Search

Background: Clinicians providing dialysis care have numerous erythropoiesis-stimulating agents (ESAs) available for treating anemia. We sought to provide a contemporary description of ESA types used in hemodialysis (HD) settings in nine European countries., Methods: Our study uses Dialysis Outcomes and Practice Patterns Study phase 5 (2012-2015) data from nine European countries (Belgium, France, -Germany, Italy, Russia, Spain, Sweden, Turkey, and the United Kingdom). A total of 164 facilities and 3,281 patients contributed cross-sectional data. ESA types captured included short-acting epoetins (e.g., epoetin alfa, beta, etc., including biosimilars), darbepoetin alfa, and continuous erythropoietin receptor agonist (CERA; methoxy polyethylene glycol-epoetin beta)., Results: We observed broad variability across countries in prescription of ESA types: prescription of epoetin alfa or epoetin beta ranged from 22% (France) to 78% (Russia), darbepoetin alfa prescription ranged from 13% (Russia) to 53% (UK), and CERA prescription ranged from <3% (Sweden) to 26% (France). Prescription of different ESA types varied substantially within some European countries from 2012-2015 but not across all countries in aggregate. Number of ESA types prescribed by a facility varied from 1, 2, 3, or 4 different ESA types in 32, 40, 21, and 8% of facilities, respectively. No differences were seen in the unadjusted distributions of achieved hemoglobin values by ESA type., Conclusion: A variety of short- and long-acting ESAs are commonly used in European HD facilities to maintain hemoglobin at remarkably similar levels with each ESA type. The availability of numerous ESA options for managing anemia has allowed European providers to optimize anemia management according to the particular circumstances of each patient., (© 2018 S. Karger AG, Basel.)

Background: To date, no data on the adherence to specific guidelines for children with chronic myeloid leukemia (CML) in chronic phase (CP) have been reported., Methods: Since 2001, guidelines for treatment with imatinib mesylate (IM) and monitoring in patients younger than 18 years with CP-CML have been shared with 9 pediatric referral centers (P centers) and 4 reference centers for adults and children/adolescents (AP centers) in Italy. In this study, the adherence to these guidelines was analyzed., Results: Thirty-four patients with a median age of 11.4 years and 23 patients with a median age of 11.0 years were managed at 9 P and at 4 AP centers, respectively. Evaluations of bone marrow (BM) and/or peripheral blood (PB) were available for more than 90% of evaluable patients. Cytogenetics and molecular monitoring of PB were more consistently performed in AP centers, whereas molecular analysis of BM was carried out more frequently in P centers. Before 2009, some patients who responded to IM underwent a transplantation, contrary to the guidelines' recommendations., Conclusions: Our experience shows that having specific guidelines is an important tool for an optimal management of childhood CP-CML, together with exchange of knowledge and proactive discussions within the network., (© 2018 S. Karger AG, Basel.)

Background: Anemia, a common complication of chronic kidney disease (CKD), has previously been attributed primarily to decreased production of erythropoietin. More recently, it has become apparent that the etiology of anemia involves several other factors, most notably dysfunctional iron metabolism, mediated via increased hepcidin activity and reduced clearance. Current management of anemia in patients with advanced CKD is based on erythropoiesis-stimulating agents and iron supplementation, along with red blood cell transfusions when necessary; however, safety considerations associated with these therapies highlight the need to pursue alternative treatment options targeting other mechanisms such as hypoxia-inducible factors (HIFs) that act as central regulators of erythropoiesis by coordinating a series of graded hypoxic responses., Summary: This review discusses the discovery of the HIF pathway and its regulation via HIF prolyl hydroxylase enzymes in the context of erythropoiesis and iron metabolism. The rationale for targeting this pathway and the clinical development of HIF prolyl hydroxylase inhibitors are reviewed, with a commentary on the potential implications of this class of agents in CKD anemia management. Key Messages: Pharmacologic activation of the HIF pathway results in a transient pseudo-hypoxic state that stimulates erythropoiesis in CKD patients with anemia. Results from clinical studies of a number of HIF prolyl hydroxylase inhibitors are increasingly available and provide support for the continued evaluation of the risk-benefit ratio of this novel therapeutic approach to the treatment of anemia in CKD., (© 2017 S. Karger AG, Basel.)

Patient morbidity and mortality rates are still very high in standard low-flux haemodialysis (lf-HD). On-line haemodiafiltration (OL-HDF) is considered the most efficient dialysis technique, as clearances of small solutes, like urea, may be even higher than in lf-HD and clearances of middle solutes, like β2-microglobulin, are much higher than in lf-HD. OL-HDF has been suggested to reduce mortality compared to HD, possibly due to more effective removal of larger uraemic retention solutes and/or better fluid removal. Only 1 out of the 3 largest randomized trials was able to demonstrate a positive effect of OL-HDF on patient survival in comparison to those randomized to HD. Post hoc analyses of these studies consistently showed that the patients randomized to OL-HDF who received the highest convection volumes had a lower risk of mortality and cardiovascular events than those randomized to HD. Four meta-analyses showed inconsistent results concerning the effect of convective treatments in improving general and cardiovascular survival, while they showed a significant reduction of the intradialytic symptomatic hypotension. An individual pooled participant analysis of the 4 largest trials confirmed these findings, suggesting a better survival when a convection volume of at least 23 litres/session was delivered, while other studies did not confirm these conclusions. Even after extensive statistical adjustments, residual confounding always remain; therefore, randomized control trials targeting different convection volumes are required to definitively confirm a dose-response effect of OL-HDF convection volume on patient survival., (© 2017 S. Karger AG, Basel.)

Erythropoiesis-stimulating agents (ESAs) and iron therapy are the standard of care for normocytic normochromic anaemia, which is a frequent comorbidity of patients with chronic kidney disease. In a large percentage of patients, ESAs and iron increase haemoglobin levels, thus reducing the risk of blood transfusions and improving patient quality of life. However, randomised trials have raised some concerns about higher haemoglobin targets and/or high ESA dose use. These concerns include higher cardiovascular and thrombosis risk, cancer progression, and increased mortality. A more cautious approach was then advised and partial anaemia correction (haemoglobin 10-12 g/dl) is now strongly suggested. The clinical concerns about ESAs and economic constraints have led to larger intravenous iron use. However, severe anaphylactic reactions, although infrequent, can occur and excessive iron use may be dangerous as well, possibly causing iron overload. Several attempts are being made to develop new drugs with theoretically better activity and safety, and/or easier manufacturing processes as compared to available ESAs. These include drugs manipulating the hypoxia-inducible transcription factor (HIF) system, which stimulates the endogenous erythropoietin (EPO) production and avoids unphysiological EPO plasma levels. Several phase I and II studies support the beneficial role of augmenting HIFs to stimulate erythropoiesis. Here we give an update on this new investigational strategy., (© 2017 S. Karger AG, Basel.)

Background/aims: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c)., Methods: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period., Results: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal., Conclusion: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels., (© 2015 S. Karger AG, Basel.)

Background/aims: Several randomised controlled trials (RCTs) have raised concerns about potential harm associated with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease patients, especially when haemoglobin (Hb) levels above 13 g/dl were targeted. We report the relationship between Hb levels and outcomes in the methoxy polyethylene glycol-epoetin beta RCT programme., Methods: We assessed the association between Hb and a composite end point, as well as its components [all-cause mortality, myocardial infarction (MI) or cerebrovascular events (CVE)], in multiple post hoc analyses of 9 prospective RCTs (3,405 chronic kidney disease patients). Mean Hb levels over time and deviation from target were analysed using a Cox regression model. Time-adjusted average Hb, deviation from target, the last Hb, Hb slope and within-patient Hb variability preceding an event were analysed using a time-dependent Cox model. Hazard ratios and 95% confidence intervals were calculated., Results: Average Hb <10 g/dl, decrease from stable baseline Hb >1 g/dl, last Hb <10 g/dl, Hb decline >1.5 g/dl/4 weeks and increased Hb variability were associated with a higher risk of the composite end point and all-cause mortality. An increased risk for CVE and MI was found with a last Hb <10 g/dl and with a decrease from baseline >1 g/dl in the preceding month., Conclusion: In multiple analyses from a large programme of prospective clinical trials of ESA treatment, risk of all-cause mortality and cardiovascular morbidity risk was consistently higher at Hb <10 g/dl and in patients whose Hb fell below target., (© 2014 S. Karger AG, Basel.)

Anemia is a common complication of patients receiving peritoneal dialysis (PD) but has been little studied compared to other chronic kidney disease (CKD) populations. A number of factors can affect its severity or response to erythropoiesis-stimulating agents (ESA). Some, such as iron deficiency, occult blood loss, infection, inflammation, oxidative stress, inadequate dialysis dose, and hyperparathyroidism are common to all dialysis patients but they may be more or less important depending on dialysis modality. The net balance of their contribution explains the fact that on average PD patients require less ESA doses compared to hemodialysis patients to correct anemia and maintain stable Hb levels. As in other CKD patients, low hemoglobin levels have been associated with increased mortality in PD patients. Unfortunately, no clinical trials have been carried out specifically in this population whether aiming at different Hb targets with ESAs may modify patient outcome. Given the lack of a vascular access, it is advisable to give PD patients ESA therapy subcutaneously. Long-acting molecules may be of advantage, especially when the drug is administered at the dialysis center., (Copyright © 2012 S. Karger AG, Basel.)

Today, hemodialysis (HD) represents a rescue therapy for an increasing number of patients worldwide. Thanks to continuous improvements, it is now better tolerated; thus, allowing patients relief from uremic symptoms and increasing survival. However, many questions regarding the best way of ameliorating the outcomes of chronic kidney disease patients requiring dialysis are still open. Recently, 2 randomized controlled clinical trials tried to give some answers to the current debates around dialysis. The first one--the IDEAL trial--evaluated the effects of beginning early or late dialysis on patient mortality and morbidity, and it did not find any significant difference between the 2 groups, suggesting that starting dialysis on the basis of an estimate of GFR alone is not suitable. The second one--the FHN daily trial--compared in-center conventional (3 times per week) with in-center frequent (6 times per week) HD. It found that daily dialysis is associated with improvements in left ventricular mass, physical health composite scores and some secondary outcomes (hypertension and hyperphosphatemia) - although it also discovered there had been more frequent interventions related to vascular access. Despite the fact that both studies presented some unavoidable limitations, they gave important information which is useful in everyday clinical practice. According to evidence-based medicine, such well-designed and well-conducted randomized controlled trials are the best way to improve our knowledge., (Copyright © 2011 S. Karger AG, Basel.)

Many observational studies have consistently shown that high-flux hemodialysis (hf-HD) has positive effects on the survival and morbidity of chronic kidney disease stage 5 dialysis (CKD5D) patients when compared with low-flux hemodialysis, but the primary analysis of the prospective randomized Hemodialysis Outcomes (HEMO) study showed that the use of hf-HD was not associated with a significant reduction of the relative risk of mortality. More recently, the Membrane Permeability Outcome (MPO) study found that survival could be significantly improved by use hf-HD compared with low-flux dialysis in high-risk patients as identified by serum albumin ≤4 g/dl and, in a post-hoc analysis, in diabetic patients. Online hemodiafiltration (HDF) is reported as the most efficient technique of using high-flux membranes. Clearances of small solutes like urea are higher than in hemofiltration and of middle solutes like β(2)-microglobulin are higher than in hf-HD. As the number of randomized prospective trials comparing HDF and hf-HD is still very limited, no conclusive data are available concerning the effect of increased convection of online HDF on survival and morbidity in CKD5D patients. A large, randomized controlled study is needed to clinically confirm the theoretical advantages of online HDF., (Copyright © 2011 S. Karger AG, Basel.)

Anemia secondary to chronic kidney disease is a complex syndrome. Adequate dialysis can contribute to its correction by removing small and possibly medium/large molecules that may inhibit erythropoiesis. A clear relationship among hemoglobin, erythropoiesis stimulating agent (ESA) dose and increase in dialysis dose has been pointed out by a number of prospective and retrospective studies. Increasing attention has also been paid to the relationship between dialysis, increased inflammatory stimulus and ESA response, as dialysate contamination and low compatible treatments may increase cytokine production and consequently inhibit erythropoiesis. As medium/large molecular weight inhibitors can be removed only by more permeable membranes, convective treatment sand, particularly, online treatments, could theoretically improve anemia correction by two mechanisms: higher removal of medium and large solutes (possibly containing bone marrow inhibitors) and reduced microbiological and pyrogenic contamination of the dialysate. Unfortunately, available results are conflicting. Large, prospective, randomized studies on this topic are still needed., (Copyright © 2011 S. Karger AG, Basel.)

The theoretical advantages of high-flux hemodialysis (HD) in treating patients with chronic kidney disease (CKD) stage 5 are related to the higher toxin removal (especially 'middle molecules'), including sodium and water, and to the better biocompatibility of the treatment, including membrane and water quality. Several observational studies have shown that high-flux HD has positive effects on the survival and morbidity of uremic patients when compared with low-flux HD. The primary analysis of the prospective randomized HEMO (Hemodialysis Outcomes) study showed that high-flux HD was associated with an 8% nonsignificant reduction of mortality in comparison with low-flux HD. However, a secondary analysis pointed to an advantage for high-flux HD in subgroups of patients. More recently, the MPO (Membrane Permeability Outcome) study found that survival could be significantly improved by using high-flux HD compared with low-flux HD in high-risk patients as identified by serum albumin ≤4 g/dl and, in a post hoc analysis, in diabetic patients as a whole. On-line hemodiafiltration (HDF) is considered the most efficient technique of using high-flux membranes. Clearance of small solutes like urea are higher than in hemofiltration, and clearance of middle solutes like β(2)-microglobulin are higher than in high-flux HD. Since there is only a very limited number of randomized prospective trials comparing HDF and high-flux HD, no conclusive data are available about the effect of increased convection of on-line HDF on survival and morbidity of CKD patients. The suggested advantages of HDF must be confirmed by a large randomized controlled study., (Copyright © 2011 S. Karger AG, Basel.)

Today, erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the main tool for anemia correction in chronic kidney disease patients. Over the past decades, a number of attempts have been made to modify the erythropoietin molecule in order to improve its pharmacokinetic and pharmacodynamic properties. More recently, small peptides, which are unrelated to erythropoietin but bind to the same receptor, have been developed. In addition to this, other strategies to stimulate erythropoiesis have been followed, such as activin inhibition or stabilization of hypoxia-inducible transcription factors. Interestingly, the latter have the advantage of being administered orally. New iron molecules, such as ferumoxytol, ferric carboxymaltose and iron isomaltoside 1000, have recently been marketed. These new agents can administered at high doses while releasing minimal free iron. Their safety profile is good, but long- term post- marketing data are still needed to evaluate the occurrence of rare adverse events., (Copyright © 2011 S. Karger AG, Basel.)

Many observational studies have consistently shown that high-flux hemodialysis has positive effects on the survival and morbidity of uremic patients when compared with low-flux hemodialysis. However, the HEMO study, a randomized trial designed to evaluate the effect of membrane permeability on patient survival, showed only an 8% non-statistically significant reduction of mortality, albeit a secondary analysis suggested an advantage for high-flux membranes in certain patient subgroups. The prospective, randomized Membrane Permeability Outcome (MPO) study investigated the impact of membrane permeability on survival in incident hemodialysis patients who had low albumin (≤4 g/dl) and normal albumin ( >4 g/dl) as separate randomization groups. Patients with serum albumin ≤4 g/dl had significantly better survival rates in the high-flux group compared with the low-flux group (p = 0.032). Moreover, a post-hoc secondary analysis showed that high-flux membranes may significantly improve survival in diabetic patients. No difference was found in patients with normal albumin levels. Considering the increasing number of dialysis patients with low serum albumin levels and with diabetes, the relevance of the MPO study led to the publication of a position statement by the European Renal Best Practice Advisory Board. This board strongly recommended that high-flux hemodialysis should be used for high-risk patients and, with a lower degree of evidence, even also for low-risk subjects due to the substantial reduction in β(2)-microglobulin levels observed in the high-flux group., (Copyright © 2011 S. Karger AG, Basel.)

The patent expirations for many biotechnological medicines have prompted the development of copies of biological medicinal products. Unlike generics, biosimilars are similar but not identical to their reference product, because their chemical characteristics are directly related to the manufacturing process which cannot be precisely duplicated. The regulatory policy for biosimilars is complex and in Europe it is regulated mainly by guidelines issued by the European Medicines Agency (EMEA); additional product-class specific guidelines have been developed as in the case of recombinant human erythropoietin (rHuEPO). In 2008, the experience gained with this drug has prompted the development of a new guideline, currently in draft. In this review we critically discuss aspects related to EMEA guidelines, particularly focusing on rHuEPO., (Copyright © 2010 S. Karger AG, Basel.)

Background: Oxidative stress, a recently identified factor related to the response to erythropoiesis-stimulating agents (ESAs), is increased in hemodialysis patients. The aim of this study was to verify whether ESA responsiveness improves if the anti-oxidant vitamin E (Vi-E) is placed on the blood-side layer of a synthetic polysulfone (PS) dialyzer., Methods: This 8-month, controlled and open randomized study involved 2 groups of patients on stable ESA therapy undergoing hemodialysis using a PS dialyzer with or without Vi-E treatment. Hemoglobin, albumin, high-sensitivity C-reactive protein, interleukin-6, iron status, parathyroid hormone (PTH), Vi-E (alpha- and gamma-tocopherol levels) and the oxidative stress markers, advanced oxidation protein products, carbonyls and advanced glycation end products were evaluated every 2 months. The primary outcome measure was ESA resistance, the weekly ESA dose divided by the product between hemoglobin level and end-dialysis body weight., Results: Nineteen of the 20 randomized patients completed the study. During the follow-up, the ESA resistance significantly decreased (p = 0.024), greater in the Vi-E group (37%) than in the PS group (20%), but this difference was not statistically significant (p = 0.596). Baseline PTH and Vi-E levels were associated with ESA resistance. In the secondary analysis, including these covariates in the model, the difference between groups in ESA resistance became significant (p = 0.042)., Conclusions: Vi-E placed on the blood-side of a dialyzer may have a possible beneficial effect on ESA resistance in hemodialysis patients; baseline PTH levels seem to predict ESA resistance and were useful in showing the possible beneficial effect of Vi-E and should be considered in designing adequate-sized trials for testing this hypothesis.

Recent observational studies of patients with stage 3-5 chronic kidney disease (CKD) not undergoing dialysis have shown that even slight increases in parathyroid hormone (PTH) levels are associated with an increased cardiovascular risk, regardless of the serum levels of calcium and phosphorus and vitamin D therapy. These studies suggest paying particular attention to monitoring PTH levels from the early stages of CKD, and preventing any mineral metabolism disorders that may trigger the excessive synthesis and secretion of PTH. However, it is not easy to determine when an appropriate response becomes maladaptive and requires the pharmacological suppression of the parathyroid gland because the gland's adaptive response can vary widely from one person to another. Furthermore, PTH levels are not always a good predictor of bone turnover and current PTH assays have various methodological limitations. Treating the early mineral metabolism abnormalities of CKD may help prevent the cardiovascular complications whose frequency, costs and mortality have a profound effect on society as a whole. For this reason, there is great interest in establishing adequate target ranges for PTH at different stages of CKD, and determining the most appropriate strategies for reaching them., (Copyright © 2010 S. Karger AG, Basel.)

The clinical benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are well established in chronic kidney disease (CKD) patients with diabetic and non-diabetic nephropathies. But despite appearance, the magnitude of this effect has been questioned particularly in mild, proteinuric nephropathies. Given that the single agents can achieve only partial and not durable suppression of the renin-angiotensin system (RAS), it has been hypothesized that dual blockage with ACE inhibitors and ARBs would be most beneficial in the management of progressive CKD than either agent alone. Available evidence indicates significant anti-proteinuric effect, but long-term data in CKD patients are lacking. Recently, the findings of the ONTARGET trial even questioned the safety of this therapeutic approach. Given that preventing cardiovascular complications is extremely important in CKD and RAS inhibition may be useful in this setting, benefits of RAS blockade must be weighed against its possible adverse effects particularly in elderly patients., ((c) 2009 S. Karger AG, Basel.)

The most appropriate dialysate composition is one of the central topics in dialysis treatment. The prescription of a certain dialysate composition could change in order to obtain not only an adequate blood purification but also a high tolerability. Sodium balance represents the cornerstone of cardiovascular stability and good blood pressure control. The goal of dialysis is to remove the amount that has accumulated in the interdialysis period. Potassium removal is adequate when hyperkaliemia is avoided. Bicarbonate in dialysate should be personalized in order to avoid acidosis and end-dialysis excessive alkalosis.

Recombinant human erythropoietin (rHuEPO) has revolutionized the management of anemia in patients with chronic kidney disease. However, being similar to the naturally occurring molecule, rHuEPO is not a perfect pharmaceutical. Given its relatively short halflife, it requires a relatively frequent administration schedule. Moreover, it can be administered only subcutaneously or intravenously and it is unstable at room temperature, making necessary a strict cold chain. Pharmacological research has focused on the development of new agents in order to circumvent these relative disadvantages. New-generation erythropoietin-stimulating agents containing increased carbohydrate content (i.e. darbepoetin-alpha) or a large water-soluble polyethylene glycol moiety (continuous erythropoiesis receptor activator) are already available or nearly for clinical use and allow less frequent administration schedules than rHuEPO. Hematide, which is a dimeric peptide with chemical structure unrelated to EPO, is undergoing phase III clinical trials. Other possible strategies currently under research include fusion EPO proteins, gene therapy, hypoxia-inducible transcription factor stabilizers, GATA inhibition and hematopoietic cell phosphatase inhibition.

Dialysis membrane characteristics are important for an effective and biocompatible dialysis. The properties of a membrane determine the size range of uremic toxins that are eliminated, but are also associated to patient morbidity and mortality. In this paper we describe dialysis the membrane characteristics that could influence the choice of a different type of dialysis.

Standard haemodialysis is not a very efficacious treatment of chronic uraemia and patient mortality rate is still very high. The 2002 results of the HEMO study showed that alternative treatments such as 'high-efficiency haemodialysis' and 'high-flux haemodialysis' are associated with a non-significant reduction in the relative risk of mortality (4 and 8%, respectively). In an attempt to define the clinical impact of haemodiafiltration, we review some of the efficacy data from clinical studies in light of a number of factors that may be related to the high mortality among haemodialysis patients.

The burden of kidney disease: Improving global outcomes. Chronic kidney disease (CKD) is a worldwide public health problem with an increasing incidence and prevalence of patients requiring replacement therapy. There is an even higher prevalence of patients in earlier stages of CKD, with adverse outcomes such as kidney failure, cardiovascular disease, and premature death. Patients at earlier stages of CKD can be detected through laboratory testing and their treatment is effective in slowing the progression to kidney failure and reducing cardiovascular events. The evidence-based care of these patients are universal and independent of their geographic location. This paper describes the need to develop a uniform and global public health approach to the worldwide epidemic of CKD. It is to this end that a new initiative Kidney Disease: Improving Global Outcomes' has been established. Some current and future activities of this initiative are described. They include among others modification of the classification of CKD, the development of guidelines on hepatitis C, the organisation of consensus conferences like on Renal Osteodystrophy, and the creation of a website allowing the comparison of the five main English language clinical practice guidelines in kidney disease worldwide.

High-flux membranes represented a major improvement in dialysis technique, but evidences supporting their clinical superiority over conventional low-flux dialysis are still inconclusive. Although several studies, most of which were observational, showed an association between high-flux dialysis and lower morbidity and mortality, the Hemodialysis (HEMO) study, the first large-scale randomized clinical trial specifically aimed at testing the effect of membrane permeability on patients' outcome, failed to demonstrate a statistical significant benefit of high-flux membranes on all-cause mortality. Although disappointing, these results should however be interpreted in light of some important limitations of the HEMO study, first of all the inclusion of both incident and prevalent hemodialysis patients, the exclusion of sicker patients and the allowance of dialyzer reuse. In this context, much is expected from the Membrane Permeability Outcome (MPO) study, a randomized clinical trial investigating the effect of high-flux membranes in a large population of incident hemodialysis patients across Europe. Inclusion of only incident patients, absence of severe exclusion criteria and no dialyzer reuse are all distinguishing features of this study. Analyses of the baseline data of the MPO study confirm the high burden of cardiovascular disease among incident dialysis patients, although comparison with the Dialysis Outcomes and Practice Patterns Study data provides further evidence of a positive selection of patients in clinical trials.

Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances that may be observed in patients with malignancies. Clinically significant TLS can occur spontaneously, but most often is seen 48-72 h after initiation of cancer treatment. The metabolic abnormalities observed in patients with TLS include hyperkalemia, hyperuricemia, and hyperphosphatemia, which leads to secondary hypocalcemia. The precise incidence of TLS is not defined, risk factors being represented by large tumor burden, neoplasms with either high growth fraction or high sensitivity to chemotherapy, and by pre-existing impairment of renal function. Neither racial, nor sex predilection exists. The pathogenesis of TLS is related to the rapid tumor cell turnover or destruction, which may result in release of intracellular ions and metabolic byproducts into the systemic circulation. Acute renal failure (ARF) may frequently complicate TLS and is mainly due to renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine. Hemodynamic changes reducing glomerular flow due to still undefined mediators are also involved in TLS pathophysiology. Pre-existing volume depletion or renal dysfunction may worsen metabolic derangements and ARF. A good comprehension of TLS pathophysiology has provided the basis for an effective and rational treatment of this complication, adversely affecting the outcome of cancer patients.

Immunosuppressive treatment of IgA nephropathy (IgAN) has been a controversial issue since many years, mainly because of skepticism on awaited results and fear of possible side effects. Some authors proposed the existence of a 'point of no return', after which the worsening in renal function becomes inexorable and treatment ineffective. Indeed, the decision to treat these patients is easily followed by disappointment due to lack of favorable results. We report the case of a 24-year-old woman with a diagnosis of IgAN with advanced sclerosis and chronic renal failure. After treatment with a 6-month steroid course, she experienced a long-lasting stabilization of renal function (serum creatinine) and decrease in proteinuria (from 2.9 to 0.46 g/24 h) that still persisted at the end of follow-up (48 months). Analysis of this case and review of the literature suggest that immunosuppressive treatment could delay the beginning of renal replacement therapy in the advanced phase of IgAN. However, the results of long-term, randomized, controlled, adequately sized trials are awaited., (Copyright 2002 S. Karger AG, Basel)

Despite the many technical advances in medical care and dialysis delivery, mortality and morbidity remain high in end-stage renal disease (ESRD) patients. A number of factors seem to contribute. Cardiovascular diseases are the leading cause of death: volume overload, anaemia, hypertension, arteriovenous fistula, uraemia-related myocardial cell injury all contribute to the development of ischaemic heart disease and congestive heart failure. The underlying disease is determinant for prognosis, with diabetics displaying an excess cardiovascular mortality. Elderly are also more likely to experience intercurrent medical conditions, vascular disease and diabetes, thus increasing the risk of death. Protein-energy malnutrition and wasting also contribute to the higher mortality in renal replacement therapy. Although nowadays high-risk patients are dialysed too, the rate of acceptance of ESRD patients still varies widely in different countries, possibly because of hidden selection criteria. The patients in the registries with a higher acceptance rate are more likely to be affected by co-morbid conditions and greater disease severity; the assessment of these co-morbid conditions is extremely important when comparing outcomes in different haemodialysis populations. Dialysis adequacy, obtained by means of longer duration of the treatment, is also of paramount importance; it allows minimizing the clinical effects of ultrafiltration and ensure that correct dry weight is reached. This means decreasing the incidence of intradialytic hypotensive episodes, but also improving blood pressure control, a strong predictor of survival. Family and social support, together with adequate medical care, greatly affect the quality of life of patients and can improve compliance to dialysis, diet and drugs and therefore survival.

There are very few data on the molecular biology of hepatitis C virus (HCV) infection in dialysis patients. 101 patients undergoing dialysis treatment in 4 units in the Lombardy, northern Italy, were analyzed by RT-PCR for HCV viremia, by line probe assay technology for HCV genotyping and by a serological analysis for detecting type-specific antibodies. 61 of 101 (60%) patients showed detectable HCV RNA in serum; HCV genotype 2a was dominant (30/53 = 57%), followed by HCV genotype 1b (20/53 = 37%). There was no relationship between HCV genotyping and the clinical or demographic features of the patients. The antibody response toward the c33-c, c100-3, and 5-1-1 antigens was more frequent in HCV genotype 1b compared with genotype 2a (p = 0.046, p = 0.001 and p = 0.0001, respectively). The antibody levels to NS-3 and NS-4 HCV proteins were significantly higher in patients with-HCV genotype 1b in comparison with HCV 2a-infected individuals (p = 0.0001). There was a high level (82%) of agreement between HCV genotyping by RT-PCR and the assessment of type-specific antibodies by serological analysis; further, it was possible to detect type-specific antibodies in 6 of 22 (27%) patients in whom PCR amplification was unsuccessful. In conclusion, HCV subtype 2a was dominant in our population of HCV-infected dialysis patients, dialysis patients infected by different genotypes showed similar demographic and clinical characteristics, the antibody response toward the NS-3- and NS-4-related antigen of HCV was genotype dependent. There was a high level of agreement between HCV genotyping by RT-PCR and the detection of type-specific antibodies by serological analysis. As significant biological differences may exist among HCV strains, the assessment of HCV types may be very useful in the routine clinical activity of nephrologists in dialysis units.

The aim of this study was to analyze the factors affecting chronic renal insufficiency (CRI) progression at diagnosis (markers of progression), their spontaneous or therapy-induced behavior, and their relationship to CRI progression during follow-up. The underlying disease is the 'determinant factor' of progression and although clinical trials usually report crude cumulative renal survival without taking into account concomitant risk factors, it is known that diabetic nephropathy, polycystic kidney disease, and glomerulonephritis are more progressive than nephroangiosclerosis and interstitial nephropathy. Among the 'effect modifiers,' the baseline level of renal function, hypertension, and proteinuria are the most important. The adverse synergistic effects of proteinuria and high blood pressure have been confirmed, and the importance of correcting hypertension (systemic and glomerular) and proteinuria for slowing disease progression has also been demonstrated. The potential adverse role of a high-protein intake, strongly suggested by experimental studies and the clinical data of uncontrolled trials, has been challenged by the data coming from large controlled trials. The role of lipids needs to be clarified by prospective randomized trials, but the effects of therapeutic interventions aimed at correcting lipid abnormalities seem very promising. The association between the DD genotype of the gene encoding the angiotensin-converting enzyme (ACE) and an increased risk of renal function loss is under evaluation with the aim of identifying the patients who may most benefit from ACE inhibition.

The aim of this prospective and randomized study was to compare the efficacy, side effects, and costs of 'pulse oral' versus intravenous calcitriol in the treatment of secondary hyperparathyroidism in hemodialysis (HD) patients. A total of 20 patients were randomized to receive over a 4-month period pulse orally administered calcitriol (pulse oral group; n = 10) or intravenous calcitriol (intravenous group; n = 10). All patients used standard dialysate calcium (1.75 mmol/l) throughout the study period. In accordance with the study design calcium dialysate concentrations were reduced when this was necessary to avoid hypercalcemic crises. The patients were stratified into two subgroups according to their initial serum PTH levels: patients with mild or moderate degree of hyperparathyroidism (17 patients) and patients with severe hyperparathyroidism (3 patients). Intravenous and pulse oral cacitriol did not significantly reduce serum PTH concentrations in patients with severe hyperparathyroidism (1,157 +/- 156 vs. 807 +/- 228 pg/ml [corrected], p = 0.09). Intermittent calcitriol, administered by intravenous or oral route, significantly reduced serum PTH levels (326 +/- 119 vs. 109 +/- 79 pg/ml [corrected], p = 0.0001) in patients with mild or moderate hyperparathyroidism. In patients with mild or moderate hyperparathyroidism, intravenous calcitriol significantly reduced PTH concentrations at the end of the 1st month, before the increase of serum ionized calcium levels, whereas 'pulse oral' calcitriol significantly suppressed parathyroid activity at the end of the 2nd month. Calcium dialysate concentration was reduced in 9 out of 10 (90%) patients of the pulse oral group and in all patients (10/10) of intravenous group. The incidence of hypercalcemic crises was 24% (39/160) in the pulse oral group and 14% (27/160) in the intravenous group. Analysis of costs showed that intravenous calcitriol was more expensive compared to pulse oral calcitriol. These data indicate that intermittent intensive calcitriol therapy, regardless of the route of administration, is effective in suppressing parathyroid activity in HD patients with mild or moderate hyperparathyroidism. In contrast, intermittent calcitriol therapy has a limited ability to achieve sustained serum PTH reductions in HD patients with severe hyperparathyroidism. Intravenous calcitriol was more expensive than pulse oral calcitriol, and we recommend the use of pulse oral calcitriol in HD patients with mild or moderate secondary hyperparathyroidism.

The prevalence of hepatitis B virus (HBV) infection in our unit was 45% (86/190); there were 77 (40.5%) and 9 (4.7%) patients with previous and persistent HBV infection, respectively. Recombinant hepatitis B vaccine was given to 118 chronic HD patients with a regimen of 3 double doses administered intramuscularly at 0, 1 and 2 months, obtaining a seroprotection rate of 67% (79/118), 57% (45/79) being high responders. At month 24, 78% (40/51) maintained protective levels of anti-HBs, 45% (18/40) of them being high responders. There was a statistically significant difference between responder and non-responder patients with regard to nutritional parameters such as serum total proteins and mean levels of transferrinemia. The number of diabetic patients was significantly increased in the nonresponder group. Patients with persistent antibodies ('persistent responders') were younger and had a shorter duration of HD treatment compared to those responders who rapidly lost anti-HBs ('transient responders'). Serological positivity for antibodies against hepatitis B core antigen significantly facilitates the decrease of anti-HBs antibodies over time. We detected seven episodes of HBV infection among HD patients at our unit before the beginning of the vaccination program. On the contrary, there were no episodes of HBV infection among responder vaccinees during the 24-month follow-up period. After the initial cost of vaccination, a savings of US$ 3,272 per year was realized by the elimination of frequent serologic screening of vaccine responders.

It has been shown that calcium carbonate (CaCO3) is an effective phosphate binder which is less toxic than Al(OH)3. However, given that its use with standard calcium dialysate (CaD) levels may lead to hypercalcemia, a decrease in CaD levels has been proposed. The aim of the present study was to elevate the acute clinical and biochemical consequences of a lowering of CaD in HD patients. Dialysate composition was otherwise the same. (1) Blood pressure levels (BP) during short hemodialysis were measured in a group of 12 patients who underwent alternate hemodialyses with dialysate calcium of 1.75 and 1.25 mmol/l. (2) Ca2+ and PTH kinetics during short hemodialysis were studied in a group of 6 patients who were sequentially treated with 1.75 and 1.25 mmol/l CaD. The results show: (1) that cardiovascular stability in chronic HD patients during short HD sessions with low CaD (LCaD) may be good; (2) that a single treatment with standard CaD (SCaD) produces positive calcium balances (JCa2+) with Ca2+ plasma increase and PTHi inhibition at the end of HD sessions; during HD with LCaD there were neutral mean JCa2+ and no changes in post-dialysis mean Ca2+ and PTHi plasma levels; furthermore 2 patients showed a small PTHi increase during HD with LCaD and neutral JCa2+ because of a high positive bicarbonate balance during HD. In conclusion, as with several aspects of dialysis treatment, dialysate calcium levels should also be individualized to avoid hypercalcemic crises or PTHi stimulation.

A multicentre trial (11 nephrology centres) was carried out to test the effects of ibopamine, an orally active dopamine-like drug, on the progression of chronic renal failure. For a 2-year period 189 chronic renal failure patients (serum creatinine level 1.5-4.0 mg/dl) were observed. They were homogeneous for basic nephropathy, degree of residual renal function, blood pressure, and proteinuria. The patients were randomly divided into two groups: 96 took ibopamine at a dosage of 100 mg/day (group A) and 93 served as controls (group B). All were on a low-protein diet (mean 0.8 g/kg body weight). By the end of the observation period, the rate of decrease of the renal function indexes in time proved significantly slower (1.8 times) in group A than in group B. The survival curves for renal function (pre-established end points were creatinine level increases equal to or > 20% and equal to or > 40% of the basal values) proved significantly better (p < 0.02 and p < 0.002 respectively) in group A than in group B. The mean plasma creatinine values rose by 17% in group A and by 36% in group B. The creatinine clearance decreased by 5% in treated patients and by 14% in the controls. Statistical analysis ruled out any possible centre effect. The trial suggests that low-dosage ibopamine administration may be used as a valid and safe pharmacological adjunct for retarding the progression of renal failure in patients with mild or moderate chronic renal impairment.

The aim of this study was to compare some common tests which are nowadays routinely used to screen and to confirm anti-HCV antibodies in renal patients. There was agreement between Ortho 2 and Abbott 2 in 94% of samples; structural and nonstructural beads of the Abbott supplementary assay were in agreement with 4-RIBA in 98 and in 85% of samples, respectively; 61% of Ortho 2 samples and 65% of Abbott 2 samples were confirmed by 4-RIBA; there was a correlation between semiquantitative analysis of screening tests (Ortho 2 and Abbott 2) and positive results by 4-RIBA; 36 and 33% of Ortho-2- and Abbott-2-positive samples were 4-RIBA indeterminate: in these instances more sophisticated techniques (polymerase chain reaction) (PCR) could be useful as a third-level assay. The comparison between Ortho 2, based on recombinant antigens, and Innotest, based on synthetic peptides, showed agreement only in 44% of samples, but this preliminary comparison cannot afford definitive conclusions. These findings suggest that second-generation assays may sometimes yield conflicting results in renal patients. These contradictions will be resolved by new HCV tests or PCR.

Growth velocity pattern and growth hormone (GH) secretion were evaluated in 18 prepubertal patients (13 males, 5 females), receiving an allogeneic (7 patients) or autologous (11 patients) bone marrow transplantation (BMT). Children were affected by oncological or hematological malignancies and the age range was between 2 and 11 years. Nine patients received a conditioning regimen consisting of chemotherapy and fractionated total body irradiation (TBI) (12 Gy in 6 fractions over 3 days), whereas 9 children also received previous prophylactic cranial irradiation during first-line chemotherapy. GH secretion in response to pharmacological stimuli (insulin, arginine and/or L-Dopa) was evaluated when growth failure occurred. The 9 prepubertal patients who had received previous prophylactic cranial irradiation during first-line chemotherapy, showed a significant decrease in growth rate already 1 year after BMT and this reduced growth rate presented a progressive further decrease in the 2nd and 3rd year after BMT. On the contrary, in the 9 prepubertal children treated with TBI and chemotherapy alone, growth rate presented an impressive decrease only during the 3rd year. In the two groups of patients, pretransplantation growth rates were comparable, while, due to the earlier growth failure in children receiving TBI and previous prophylactic cranial irradiation, mean standard deviation score (SDS) significantly differed at 1 and 2 years following BMT. Such a difference disappeared at 3 years after BMT, because of the late decrease in growth rate in patients given TBI and chemotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)