-up, acute hepatitis C infection was not a short-term independent risk factor of death. CONCLUSIONS: Three years after acute hepatitis C, 87.5% of the hemodialysis patients remained HCV-RNA positive and 56.2% evolved to chronic liver disease. It is important to stress that HCV infection spontaneously cleared in 4 out of 19 patients (21%).

Alpha-interferon therapy increases serum beta2-microglobulin levels in hemodialysis patients.

BACKGROUND/AIMS: Beta2-microglobulin is the main component of dialysis-associated amyloid. Interferons (IFNs) have the ability to induce an increase in the formation and release of this protein. The aim of this study was to evaluate serum beta2-microglobulin levels in 11 hemodialysis patients with chronic hepatitis C treated with IFNalpha. METHODS: Eleven hemodialysis patients with chronic hepatitis C that received IFNalpha treatment were included in this study. No patient had residual renal function. High-flux membranes were used in 5 patients, and low-flux membranes in the remaining 6 patients. Beta2-microglobulin was analyzed at baseline, during IFNalpha treatment and after IFNalpha was stopped. RESULTS: Serum beta2-microglobulin concentration rose in all patients during the IFNalpha therapy. Compared with baseline values (43 mg/l, range 22-59) the median beta2-microglobulin levels increased significantly at one month (65 mg/l, range 37-142, p = 0.008) and at 12 months (59 mg/l, range 42-137, p = 0.003) after the beginning of IFN therapy. One month after IFNalpha was discontinued, beta2-microglobulin decreased significantly (median 48, range 34-75 mg/l, p = 0.05) in comparison with that obtained at the end of the therapy. The increase observed during IFN therapy was lower in patients treated with high-flux membranes than in those with low-flux membranes, although it was not statistically different. CONCLUSION: Our results show that IFNalpha therapy increases serum beta2-microglobulin levels in hemodialysis patients. Further studies are needed to clarify whether the use of high-flux membranes should be recommended in hemodialysis patients requiring IFN treatment.

Interferon therapy in hemodialysis patients with chronic hepatitis C virus infection induces a high rate of long-term sustained virological and biochemical response.

AIM: The aim of the present study was to analyze the efficacy and tolerance of interferon (IFN) therapy in hemodialysis (HD) patients with chronic hepatitis C virus (HCV) infection. Specifically, we assessed whether the "normalization" of serum ALT levels was associated with the disappearance of the HCV-RNA. METHODS: Thirteen hemodialysis patients with chronic hepatitis C were treated for one year with 3 MU of alpha-IFN. The primary end point was a sustained virological response defined as the absence of HCV-RNA in the last follow-up; the secondary end points were normalization of the serum ALT levels and histological improvement. ALT was considered "normal" below 27 IU/l. RESULTS: Ten patients completed the treatment, which was discontinued in the other 3 (23%). By the end of the treatment a virological response was observed in 8 of the 10 patients (80%) who completed the one-year IFN therapy. Biochemical response was associated with a virological response in 8 of the 9 patients in whom ALT levels became normal. Three patients had a biochemical and virological relapse in the follow-up. Two of them received a further year of IFN therapy, which resulted in a sustained biochemical and virological response. In all patients who underwent a liver biopsy (n = 5), the inflammation score improved. After a median follow-up of 5 years (range 2 - 7), a sustained response was observed in 6 (46%) of the 13 patients enrolled. Two patients with a sustained response received a kidney transplant and after more than 6 years still maintain a biochemical and virological response. Side effects included flu-like syndrome (n = 8), hemoglobin decrease (n = 8), thrombocytopenia (n = 3), depression (n = 1) and seizures (n = 1). CONCLUSION: IFN treatment over a one-year period produces a high rate of long-term virological response in HD patients, associated to a biochemical response in all cases.

The effect of dialysate osmolarity on ultrafiltration and vascular refilling rate.

The osmotic gradient is the main driving force for ultrafiltration (UF) in continuous ambulatory peritoneal dialysis (CAPD). Depending on glucose absorption, its changes over a period of time could influence the plasma refilling rate. The aim of this study was to evaluate the influence of changes in the plasma refilling rate obtained by dialysates of different osmolalities upon the rate of UF. Stable CAPD patients were studied twice during a 4-hour exchange 2 weeks apart with dialysate containing 1.5% and 4.25% glucose, respectively. UF was estimated by the autologous hemoglobin dilution method every 30 minutes. Hematocrit and colloidosmotic pressure (COP) decrease when using 1.5% glucose dialysate, reflecting a rise in plasma water mediated by the plasma refilling rate. This water shift is greater than the osmotic gradient generated between peritoneal and intravascular compartments as reflected by a low UF rate. However, when the osmotic gradient increases by means of 4.25% glucose dialysate, the plasma refilling rate is efficiently counter-balanced by UF.

Factors affecting beta 2-microglobulin plasma concentration during hemodialysis.

We studied ten patients on hemodialysis (HD) treated in sequence with cuprophan (CU), ethylenevinylalcohol (EVAL), polyacrylonitrile (A-69) and polysulphone (PSP) membrane dialyzers. beta 2-microglobulin (beta 2m) was measured by radioimmunoassay in plasma and dialysate samples. Plasma concentrations were corrected for changes in extracellular volume (ECV). We also studied adsorption in vitro by incubating the above membranes with I-125-labelled beta 2m. There were no changes in beta 2m plasma concentration after HD with CU dialyzers, but a significant decrease was observed with the other membranes tested. Filtration of beta 2m across the dialyzer was absent with CU and minimal with EVAL. However, large amounts were recovered from dialysate with the high-permeability dialyzers, AN-69 and PSP. In vitro studies showed that maximal adsorption capacity was obtained with AN-69 (13%) compared to 9% with CU, 4% with EVAL and 7% with PSP. In summary, beta 2m clearance with PSP is achieved through greater removal of this protein by mass transport across the membrane. The mechanism by which beta 2m is removed from blood during AN-69 dialysis seems to include both adsorption to and filtration by the membrane itself.