Response to the hepatitis B virus vaccine in haemodialysis patients: influence of malnutrition and its importance as a risk factor for morbidity and mortality

OBJECTIVE.: To assess if malnutrition influences the response to the hepatitisB virus vaccine in haemodialysis patients and whether this correlateswith morbidity and mortality in these patients. DESIGN.: A 4-year prospective open study. SETTING.: Haemodialysis unit of a 434-bed University Hospital. PATIENTS.: Sixty-four patients with end-stage chronic renal failure onmaintenance haemodialysis. INTERVENTIONS.: Three-dose vaccination series with recombinant hepatitis B virusvaccine. MEASUREMENTS.: Antibody formation against the vaccine, predialysis serum urea,serum albumin and prealbumin, dialysis efficacy (Kt/V), proteincatabolic rate (PCR), arm muscle circumference, triceps skinfold,serum parathyroid hormone concentration, mortality and morbidity(hospital days per year of dialysis). RESULTS.: Increase in age negatively influences the formation of antibodies(P=0.01), whereas serum albumin (P=0.008) and predialysis bloodurea concentration (P=0.004) are positively correlated withthe formation of antibodies. Responders had significantly higherlevels of serum albumin and prealbumin and predialysis bloodurea than non-responders. The percentage of non-responders washigher (70%) in the group with predialysis blood urea concentrationbetween 90 and 125 mg/dl than in those with predialysis bloodurea concentrations between 176 and 225 mg/dl (14.2%). Patientswith serum albumin levels between 3 and 3.5 g/dl were non-respondersin a higher percentage (87.5%) than those with serum albuminlevels between 4.5 and 5 g/dl (18.8%). After a 4-year follow-up, survival was 20% higher in the respondergroup (P<0.05). Morbidity, expressed as hospital days peryear of haemodialysis, was markedly lower in the responder group(10.4±2 versus 32±14 days, P=0.03). CONCLUSIONS.: Malnutrition negatively influences the response to the hepatitisB virus vaccine in haemodialysis patients. Non-responders havehigher morbidity and mortality than responders, and thereforethe absence of response to the hepatitis B vaccine can be consideredas a risk factor in the haemodialysis population.     

Improvement of Anaemia With Desferrioxamine in Haemodialysis Patients

We have prospectively investigated the effect of desferrioxamine(DFO)administration (2 g i.v. after every haemodialysis session for6 months) on the normocytic and normochromic anaemia of sevenhaemodialysis patients. None had either clinical or analyticaldata characteristic of chronic aluminium intoxication. At theend of DFO therapy, the haematocrit had increased from 20.5±2.7%to 30.4±7.7% (P< 0.005), and the transfusional requirementsdecreased from 3.5±2.2 units (range 1–8 units)in the 6 months prior to DFO, to 0.7±0.9 units (range0–2 units) during DFO administration (P<0.01). No transfusionwas required during the second half of the DFO therapy period.Serum ferritin decreased from 1059±532 nmol/l (2649±1331ng/ml) to 507±403 nmol/l (1268±1008 ng/ml) (P<0.025).Two months after DFO withdrawal the haematocrit value fell significantlyto 22.2±1.6% (P<0.01). DFO therapy was restarted inone patient at a lower dose (1 g i.v. after every haemodialysissession) and an increase of haematocrit from 23.8% to 40.2%was again observed after 3 months of treatment. The toleranceto DFO was excellent. We conclude that DFO therapy should beconsidered in haemodialysis patients with severe anaemia andincreased blood transfusion requirements.     

Skin surface pH, moisture, and pruritus in haemodialysis patients

Pruritus is one of the most common complaints of haemodialysedpatients. However, its patho-genesis remains unclear. Drynessof the skin and the effects of pH changes on the nerve endingsin the skin have been suggested as related factors. In the presentstudy we measured skin pH using a skin pH meter and skin moistureusing a corneometer at four different sites in 41 haemodialysispatients, before and after dialysis, and in 40 healthy controls.Thirty patients (73%) complained of pruritus, six severe constant,12 moderate and 12 mild. Skin surface pH was higher in patientsthan in controls in the upper back (5.54 + 0.14 versus 5.22± 0.08, P<0.02), forearm (5.5±0.1 versus 5.13± 0.1, P<0.01) and forehead (5.35±0.08 versus5.04±0.07, P<0.004), whereas there was no differencein the axilla. Haemodialysis had no effect on skin pH, and therewas no correlation with blood pH, blood bicarbonate and serumelectrolytes. There was no correlation between skin surfacepH and pruritus. Skin moisture was lower in haemodialysis patientsthan in controls in the forehead and axilla. There was no correlationwith pruritus. Skin surface pH is higher in haemodialysed patients than inhealthy controls in most areas of the body, despite the factthat these patients have a decreased blood pH. Thus, the skinpH is not related to systemic acid-base balance. It is possiblethat the uraemic state affects the ability of the dermal cellsto secrete acid, making the skin more susceptible to bacterialand fungal infections. Pruritus, however, is not related tothis defect in skin acid secretion. Moreover, pruritus is notrelated to skin moisture. The pathogenesis of pruritus in haemodialysispatients continues to be an enigma.     

Influence of blood volume on the blood pressure of predialysis and peritoneal dialysis patients treated with erythropoietin

Twenty-seven patients with renal failure (16 on CAPD and 11predialysis) were treated with erythropoietin. At 12 weeks,the mean haemoglobin concentration (±SEM) in the CAPDpatients had increased from 7.07 ± 0.20 to 10.88 ±0.45 g/dl (two-tailed paired t test, P<0.0001) and in thepredialysis patients from 6.90 ±0.35 to 10.05 ±0.47 g/dl (P< 0.0001). Predialysis patients were taking moreantihypertensive medication at baseline. No increase was requiredin either group after erythropoietin; there was no change inblood pressure in the CAPD patients, though in the predialysispatients the systolic blood pressure rose slightly from 132to 146 mmHg (P=0.029) and the mean blood pressure from 95 to103 mmHg (P=0.028). In 12 patients (6 on CAPD and 6 predialysis) the red cell volume,plasma volume, and total blood volume were measured before andafter treatment. In the CAPD patients there was a marked expansionof the red cell volume from 912±127 to 1471±222ml (P=0.004) and a concomitant contraction of the plasma volumefrom 3932 ±250 to 3178 ±326 ml (P=0.005), leavingthe blood volume unchanged from 4843 ± 352 to 4649 ±503ml. Predialysis patients had a similar expansion of the redcell volume from 733 ± 59 to 1304± 161 ml (P=0.017)but no contraction of the plasma volume (from 3417 ±354to 3314 ±260 ml), so that the blood volume tended toexpand from 4149 ±347 to 4618 ±414 ml (P= 0.053).The mean contraction of the plasma volume in the predialysisgroup was trivial (– 102 ±214 ml), whereas in theCAPD group it was large (–754 ±158 ml, P=0.034,two-tailed unpaired t test). Thereby the predialysis group experiencedan expansion of the total blood volume of 469±186ml,whereas the CAPD group experienced a contraction of the bloodvolume of –195±189 ml(P=0.031). We conclude that (a) increased blood volume may contribute tothe exacerbation of hypertension induced by erythropoietin therapy;(b) gradual reduction of plasma volume, aiming for a stabletotal blood volume, is an important strategy for the preventionand control of erythropoietin-induced hypertension; (c) as reductionof plasma volume may be more problematic in predialysis patients,adequate blood pressure control may consequently be slightlymore difficult, placing more reliance on antihypertensive medication.     

Acute Responses of Parathyroid Hormone and 1,25 Dihydroxyvitamin D3 to Unilateral Nephrectomy in Healthy Donors

Plasma immunoreactive parathyroid hormone (iPTH), 1,25(OH)₂D3calcium and phosphate and urinary creatinine, calcium and phosphatewere measured before and following unilateral nephrectomy insix kidney donors. Unexpectedly, plasma calcium rose, from 2.27±0.02mmol/l (mean±SEM) to 2.41±0.03 mmol/l on day 7and to 2.37±0.02 mmol/l on day 30 (P<0.02). A parallelrise in iPTH occurred, from 0.61±0.16 ng/ml initially,to 1.83±0.54 ng/ml on day 7 (P<0.05) and to 1.18±0.18on day 30 (P<0.01). The ratio of maximal tubular reabsorptionof phosphate to GFR (TmP/GFR) fell by day 2 (P<0.001), remainingreduced on day 30 (P<0.05). The significance of elevated iPTH in renal insufficiency wasfurther assessed by determining the time course of the disappearanceof iPTH after parathyroidectomy in three haemodialysis subjects.Fifty per cent baseline iPTH level occurred after an averageof 104.7 min, suggesting that the assay did not predominantlyrecognize C-terminal PTH fragments. By day 2, plasma 1,25(OH)₂D3had fallen from 34.3±4.5 pg/ml to 22.8±3.8 pg/ml(P<0.001), but by day 4 had regained its pre-nephrectomyvalue. Our results suggest that hypocalcaemia may not be thesole stimulus to parathyroid hormone secretion. It is speculatedthat reduction in circulating 1,25(OH)₂D3 may be involved.     

Altered Lung Vascular Permeability During Intermittent Haemodialysis

Hypoxia is known to develop during intermittent haemodialysis.To investigate if increased pulmonary capillary permeabilityto protein contributes to this phenomenon, a dual-isotope techniqueusing Indiumlabelled transferrin and Technetium-labelled redblood cells was used. Lung vascular permeability was measuredin eight patients with dialysis-dependent chronic renal failureimmediately before and during intermittent haemodialysis withcuprophane membranes. As a group there was a significant increasein lung vascular permeability during the early stages of haemodialysis,compared to predialysis values (P <0.05) and this increaseoccurred during the period when the patients were leucopenicand maximally hypoxic. During the haemodialysis period, butnot the predialysis period, the permeability index was alsosignificantly increased compared to a group of eight controls(P<0.05). These results suggest that increased vascular permeability maycontribute to dialysis-induced hypoxia and that this may relateto neutrophil activation within the pulmonary vascular bed.     

Effect of calcium-channel blockers on calcium--phosphate metabolism in patients with end-stage renal disease

BACKGROUND: After EDTA-induced hypocalcaemia, healthy volunteers treatedwith diltiazem display more severe hyperparathyroidism thansubjects on felodipine studied under identical conditions. Thereforepatients with end-stage renal disease (ESRD) and severe secondaryhyperparathyroidism might be particularly sensitive to thisside-effect. METHODS: To test this hypothesis, seven patients with ESRD on chronichaemodialysis (3 women and 4 men) with serum levels of intactPTH ranging from 204 to 675 pg/ml were studied both before andduring the first 180 min of haemodialysis against a dialysatewith low calcium concentration (0.75 mmol/1, n=6 and 1 mmol/1,n=1) under the following three experimental conditions: control,felodipine (10 mg/day) and diltiazem (120 mg b.i.d.). RESULTS: At onset of dialysis, plasma phosphorus level was higher ondiltiazem (2.03±0.08 mM) than on felodipine (1.64±0.10,P<0.02), and on the latter it was lower than in control condition(1.88±0.16, P<0.02). As a probable consequence, bloodionized calcium concentration was lower on diltiazem (1.14 mM±0.02,mean±SEM) than on felodipine (1.2±0.03, P<0.05)or in control condition (1.17±0.01, NS). There was atrend for intact PTH to be higher on diltiazem (324±47pg/ml) than on felodipine (246±55) or in control condition(305±49) and 1,25-dihydroxyvitamin D was higher indeedon diltiazem (6.70±0.92 pg/ml) than on felodipine (4.75±0.91,P<0.02) or control (3.87±0.62, P<0.05). Area underthe curve PTH over the first 60 min of dialysis was higher by16±7% on diltiazem than on felodipine (P<0.05). CONCLUSIONS: While on diltiazem rather than on felodipine, patients withESRD display higher plasma phosphorus levels, and slightly aggravatethe degree of severity of hyperparathyroidism recorded duringhaemodialysis against low-calcium dialysate. The longterm effectof this new observation remains to be evaluated.     

Caloric rather than protein deficiency predominates in stable chronic haemodialysis patients

BACKGROUND.: The monitoring of energy and protein intake is considered fundamentalin uraemic patients. However, in the clinical practice onlyprotein ingestion is indirectely evaluated by the protein catabolicrate. METHODS.: In a cross-sectional study we evaluated the relationship betweencaloric and protein intake of 29 stable chronic haemodialysispatients (18M, 11 F, mean age 49 ± 17 years, 68 ±6 months on maintenance haemodialysis), and the validity ofprotein catabolic rate determination. Normalized protein catabolicrate was obtained according to Sargent's formula, and Watson'sequation was used to calculate urea distribution volume. Caloricand protein intake were recorded during a 3-day period, andaverage daily ingestion of nutrients was calculated using acomputerized diet analysis system. RESULTS.: A greater reduction of daily energy intake (26.8±11.9Kcal/kg bw) than daily protein intake (1.02±0.4 g/kgbw) was observed. Fifty-nine percent of patients had low proteinintake while 86% of patients had lower caloric intake than recommended.An inverse relationship between age and protein (r=–0.65,P<0.00l) or caloric intake (r=–0.67, P<0.001) wasobserved. Negative relationships between daily protein (r=–0.60,P <0.01) and also caloric intake (r=–0.39, P<0.05)and the ratio between the urea generation rate and the totaldietary nitrogen were found, indicating that in patients withlow nutrient intake the nitrogen balance tends to be negative. Normalized protein catabolic rate was directly correlated withprotein intake (r=0.77, P<0.001). A protein catabolic ratecut-off of 1 g/kg bw correctly identified all patients withnormal daily protein intake, and 14 of 17 patients with deficientdaily protein intake (<1g/kg bw). Thus in only 10% of haemodialysispatients an imbalance between both parameters was observed.Moreover, patients with a daily protein intake lower than 1g/kg bw were older and showed lower BUN and protein catabolicrate values than their counterparts. CONCLUSIONS.: Nutritional abnormalities are frequently found, even in apparentlyclinically stable patients on chronic haemodialysis. Caloricrather than protein undernutrition is the major abnormalityof their wasting. Inadequate intake of proteins and caloriesappears more commonly in older patients, and in associationwith lower BUN and protein catabolic rate values. Although normalizedprotein catabolic rate shows a direct correlation with a dailyprotein intake, the identity line shows that when daily proteinintake was lower than 1 g/kg bw, it was overestimated by proteincatabolic rate. Conversely, when daily protein intake is higherthan 1 g/kg bw it is underestimated by the protein catabolicrate. This relationship should to be considered when interpretingthe protein catabolic rate in a clinical setting.     

Effect of L-carnitine administration on erythropoietin use in thalassemic minor haemodialysis patients.

Sir, We read with great interest the recent letter by Arduini etal. [1], on the effect of L-carnitine (LC) on erythrocyte survivalin haemodialysis patients. In the same issue, there is a paperby Hothi et al. [2] showing that plasma free-carnitine (FC)levels fell from 26.54 ± 2.99 to 15.6 ± 2.34 µmol/l(P < 000.1) in nocturnal haemodialysis (NHD). A similar reductionin plasma acyl-carnitine (AC) levels was observed (from 13.22± 1.34 to 6.24 ± 1.20 µmol/l (P < 0.001)).The AC : FC ratio improved from 0.51     

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.     

Time course of inulin and creatinine clearance in the interval between two haemodialysis treatments

BACKGROUND: Urinary volume of haemodialysis patients with residual renalfunction increases during the interdialytic interval. The contributionof GFR to this change in water and solute excretion has notbeen quantified in detail. The creatinine clearance (Cl^c) asa determinant of the GFR may overestimate GFR caused by thetubular secretion of creatinine. Cimetidine has been used toinhibit the secretion of creatinine in non-dialysed patients.No data are available on its usefulness in haemodialysis patients. METHODS: Two identical interdialytic intervals (DI) of 3 days (DI-1,DI-2) were investigated in 11 patients. The interval betweenDI-1 and DI-2 was 1 week. During DI-2 cimetidine 800 mg dailywas administered. Each DI was divided in four urine-collectionperiods. RESULTS: The water and solute excretion in DI-1 and DI-2 were similar.Urinary production increased from 0.37 ±0.30 ml/min to0.66 ±0.33 ml/min (P<0.05), inulin clearance (C1¹)increased from 1.8±1.1 ml/min to 2.7 ± 1.2 ml/min(P<0.05), fractional sodium excretion from 9.0 ± 5.7%to 14.5 ± 9.0% (P<0.05). In contrast to Cl_i;; theCl_c showed no increase during the interdialytic interval bothin DI-1 and DI-2. The overestimation of GFR by creatinine (Cl_i– Clⁱ) decreased during DI-1 from 1.35 ±1.69 ml/minto 0.26 ± 0.60 (P<0.05) and during DI-2 from 1.01±1.33 ml/min to 0.10 ± 0.67 (P<0.01). The ratioCl^c/Clⁱ decreased during DI-1 from 1.78 ± 0.53 to 1.09± 0.19 (P< 0.01) and during DI-2 from 2.02 ±1.13to 1.05 ± 0.30 (P<0.01). All parameters were not differentbetween the comparable days of DI-1 and DI-2. CONCLUSION: We conclude that the urinary volume in the interdialytic intervalis directly related to changes in GFR. During the interdialyticinterval GFR increased and tubular secretion of creatinine decreased.The administration of cimetidine did not improve the accuracyof Cl_c as a measurement of GFR in end-stage renal failure.     

Circulating soluble adhesion molecules in systemic vasculitis

The plasma levels of soluble intercellular adhesion molecule-1(sICAM-1), E-selectin (sE-selectin), and vascular cell adhesionmolecule-1 (sVCAM-1), might reflect endothelial activation andinjury and would therefore be useful markers of disease activityin vasculitis. To investigate this we measured the levels ofsICAM-1, sE-selectin, and sVCAM-1 by two-site ELISAs in theplasma of patients with (a) active vasculitis (n = 16), (b)vasculitis in remission (n = 15), (c) chronic renal failure(CRF) (n = 10), and (d) normal healthy controls (n = 10). PlasmasICAM-1 levels were significantly higher in patients with activevasculitis, 323 ng/ml (193–607) compared with patientswith inactive vasculitis, 199 ng/ml (131–297); P = 0.0006and healthy controls, 188 ng/ml (138–259); P =0.0002.Plasma sE-selectin levels were also significantly higher inthe patients with active vasculitis, 45 ng/ml (15–65)compared with patients with inactive vasculitis, 25 ng7sol;ml(15–55); P=0.027 but not when compared with healthy controls,35 ng/ml (20–55); P=0.16. There was no difference in plasmasVCAM-1 levels between patients with active vasculitis, OD 0.56(0.45–0.85) and inactive disease, OD 0.58 (0.47–0.79)(P=0.12) or with healthy controls OD 0.49 (0.42–0.68)(P=0.48). There were no significant differences between theplasma levels of any of the soluble adhe sion molecules betweenpatients with active vasculitis and patients with chronic failure.In patients with a vasculitis there was a significant correlationbetween sICAM-1 and plasma C-reactive protein (CRP) (r=0.60,P=<0.01) and plasma von Willebrand factor (vWF) (r=0.42,P<0.05). Likewise there was a cor relation between sE-selectinand CRP (r=0.45, P<0.02) but not with vWF. There was a significantcorrelation between sICAM-1 and sE-selectin (r=0.38, P<0.05),but not between sICAM-1 and sVCAM-1 or sE- selectin and sVCAM-1.No correlation was found between sVCAM-1 levels and CRP andvWF concentrations or between the levels of any of the solubleadhesion molecules and serum creatinine. Plasma levels of sICAM-iand of sE-selectin but not of sVCAM-1 reflect disease activityin vasculitis and may be markers of endothelial and or tissueinjury in these disorders.     

Secondary hyperparathyroidism and acute tubular necrosis following renal transplantation

In the present study we investigated the relationship betweensecondary hyperparathyroidism in renal graft recipients andpost-transplantation acute tubular necrosis (ATN). Patientswere divided into two groups according to graft function: groupA consisted of 28 patients who had an uneventful postoperativeperiod and did not require haemodialysis. Group B comprised26 patients with primary non-function of the graft due to biopsy-provenATN who required continued haemodialysis for the first postoperativeweek or longer (mean 14.2 ±8.7 days). Both groups hadcomparable donor characteristics, HLA-matching and ischaemiatimes. All patients were given cyclospo-rin and low-dose prednisolonefor immunosuppression. Pretransplant levels of intact PTH weresignificantly greater in group B than in group A (203.5 ±193.1pg/ml versus 81.7±45.2 pg/ml, P<0.01). Group B patientshad more transplant biopsies (50 versus 7) and a longer hospitalizationtime (33.4 ± 10.9 days versus 21.9 ± 11.9 days,P<0.01), although serum creatinine on the day of dischargewas higher in group B (1.77 ± 0.51 mg/dl versus 1.5±0.45mg/dl, P<0.05). We conclude that patients with secondaryhyperparathyroidism as assessed by measuring circulating levelsof intact PTH have an increased incidence of ATN.     

Serum chromogranin A concentration and intradialytic hypotension in chronic haemodialysis patients

Aim The aim of this study was to investigate the influence of haemodialysis on plasma chromogranin A (CgA) concentration and to assess the relationship between CgA, blood pressure, occurrence of intradialytic hypotension episodes and residual renal function, respectively. Methods The study included 38 chronic haemodialysis patients (24 M, 14 F; mean age 56.2 ± 13.6 years). Plasma CgA and blood pressure were measured before and after a mid-week dialysis. Control group included 10 age- and sex-matched healthy subjects. Results Plasma CgA levels were on average 50-fold higher in HD patients than in the controls (699 ± 138 vs. 14 ± 6 U/L). In HD patients plasma CgA corrected for ultrafiltration rates significantly increased (to 836 ± 214 U/L, P < 0.001) at the end of dialysis procedure. In patients with (n = 8) and without frequent symptomatic intradialytic hypotension episodes predialysis values of CgA were similar (701 ± 169 vs. 698 ± 132 U/L) but post-dialysis were significantly lower in the former group (746 ± 312 vs. 860 ± 177 U/L; P = 0.03) despite a similar rate of ultrafiltration (2675 ± 1009 and 2583 ± 1311 ml, respectively). Accordingly, in patients with intradialytic hypotension an increase of plasma CgA during dialysis was also much lower than in patients without hypotension (45 ± 81 vs. 163 ± 144 U/L; P = 0.001). Conclusions CgA undergoes marked accumulation in renal failure. The increase of plasma CgA during dialysis is impaired in subjects with intradialytic hypotension episodes, which confirms the role of autonomic dysfunction in the pathogenesis of this complication.     

Biochemical markers for non-invasive diagnosis of hyperparathyroid bone disease and adynamic bone in patients on haemodialysis

The diagnostic and predictive value of serum intact parathyroidhormone (iPTH) and osteocalcin (bone Gla protein, BGP), aloneor in combination, have been examined in only a small numberof haemodialysis patients. METHODS.: We studied prospectively 114 patients (46 women, 68 men; meanage 52±12 years) on regular haemodialysis for a meanof 55 (6–185) months. All patients underwent labelledtransiliac bone biopsy, and serum levels of iPTH, BGP and alkalinephosphatase were determined. RESULTS.: Seventy-one patients (62%) showed histological findings of hyperparathyroidbone disease, 24 (21%) mixed bone disease, six (5.5%) osteomalaciaand 13 (11.5%) adynamic bone. Bone aluminium deposition overmore than 25% of the trabecular bone interface was found in66 patients (58%). Serum iPTH and BGP correlated with the majorityof histomorphometric indices of bone formation, mineralizationand resorption (r>0.5, P<0.01). iPTH levels200pg/ml andBGP50 ng/ml were found to be indicative of hyperparathyroidbone disease, whilst iPTH levels <65 pg/ml and BGP<20ng/ml were indicative of adynamic bone. However, the positivepredictive value of these indices was limited (less than 80%),although their negative predictive value, especially when usedin combination, was good (more than 90%) and the exclusion ofhyperparathyroid bone disease and adynamie bone was possible.The diagnostic and predictive value of these bone markers wereimproved when patients with bone aluminium deposition were excluded. CONCLUSIONS.: Diagnosis of hyperparathyroid bone disease and adynamic boneis difficult on the basis of iPTH and BGP, especially when bonealuminium deposition is prevalent. However, using these bonemarkers, preferably in combination, the exclusion of these lesionsis feasible.     

Human Recombinant Erythropoietin in Anaemic Patients on Maintenance Haemodialysis. Secondary effects of the Increase of Haemoglobin

Twelve anaemic patients on haemodialysis were treated with recombinanthuman erythropoietin, starting with 72 IU/kg/week. The dosewas doubled after 2 weeks until an increase of 2 g/dl of haemoglobinwas observed. The effects on various parameters were studiedduring a 3-month period. Haemogiobin increased from 6.70±0.74to l0.49±1.04g/dl (mean±SD, P<0.00l), potassiumfrom 5.51±0.50 to 6.06±0.65mmol/1 (P<0.005),phosphate from 1.78±0.40 to 2.17±0.4Ommol/1 (P<0.001)and the calcium phosphorus product from 4.3 to 5.2 (P<0.001)Three patients developed marked periarticular inflammation dueto calcified deposits with a high calcium-phosphorus productof 6.8. An increase in arterial blood pressure was observedin three previously well-controlled hypertensive patients, oneof whom developed hypertensive encephalopathy. We conclude thatrecombinant human erythropoietin is very effective in treatingthe anaemia of end-stage renal failure on haemodialysis. Regularestimations of serum potassium and phosphate are mandatory.In hypertensive individuals a further increase in blood pressureis possible.     

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.     

Adynamic bone disease with negative aluminium staining in predialysis patients: prevalence and evolution after maintenance dialysis

Aplastic bone disease (ABD) is a common form of renal osteodystrophyand is characterized by a defect in bone matrix formation andmineralization without an increase in osteoid thickness. Theprevalence and pathogenesis of ABD in predialysis patients islargely unknown. We prospectively studied 92 unselected predialysispatients with a creatinine clearance <10 ml/min/1.73 m² anda mean age of 45±2 years (61 M, 31 F). None of the studypatients had received any form of vitamin D therapy, and CaCO₃was the primary phosphate binder. Aplastic bone disease wasobserved in 30 (32%) patients. Stainable bone aluminium surfacewas <3% in all ABD patients. Patients with ABD were older(52±3 versus 42±2 years; P<0.01) and had reducedserum intact PTH compared to non-ABD patients (199±25versus 561 ±87 pg/ml; P<0.001). Patients with diabetesmellitus showed lower PTH values (179±31 versus 432±62pg/ml; P<0.001) and a lower incidence of advanced by chperparathyroidismbone lesions (16% versus 46%; P<0.05) than non-diabetic patients.However, diabetes was not clearly associated with low bone turnoverdisease (56% in diabetics versus 41% in non-diabetics; P=0.1). A second bone biopsy was obtained in eleven ABD patients aftera period of 16.6±2.2 months on maintenance dialysis witha dialysate calcium of 7 mg/dl. Bone histology was unchangedin 10 patients, and one evolved to mild hyperparathyroidism.Trabecular bone volume did not change (22.7± 1.7 versus20.7±1.7%), and the stainable bone aluminium surfaceremained <3%. In summary, ABD not associated with positive histological stainingfor aluminium is a common finding in asymptomatic end-stagerenal failure patients in the Canary Islands. Older age andrelatively low PTH values are associated with this form of bonedisease. After a period of 12–36 months of dialysis, progressiveosteopenia and other clinical problems do not occur.     

Relationship between blood pressure during haemodialysis and ambulatory blood pressure in between dialyses

BACKGROUND.: Ambulatory blood pressure measurements in haemodialysis patientsare relevant in view of the high cardiovascular morbidity andmortality in chronic haemodialysis patients. METHODS.: Twelve normotensive patients were studied from the beginningof one dialysis until the end of the next (mean 64 h, SD 19h) using a Spacelabs oscillometric blood-pressure recorder. RESULTS.: A circadian blood pressure rhythm was present in six of the12 patients. In seven patients the lowest pressure recorded(including the dialysis sessions) occurred 5–6 h afterdialysis (late post-dialysis dip). Blood pressure did not increasesharply in the hours before dialysis although it increased slightlyin the interdialytic interval as a whole, at a mean rate of5.6 mmHg per 24 h (SD 4.1, P<0.001). We could not find ablood pressure measurement during dialysis (or combination ofmeasurements) which reliably reflects interdialytic blood pressure:the 95% confidence intervals were 25 mmHg or higher. CONCLUSION.: Ambulatory blood pressure measurements are needed for adequatemonitoring of the control of blood pressure in haemodialysispatients.     

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year

BACKGROUND: A new galenic form of cyciosporin A has been developed, basedon microemulsion technology. The bioavailability of the compoundis reiativeiy independent of food intake and bile flow. It wasthe purpose of this prospective clinical trial to study thesafety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratifiedaccording to transplant age, were switched from the conventionalto the new micro-emulsion formulation of cyclosporin A. A 1:1conversion ratio was used. Measurements included CsA levels,S-creatinine, liver enzymes, uric acid, and blood pressure.Measurements were performed at baseline and on days 4, 8, 15,29 and months 3, 6 and 12 after conversion. Dose adjustmentswere performed to achieve trough levels of 80–120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dosewas reduced by 14.7% (from 204±60 mg/day at baselineto 174±51 mg/day after conversion, P<0.001). Acutely,i.e. by day 8, a 1:1 dose conversion resulted in a modest increaseof mean drug trough levels (from 114 ng/ml at baseline to 120ng/ml, P<0.01). This increase was accompanied by an increasein serum creatinine concentration, a decrease in calculatedcreatinine clearance, and an increase in uric acid values (P0.05).Liver enzymes remained unchanged while systolic and mean arterialblood pressure decreased (P<0.05). After 1 month, drug troughlevels had decreased to baseline (112 ng/ml) and remained thereuntil month 6. They were significantly lower after 12 months(102±33 ng/ml, P<0.001). Creatinine clearance valuesincreased to above baseline at 6 and 12 months. Within the 1-yearperiod there occurred 24 (=8%) episodes of biopsy-proven rejectionand seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsionformulation is efficacious and safe, but an initial dose reductionof 10% is advised in patients with trough levels in the high-normalrange.