No generation of bradykinin with a new polyacrylonitrile membrane (SPAN) in haemodialysis patients treated with ACE inhibitors

BACKGROUND: Anaphylactoid reactions occurring in uraemic patients haemodialysedwith polyacrylonitrile haemodialysis (HD) membranes and beingtreated with ACE inhibitors have been attributed to an excessivegeneration of bradykinin. METHODS: Here we tested in a prospective trial a new type of polyacrylonitrilemembrane (SPAN) with respect to bradykinin generation in nineHD patients receiving either captopril or enalapril. Each patienthad three consecutive HD sessions with each of the three testedmembranes, high-flux SPAN, high-flux polysulphone (F60) andlow-flux Hemophan (GFS Plus 16). RESULTS: No clinical signs of anaphylactoid reactions were observed inany of these patients but the number of patients was relativelysmall and the duration of exposure to different membranes relativelyshort. At 5 min after the start of HD session, plasma bradykininlevels were significantly higher in the venous than in the arterialline for all three HD membranes: SPAN, 18.5±11.9 versus12.4±5.3 fmol/ml (p<0.05); F60, 19.0±13.8 versus11.5±6.5 fmol/ml (P<0.01); and GFS Plus 16, 39.1±22.9versus 15.8±12.4 fmol/ml (P<0.005), mean±SDrespectively. Higher venous line levels were still observedat the 15 and 60 min time points for F60 and GFS Plus 16, butnot for SPAN. However, these levels were still insignificantcompared to levels measured during episodes of anaphylacticshock from the literature. Plasma histamine and C5a anaphylatoxinlevels did not show any increase during HD with SPAN. CONCLUSIONS: The SPAN membrane did not induce significant bradykinin releasein dialysis patients on ACE-inhibitor therapy. It may thereforebe used for high-flux dialysis in such patients.     

High-normal calcium (1.35 mmol/I) dialysate in patients on CAPD: efficient and safe long-term control of plasma calcium, phosphate, and parathyroid hormone

AIM.: The aim of the present study was to examine the long-term efficacyand safety of treatment with a high-normal calcium dialysatewith a calcium concentration of 1.35 mmol/l in patients on CAPD.This dialysate calcium concentration is close to the high-normalplasma ionized calcium level aimed at in dialysis patients inorder to suppress the parathyroid hormone secretion. The end-pointsof the study were (1) plasma ionized calcium (iCa) and phosphate(P) levels, (2) plasma intact parathyroid hormone (PTH) levels,(3) doses of calcium carbonate and alfacalcidol, (4) requirementsof Al-containing phosphate binders, and (5) bone mineral density(BMD). RESULTS.: Thirty-seven non-selected patients on CAPD treatment were followedfor an average of 10 months after switching from a dialysateCa of 1.75 to 1.35 mmol/l. After 1 week, a significant decreaseof mean iCa from 1.26±0.01 to 1.23±0.01 mmol/l(P<0.05) and an increase of median PTH from 80 to 135 pg/ml(P<0.01) were seen. From the 2nd week and onwards, however,basal levels of iCa and PTH were restored and remained stable.Mean plasma iCa was kept within 1.23–1.31 mmol/l; meanplasma P below 1.65 mmol/l and median PTH within 52–135pg/ml. Episodes of hypercalcaemia were few (1.2 cases of plasmaiCa>1.45 mmol/l per 100 treatment weeks), and the need forAl-containing P binders low with only five patients requringthis treatment for isolated and four patients for repeated episodesof hyperphosphataemia or hypercalcaemia. After switching froma dialysate Ca of 1.75 to 1.35 mmol/l, the doses of calciumcarbonate and alfacalcidol could be significantly increased.Furthermore, using the dialysate Ca of 1.35 mmol/l made it possibleto induce a controlled increase of PTH levels to 80–100pg/ml by a temporarily discontinuation of alfacalcidol and/ora reduction of calcium carbonate dosage in the patients wherePTH had become suppressed to levels below the upper normal limit.The intention of the treatment was to maintain PTH levels within1.5–2.5 times the upper normal limit for non-uraemic patients.Pre-study BMD of the vertebral bodies L2–L4 and of thefemoral neck were normal and not significantly different frompost-study measurements. CONCLUSIONS.: The present study demonstrated that when using a high-normaldialysate Ca concentration of 1.35 mmol/l in non-selected patientson CAPD treatment, high-normal plasma iCa and near-normal plasmaP levels could be readily achieved with a minimal risk of incidentalhypercalcaemia despite use of calcium carbonate as the mainP binder. As a consequnce of the tight Ca and P regulation,minimal doses of alfacalcidol were required to keep PTH withinacceptable limits. We recommend this dialysate Ca concentrationas a first-choice therapy for the majority of patients startingon CAPD treatment.     

Calcium balance and serum ionized calcium fluctuations in on-line haemodiafiltration in relation to ultrafiltration rate and dialysate calcium concentration

The use of high ultrafiltration rates in haemodiafiltration(HDF) has been suggested for improving the clearance of smalland large molecules. This strategy has become economically applicablewith the development of safe techniques for on-line productionof sterile infusate from dialysate, which enables us to infuselarge substitution fluid volumes without further increasingthe cost of the sessions. The effect of increasing the ultrafiltrationrate in HDF on electrolyte balance has not yet been evaluated.The aim of this study was to evaluate the effects of variationsof the ultrafiltration rate on calcium kinetics in HDF usingthree different dialysate calcium concentrations. Since theincrease in ultrafiltration rate augments the convective calciumloss, variations of intrasession calcium balance could resultfrom modifications of the ultrafiltration rate. In the present study we found no significant variations in calciumbalance and serum ionized calcium (iCa) levels during on-lineHDF treatment when increasing the mean ultrafiltration ratefrom 60 to 100 ml/min in the presence of an adequate and correspondingincrease in the infusion rate (from 2.5 to 5 l/h). During thebalance studies, pretreatment serum iCa was on the average 1.32mmol/l and weight loss 3.2 kg. Mean calcium loss during treatmentwas 2.8 and 3.3 mmol at infusion rates of 2.5 and 5 l/h with1.63 mmol/l of calcium in both the dialysate and infusate; calciumloss rose to 5.9 and 11.2mmol at infusion rates of 2.5 l/h andto 5.7 and 14.2 mmol at infusion rates of 5 l/h when the dialysateand infusate calcium was reduced respectively to 1.5 and 1.25mmol/l. Serum iCa significantly increased at the end of thesession with the higher dialysate concentration, while it decreasedto 1.28 mmol/l and 1.20 mmol/l with the lower two concentrations.Linear regression ana lysis showed no variation in serum iCaduring treatment when the iCa concentration in the dialysatewas equal to pretreatment serum iCa. A neutral calcium balancewould be expected using 1.75 mmol/l of calcium in the dialysate. In conclusion, increasing the ultrafiltration rate from 60 to100 ml/min did not significantly affect calcium kinetics inon-line HDF. The main factors affecting calcium mass transferand serum iCa fluctuation during treatment were the dialysatecalcium concentration and the iCa gradient between dialysateand pretreatment serum levels.     

Effect of treatment with 1.25 and 1.75 mmol/l calcium dialysate on bone mineral density in haemodialysis patients

The effect of two different dialysate solutions with a calciumconcentration of 1.25 and 1.75 mmol/l was evaluated in 14 patients,using a cross-over design. Patients were treated with each solutionduring a period of 6 months. Treatment with calcium supplements,vitamin D and aluminium hydroxide was adapted weekly, accordingto the results of blood chemistry. PTH, SAP, and ionized calciumwere determined monthly, bone density with DXA and QCT beforeand after 6 months of treatment. During treatment with both1.25 and 1.75 calcium dialysate (cad), the control of serumcalcium and phosphate was similar. PTH did not change duringeither treatment. SAP decreased during treatment with 1.75,but remained stable with 1.25 mmol/1 cad. Bone density evaluatedwith DXA remained unchanged during both treatments. QCT measuredbone density increased from 101.29± 13.50 to 106.79±13.14mg/ml in the 1.75 cad group, while it did not vary in the 1.25cad group, (107.75 ±13.48 versus 108.97 ±13.40mg/ml). It is concluded that lowering the calcium content ofthe dialysate does not negatively influence the control of serumcalcium and phosphate, nor does it aggravate hyper-parathyroidismwhen vitamin D is administered simultaneously. Under the presentconditions, osteopenia and possibly bone mineralization improveonly in the group dialysed with 1.75 Ca.     

Convective and diffusive losses of vitamin C during haemodiafiltration session: a contributive factor to oxidative stress in haemodialysis patients.

BACKGROUND: Enhanced oxidative stress in haemodialysis (HD) patients may be considered as a risk factor for accelerated atherosclerosis. Reduced antioxidant defences include impairment in enzyme activities and decreased plasma levels of hydrophilic vitamin C (vit C), and cellular levels of lipophilic vitamin E (vit E). METHODS: We investigated plasma levels of vit C in 19 patients undergoing regular haemodiafiltration (HDF) (mean age 62+/-7 years) and in 1846 healthy elderly subjects (HS) (mean age 69+/-5 years). The contribution of convection and diffusion was determined using paired filtration dialysis (PFD), a modified HDF technique which physically separates convective from diffusive fluxes. Blood samples were collected before and after the HDF session; in addition at 60 min of HDF, samples were drawn from arterial lines (AL) and venous lines (VL), dialysate (D) and ultrafiltrate (UF). Blood levels of total vit C were determined using an HPLC fluorescence method. Markers of oxidative stress were also assessed in both populations as follows: levels of malondialdehyde (MDA) were determined by fluorometric assay, measurements of advanced oxidation protein products (AOPP) and glutathione peroxidase (GSH-Px) activity were performed by spectrophotometric assay, and plasma vit E content was obtained by an HPLC procedure. RESULTS: A significant reduction in plasma vit C level was observed in HDF patients when compared with HS (1.6+/-1.4 microg/ml in HDF vs 6.6+/-3.7 microg/ml in HS; P<0.01). The HDF session was associated with a dramatic reduction in vit C levels (1.87+/-1.57 microg/ml before HDF and 0.98+/-0.68 microg/ml after HDF); at 60 min of HDF, concentrations were as follows: AL=1.35+/-1.27 microg/ml; VL=0.37+/-0.31 microg/ml, D=0.40+/-0.34 microg/ml, UF=1.24+/-1.18 microg/ml; corresponding to a diffusive flux of 271 microg/min and a convective flux of 126 microg/min. Total loss of vit C could be assessed at 66 mg/session (8--230 mg/session). According to this loss of vit C, presence of an oxidative stress was demonstrated in HD population as shown by a significant increase in MDA (1.66+/-0.27 microM in HD vs 0.89+/-0.25 microM in HS; P<0.01) and AOPP (77.5+/-29.3 microM in HD vs 23.5+/-13.2 microM in HS; P<0.01) levels, and a decrease in GSH-Px activity (259.2+/-106.3 U/l in HD vs 661.2+/-92.2 U/l in HS; P<0.01). No change in plasma vit E between both populations (30.7+/-9.1 microM in HD vs 35.3+/-7.34 microM in HS) was observed. CONCLUSIONS: These results suggest that HDF with highly permeable membranes is associated with a significant loss of vit C. Diffusive transport is responsible for two-thirds whereas convective phenomenon accounts for only one-third of this loss.     

Calcium and phosphate balance in adolescents on home nocturnal haemodialysis

Studies in adults show superior serum phosphate and parathyroid hormone (PTH) control on slow nocturnal haemodialysis (NHD) compared with conventional haemodialysis. We studied the progress of four children aged 12, 13, 14 and 16 years after they had been initiated on NHD. The follow-up period ranged from 6 months to 20 months. Biochemical indices of bone metabolism were collected prospectively. All four children were initially dialysed against a 1.5 mmol/l calcium bath. In two patients, owing to biochemical hypocalcaemic episodes, the dialysate calcium concentration was increased to 1.75 mmol/l. One patient became hypercalcaemic and received calcitonin for bone pain secondary to osteoporosis and was dialysed against a 1.0 mmol/l calcium bath. Including an evaluation of dietary intake, all four patients had a net positive calcium balance, ranging from 5.1 mmol/m² body surface area (BSA) per day to 24.3 mmol/m² BSA per day. A significant reduction in the pre-dialysis phosphate level was observed in all four patients, such that none required dietary restrictions or phosphate binders, and dialysate phosphate supplements of 0.8–2.03 mmol/l were employed to prevent hypophosphataemia. The (Ca×PO4) dropped below 4.4 mmol² l⁻² in all four patients. Concurrently, significant reductions in intact PTH levels were seen in all four patients, but the level dropped to below normal range in two. In our cohort of patients, NHD rapidly lowered plasma phosphate and PTH levels, and additional dialysate phosphate and possibly calcium may be necessary to prevent bone demineralisation due to chronic losses and to prevent oversuppression of PTH.     

Hemodialysis with high-calcium dialysate impairs cardiac relaxation

BACKGROUND: During hemodialysis (HD), serum ionized calcium is directly related to the dialysate calcium concentration. We have recently shown an acute induction of hypercalcemia to impair left ventricular (LV) relaxation. In the current study we sought to establish whether changes in serum Ca++ also affect LV function during HD. METHODS: We echocardiographically examined the LV relaxation and systolic function of 12 patients with end-stage renal disease before and after three HD treatments with dialysate Ca++ concentrations of 1.25 mmol/liter (dCa++1.25), 1.5 mmol/liter (dCa++1.50), and 1.75 mmol/liter (dCa++1.75), respectively. Age- and sex-matched healthy controls were also examined echocardiographically. RESULTS: The LV posterior wall thickness and the interventricular septum thickness, and the LV end-diastolic dimension and the end-systolic dimensions were significantly greater in the patients when compared with the controls, and the LV fractional shortening, the ratio of peak early to peak late diastolic velocities (E/Amax), and the isovolumic relaxation time (IVRT) showed impairment of LV relaxation and systolic function in the patients. Serum ionized calcium increased significantly during the dCa++1.5 HD (1.24 +/- 0.10 vs. 1.34 +/- 0.06 mmol/liter, P = 0. 004) and dCa++1.75 HD (1.19 +/- 0.10 vs. 1.47 +/- 0.06 mmol/liter, P = 0.002), and plasma intact parathyroid hormone decreased significantly during the dCa++1.75 HD (medians 8.2 vs. 2.7 pmol/liter, P = 0.002). LV systolic function was not altered during any of the treatments. The changes in E/Amax and IVRT suggested impairment of relaxation during all sessions, but only during the dCa++1.75 HD was the impairment statistically significant (E/Amax 1. 153 +/- 0.437 vs. 0.943 +/- 0.352, P < 0.05; IVRT 147 +/- 29 vs. 175 +/- 50 msecond, P < 0.05). CONCLUSION: HD with high-calcium (dCa++1. 75 mmol/liter) dialysate impairs LV relaxation when compared with lower calcium dialysate (dCa++1.25 and dCa++1.5 mmol/liter) treatments.     

Mid-dilution on-line haemodiafiltration in a standard dialyser configuration

Background. Mid-dilution haemodiafiltration (HDF) results inan improved middle molecule removal compared with standard HDF.The OLpr^TM MD 190 haemodiafilter represents a new dialyser designexclusively for mid-dilution on-line HDF. Compared with standardhaemodialysers, structural changes in the headers allow theinfusion of high replacement fluid volumes after a first post-dilutionand before a second pre-dilution stage. Methods. We compared in vitro the new device [blood flow (Q_B)400 ml/min, substitution flow (Q_S) 100 and 200 ml/min, dialysateflow (Q_D) 800 ml/min] with a conventional high-flux dialyserof the same surface area in haemodialysis (HD) (Q_D 500 ml/min)and post-dilution HDF (at Q_S 60, Q_D = 500 ml/min and at Q_S 100,Q_D = 800 ml/min) modes. Subsequently, we performed an initialclinical application of the new device in six mid-dilution HDFtreatments of five end-stage renal disease patients (Q_B 400ml/min, Q_S 200 ml/min, Q_D 800 ml/min, treatment duration 205±23min). Results. In vitro urea and ß₂-microglobulin clearancesin mid-dilution HDF were, respectively, 309.2±5.5 and144.4±15.2 ml/min (Q_S 100) and 321.6±4.1 and 204.9±4.1ml/min (Q_S 200), compared with 278.6± 17.2 and 94.0±7.6ml/min in HD, and 310.8±10.2 and 123.0±6.5 ml/min(Q_S 60) and 323.6±11.2 and 158.0±10.3 ml/min (Q_S100) in post-dilution HDF. The in vivo trials showed the clinicalutility of the device and confirmed the in vitro data: ureaand ß₂-microglobulin clearances were, respectively,324.6± 10.9 and 207.9±29.3 ml/min, while reductionratios were 75.0±5.5 and 83.6±4.7%. Conclusion. Our preliminary results need confirmation in a prospectivecross-over study. However, the Nephros MD 190 haemodiafilterpromises to be a true technological step ahead in terms of improvedß₂-microglobulin removal.     

Endotoxins modulate chronically tumour necrosis factor {alpha} and interleukin 6 release by uraemic monocytes

We examined in vivo the release of tumour necrosis factor alpha(TNF) and interleukin 6 (IL-6) by uraemic monocytes upon stimulationwith endotoxin-contaminated bicarbonate concentrate. Twelveuraemic patients underwent 1-month-subsequent periods of standardhaemodialysis (SHD) with cuprophane (CU), a high-complement-activatingmembrane (6 patients), or haemodiafiltration (HDF) with polyacrylonitrile(PAN), a low-complement-activating membrane (6 patients), byusing a dialysate prepared with either non-sterile bicarbonateconcentrate tanks (phase 1) or sterile bicarbonate concentratebags (phase 2). TNF and IL-6 concentrations were determinedin monocyte supernatants by ELISA; endotoxin levels in bicarbonateconcentrates were measured by a chromogenic limulus amoebocytelysate (LAL) assay. A significant increase in LAL reactivity was found in bicarbonateconcentrate tanks compared to sterile bags (P<0.001). Non-steriledialysate caused a significant (P<0.001) predialytic increasein monocyte TNF release as compared to controls and nondialyseduraemic patients. One month treatment with sterile bicarbonatesignificantly decreased TNF predialytic activity in monocytesupernatants (P<0.001) to levels closer to those of non-dialyseduraemic patients. A similar decrease was observed for IL-6 production.Dialytic treatment induced a further increase in both TNF andIL-6 production, particularly in phase 1. When uraemic patientswere examined separately according to the different dialyticprocedures (SHD-CU or HDF-PAN), the use of sterile dialysate(phase 2) caused a significant decrease of predialysis TNF releasein both SHD CU patients (24.1±8.4 pg/ml versus 55.3±5.7pg/ml, P<0.001) and HDF PAN-treated patients (16.6±5.3pg/ml versus 29.1±5.4pg/ml, P<0.005), so that thedifferences between the dialytic procedures were completelyabolished. In conclusion, TNF and IL-6 release may be induced by endotoxin-contaminateddialysate during haemodialysis. The use of sterile bicarbonatecan ameliorate the bioincompatibility of CU membranes and probablyinfluences the biocompatibility of PAN membranes. Therefore,regardless of the type of dialyser used, all attempts to obtainan ultrapure dialysate are important to optimize dialytic treatment,in order to attenuate the chronic monocyte activation whichoccurs during haemodialysis.     

Removal of clodronate by haemodialysis in end-stage renal disease patients

BACKGROUND: Clodronate is a potent calcium-lowering drug. The effect ofhaemodialysis on clodronate pharm-acokinetics is unknown. METHODS: The removal of clodronate by haemodialysis was determined in10 end-stage renal disease patients (ESRD). A 2-h infusion of300 mg of clodronate was followed immediately by a 4-h haemodialysis.Vascular access was by AV fistula. A 1.5-m² cuprophane hollow-fibredialyser was applied. Blood flow was 205±15ml/min, dialysateflow 523±29 ml/min. Clodronate was determined by high-performanceliquid chromatography in total collected dialysate, and in bloodbefore and after the dialyser at initiation, 2 h, and 4 h ofHD. RESULTS: The initial predialyser serum concentration of clodronate was13.6 ± 4 ug/ml. It decreased to 4.9 ± 0.5 ug/mland 2.6 ± 0.5 ug/ml at 2h and 4h respectively. The clearanceof clodronate (86 ± 10 ml/min) remained unchanged duringHD. Clodronate in total collected dialysate per single 4-h HDwas 105 ± 16 mg (35% of injected dose). CONCLUSIONS: We conclude that clodronate is effectively removed from plasmaby HD. The present data together with information provided byprevious studies suggest that 300 mg of clodronate given asan 2-h infusion immediately prior to haemodialysis is an adequatedosage for ESRD patients.     

Calcium balance and intact PTH variations during haemodiafiltration

BACKGROUND.: Recent approaches to prevent and treat secondary hyperparathyroidismin dialysis patients include decreasing dialysate Ca contentfrom 1.75 to 1.5 mM or lower. We have recently observed thatby decreasing dialysate Ca to 1.25 mM a rise in intact parathormoneserum levels occurs despite adequately controlled predialysisCa and phosphate serum levels. In that study complementary treatmentwith high-dose 1(OH) vitamin D3 was required to suppress theparathormone. In the present study we aimed to assess the totalCa balance as well as the modifications in parathormone inducedby the dialysis session in order to understand the reasons forwhich the rise in parathormone was induced. METHODS.: Fourteen HD patients treated with haemodi-afiltration threetimes/week gave their informed consent for the study. They weredistributed in two groups with identical treatment but for thedialysate Ca content which was 1.5 and 1.25 mM respectivelyand for the amount of oral CaCO₃ received. Total and ionizedCa, phosphate, pH, and albumin as well as parathormone weremeasured in serum before and after dialysis and in the spentdialysate during two dialysis sessions. RESULTS.: Serum ionized Ca (normalized to pH 7.4) did not change during1.25 mM dialysate Ca and significantly increased with 1.5mM(P<0.001). The end-dialysis values being 1.25±0.02and 1.38±0.02 mM respectively. Total Ca significantlydecreased with 1.25mM dialysate Ca (P<0.04) and increasedwith 1.5mM (P<0.003), the end-dialysis values being 2.51±0.03and 2.75±0.04mM respectively. In the dialysate the differencein ionized Ca concentrations, fresh minus spent dialysate was–1.78±1.12 mmol/l (NS) and 4.26±1.47 mmol/l(P<0.02) respectively for 1.25 and 1.5 mM dialysate Ca. Thedifference in total Ca concentrations, fresh minus spent dialysatewas –0.1±0.01 mmol/l (P<0.005 and –0.002±0.01 mmol/l (NS) respectively. Phosphate removal was higherin 1.25 mM dialysate-Ca-treated patients (40.4±1.75 mmol/sessionversus 34±1.3 mmol/session respectively, P<0.015).The use of 1.25 mM dialysate Ca did not result in a change inserum parathormone, while the use of 1.5 mM resulted in a decreaseof 43±15% (P<0.02) in patients with marked hyperparathyroidism. CONCLUSIONS.: Our data remind us of the difficulty in assessing Ca balancesand identifies the phosphate content as one of the factors influencingthe amount of ionized Ca in the dialysate. Although the long-termparathormone increase we observed using 1.25 mM dialysate Camay well not be explained only by the acute intradialytic modifications,the negative Ca balance identified here (which was missed withthe analysis of ionized Ca alone), and the lack of parathormoneinhibition may participate in the relapse of hyperparathyroidism.     

探讨透析液钙浓度对血液透析患者血压及血清钙磷变化的影响

目的观察不同钙离子浓度的透析液对血液透析患者血压及血清钙磷代谢的影响,为血液透析患者的高血压及高钙血症的防治提供参考。方法选取我院血液净化中心维持性血液透析患者15例,采取自身对照的方法,先后应用钙浓度为1．75mmol／L（dCa2＋1．75）及1．50mmol／L（dCa2＋ 1．5）的透析液各连续进行35次透析,记录每次透析上机前、1h、2h、3h及透析结束后的血压,并分别于第1次及第35次透析前后观察一般临床指标及血清总钙、磷、钙磷乘积、甲状旁腺素及碱性磷酸酶的变化。结果两种透析液一般指标差异无显著性（P〉O．05）。与采用dCa2＋ 1．75相比,采用dCa2＋ 1．5进行透析,患者的血压降低,尤其在透析3h及透析结束后,差异有显著性（P〈0．05或P〈0．01）,透析后磷升高,差异有统计学意义（P〈0．05）,其他指标变化无显著性（P〉0．05）。结论透析液钙离子浓度与血液透析患者血压呈正相关,低钙透析液透析有助于维持性血液透析患者高血压的控制,但本研究未观察到其对血清钙浓度的影响。     

Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality.

BACKGROUND: Advanced glycation end products (AGEs) accumulate in patients with end-stage renal disease (ESRD). The aim of this study was to investigate the potential influence of different modalities of renal replacement therapies on plasma AGE levels. METHODS: The removal of AGEs by high-flux haemodialysis (HD) using standard and ultrapure dialysis fluid (SDF and UDF), by haemodiafiltration (HDF) and by haemofiltration (HF) was studied by fluorescence spectroscopy and by a carboxymethyllysine (CML)-specific ELISA. In addition, molecular weight distribution of fluorescent AGE products in serum of several patients was analysed by gel filtration. RESULTS: The highest AGE-typical fluorescence was found in the serum of patients on HD using SDF (114,667+/-18,967 arbitrary units (AU)), followed by patients on HDF (86,912+/-24,411 AU, P<0.005), by patients on HD using UDF (74,953+/-21,152 AU, P<0.0001) and by patients on HF (74 039+/-17 027 AU, P<0.0001). Similar results were found for serum CML levels with the highest values in HD patients on SDF (1609+/-504 ng/ml), followed by patients on HF (1354+/-614 ng/ml, P<0.001), then by HD patients on UDF (1310+/-403 ng/ml, P<0.001) and by patients on HDF (1132+/-338 ng/ml, P<0.001). The removal rate of AGEs, as evaluated by the determination of the pre-/post-dialysis AGE differences, was comparable across all groups. CONCLUSION: These findings suggest that factors other than removal are responsible for the lower pre-dialysis AGE levels found in patients on convective dialysis as well as on HD with UDF. A role of water quality is assumed. This is corroborated by the finding that the high molecular weight AGE-fraction is preferentially lowered in comparison with patients on HD with SDF, as analysed by gel filtration chromatography. These findings could be best explained by a less severe oxidative stress (i.e. resulting in decreased AGE generation) with HF and HDF, as well as with ultrapure HD.     

Effect of chronic intravenous calcitriol on parathyroid function and set point of calcium in dialysis patients with refractory secondary hyperparathyroidism.

This study evaluates the effect of intravenous calcitriol on parathyroid function and ionized calcium-PTH sigmoidal curve obtained during low- and high-calcium haemodialysis in 10 patients with osteitis fibrosa whose secondary hyperparathyroidism was refractory to conventional therapy. After 4 months of intravenous calcitriol, serum ionized calcium increased from 1.28 +/- 0.08 to 1.37 +/- 0.11 mmol/l (P less than 0.001), serum phosphate from 1.54 +/- 0.18 to 1.79 +/- 0.4 mmol/l (P NS), serum calcitriol from 16.7 +/- 9.9 to 34.3 +/- 6.4 pg/ml (P less than 0.001), while alkaline phosphatase decreased from 366 +/- 340 to 226 +/- 180 IU/l (P less than 0.05), osteocalcin from 46.4 +/- 20 to 34.5 +/- 15.3 ng/ml (P less than 0.05), and basal intact PTH from 1069 +/- 700 to 305 +/- 270 (P less than 0.01). Basal PTH started to decrease after 1 month of treatment prior to the increase in the ionized calcium. Because of hypercalcaemia the dialysate calcium was decreased from 1.75 to 1.5 mmol/l in three of five patients on haemodialysis, and calcium-containing solutions were replaced by calcium-free fluids in four of five patients on haemodiafiltration. Calcitriol dose, at the first month of therapy was 5.6 +/- 0.8 micrograms/week, but it was successively decreased because of hypercalcaemia to a final dose of 3.6 +/- 1.3 micrograms/week. After intravenous calcitriol the ionized calcium-PTH sigmoidal curve shifted to the left and downward. Maximally stimulated PTH and maximally inhibited PTH obtained during low- and high-calcium dialysis significantly decreased, as well as the ratio of basal PTH/PTHmax and the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Review Article: Is it time to embrace haemodiafiltration for centre‐based haemodialysis? (Review Article)

SUMMARY:   Improvements in survival in dialysis patients over the past few decades have been disappointing. Recent prospective trials such the haemodialysis study have not shown conclusive improvements. Two recent observational studies have found a striking survival advantage for haemodiafiltration (HDF). This review covers the differences between HDF and conventional haemodialysis (HD) and the history of the technological advances in the HDF technique. In addition, it explores the putative benefits of HDF over HD. While the observational studies provide a basis for optimism that HDF will provide benefit to dialysis patients, definitive conclusions cannot be drawn until the results of randomized controlled trials are available. While the evidence in favour of HDF at this stage is observational only, there are no studies suggesting that the treatment is detrimental. The use of HDF should probably be increased, particularly in centres where an increase in the frequency and duration of dialysis cannot be readily achieved.     

Dialysis efficacy during acetate-free biofiltration

Background. Acetate-free biofiltration (AFB) is a haemodiafiltration technique based on continuous post-dilution infusion of a sterile isotonic bicarbonate solution. We performed a long-term randomized prospective trial to compare dialysis efficacy and metabolic control of AFB versus bicarbonate haemodialysis (HD). Methods. The AFB group consisted of 11 and the HD group of nine patients, matched for age, sex and urea reduction rate. Biochemical parameters were obtained every 3 months for 1 year (haemoglobin, calcium, phosphate, urea, pre- and post-dialysis bicarbonate, and parathormone (PTH)) and medication was updated. Efficacy of dialysis calculated by KT/V using the dialysate sampling method was determined every 3 months. In AFB patients, the infusion rate of bicarbonate solution was adjusted individually to obtain bicarbonate values of ⩾22 mmol/l before dialysis and ⩽32 mmol/l after dialysis. In the HD group, bicarbonate was added as oral medication to match these bicarbonate concentrations. Statistical analysis was performed using ANOVA for repeated measurements. Results. Pre-dialysis serum bicarbonate levels had risen to the same extent in both groups at the end of the study period (AFB from 21.8 to 26.1 mmol/l, P<0.001, and HD from 20.8 to 24.9 mmol/l, P<0.001). Post-dialysis bicarbonate level was higher in the AFB than in the HD group (P<0.01). Calcium and phosphate levels remained stable in both groups. PTH increased in both groups (AFB from 10.6 to 23.7 pmol/l, and HD from 24.6 to 32.8 pmol/l), with a significant rise only in the AFB patients (P<0.013). Finally, haemoglobin levels and erythropoietin dosage did not change in either group. No significant differences between the two groups were observed. Conclusions. Acidosis was better corrected in AFB without the need for oral supplementation of bicarbonate. However, neither serum calcium nor phosphate levels changed. The observed increase in PTH in the AFB group remains to be clarified. Dialysis efficacy, measured as KT/V, improved during AFB.     

Endotoxin transfer through dialysis membranes: small- versus large-pore membranes.

In this in-vivo study, dialysate and serum endotoxin was evaluated before and after haemodialysis with small-pore (PS400) and large-pore (PS600) polysulphone dialysers, and before and after haemodiafiltration with the PS600 filter. The source of the endotoxin was the presence in dialysate of Pseudomonads at a concentration of 10(3)-10(4) CFU/ml. Endotoxin was measured by a modified chromogenic limulus amoebocyte lysate (LAL) assay. In spite of dialysate endotoxin concentrations greater than 100 pg/ml, no changes in pre- versus posttreatment LAL reactivity were observed in PS400 dialysis and PS600 haemodiafiltration. In contrast, PS600 haemodialysis was related to an increase in serum LAL reactivity from 1.3 +/- 1.5 to 3.8 +/- 2.0 pg/ml (n = 15, P less than 0.01), and five patients (33.3%) showed a post-dialysis value in excess of 5 pg/ml. Our data are consistent with the absence of in-vivo endotoxin transfer during haemodialysis with small-pore dialyser membranes, and during haemodiafiltration with membranes with larger pores. An increase in LAL reactivity during haemodialysis with membranes with larger pores is, however, present, presumably due to the occurrence of backdiffusion/filtration with that specific strategy.     

Citrate‐Buffered Dialysis Solution (Citrasate) Allows Avoidance of Anticoagulation During Intermittent Hemodiafiltration—At the Cost of Decreased Performance and Systemic Biocompatibility

Reportedly, citrate‐based dialysis solution enables heparin dose tapering or even complete exclusion, particularly in postdilution hemodiafiltration (HDF). The aim of the study was to verify this strategy in predilution setting and to assess its short‐term safety, efficacy, and biocompatibility. Ten regular hemodialysis patients were assigned to predilution HDF on acetate‐ and citrate‐based dialysis solutions (0.8 mmol/l trisodium citrate) at random order. Acetate HDF was performed using routine dose of heparin while citrate HDF was heparin free. Plasma calcium, thrombin‐antithrombin complexes (TAT), and citrate levels were measured at 0, 30, 60, 120, and 240 min. Following each session, a semiquantitative dialyzer clotting score (DCT 1‐5) was assessed and HDF adequacy was determined as spKt/V. Statistical relevance was tested by ANOVA with pP < 0.05 held significant, data are given as means ± standard deviations. All sessions were accomplished successfully, premature termination or circuit re‐setting was not necessary. However, DCT was significantly higher in citrate‐HDF compared to acetate‐HDF regimen (3.4 ± 0.65 and 1.8 ± 0.79, respectively, P = 0.002) as well as TAT generation rate (increase per session by factor 11.0 ± 8.43 and 2.1 ± 1.26, respectively, P = 0.004 between regimens). Ionized calcium declined only by the end of citrate‐HDF (from 1.09 ± 0.086 to 0.99 ± 0.030 mmol/L, P = 0.002) yet without accompanying clinical symptoms. Systemic citrate levels increased along the citrate‐HDF session but stayed an order of magnitude below concentrations needed to establish citrate anticoagulation (peak at 0.276 ± 0.112 mmol/L). Dialysis adequacy estimated by spKt/V was found lower in citrate‐HDF vs. acetate‐HDF (1.48 ± 0.163 and 1.58 ± 0.165, respectively, P = 0.006). Although predilution HDF using citrate‐based dialysate is feasible without heparin, both dialysis adequacy and biocompatibility is significantly compromised. Therefore, this approach can be adopted for a single procedure but is not acceptable on a regular basis.