Predictors of first ischemic lower limb ulcer in dialysis patients: an observational cohort study.

BACKGROUND: Lower limb ischemia affects the quality of life, physical activity and life expectancy of dialysis patients. The aim of this study was to investigate the risk factors associated with ischemic foot ulcers considering clinical, laboratory and therapeutic domains. METHODS: This observational cohort study was based on data from the Nephrology and Dialysis Department database of Alessandro Manzoni Hospital, Lecco (Italy). All of the incident patients who started dialysis between 1 January 1999 and 29 February 2012 were enrolled, excluding temporary guests, patients with acute renal failure and patients with previous limb ischemia or amputation. Multivariate Cox regression analysis identified the predictors in each domain, which were matched in the final model. A time-dependent approach was used to take into account the evolution of some of the prognostic covariates. RESULTS: Of the 526 incident dialysis patients, 120 developed a lower limb ischemic lesion after a median of 13 months. The incidence of new ulcers was constant during the study period (6 per 100 person-years), but higher in the diabetics with a relative rate of 4.5. The variables significantly related to an increased risk of lower limb ulcers were age, male gender, diabetes, ischemic heart disease, treatment with proton pump inhibitors, iron, anticoagulants and calcium-based binders, and blood levels of phosphorus, triglycerides and C-reactive protein. CONCLUSION: The incidence of lower limb ulcers was highest during the early dialysis follow-up and was associated with, in addition to diabetes, modifiable laboratory and therapeutic predictors such as anticoagulants, proton pump inhibitors, calcium-containing binders, calcimimetics and iron.

The Membrane Permeability Outcome study.

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 ß(2)-microglobulin levels observed in the high-flux group.

Recent trials on hemodiafiltration.

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 ß(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.

Long-term effects of high-efficiency on-line haemodiafiltration on uraemic toxicity. A multicentre prospective randomized study.

BACKGROUND: Haemodiafiltration (HDF) may improve survival of chronic dialysis patients. This prospective, multicentre randomized cross-over study evaluated the effects of long-term on-line HDF on the levels of solutes of different molecular weight markers or causative agents of the most common metabolic derangements in uraemia. METHODS: Sixty-nine patients from eight Italian centres were randomly assigned to two 6-month treatment sequences: A-B and B-A [A, low-flux haemodialysis (HD) and B, on-line HDF]. Comparative evaluation of basal levels of small, medium-sized and protein-bound solutes at the end of the two treatment periods and analysis of parameters dependence during the interventions were performed. RESULTS: On-line HDF showed greater efficiency than low-flux HD in removing small solutes (eKt/Vurea 1.60 ± 0.31 versus 1.44 ± 0.26, P < 0.0001) and in reducing basal levels of beta2-microglobulin (22.2 ± 7.8 versus 33.5 ± 11.8 mg/L, P < 0.0001), total homocysteine (15.4 ± 5.0 versus 18.7 ± 8.2 µmol/L, P = 0 .003), phosphate (4.6 ± 1.3 versus 5.0 ± 1.4 mg/dL, P = 0.008) and, remarkably, of intact parathyroid hormone (202 ± 154 versus 228 ± 176 pg/mL, P = 0.03). Moreover, in on-line HDF, lower levels of C-reactive protein (5.5 ± 5.5 versus 6.7 ± 6.1 mg/L, P = 0.03) and triglycerides (148 ± 77 versus 167 ± 87 mg/dL, P = 0.008) and increased HDL cholesterol (49.2 ± 12.7 versus 44.7 ± 12.4 mg/dL, P = <0.0001) were observed. The asymmetric dimethylarginine level was not significantly affected (0.97 ± 0.4 versus 0.84 ± 0.37 µmol/L). Erythropoietin and phosphate binders' doses could be reduced. CONCLUSIONS: On-line high-efficiency HDF resulted in enhanced removal and lower basal levels of small, medium-sized and protein-bound solutes, which are markers or causative agents of uraemic pathologies, mainly inflammation, secondary hyperparathyroidism and dyslipidaemia. This may contribute to reducing uraemic complications and possibly to improving patient survival.

Hemodiafiltration - state of the art.

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 ß(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.

Management of anemia by convective treatments.

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.

Effect of synthetic vitamin E-bonded membrane on responsiveness to erythropoiesis-stimulating agents in hemodialysis patients: a pilot study.

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.

Can convective therapies improve dialysis outcomes?

PURPOSE OF REVIEW: Convective treatments are characterized by enhanced removal of middle and large molecular weight solutes, important in the genesis of many complications of hemodialysis, compared with conventional low-flux hemodialysis. The availability of these techniques represented an intriguing innovation and a possible means to improve the still poor prognosis of hemodialysis patients. In this study we will critically review the most important published studies evaluating the impact of convective treatments on dialysis outcomes. RECENT FINDINGS: The Hemodialysis (HEMO) study showed that greater urea removal nonsignificantly reduces the relative risk of mortality and that also high-flux hemodialysis was associated with a nonsignificant reduction, although a secondary analysis pointed to an advantage for high-flux membranes in subgroups of patients. More recently, the Membrane Permeability Outcome (MPO) study found that survival could be improved by use of high-flux membranes compared with low-flux dialysis in high-risk patients as identified by serum albumin < or =4 g/dl as well as in people with diabetes. In an observational study, hemodiafiltration with large reinfusion volume has been associated with a lower relative risk of mortality, compared with low-flux hemodialysis. SUMMARY: The biologic plausibility of advantages of convective treatments and the results of the MPO and Dialysis Outcomes and Practice Patterns (DOPPS) studies are supporting rationales for the use of convective treatments to improve survival and delay long-term complications of hemodialysis patients.

Dialysate composition.

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.

Membrane characteristics.

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.

Nephrology: main advances in the last 40 years.

Modern nephrology has become one of the liveliest and most productive branches of medicine. Once seen as a temporary means of rescue from uremic coma, hemodialysis (HD) has allowed thousands of people with irreversible uremia to survive for many years, and evolving treatment modalities have led to a significant increase in efficacy and tolerability. At the same time, two other forms of renal replacement therapy (RRT) have been developed: peritoneal dialysis (PD) and renal transplantation. The number of end-stage renal disease (ESRD) patients requiring RRT has increased dramatically throughout the world for a number of reasons: the improved survival of patients affected by other diseases, a real increase in the incidence of chronic kidney disease (CKD) mainly due to the burden of 'metabolic syndrome', and the significant broadening of RRT acceptance criteria. This last factor means that RRT has become available to increasing numbers of elderly patients, diabetics and patients with other severe comorbidities, among whom the leading cause of death is cardiovascular disease (CVD). However, nephrology is not just a case of substituting the function of failing kidneys; it also covers the treatment of glomerular diseases, slowing down CKD progression and managing the related comorbidities, all of which have substantially improved over the last 40 yrs.

The relevance of convection in clinical practice: a critical review of the literature.

Convective treatments (high-flux hemodialysis (HD), hemodiafiltration and hemofiltration) are characterized by enhanced removal of middle and large molecular weight solutes compared with conventional low-flux HD. As these molecules are claimed to play an important role in the genesis of many complications of chronic HD, the availability of these techniques represented an intriguing innovation and a possible means to improve the still poor prognosis of HD patients. Here we will critically review the most important published studies comparing convective treatments with low-flux HD on chronic morbidity, preservation of residual renal function, and long-term survival.

Relationship between urea clearance and ionic dialysance determined using a single-step conductivity profile.

BACKGROUND: On-line determination of ionic dialysance (ID) has been used to measure the clearance of small solutes like urea. However, attempts to determine the in vivo relationship between ID and urea clearance have led to discordant findings. The aim of this study was to determine the relationship between the mean values of repeated instantaneous determinations of ID throughout a dialysis session ((m)ID), obtained using a single-step inlet dialysate conductivity profile, and the mean values of urea clearance corrected for access recirculation (K(eu1)), total recirculation (access plus cardiopulmonary recirculation, K(eu2)), and the entire postdialysis urea rebound (K(wb)). METHODS: Eighty-two anuric patients on chronic thrice-weekly hemodialysis were studied using an Integra machine equipped with the Diascan module for the automatic determination of ID. The mean values of repeated ID measurements made at 30-minute intervals were compared with K(eu1) (available for only 31 patients), K(eu2), and K(wb). RESULTS: The results in all 82 patients were: (m)ID = 176 +/- 23 mL/min; K(eu2) = 181 +/- 25 mL/min; K(wb) = 159 +/- 22 mL/min. The mean (m)ID/K(wb) and (m)ID/K(eu2) ratios were, respectively, 1.11 +/- 0.06 and 0.98 +/- 0.06. The results in the 31 patients for whom K(eu1) values were available were: (m)ID = 179 +/- 24 mL/min and K(eu1) = 200 +/- 27 mL/min; the mean (m)ID/K(eu1) ratio was 0.90 +/- 0.05. CONCLUSION: The mean value of repeated ID determinations obtained using a single-step conductivity profile underestimates urea clearance corrected for access recirculation, and may be considered an adequate estimate of urea clearance corrected for total recirculation.

Ionic dialysance allows an adequate estimate of urea distribution volume in hemodialysis patients.

BACKGROUND: An adequate estimation of urea distribution volume (V) in hemodialysis patients is useful to monitor protein nutrition. Direct dialysis quantification (DDQ) is the gold standard for determining V, but it is impractical for routine use because it requires equilibrated postdialysis plasma water urea concentration. The single pool variable volume urea kinetic model (SPVV-UKM), recommended as a standard by Kidney Disease Outcomes Quality Initiative (K/DOQI), does not need a delayed postdialysis blood sample but it requires a correct estimate of dialyser urea clearance. METHODS: Ionic dialysance (ID) may accurately estimate dialyzer urea clearance corrected for total recirculation. Using ID as input to SPVV-UKM, correct V values are expected when end-dialysis plasma water urea concentrations are determined in the end-of-session blood sample taken with the blood pump speed reduced to 50 mL/min for two minutes (U(pwt2')). The aim of this study was to determine whether the V values determined by means of SPVV-UKM, ID, and U(pwt2') (V(ID)) are similar to those determined by the "gold standard" DDQ method (V(DDQ)). Eighty-two anuric hemodialysis patients were studied. RESULTS: V(DDQ) was 26.3 +/- 5.2 L; V(ID) was 26.5 +/- 4.8 L. The (V(ID)-V(DDQ)) difference was 0.2 +/- 1.6 L, which is not statistically significant (P= 0.242). Anthropometric volume (V(A)) calculated using Watson equations was 33.6 +/- 6.0 L. The (V(A)-V(DDQ)) difference was 7.3 +/- 3.3 L, which is statistically significant (P < 0.001). CONCLUSION: Anthropometric-based V values overestimate urea distribution volume calculated by DDQ and SPVV-UKM. ID allows adequate V values to be determined, and circumvents the problem of delayed postdialysis blood samples.

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.

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.