Effect of dialysis dose and membrane flux in maintenance hemodialysis.
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Hemodialysis Solutions↗
Biomedical subjects
Francesco Locatelli
Publications and source records attributed to Francesco Locatelli.
Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.
BACKGROUND: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause. OBJECTIVE: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo. DESIGN: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used. SETTING: 209 centers in the Americas, Europe, Israel, and Australasia. PARTICIPANTS: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 micromol/L (1.0 mg/dL) to 266 micromol/L (3.0 mg/dL) in women and 106 micromol/L (1.2 mg/dL) to 266 micromol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d. INTERVENTION: Treatment with irbesartan, amlodipine, or placebo. MEASUREMENTS: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization. RESULTS: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004). CONCLUSION: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.
Amlodipine↗
Health-related quality of life as a predictor of mortality and hospitalization: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
BACKGROUND: We investigated whether indicators of health-related quality of life (HRQOL) may predict the risk of death and hospitalization among hemodialysis patients treated in seven countries, taking into account serum albumin concentration and several other risk factors for death and hospitalization. We also compared HRQOL measures with serum albumin regarding their power to predict outcomes. METHODS: We analyzed data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international, prospective, observational study of randomly selected hemodialysis patients in the United States (148 facilities), five European countries (101 facilities), and Japan (65 facilities). The total sample size was composed of 17,236 patients. Using the Kidney Disease Quality of Life Short Form (KDQOL-SFTM), we determined scores for three components of HRQOL: (1) physical component summary (PCS), (2) mental component summary (MCS), and (3) kidney disease component summary (KDCS). Complete responses on HRQOL measures were obtained from 10,030 patients. Cox models were used to assess associations between HRQOL and the risk of death and hospitalization, adjusted for multiple sociodemographic variables, comorbidities, and laboratory factors. RESULTS: For patients in the lowest quintile of PCS, the adjusted risk (RR) of death was 93% higher (RR = 1.93, P < 0.001) and the risk of hospitalization was 56% higher (RR = 1.56, P < 0.001) than it was for patients in the highest quintile level. The adjusted relative risk values of mortality per 10-point lower HRQOL score were 1.13 for MCS, 1.25 for PCS, and 1.11 for KDCS. The corresponding adjusted values for RR for first hospitalization were 1.06 for MCS, 1.15 for PCS, and 1.07 for KDCS. Each RR differed significantly from 1 (P < 0.001). For 1 g/dL lower serum albumin concentration, the RR of death adjusted for PCS, MCS, and KDCS and the other covariates was 1.17 (P < 0.01). Albumin was not significantly associated with hospitalization (RR = 1.03, P> 0.5). CONCLUSION: Lower scores for the three major components of HRQOL were strongly associated with higher risk of death and hospitalization in hemodialysis patients, independent of a series of demographic and comorbid factors. A 10-point lower PCS score was associated with higher elevation in the adjusted mortality risk, as was a 1 g/dL lower serum albumin level. More research is needed to assess whether interventions to improve quality of life lower these risks among hemodialysis patients.
Aged↗
Pure red cell aplasia secondary to treatment with erythropoietin.
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Anemia↗
Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo).
BACKGROUND: Darbepoetin alfa is an erythropoietic agent with a 3-fold longer elimination half-life than recombinant human erythropoietin (rHuEpo), which allows less frequent dosing. This study investigated the safety and efficacy of darbepoetin alfa for treating anaemia in dialysis patients, using a dosing regimen that was independent of the patient's body weight (unit dosing). METHODS: Dialysis patients (n=341) maintained on rHuEpo treatment (alfa or beta) were switched to darbepoetin alfa at a reduced dosing frequency, but by the same route of administration [intravenous (i.v.) or subcutaneous (s.c.)]. Patients receiving rHuEpo two or three times weekly changed to once-weekly darbepoetin alfa, and those receiving rHuEpo once weekly changed to once every other week darbepoetin alfa. The unit doses of darbepoetin alfa (10-150 microg) were titrated to maintain haemoglobin concentrations within -1.0 and +1.5 g/dl of the individual mean baseline haemoglobin and between 10 and 13 g/dl for 24 weeks. RESULTS: Mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was 0.13 g/dl (95% CI, 0.01, 0.25), which was not clinically relevant. An analysis by route of administration revealed that mean haemoglobin concentrations had increased by 0.58 g/dl (95% CI, 0.33, 0.82) in patients receiving i.v. darbepoetin alfa, and previously treated with i.v. rHuEpo, while remaining unchanged in s.c. patients (0.00 g/dl; 95% CI, -0.13, 0.13) previously treated by s.c. rHuEpo. In addition, there was a statistically significant decrease in mean weekly i.v. darbepoetin alfa dose requirements from 25.2 microg/week at baseline to 21.5 microg/week (P=0.004) during the evaluation period (-17.3%). Subcutaneous weekly dosage requirements increased slightly during the study period (20.8 to 22.7 microg/week; P=0.014). An i.v./s.c. dose ratio of 0.95 (95% CI, 0.78, 1.14) at evaluation confirms previous findings that dose requirements by the i.v. and s.c. routes were not different in patients treated with darbepoetin alfa. Haemoglobin concentrations were also effectively maintained in patients who received darbepoetin alfa once weekly and once every other week. Darbepoetin alfa was well tolerated. CONCLUSIONS: The treatment of renal anaemia in dialysis patients with unit doses of darbepoetin alfa effectively and safely maintains target haemoglobin concentrations with less frequent dosing. Dose requirements for darbepoetin alfa following i.v. and s.c. administration were not different. The results of this study demonstrate that darbepoetin alfa administered i.v. once weekly, or once every other week is an effective treatment regimen for haemodialysis patients with renal anaemia.
Aged↗
Oxidative stress in end-stage renal disease: an emerging threat to patient outcome.
INTRODUCTION: Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors. Among emerging CVD risk factors, oxidative stress is currently being given emphasis. METHODS: We achieved a consensus on key points relating to oxidative stress in ESRD patients. RESULTS: ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bio-incompatibility of dialysis membranes and solutions). Oxidative stress and inflammation are deeply inter-related, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response. There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia. Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies). At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic anti-oxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated. However, many laboratory methods assessing various oxidative stress components still have to be standardized. Moreover, it is still uncertain whether it is better measuring plasma and/or intracellular concentrations or activities of these components. The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, e.g. by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive. CONCLUSIONS: It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena. Further well-designed, randomized controlled clinical trials with anti-oxidants (e.g. vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice.
Cardiovascular Diseases↗
Epidemiology of cardiovascular risk in patients with chronic kidney disease.
BACKGROUND: Chronic kidney disease (CKD) patients are highly prone to cardiovascular disease for a number of reasons. At the time of starting renal replacement treatment, their cardiovascular condition is already severely compromised, suggesting that cardiovascular risk factors begin to operate very early in the progression of CKD. Moreover, those patients reaching end-stage renal disease without cardiovascular abnormalities have a high probability of developing de novo cardiovascular disease. METHODS: In this review, we analyse the prevalence of the major cardiovascular risk factors in CKD patients and their importance as contributors to the excess cardiovascular disease in this population. We also describe and discuss the main results obtained in the management of these risk factors in terms of preventing cardiovascular morbidity and mortality. RESULTS: Hypertension plays a major role in determining cardiac damage at all stages of CKD, including the dialytic phase. Anaemia is a major determinant of the development of left ventricular hypertrophy and therefore its correction can be expected to improve cardiovascular status and long-term survival, but this needs to be done before changes in cardiac structure become well established. Calcium-phosphate disorders are increasingly acknowledged to be cardiovascular risk factors in CKD, yet their medical control is still far from being satisfactory. Dyslipidaemia is particularly frequent in CKD patients, but the benefit of lipid-lowering treatments still has to be proven. Finally, CKD is associated with newly recognized risk factors for atherosclerosis, although their importance as cardiovascular risk factors is still controversial. CONCLUSIONS: Nephrologists should attempt to give optimal treatment for well-established cardiovascular risk factors, even if this generally fails to prevent the excess cardiovascular disease of CKD patients. Increasing attention is now being paid to newly recognized CKD-related risk factors for atherosclerosis, although their real importance is still under debate and, before therapeutic prescriptions can be applied to CKD patients, further studies in these new fields are needed.
Cardiovascular Diseases↗
The quality of dialysis water.
INTRODUCTION: Every week, haemodialysis patients are exposed to approximately 400 l of water used for the production of dialysis fluids which, albeit with the interposition of a semi-permeable artificial membrane, come into direct contact with the bloodstream. It is therefore clearly important to know and monitor the chemical and microbiological purity of dialysis water. METHODS: In this review, we analyse the sources of chemical and microbiological water contamination, and the problems involved in water purification systems and modalities. We also analyse the compliance of dialysis units with the microbiological standards established by the most widely accepted guidelines relating to the quality of dialysis fluids. RESULTS: The risk of chemical contamination is due mainly to the primary pollution of municipal water, whereas the most important microbiological problem is the control of bacterial growth in the water treatment and distribution system. Dialysis water treatment implies various levels of pre-treatment, a final purification module (which, in many cases, is reverse osmosis: RO) and a hydraulic circuit for the distribution of the purified water. RO-based treatment systems produce water of optimal chemical and microbial quality, and so dialysis units need to concentrate on maintaining this quality level in the long term by means of effective maintenance and disinfection strategies. The most widely accepted standards for water purity are those recommended by the Association for the Advancement of Medical Instrumentation and the European Pharmacopea, which respectively allow bacterial growth of <200 and <100 c.f.u./ml, and an endotoxin concentration of <2 and <0.25 IU/ml. However, a number of multicentre studies have reported that 7-35% of water samples have bacterial growth of >200 c.f.u./ml, and up to 44% have endotoxin levels of >5 IU/ml. CONCLUSIONS: The results of multicentre studies indicate that the microbial quality of dialysis fluids is still a too often neglected problem, particularly as there is evidence of a possible relationship between dialysis fluid contamination and long-term morbidity. The time has now come to take advantage of innovations in water treatment processes and improvements in dialysis machines in order to modify clinical practices and start improvement processes aimed at decreasing the risk of microbial contamination to the minimum, as it has already been successfully done in the case of chemical contamination.
Dialysis Solutions↗
Sodium removal during pre-dilution haemofiltration.
BACKGROUND: Cardiovascular instability still affects a large percentage of uraemic patients undergoing extracorporeal substitutive treatments. Post-dilution haemofiltration has been reported to be a method for improving cardiovascular stability; however, the limited removal of small molecular weight solutes together with the need for high blood flow from the fistula greatly restrict the use of this treatment. To increase the solute clearances and to partially resolve the necessity for high blood flow, the replacement solution, in a quantity about double that used in post-dilution mode, can be administered in pre-dilution mode. A high vascular stability has also been observed for pre-dilution haemofiltration. Since the lower morbidity may be due to less sodium removal when compared with haemodialysis, it would be important to characterize the sodium transport in this kind of treatment. METHODS: Nine patients underwent nine pre-dilution haemofiltration treatments (one for each patient) with on-line prepared substitution fluid. RESULTS: As mean values, total (NaF(pw)) and ionized (NaE(pw)) plasma water sodium concentrations increased from 149.4 +/- 2.8 mEq/l to 151.1 +/- 2.4 mEq/l, and from 143.1 +/- 2.8 to 144.5 +/- 1.2 mEq/l, respectively, during the treatment, suggesting a hypotonic concentration of net ultrafiltrate. Plotting the difference between final and initial ionized plasma water concentrations (fNaE(pw) - iNaE(pw)) against the difference between initial plasma water values and ionized sodium concentration in the reinfusate (iNaE(pw) - NaE(R)), a significant negative correlation was found, with the regression line that intercepts the abscissa at the (iNaE(pw) - NaE(R)) value of 8.8 mEq/l; this means that to avoid changes in NaE(pw) in our patients, the NaE(R) should be lower than the iNaE(pw) by this amount. This is quite different from the theoretical value of approximately 4 mEq/l necessary to avoid changes in NaE(pw) during haemodialysis. The ratio between the total sodium concentration in the ultrafiltrate (NaF(uf)) and NaF(pw) (alpha) at the post-reinfusion site was 0.96 and decreased to 0.94 when NaF(pw) values at the pre-reinfusion site were considered. This last value is quite close to the theoretical alpha value of post-dilution haemofiltration. CONCLUSION: As for post-dilution haemofiltration, less sodium removal, compared with haemodialysis, can partly explain the improved cardiovascular stability during pre-dilution haemofiltration.
Hemofiltration↗
Convection versus diffusion in dialysis: an Italian prospective multicentre study.
The concept of dialysis adequacy has to be widened to include medium size and large molecule removal in addition to urea kinetics. The HEMO study found a non-significant trend toward a beneficial effect on mortality of high-flux dialysis compared with low-flux dialysis. In that study, the beneficial effect of convection could have been attenuated by the fact that 'internal filtration' in high-flux haemodialysis (HD) is lower than that expected by convection in haemofiltration (HF) or haemodiafiltration (HDF). To explore the putative beneficial effect of convection, this Italian multicentre study was planned, comparing on-line convective treatments (HF and HDF) with standard, low-flux HD. The enrolled patients will be evaluated prospectively on their usual treatment for 2 months (baseline period) and subsequently randomized to continue either with low-flux HD (50%) or to start on-line convective treatment (50%), HF or HDF according to a 1:1 ratio. The primary end point of the study will be cardiovascular stability and blood pressure control. As secondary aims of the study, the impact on symptoms, morbidity and mortality will be assessed. Feasibility and patient compliance during HF and HDF treatments will also be evaluated. The experimental phase of the study, of at least 2 years, is divided into a 3-month adaptation period and a subsequent evaluation period. A recruitment period of 1 year is planned. The study design has adequate power to detect an absolute reduction of 3% hypotensive episodes with the experimental convective treatments compared with standard low-flux HD.
Convection↗
Dose of dialysis, convection and haemodialysis patients outcome--what the HEMO study doesn't tell us: the European viewpoint.
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Adolescent↗
The importance of diabetic nephropathy in current nephrological practice.
BACKGROUND: Diabetic nephropathy has become the major cause of end-stage renal disease (ESRD) in the western world and is forecast to become the most frequent cause of ESRD in the African continent and in developing countries in other areas. METHODS: A discussion to achieve a consensus on key points relating to diabetic nephropathy. RESULTS: Given the catastrophic consequences of diabetes not only for renal function but also for the cardiovascular system, major efforts should be aimed at prevention. The cornerstone of primary prevention (development of microalbuminuria) is a tight control of blood pressure and blood glucose. Although ACE inhibitors have proved effective in preventing the development of microalbuminuria in normotensive patients, this is not the case, in comparison with other classes of antihypertensive drugs, in those who are hypertensive but normoalbuminuric. Secondary prevention (transition to overt nephropathy) and tertiary prevention (progression of established nephropathy to ESRD) benefit from the use of inhibitors of the renin-angiotensin system, whilst the role of tight glycaemic control is more controversial at these stages. Therapeutic lifestyle changes are also important. They should include body weight control combined with regular physical exercise, cessation of smoking and reduced salt intake. The pathogenesis of diabetic nephropathy and its association with hypertension, accelerating renal damage, is complex. It involves genetic factors, altered renal sodium handling with sodium retention, metabolic disturbances and oxidative stress with the formation of advanced-glycation end products (AGEs) and reactive oxygen species. CONCLUSIONS: Although the awareness of the importance of normalizing blood pressure levels and tight glycaemic control have allowed improved survival of diabetic patients, the mortality excess remains unacceptably high in patients with diabetic nephropathy. New treatment strategies are under investigation, including inhibitors of AGE formation, protein kinase C inhibitors, antioxidants, glycosaminoglycans, PPAR-gamma agonists and COX-2 inhibitors.
Diabetes Complications↗
Stopping a medical research project for financial reasons.
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Clinical Trials as Topic↗
Advanced IgA nephropathy: to treat or not to treat?
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Adrenal Cortex Hormones↗
Lanthanum carbonate (Shire).
Shire Pharmaceuticals Group plc, under exclusive license from AnorMED Inc (a subsidiary of Johnson Matthey), is developing lanthanum carbonate, a phosphate-binding lanthanum salt, for the potential treatment of hyperphosphatemia in dialysis patients. It is currently in pre-registration in the US, Canada and Western Europe, and earlier stage clinical trials are ongoing in Japan.
Clinical Trials, Phase I as Topic↗
The importance of convective transport.
BACKGROUND: Despite technological advances in dialysis equipment and modalities, survival, morbidity, and quality of life of hemodialysis patients are still severely affected by acute intradialytic and long-term complications, possibly related to the treatment itself. Convective treatments, such as high-flux hemodialysis, hemodiafiltration, and hemofiltration are increasingly suggested as further improvements over standard diffusive hemodialysis. The membranes used for these techniques are high-flux semisynthetic and synthetic membranes. Characteristics of these membranes are high permeability, which allows convective removal of water and electrolytes and higher clearance of middle and large molecular weight solutes, and high biocompatibility, which minimizes the "inflammatory response" secondary to interactions between blood and the artificial material of the hemodialysis system. METHODS: With the specific aim of verifying the superiority of convective treatments in reducing morbidity and mortality, we performed a review of the published literature. RESULTS: Some epidemiological studies suggest that convective treatments reduce morbidity and mortality among dialysis patients. However, the results of the published prospective randomized controlled trials are conflicting. Moreover, since convective treatments are usually performed with synthetic biocompatible membranes, it is hard to separate the effect of convection from the effect of biocompatibility. CONCLUSIONS: To finally assess the effect of high-flux membranes on morbidity and mortality, the results of two randomized, controlled clinical trials (HEMO study and MPO study) specifically designed with this aim are needed.
Amyloidosis↗
Role of combination therapy with ACE inhibitors and calcium channel blockers in renal protection.
Over recent years, a target blood pressure of 125/75 mm Hg has been sought in order to reduce the rate of chronic renal disease (CKD) progression and cardiovascular mortality. Some antihypertensive agents, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and calcium channel blockers also may be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage. The possibility that combination treatments with ACE inhibitors and calcium-channel blockers may confer additive or even synergistic renoprotective effects other than blood pressure control is not only fascinating, but also particularly important because multidrug antihypertensive regimens are required to obtain adequate blood pressure in the majority of patients with CKD. This combination may provide better blood pressure control, appears to be better tolerated with fewer side effects than either drug alone, and may exert a greater renoprotective effect in patients at risk for renal failure than either an ACE inhibitors or a calcium channel blocker. However, the current available data are too few to confirm this hypothesis. Cardiovascular disease accounts for more than 50% of the deaths of hemodialysis patients. Thus, care must be taken to prevent and treat the cardiovascular risk factors optimally from the early phase of CKD, and for this reason effective antihypertensive therapy is the most important treatment, not only in order to delay CKD progression, but also to reduce the burden of cardiovascular disease. In this perspective combination therapy with ACE inhibitors and calcium channel blockers can give further advantages.
Angiotensin-Converting Enzyme Inhibitors↗
Once-weekly compared with three-times-weekly subcutaneous epoetin beta: results from a randomized, multicenter, therapeutic-equivalence study.
BACKGROUND: The ability to reduce the administration frequency of subcutaneous (SC) epoetin could provide benefits. This multicenter open-label study investigated the therapeutic equivalence of SC epoetin beta once-weekly and thrice-weekly administration regimens in maintaining anemia correction in stable hemodialysis (HD) patients. METHODS: One hundred seventy-three patients were randomly assigned to either once-weekly epoetin beta (n = 84) or their original thrice-weekly regimen (n = 89) for 24 weeks. All patients were administered intravenous iron supplementation, as required. RESULTS: The per-protocol analysis included 134 patients (69 patients, once-weekly group; 65 patients, thrice-weekly group). Mean hematocrits in both groups remained stable throughout the study. The difference in mean time-adjusted area under the curve for hematocrits between the once-weekly and thrice-weekly groups (-0.54 vol%) and 90% confidence intervals (-1.27 to 0.19) were within the prespecified equivalence range (-2 to +2 vol%). There was no significant change in epoetin beta dose during the study. The ratio of mean weekly epoetin beta doses in the once-weekly and thrice-weekly groups (1.11) and 90% confidence interval (0.99 to 1.23) also remained within the prespecified range (0.8 to 1.25). Intention-to-treat analysis results were similar to per-protocol analysis results. Both regimens were well tolerated. CONCLUSION: Once-weekly and thrice-weekly SC epoetin beta administrations are statistically equivalent in terms of maintaining both stable hematocrits and epoetin beta dose requirements in HD patients. These findings may improve compliance among patients.
Anemia↗