Peripheral microcirculatory blood flow in haemodialysis patients treated with erythropoietin.

BACKGROUND: Haemodialysis patients have abnormal blood vessels, and increased morbidity from vascular causes, effects which may potentially be enhanced by erythropoietin (EPO) therapy. METHODS: Microcirculatory blood flow was assessed using a laser-Doppler flowmeter in a group of 19 haemodialysis patients before and during treatment with recombinant human (EPO). RESULTS: Haemodialysis patients had significantly impaired microcirculatory blood flow under both basal (25 degrees C) and hyperaemic (44 degrees C) conditions by comparison with 19 normal controls (baseline flow, median and range: patients 1.54 (0.28-2.54) volts, controls 3.39 (0.94-5.23) volts, p < 0.001 Mann Whitney U Test; hyperaemic flow, patients 2.69 (1.08-3.82) volts, controls 3.81 (1.32-8.00) volts, p < 0.001). There was no significant influence on microcirculatory blood flow of patient age, duration of haemodialysis, short-term EPO therapy (subcutaneous or intravenous), therapy with a calcium-channel blocker/vasodilator (nifedipine), or radiological evidence of vascular calcification. CONCLUSIONS: Haemodialysis patients have an abnormal peripheral microvasculature, which may be relevant to their increased risk of ischaemic tissue damage and poor wound healing.

Effect of nifedipine on changes in fibrinogen and von Willebrand factor in haemodialysis patients treated with recombinant human erythropoietin.

Erythropoietin (EPO) therapy in haemodialysis patients may be associated with the development of hypertension and vascular access thrombosis. Raised levels of fibrinogen and von Willebrand factor have been implicated in the pathophysiology of thrombosis under these circumstances. The effect of nifedipine, used to treat EPO therapy-related hypertension, on levels of fibrinogen and von Willebrand factor antigen (vWf) was studied in a group of 21 EPO-treated haemodialysis patients. Significant increments in both fibrinogen and vWf following EPO therapy were observed in the 13 patients who did not receive nifedipine (fibrinogen (median range), pre-EPO: 3.73 (2.41-6.38) mg/ml, post-EPO: 4.59 (3.03-8.80) mg/ml, P < 0.05; vWf pre-EPO: 183 (118-374)% normal, post-EPO: 253 (124-392)% normal, P < 0.01). Similar changes were not seen in the eight nifedipine-treated patients (fibrinogen, pre-EPO: 3.35 (2.58-6.32) mg/ml, post-EPO: 3.36 (2.69-7.20) mg/ml, P = NS; vWf, pre-EPO: 176 (104-298)% normal, post-EPO: 175 (82-371)% normal, P = NS). These effects were independent of blood pressure control. The use of nifedipine to treat EPO therapy-related hypertension may therefore potentially help to reduce the risk of vascular access thrombosis.

Persistence of microflora in biofilm within fluid pathways of contemporary haemodialysis monitors (Gambro AK-10).

Growth of bacteria within a biofilm, visible macroscopically as a yellow coating, was seen on the interior walls of semi-transparent plastic dialysis monitor fluid pipes. The level of bacterial growth along the water/dialysis fluid pathway, and the effect of in-line bacterial filters, on colony counts in reverse osmosis reject water and monitor effluent were examined. Little difference in colony counts was seen at either sampling point in monitors fitted with and without filters. Because of the increasing use of high-flux dialysis, and its potential for transmembrane transport of endotoxin and bacteria into patients, staff should be aware that dialysis fluid pathways may be colonized with viable bacteria, which are not readily killed by conventional heat and chemical cleaning processes.

Erythropoietin response and route of administration.

The effect of route of erythropoietin (EPO) administration was assessed in sixteen hemodialysis patients who completed a randomised crossover study of thrice weekly subcutaneous (SC) and intravenous (IV) erythropoietin with an EPO-free washout period separating the two phases of treatment. Route of EPO administration had no significant effect on absolute reticulocyte counts, and change in hemoglobin (Hb) during the first six weeks of therapy, at a constant EPO dose (120 iu/kg/week). Similarly, there was no significant difference in EPO dose requirement between the two routes, both during and after correction of anemia, and after maintenance of target Hb (10-12 g/dl) for an eight-week period (end of maintenance period dose; median [range]; SC EPO: 120 [30-367] iu/kg/week, IV EPO: 124.5 [37-377] iu/kg/week). Following EPO withdrawal, Hb fell at a rate of 0.38 (0.14-0.69) g/dl/week. Route of EPO administration did not influence the incidence of thrombotic and hypertensive side effects, or increases in dialysis heparin requirement and albumin, and decreases in ferritin, alpha-1-antitrypsin and ceruloplasmin during the study period. In conclusion, thrice weekly SC and IV EPO are comparable in terms of efficacy and safety.

Effect of erythropoietin therapy and withdrawal on blood coagulation and fibrinolysis in hemodialysis patients.

Erythropoietin (EPO) therapy in hemodialysis patients may be associated with an enhanced risk of vascular access and extracorporeal thrombosis. Assessment of blood coagulation and fibrinolysis was performed monthly on a group of 21 hemodialysis patients treated with EPO, and on four iron-deficient hemodialysis patients treated with iron dextran infusions alone. Seventeen of the EPO treated patients were also monitored after withdrawal of EPO to allow hemoglobin to fall to pre-EPO levels, and 16 of these patients during a second subsequent phase of EPO therapy with EPO administered using the alternative route (subcutaneous/intravenous) from the first phase of treatment. Ten untreated hemodialysis patients with intrinsically high hemoglobins were studied as controls. EPO was associated with significant increases in the endothelial product Factor VIII von Willebrand factor antigen (FVIIIvWFAg), and plasma fibrinogen, to levels comparable to those observed in the untreated control patients. Both FVIIIvWFAg and fibrinogen remained significantly elevated when EPO was withdrawn. Whole blood platelet aggregation (spontaneous, collagen, and ADP-induced) also increased following EPO, collagen and ADP-induced aggregation, increasing further when EPO was withdrawn. Transient but significant changes occurred in plasma measures of thrombin-antithrombin III complex, prostacyclin stimulating factor, and protein C during the first EPO treatment phase, and also thrombin-antithrombin III complex during the second treatment phase, all favoring a tendency to thrombosis. D-dimer increased significantly following EPO withdrawal. Erythrocyte deformability, and granulocyte aggregation did not change. There was no effect of route of EPO administration (subcutaneous or intravenous) or EPO dose on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen free radicals and platelet and granulocyte aggregability in renal transplant patients.

Oxygen free radical reaction products (plasma malondialdehyde), the free radical scavengers plasma thiol and red cell superoxide dismutase (SOD), and whole blood platelet and granulocyte aggregation were measured in 23 renal transplant patients and 23 age-matched controls. Malondialdehyde-like material (MDA) was significantly increased in transplant patients compared with controls (transplants MDA [median, range], 7.7 [5.3-11.5] nmol/ml; controls MDA, 6.3 [5.4-8.7] nmol/ml; P < 0.001). The patients also had increased red cell superoxide dismutase (transplants SOD, 128.1 [89.4-93.8] U/0.5 ml red cells; controls SOD, 95.9 [62.0-132.6] U/0.5 ml red cells; P < 0.001) and reduced plasma thiol (transplants thiol, 428 [266-496] mumol/L; controls thiol, 445 [358-501] mumol/L; P < 0.05). These factors were not influenced by immunosuppressive therapy, duration of transplantation, or creatinine concentration. Transplant patients had significantly higher levels of collagen-induced and spontaneous whole blood platelet aggregation compared with controls (collagen: transplants, 72 [4-93%]; controls 43 [6-94]%; P < 0.001; spontaneous: transplants 46 [11-93]%; controls 37 [10-75]%; P < 0.05). Spontaneous platelet aggregation, however, was significantly correlated with creatinine concentration (r = 0.525, P < 0.02, Spearman's correlation), and was raised only in those patients with a degree of renal impairment. Granulocyte aggregation was increased in patients receiving cyclosporine (CsA [n = 15], 57 [36-66]%; no cyclosporine [n = 8], 45 [37-62]%; controls [n = 23]; 39 [31-61]%; P = 0.004). Renal transplant patients are subject to oxidative cell damage, and may be at increased risk of vascular thrombosis. Possible contributory factors include an immunological reaction to the graft and/or the effects of immunosuppressive therapy.

Evaluation of a nisin-based germicidal formulation on teat skin of live cows.

A purified preparation of the nontoxic antimicrobial peptide, nisin (AMBICIN N), was used in the formulation of a germicidal sanitizer suitable for use on cow teats. The germicidal activity of the formulation against mastitis pathogens was measured on teat skin of live cows. The nisin-based formulation gave a mean log reduction of 3.90 against Staphylococcus aureus and 4.22 log reduction against Escherichia coli after exposure for 1 min to the germicide. This activity was comparable with that exhibited by a 1% iodophor teat dip but was significantly greater than that exhibited by the .1 and .5% iodophors and by the .5% chlorhexidine digluconate teat dips. The nisin-based formulation showed little or no potential for skin irritation after multiple application to skin, but iodophor and chlorhexidine digluconate teat dips showed significant potential for skin irritation in comparable studies.

Effect of dialyzer geometry during hemodialysis with cuprophane membranes.

The effect of dialyzer geometry, both flat plate (FP) and hollow fiber (HF), on platelet and granulocyte activation during dialysis with cuprophane membranes was studied in 12 patients. A subset of six patients was restudied after correction of their anemia with recombinant human erythropoietin (EPO). Granulocyte count and aggregation in vitro fell significantly (P less than 0.01) at 20 minutes of dialysis, followed by a gradual return towards pre-dialysis values at 240 minutes. Malondialdehyde (MDA), a product of free radical reactions generated by activated granulocytes, increased significantly during dialysis [predialysis MDA (median, range): 8.4 (5.8 to 11.6) nmol/ml, 240 minutes MDA: 9.7 (6.6 to 12.5) nmol/ml, P less than 0.01 Wilcoxon test). This increase, however, was not affected by dialyzer geometry or EPO therapy. Neither type of dialyzer was associated with significant platelet loss at the end of dialysis. Whole blood platelet aggregation in vitro (spontaneous and collagen-induced) decreased significantly, (P less than 0.01) during dialysis, the fall in spontaneous aggregation being significantly less following EPO therapy [spontaneous aggregation 240 minutes; pre-EPO: 34 (13 to 52)%; post-EPO 50: (16 to 76)%, P less than 0.01)]. The ratio of the platelet release proteins beta-thromboglobulin and platelet factor 4 increased significantly during dialysis, indicating platelet activation in vivo, although there was no effect of dialyzer geometry or EPO. Factor VIII von Willebrand Factor antigen, a putative marker of endothelial damage, was raised pre-dialysis, and increased further during dialysis, irrespective of dialyzer geometry or EPO. In conclusion, dialyzer geometry had no significant effect on granulocyte and platelet counts and activity during hemodialysis with cuprophane membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Urine transparency as an index of absence of infection.

A visual assessment of the clarity of urine was used as an exclusion test to indicate the absence of infection; verified by dipslide culture, it was applied to 363 urine samples collected from patients attending 2 adult nephrology clinics over a period of 6 months. The crimped aluminium bowl used for collection of samples assisted the assessment of clarity. The sensitivity of the method compared with dipslide culture was 73%, with specificity and efficiecy both 58%. The predictive value of a negative test (clarity) was 97% with a false negative rate of 3%, enabling this simple examination to be used as an exclusion test for further testing. In simple terms, a clear urine is unlikely to be infected. It is also an advantage to have an immediate indicator of the absence of infection available at the clinic. Analysis of only those urines assessed as cloudy could result in financial savings and, from the clinics, a 56% reduction in workload.

Microbial growth and blockage of sub-floor drains in a renal dialysis centre: a problem highlighted.

The accumulation of microorganisms embedded in biofilm within the drainage pipework leading from individual dialysis monitors in a renal dialysis centre, represents a significant threat to the safe operation of the whole centre due to blockage of the pipes and overflow of waste water. Attempts to disperse the growth with chemicals and disinfectants have been unsuccessful. Only mechanical rodding has removed the deposit, and regrowth has occurred. Those planning new dialysis centres should ensure that effluent pipework is readily accessible with multiple rodding eyes and is made of material able to withstand rodding and chemicals.

Atrial natriuretic factor improves renal function and lowers systolic blood pressure in renal allograft recipients treated with cyclosporin A.

OBJECTIVE: Atrial natriuretic factor (ANF) has several properties which suggest that it may ameliorate cyclosporin A nephrotoxicity. We therefore investigated the response to a pharmacological dose of ANF in renal transplant recipients treated with cyclosporin A. DESIGN: A single-blind randomized crossover design comparing the renal and haemodynamic effects of D-glucose (placebo) with ANF. METHODS: Seven patients with stable renal function following renal transplantation were studied under maximal water diuresis. Glomerular filtration rate and effective renal plasma flow were estimated from clearances of inulin and para-aminohippurate, respectively. RESULTS: Plasma ANF levels increased significantly in association with increased diuresis and natriuresis. Glomerular filtration rate was unchanged after placebo but increased significantly after ANF fusion. Likewise, effective renal plasma flow increased significantly with ANF infusion. There was a significant fall in systolic blood pressure, with no apparent change in heart rate and diastolic blood pressure. CONCLUSIONS: These results suggest that ANF may have beneficial effects in protecting against cyclosporin A-induced nephrotoxicity and hypertension.

Parathyroidectomy in uraemic hyperparathyroidism: a clinical study.

Osteodystrophy is a common and sometimes debilitating complication of renal failure. Hyperparathyroidism plays a crucial role in the development of this condition. Significant morbidity is also incurred by the effects of calcium deposition in other tissues. We report a series of 27 patients undergoing parathyroidectomy between May 1988 and November 1989. All had biochemical, radiological and clinical evidence of hyperparathyroidism. Surgery was well tolerated leading to an improved quality of life and avoidance of the need for aluminium containing phosphate binders.

Dextran antibodies, complement conversion and circulating immune complexes after intravenous iron dextran therapy in dialysed patients.

Serum immune complexes, plasma dextran antibodies and percentage conversion of complement have been measured in 20 dialysed patients before and after an intravenous infusion of iron dextran providing 600 mg elemental iron. Complement conversion was unmeasurable and there were no changes in circulating immune complexes. The presence of dextran antibodies in nine patients before the infusion was not related to prior exposure to iron dextran. They became undetectable in these patients within hours after the infusion, reappearing 1 month later in three. Two of three patients reporting mild aches and shivers on the day following the infusion had no detectable dextran antibodies. An adverse reaction involving inflamed joints occurred 1-2 days after a second infusion given to one of the patients studied above. The parameters under study were again measured and did not appear to relate to the reaction. The presence of dextran antibodies does not preclude the giving of iron dextran to patients on dialysis, and the immune complex and complement systems remain undisturbed by iron dextran infusions.

Prothrombotic effect of erythropoietin in dialysis patients.

Thrombin-antithrombin III complex concentrations (TAT-III) were measured in 18 anaemic haemodialysis patients treated with erythropoietin (Epo) and in four haemodialysis patients treated with i.v. iron dextran. There was a significant early increase in thrombin-antithrombin III in erythropoietin-treated patients which appeared to be independent of the response to erythropoietin (Epo responders (n = 14), pretreatment TAT-III median (range) 3.10 (2.70-9.10) micrograms/l; maximum TAT-III 19.48 (11.18-60.00) micrograms/l, P less than 0.001, Wilcoxon; Epo non-responders (n = 4), pretreatment TAT-III 3.15 (2.90-4.50) micrograms/l, maximum TAT-III 16.00 (10.31-36.12) micrograms/l, P less than 0.001). This was not seen in iron-dextran-treated patients (Pretreatment TAT-III 2.05 (1.90-9.48) micrograms/l, maximum TAT-III 5.60 (2.10-14.50) micrograms/l). The change was not related to haemoglobin, erythropoietin dose, or method of administration, and was transient in nature, thrombin-antithrombin III returning to pretreatment values after approximately 6 months in all patients (Epo responders 6.0(4.0-9.0) months, TAT-III 2.47 (1.30-9.23) micrograms/l; Epo non-responders 7.0 months, TAT-III 5.04 (2.10-7.00) micrograms/l). Increased thrombin-antithrombin III complex may reflect an effect of erythropoietin on microcirculatory factors, which could be relevant to the occurrence of adverse events during treatment.

Dialysis efficiency in continuous ambulatory peritoneal dialysis patients treated with erythropoietin.

OBJECTIVE: To determine the effect of subcutaneous erythropoietin treatment on dialysis efficiency in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Dialysis efficiency, platelet and white cell aggregation, and red cell deformability were measured monthly for six months in nine anaemic CAPD patients treated with erythropoietin, and on a single occasion in seven control CAPD patients with intrinsically high haemoglobin concentrations. SETTING: Renal dialysis unit. PATIENTS: Nine patients stable on CAPD for a minimum of six months and with haemoglobin concentrations less than 8.5 g/dl were treated with erythropoietin. Seven CAPD patients matched for age and renal function, with haemoglobins greater than 9.0 g/dl served as controls. RESULTS: Daily peritoneal clearances and net ultrafiltration volumes were unchanged when haematocrit increased from 25.0 +/- 2.2% to 36.5 +/- 3.5%. Spontaneous whole blood platelet aggregation was significantly increased from week twelve (pre-treatment aggregation 46 +/- 23%; 12 weeks: 67 +/- 19%, p less than 0.05; 16 weeks: 64 +/- 19%, p less than 0.01; 20 weeks: 71 +/- 16%, p less than 0.01; 24 weeks: 73 +/- 10%, p less than 0.01). CONCLUSIONS: The increase in haematocrit and platelet aggregation associated with erythropoietin treatment did not affect peritoneal clearances or ultrafiltration capacity.