Donor-Specific Antibodies After Starting Hemodialysis in Nonrenal Solid Organ Transplant Recipients: Role of TH17.

BACKGROUND: Nonrenal transplantation could cause a progressive deterioration in renal function until need dialysis. It is important to know if these patients increased their risk to develop de novo donor-specific anti-HLA antibody (DSA) after starting hemodialysis (HD) and if so, try to find the mechanism. MATERIAL AND METHODS: In this double-phase study, we first analyzed the incidence of development DSA in nonrenal transplant recipients after starting HD by a retrospective study. Secondly, a prospective study was designed to analyze the pharmacokinetics of immunosuppressive drugs and the cytokine profile of these patients. RESULTS: Of 179 pancreas transplant recipients, 16 needed to start HD, and 62.5% of these patients developed de novo DSA after starting HD, with 80% of them class I DSA. In the second phase of the study, the plasma levels of the immunosuppressive drugs as measured by a limited sampling strategy of 3 sample time points (C0, C2, and C4) were stable. The cytokine profile showed that there was an increase in Th1 cytokine (interferon gamma of 0.045 ng/mL) and also in Th17 cytokines (transforming growth factor ß >10 ng/mL). CONCLUSION: Our data suggest that the development of DSA after starting HD in nonrenal transplant recipients could be mediated by Th17 immune response mechanisms.

[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.

PHF on-line sin acetato: cómo mejorar la hiperacetatemia y la tolerancia hemodinámica / No disponible

Antecedentes: la presencia de acético en el Líquido de Diálisis (LD) expone al paciente a una concentración de acetato 30-40 veces superior a la normal. Dicha exposición aumenta en técnicas de Hemodiafiltración (HDF) online. El objetivo de dicho estudio fue evaluar los cambios clínico-analíticos al usar tres técnicas de Hemodiálisis(HD) diferentes. Métodos: se reclutaron 35 pacientes en HD estable. Se dializaron tres meses con HD convencional y luego fueron aleatorizados para pasar a una técnica de PHF on-line con concentrado convencional seis meses, y después pasaron a PHF on-line sin acetato otros seis meses. El otro grupo invertía estos dos períodos. Se obtuvieron análisis de sangre y datos clínicos de HD. Resultados: las medias de los acetatos posdiálisis fueron significativamente superiores durante los períodos de tratamiento con acético respecto al período sin acetato. El porcentaje de valores patológicos de acetato posdiálisis fue significativamente superior durante los períodos de tratamiento con acético (61 respecto al 30%). Las concentraciones de cloro pos-HD fueron superiores y las de bicarbonato pre y pos-HD fueron menores durante el período sin acético. El número de hipotensiones fue significativamente inferior en el período de PHF on-line con LD estándar respecto a los otros períodos. Conclusiones: la técnica de PHF on-line sin acetato disminuye la exposición a concentraciones elevadas de acetato y consigue que la mayoría de pacientes termine la HD con una acetatemia en el rango fisiológico. La PHF on-line es un tratamiento de HDF predilucional con mejor tolerancia que la HD estándar con bicarbonato (AU)

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 amountis 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 6months or to invert the two last periods. Blood samples were drawn monthly throughout the study and clinical data were obtained. Results: Posdialysis 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 posdialysis 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 posdialysis were higher and serum concentrations of bicarbonate pre and poshemodialysis 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 (AU)

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%).

Risk of death and liver cirrhosis in anti-HCV-positive long-term haemodialysis patients.

BACKGROUND: Hepatitis C virus (HCV) infection is the most common cause of chronic liver disease in haemodialysis patients. The aim of this study was to assess the impact of HCV infection on patient survival in a cohort of long-term haemodialysis patients and to evaluate the percentage of anti-HCV-positive patients that evolve to liver cirrhosis. METHODS: In 1992, 175 patients who had been on intermittent haemodialysis therapy for at least 6 months were included in the study (57 anti-HCV-positive and 118 anti-HCV-negative patients). Evaluation of patient outcome included date and cause of death, kidney transplantation, and the diagnosis of liver cirrhosis. Patient survival was estimated by the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazards model was used to estimate the risk of death among dialysis patients who were anti-HCV positive. Other prognostic variables studied included age, gender, diabetes mellitus as cause of end-stage renal disease (ESRD), history of previous transplant, transplantation during follow-up, and time on haemodialysis treatment. The diagnosis of liver cirrhosis was made based on clinical and/or histological criteria. RESULTS: Eight-year patient survival in anti-HCV-positive subjects was lower (32%) than in anti-HCV-negative patients (52%) (log-rank, P=0.03). Four variables were found to be independent prognostic factors in patient survival: age (relative risk (RR) 1.04); diabetes as cause of ESRD (RR 3.6); transplantation during follow-up (RR 0.66) and presence of HCV antibodies (RR 1.62). The causes of death did not differ significantly between groups, except that four anti-HCV-positive patients died from liver disease. Ten (17.5%) of the 57 anti-HCV-positive patients were diagnosed to have liver cirrhosis at a median of 10 years after renal replacement therapy initiation and a median of 7 years after the first ALT level increase. CONCLUSION: In conclusion, our study shows an increased risk of death among long-term haemodialysis patients infected with HCV compared with non-infected patients. This might be partly explained by the high proportion of these patients that evolve to liver cirrhosis.

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.

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.

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.