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.     

Parathyroid hormone and platelet cytosolic calcium concentration in essential hypertension

To investigate the possible relationships between blood pressure,parathyroid hormone (PTH) and platelet cytosolic Ca²⁺ concentration([Ca²⁺]_i) in patients with essential hypertension, we studied17 patients with this disease aged 48±2 years and 17normotensive controls aged 44±3 years. Platelet [Ca²⁺]_iwas measured by spectrofluorimetry using the dye Fura-2 acetoxymethylester.Patients with essential hypertension displayed lower levelsof serum ionized Ca²⁺ (0.99±0.03 versus 1.1±0.01mmol/l, P<0.05) and higher serum intact PTH levels (37±3versus 26±2 pg/ml, P<0.01) than the normotensive controls.Although serum levels of intact PTH were significantly correlatedwith mean arterial pressure (MAP) in the combined group of subjects(r=0.42, P<0.05), there was no correlation when each groupwas considered separately. Resting platelet [Ca²⁺]_i was alsohigher in patients than in controls (57±3 versus 48±2nmol/l,P<0.005). When platelets were stimulated in vitro with thrombin,the increment in [ca²⁺]_i was also greater in patients than incontrols in the presence of extracellular Ca²⁺ (264±24versus 194±19 nmol/l, P<0.05) but not in its absence(123±12 versus 112±10 nmol/l). The thrombin-inducedincrement in [ca²⁺]_i was correlated with MAP in the hypertensivepatients (r=0.64, P<0.01) and in the combined group of subjects(r=0.42, P<0.05). There was no relationship between restingor thrombin-induced [Ca²⁺]_i and serum PTH in either group ofpatients or in the combined group of subjects. Furthermore,preincubation of platelets in vitro with PTH had no effect neitheron resting platelet [Ca²⁺]_i or on thrombin-induced incrementsin [ca²⁺]_i, both in the presence and in the absence of extracellularCa²⁺ in either group of subjects. Therefore, despite platelet[Ca²⁺]_i and serum PTH seem to be related to blood pressure,it appears that PTH does not participate directly in the elevatedplatelet [Ca²⁺]_i found in patients with essential hypertension.     

Effect of the mode of calcitriol administration on PTH-ionized calcium relationship in uraemic patients with secondary hyperparathyroidism

To assess the effect of the different modes of calcitriol administrationon PTH-ionized calcium relationship we conducted a prospectiveclinical trial in 33 patients on chronic haemodialysis withsecondary hyperparathyroidism (four times upper normal limitintact PTH) who were randomly assigned, with stratificationto PTH levels, to receive daily oral, intermittent oral, orintermittent intravenous calcitriol at the same dose of 0.045µg/kg/weekly. PTH-iCa curves were generated by inducinghypo- or hypercalcaemia in sequential haemodialysis 1 week apart,before and after 10 weeks on treatment. All patients were dialysedagainst a dialysate calcium concentration of 2.5 mEq/l throughoutthe study period. After drop-outs, 26 patients completed the study: 11 on intravenouscalcitriol (mean basal PTH±SD: 666±280 pg/ml),eight on intermittent oral calcitriol (mean basal PTH: 831±361),and seven on daily oral calcitriol (mean basal PTH: 719±280).Serum ionized calcium and phosphorus significantly increasedin intravenous and daily oral groups after calcitriol treatment,but not in the intermittent oral group. Basal PTH did not significantlychange in the three groups after 10 weeks on treatment. MaximalPTH significantly decreased in intravenous group (1449±660versus 1122±691 pg/ml, P=0.0085) and at the limit ofstatistical significance in the intermittent oral group (1701±774versus 1445±634, P=0.12), but it did not change in thedaily oral group. Minimal PTH did not modify in the three groups.In all three groups, a shift to the right in the PTH-iCa relationshipswere observed, with significant changes in the set point ofcalcium. The slope of the post-treatment curves only becameless steep in the intermittent oral and intravenous groups. In conclusion, intermittent administration of calcitriol seemsto be more effective in reducing maximal PTH than daily oraladministration, but at the conditions under which this studywas carried out all the modes of calcitriol administration shiftedPTH-iCa relationships to the right.     

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.     

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.     

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.     

Increased Serum 1,25-Dihydroxyvitamin D after Growth Hormone Administration is not Parathyroid Hormone-Mediated

To assess the effects of growth hormone (GH) on serum 1,25-dihydroxyvitamin D [1,25(OH)₂D], we performed the following prospective crossover study in six healthy, young, adult, white men. During each of two admissions for 2? days to a general clinical research center, subjects were placed on a daily dietary calcium intake of 400 mg. Serum calcium, phosphorus, 1,25(OH)₂D, immunoreactive intact parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP3), tubular reabsorption of phosphate (TRP), and maximum tubular reabsorption of phosphate (TMP/GFR) were measured. Recombinant human GH (rhGH, Humatrope) (25 μg/kg/day subcutaneously for 1 week) was administered prior to and during one of the admissions. Results are expressed as mean ± SEM. Whereas serum 1,25(OH)₂D (58.9 ± 7.7 versus 51.6 ± 7.4 pg/ml, P < 0.01), serum phosphorus (4.5 ± 0.1 versus 3.7 ± 0.1 mg/dl, P < 0.01), TRP (92.0 ± 0.5 versus 87.8 ± 0.7 mg/dl, P < 0.005), TMP/GFR (4.6 ± 0.1 versus 3.5 ± 0.2, P < 0.005), and urinary calcium (602 ± 49 versus 346 ± 25 mg/day, P < 0.001) increased significantly, serum PTH decreased significantly (19.9 ± 1.9 versus 26.8 ± 4.0 pg/ml, P < 0.05) and serum calcium did not change when subjects received rhGH. These findings indicate that in humans, GH affects serum 1,25(OH)₂D independently of circulating PTH and that this effect is mediated by IGF-I. We propose, therefore, that one potential mechanism by which GH stimulates increases in bone mass is via modest increases in serum 1,25(OH)₂D. Received: 2 May 1996 / Accepted: 18 October 1996     

The calcitonin-calcium relation curve and calcitonin secretory parameters in renal patients with variable degrees of renal function

Increased calcitonin (CT) levels have been reported in chronicrenal failure, even before the uraemic phase and in the absenceof hypercalcaemia. Furthermore, a sigmoidal CT-calcium relationshipwas recently observed in rats and haemodialysed patients. We carried out the present investigation in order to assess:(a) whether the sigmoidal CT-calcium relationship is also evidentin renal patients with a variable degree of renal failure andin normal subjects; (b) whether the four secretory parametersalready described for the PTH-calcium relation curve might bedescribed for CT too; (c) whether any change in some, if any,of these secretory parameters could be found at a variable degreeof renal insufficiency. We studied 33 renal patients (RP), with a variable degree ofrenal failure (creatinine clearance ranging from 16 to 164ml/min),and 10 normal subjects (C). All RP and C were submitted to abasal evaluation including the assessment of (1) basal concentrationsof 1,25(OH)₂ vitamin D, 25(OH) vitamin D, mono-meric CT, intactPTH; (2) GFR by Cr⁵¹EDTA clearance. On the 2 subsequent days,a hypocalcaemic test (Na₂-EDTA about 37 mg/kg of body-weight/2h) and a hypercalcaemic test (Ca gluconate giving 8 mg/kg body-weight/2h of Ca element) were carried out for the assessment of bothCT and PTH secretory parameters. According to GFR values, theRP were divided into three groups: group RP1 (GFR > 70 ml/minper 1.73 m²; n = 10), group RP2 (GFR between 30 and 70 ml/minper 1.73 m²; n=15), group RP3 (GFR < 30 ml/min per 1.73 m²;n = 8). In most, but not all, RP and C a sigmoidal CT-calcium relationshipwas evident, opposite in direction to the PTH-calcium relationcurve. In these RP and C the four secretory parameters, characteristicfor the PTH-calcium secretion curve, were calculated for CTtoo. When pooled RP and C were considered, both minimal (9.0± 6.4 pg/ml) and maximal CT levels (71.8 ± 56.2pg/ml) significantly differed from basal levels (24.3±18 pg/ml; P<0.001). The CT set point (CT SP) and sensitivity(CT SENS) values were significantly higher and lower than thecorresponding PTH secretory parameters (CT SP 1.39 ±0.08 mmol/1, PTH SP 1.23 ± 0.05 mmol/1,P<0.001) (CTSENS 243 ± 67%/mmol, PTH SENS 598 ± 329%, P<0.001).However, the CT SP values were strictly correlated with PTHSP values (r = 0.78, P<0.001). When CT secretory parameterswere considered separately in the RP groups, increased levelsof basal (36.1±28.6pg/ml), minimal (17.9±10.4),and maximal (139.9 ± 39.7) CT levels were found in theRP3 group, when compared with both the other RP groups and C.No significant difference was found as regards the CT SP andCT SENS values between RP and CT. These results suggest that (1) CT secretion is homeo-staticallycontrolled by calcium changes in the same range of the PTH-calciumsystem; (2) a sigmoidal CT-calcium relationship is demonstrablein most (but not all) RP and C; in these subjects it is possibleto calculate the CT secretory parameters as for PTH; (3) theincrease in CT levels in the course of chronic renal failureis quite similar to the already known increase of PTH, and ischaracterized by the increase of basal, minimal and maximalCT values, suggesting that an increased secretion of CT by thethyroid C-cells (rather than CT retention due to a decreasein renal function), is responsible for these findings.     

Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome

BACKGROUND.: Oedema formation in the nephrotic syndrome is primarily dueto tubular sodium retention. The pathogenetic role of alphaatrial natriuretic peptide (ANP), a hormonal promoter of natriuresisis unknown. METHODS.: In 31 patients (aged 35±11 years) with nephrotic syndromeand histopathological evidence of primary glomerulonephritis,we investigated plasma ANP concentration and its influence onrenal haemodynamics, natriuresis, and proteinuria (total protein,albumin, IgG excretion). Patients with a compensated treatedform of nephrotic syndrome due to primary glomerulonephritiswere included in the study. Serum creatinine levels were 1.4mg/dl. Diuretic medication was discontinued at least 24 h beforethe investigation was started. Patients were randomly assignedto ANP infusion (0.005 µg/kg*min; group II, n=15) or receivedplacebo (group III, n=16). Ten healthy subjects (group I) servedas normal controls. RESULTS.: In normal subjects (group I), ANP caused an increase in natriuresisfrom 14.5±4.2mmol/h to 26.4±11.1 mmol/h (P<0.01).In patients with nephrotic syndrome (group II), baseline sodiumexcretion of 10.5±6.0 mmol/h was increased to 19.6±14.8mmol/h with ANP infusion (P<0.01). No changes were seen inthe placebo group III. The absolute increase in ANP inducednatriuresis was not significantly different between group Iand II. However, plasma ANP levels were significantly higherin patients with nephrotic syndrome (166±87 pg/ml vs.74±21 pg/ml, P<0.05) and also reached higher levelsafter ANP infusion (P<0.01). Therefore, natriuresis was significantlyreduced when circulating ANP levels were taken into account(P<0.05). ANP administration resulted in an increase of totalprotein excretion in patients with the nephrotic syndrome (groupII, from 219±277 mg/h to 264±268 mg/h). Albuminelimination rose from 128±151 mg/h to 167±170mg/h (P<0.05) and IgG excretion from 4.91±6.67mg/hto 9.27±10.78mg/h (P<0.05). Healthy subjects alsoshowed a small but significant increase in albuminuria (48±38%,P<0.05). Low-dose ANP infusion did not, however, induce anysignificant alteration in GFR, ERPF and blood pressure. CONCLUSION.: ANP plasma concentrations in the steady state are elevated inpatients with the nephrotic syndrome. The natriuretic effectof ANP is reduced when referring to circulating ANP plasma levels.Elevated ANP levels enhance urinary protein excretion in thenephrotic syndrome. This is not due to modulation of GFR orFF, but is most probably attributable to increased glomerularpermeability.     

Atherogenic lipid profile and lipoprotein(a) in relation to serum albumin in haemodialysis patients

Malnutrition in haemodialysis patients is associated with anincreased cardiovascular mortality. Lipoprotein(a) (Lp(a)) isan independent risk factor for atherosclerotic cardiovasculardisease. To evaluate the relationship between atherogenic lipidprofile and serum albumin in haemodialysis patients we measuredfasting serum Lp(a), total cholesterol (TC), high-density lipoprotein-cholesterol(HDL-C), triglyceride (TG), apoprotein A-I (ApoA-I), apoproteinB (ApoB) and albumin in 101 haemodialysis patients and in 46healthy subjects as a control. The haemodialysis patients weredivided into two groups on the basis of the level of serum albumin:group I, serum albumin <4.0 g/dl; group II, serum albumin>4.0 g/dl. Haemodialysis patients as a whole (n=101, 17.1 mg/dl (10.3–30.9))had higher serum Lp(a) than normal subjects (n = 46, 10.5 mg/dl(3.3–24)) (P<0.05). Lp(a) in group I (n = 38, 27.1mg/dl (14.6-35.0)) was significantly higher than in group II(n = 63, 14.5mg/dl(7.7–21.7), P<0.005) and normal subjects(P<0.0005). However, serum Lp(a) level of group II was notdifferent from those of normal subjects. There was a significantinverse correlation between serum Lp(a) and albumin concentration(r_s = -0.26, P<0.01). TC, TG, HDL-C, ApoA-I, ApoB, TC/HDL-C,and ApoA-I/ApoB ratios were not different between group I andgroup II. No correlation was found between albumin and TC, TG,HDL-C, TC/HDL-C, and ApoA-I/ApoB ratios. These results suggest that Lp(a) could be responsible for anincreased cardiovascular mortality in haemodialysis patientswith malnutrition.     

Peritoneal dialysis catheters: a comparison between percutaneous and conventional surgical placement techniques

Percutaneous peritoneal dialysis catheter (PDC) placement isa well-tolerated, rapidly performed side-room procedure thatallows the rapid initiation of dialysis without the delay imposedin co-ordinating a surgeon, theatre time, and theatre staff.We retrospectively reviewed the clinical outcome of 230 PDCinserted over a 30-month period. Fifty were placed percutan-eously(group P) and 180 were placed using conventional surgical techniques,107 in patients commencing CAPD (group A) and 73 in patientspreviously established on CAPD (group B). Total experience accumulatedwas 2563 patient months: 270 patient months group P, 1381 patientmonths group A, 912 patient months group B. Percutaneous PDCinsertion was non-elective, and reserved for patients unfitfor general anaesthesia or haemodialysis. Group P patients wereolder (P<0.001) and had increased early mortality (P<0.005)due to underlying pathology. Death and early mechanical failurecontributed to a shorter mean duration of catheter use in groupP (9.0 ± 2.3 months compared to 15.3 ± 9.6 monthsgroup A and 17.3 ±9.7 group B) (P<0.05). The peritonitisrate was similar in group P (1 per 6.75 patient months) andgroup B (1 per 7.4 patient months) but significantly lower ingroup A (1 per 15.7 patient months) (P<0.01). We concludethat percutaneous PDC placement provides a safe, reliable accessfor peritoneal dialysis and is especially suitable for ill patientswho would not tolerate general anaesthesia.     

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.     

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.     

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.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (l000 mg elementalcalcium together with a standard breakfast) was studied in 13healthy male controls and 21 recurrent idiopathic renal calciumstone formers, 12 with hypercalciuria (U_CaxV>7.50 mmol/24h) and nine with normocalciuria. In controls, serum 1,25(OH)₂vitamin D3 (calcitriol) remained unchanged 6 h after oral calciumload (50.6±5.1 versus 50.9±5.0 pg/ml), whereasit tended to increase in hypercalciuric (from 53.6±3.2to 60.6±5.4 pg/ml, P=0.182) and fell in normocalciuricstone formers (from 45.9±2.6 to 38.1±3.3 pg/ml,P=0.011). The total amount of urinary calcium excreted afterOCL was 2.50±0.20 mmol in controls, 2.27±0.27mmol in normocalciuric and 3.62±0.32 mmol in hypercalciuricstone formers (P=0.005 versus controls and normocalciuric stoneformers respectively); it positively correlated with serum calcitriol6 h after calcium load (r=0.392, P=0.024). Maximum increasein urinary calcium excretion rate, Ca-E_max, was inversely relatedto intact PTH levels in the first 4 h after calcium load, i.e.more pronounced PTH suppression predicted a steeper increasein urinary calcium excretion rate. Twenty-four-hour urine calciumexcretion rate was inversely related to the ratio of calcitriol/PTH_maxafter calcium load (r=–0.653, P=0.0001), indicating thatan abnormally up-regulated synthesis of calcitriol and consecutiverelative PTH suppression induce hypercalciuria. Finally, lateabsorption of calcium as suggested by maximum urinary calciumexcretion beyond 4 h after oral calcium load was as rare inhypercalciuric stone formers (2 of 12) as in controls (1 of13) and did not occur in normocalciuric stone formers.     

Enhanced platelet reactivity with erythropoietin but not following transfusion in dialysis patients

Although the haemostatic defects that occur in uraemia are complex,a major factor is the anaemia of renal failure. This may nowbe corrected by recombinant human erythropoietin (rHuEpo) therapyrather than by repeated blood transfusion. Platelet reactivityto shear stress and collagen was measured using non-anticoagulatedblood to study the effect of erythropoietin or blood transfusionon platelet function. Twenty dialysis patients were commencedon 25–50 U/kg rHuEpo twice weekly. The dose was adjustedafter 3 months to maintain target Hb 10–10.5 g/dl. A further15 patients were studied before and 10–12 days after receivingblood transfusion. Baseline platelet reactivity was subnormalin both groups versus control (P<0.0001). In the rHuEpo group,a significant increase in platelet reactivity was observed at2 months (P<0.005) which disappeared at 3 months. This wasnot related to the increase in Hb (7.3±0.3 to 10.2±0.3g/dl, P<0.0001). There was no change in platelet reactivityafter transfusion, despite an increase in Hb (6.2±0.2to 8.8±0.2 g/dl, P<0.0001) similar to that occurringin the rHuEpo group. We conclude that after rHuEpo therapy butnot after transfusion a transient increase in platelet reactivityoccurs which is dissociated from changes in platelet and redcell numbers.     

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.     

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.     

The Use of Calcium Carbonate to Treat the Hyperphosphataemia of Chronic Renal Failure

This study evaluates the use of calcium carbonate in chronicrenal failure. Forty-eight patients (25 male, 23 female, meanage 54.3 years, six pre-dialysis, 12 CAPD, 30 haemodialysis)on phosphate restriction and requiring aluminium hydroxide (mean2.4±0.8 g/ day) to control serum phosphate, were convertedto an equivalent dose of calcium carbonate (2.5±0.6 g/day).None received vitamin D analogues. Three months post-conversionthere was a significant decrease in mean (±SEM) serumphosphate (1.86±0.08 versus 1.66±0.05 mmol/l,P<0.01) and serum aluminium (28.3±5.4 versus 13.2±3.0µg/l,P<0.0001); calcium/phosphate product was unchanged. Post-conversionthere was an increase in serum bicarbonate, (20.6±0.5versus 22.1±0.6 mmol/l, P<0.01) and serum calcium(2.32±0.02 versus 2.45±0.03 mmol/l, P<0.0001).No change in serum creatinine, alkaline phosphatase or parathormoneoccurred. No adverse effects were reported but nine (18%) patientsbecame hypercalcaemic (2.7 to 2.93 mmol/l), eight of whom respondedto dose reduction. Hypercalcaemia did not correlate with pre-conversionserum calcium, parathyroid hormone, alkaline phosphatase oraluminium. Calcium carbonate is an effective alternative toaluminium-based phosphate binders. It produces a beneficialincrease in serum calcium and bicarbonate and a significantdecrease in serum aluminium. Hypercalcaemia is unpredictablebut is easily reversible in the majority of patients.     

Correlation between glomerular morphology and renal haemodynamic response to amino-acid administration in patients with IgA nephropathy

RATIONALE.: To establish relationship, if any, between renal morphologyand renal haemodynamic response to amino acids. DESIGN AND METHODS.: We investigated the correlation between renal haemodynamic regulationand morphology in a group of 15 patients with primary IgA nephropathy(IgAN) (age 26±2 years, BMI 24.4±1, GFR 64±5ml/min, RPF 377±34 mI/mm, FF 0.17±0.02). Twelvenormal subjects (age 30±3 years, BMI 24±1, GFR82±6 ml/min, RPF421±42 ml/min, FF 0.19±0.02)were studied as controls. IgA patients were divided into twogroups according to the histological staging of glomerular lesions:group I (n=7) stage II, and group II (n=8) stage III–IV. RESULTS.: In the basal state GFR was similar in the two groups and averaged64±9 and 64±6 ml/mm respectively. In contrast,FF was significantly lower in group II(0.14±0.01) (P<0.05)in comparison to group I (0.21±0.03) and controls (0.19±0.02).In order to evaluate the renal functional reserve, all studygroups underwent to an intravenous amino-acid infusion designedto increase plasma amino acid levels twofold (total from 2096±145to 4301±221 µmol/l in IgA nephropathy patientsand from 2272±83 to 3844±238 µmol/l in controls).In response to amino-acid infusion, GFR rose significantly ingroup I (GFR 20±2% and RPF 37±4% versus basal)and controls (GFR 20±2% and RPF 20±3% versus basal)(both P<0.01 vs basal). In contrast, in patients with moresevere glomerular lesions (group II) neither GFR nor RPF rosesignificantly (GFR –1±4% and RPF –8±6%versus basal) (P NS versus basal, P<0.01 versus group I andcontrols). CONCLUSIONS.: The data show that in IgA nephropathy: severe forms of glomerularlesions are associated with a complex alteration of glomerularhaemodynamic regulation, characterized by lower basal FF andloss of haemodynamic response to hyperaminoacidaemia.