Influence of azathioprine on the ferrokinetics of patients with renal failure before and after treatment with erythropoietin.

In 16 patients (9 on azathioprine, 7 not) the ineffective iron turnover (IIT) was much higher in the azathioprine group (62.7 +/- 6.7 vs. 23.5 +/- 3.5 mumol/l blood/day, p < 0.0001, 2-tailed t test), though the red cell iron turnover (RCIT) was similar (42.8 +/- 2.9 vs. 41 +/- 4.8). Erythropoietin improved the anaemia in all patients and raised the RCIT (4 still on azathioprine to 72.2 +/- 9.8, p < 0.003; 7 non-azathioprine patients to 62.7 +/- 5.3, p < 0.01); the IIT remained higher in the azathioprine-treated (85.5 +/- 19.3 vs. 37.1 +/- 5.4; p < 0.013). In 2 patients who discontinued azathioprine, the IIT declined markedly to normal. In summary, azathioprine exacerbates the anaemia of renal failure by augmenting ineffective erythropoiesis, while erythropoietin benefits those on azathioprine as much as other renal patients by stimulating both effective and ineffective erythropoiesis.

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 11 predialysis) were treated with erythropoietin. At 12 weeks, the mean haemoglobin concentration (+/- SEM) in the CAPD patients had increased from 7.07 +/- 0.20 to 10.88 +/- 0.45 g/dl (two-tailed paired t test, P < 0.0001) and in the predialysis patients from 6.90 +/- 0.35 to 10.05 +/- 0.47 g/dl (P < 0.0001). Predialysis patients were taking more antihypertensive medication at baseline. No increase was required in either group after erythropoietin; there was no change in blood pressure in the CAPD patients, though in the predialysis patients the systolic blood pressure rose slightly from 132 to 146 mmHg (P = 0.029) and the mean blood pressure from 95 to 103 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 and after treatment. In the CAPD patients there was a marked expansion of the red cell volume from 912 +/- 127 to 1471 +/- 222 ml (P = 0.004) and a concomitant contraction of the plasma volume from 3932 +/- 250 to 3178 +/- 326 ml (P = 0.005), leaving the blood volume unchanged from 4843 +/- 352 to 4649 +/- 503 ml. Predialysis patients had a similar expansion of the red cell volume from 733 +/- 59 to 1304 +/- 161 ml (P = 0.017) but no contraction of the plasma volume (from 3417 +/- 354 to 3314 +/- 260 ml), so that the blood volume tended to expand from 4149 +/- 347 to 4618 +/- 414 ml (P = 0.053).(ABSTRACT TRUNCATED AT 250 WORDS)

Monitoring of iron requirements in renal patients on erythropoietin.

We studied 38 patients (9 haemodialysis, 18 peritoneal dialysis, 11 advanced renal failure) over the first 12 weeks of erythropoietin therapy. In 14 iron-overloaded patients (ferritin > 500 micrograms/l the haemoglobin (+/- SEM) increased from 6.74 +/- 0.27 to 9.85 +/- 0.36 g/dl (P < 0.0001) entirely by mobilizing iron reserves (reduced from 1,220 +/- 73 to 739 +/- 111 mg, P < 0.0001). In the 24 non-overloaded patients (ferritin < 500 micrograms/l) the haemoglobin rose similarly from 7.04 +/- 0.18 to 10.70 +/- 0.36 g/dl (P < 0.0001), partly from iron reserves (depleted from 200 +/- 74 to -44 +/- 77 mg, P = 0.016) and partly from oral iron supplements (305 +/- 110 mg). In the overloaded patients the ferritin declined from 1057 micrograms/l (geometric mean, range 504-3699) to 317 micrograms/l (42-1505, P < 0.0001). In the non-overloaded patients it declined from 82 micrograms/l (8-461) to 45 micrograms/l (5-379, P = 0.016). The transferrin saturation (TS) in the overloaded patients appeared to decline from 38.3 +/- 7.2% to 24.0 +/- 3.7% but this was not statistically significant. In the non-overloaded the TS was unchanged (23.3 +/- 2.4 before and 28.1 +/- 3.6% after treatment). Considering all 38 patients together, the haemoglobin correlated negatively with the ferritin (r = 0.3731, P < 0.001) but not with the TS. The TS correlated with the serum ferritin initially (r = 0.75, P < 0.001) but not after the first 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of azathioprine on response of renal anaemia to subcutaneous recombinant human erythropoietin.

AIMS: To determine the effect of concomitant azathioprine treatment on the response of patients with renal failure to treatment with subcutaneous recombinant human erythropoietin (r-HuEPO). METHODS: Two groups of patients with renal failure not receiving haemodialysis were studied. One comprised seven patients receiving erythropoietin alone, the second consisted of nine patients who were also treated with azathioprine. The haematological changes were monitored, and the functional erythropoietic response was studied by two different ferrokinetic models. One analysed the initial, the other the extended plasma iron clearance. Studies were performed before r-HuEPO treatment on all 16 patients, and repeated on 11 of these when the target haemoglobin (10-11 g/dl) was achieved and stabilised. Total erythropoiesis was determined using both techniques. Analysis of the extended plasma iron clearance also permitted calculation of both effective and ineffective erythroid activity. RESULTS: The haematological response to r-HuEPO was the same for both patient groups. Measurement of total erythropoiesis by both ferrokinetic methods showed good correlation. For those receiving long term azathioprine, the percentage ineffective erythropoiesis was high compared with that of the other patients, and remained so for as long as they continued with azathioprine. For those uncomplicated by azathioprine treatment, r-HuEPO increased levels of both effective and ineffective erythropoiesis by the same degree. A substantial reduction in ineffective erythropoiesis was shown only by those patients who either discontinued or reduced their azathioprine once they started r-HuEPO treatment. CONCLUSIONS: Azathioprine increases ineffective erythropoiesis. In this study, the r-HuEPO dose was sufficient to overcome this effect and promoted effective erythropoiesis so that the anaemia lessened. Measurement of total erythropoiesis provided limited information on the functional changes involved, differentiation of effective from ineffective erythropoiesis being necessary to define the changes after azathioprine reduction or withdrawal.

Quality of life improvements in CAPD patients treated with subcutaneously administered erythropoietin for anemia.

Twenty-two continuous ambulatory peritoneal dialysis (CAPD) patients, mean age 48 years, at 3 U.K. renal units were assessed with the Nottingham Health Profile (NHP) before and after treatment with recombinant human erythropoietin (r-HuEPO). Mean (SD) hemoglobin (Hb) at baseline was 7.5 (1.0) gm/dL and 10.8 (1.5) gm/dL at retest. There were significant improvements in energy (p less than 0.0001), social life (p less than 0.005), relationships at home (p less than 0.05) and leisure pursuits (p less than 0.05). Twelve patients, mean age 51 years, who had already completed more than 9 months on r-HuEPO treatment were reassessed to determine the changes sustained. Mean (SD) Hb at second retest was 12.8 (1.3) gm/dL. Improvement in energy continued to be significant, and emotional wellbeing showed further improvement. Problems with household tasks, which had not shown significant improvement at Test B, were now considerably reduced (p = 0.016). The study showed far-reaching benefits similar to those reported in hemodialysis patients, in a population with a higher mean age and higher potential coexisting illness or disability than most reported hemodialysis studies.

A low-molecular-weight heparin (Kabi 2165, 'Fragmin') in repeated use for haemodialysis: prevention of clotting and prolongation of the venous compression time in comparison with commercial unfractionated heparin.

We have compared a low-molecular-weight heparin (LMWH), Kabi 2165, with commercial unfractionated heparin (UFH) in 21 patients undergoing haemodialysis (1 month with each heparin). The UFH dose regimen comprised a UFH-saline prime of the extracorporeal circuit, an initial bolus of 5000 international units (IU) and an infusion of 1500 IU/h. The LMWH dose regimen comprised a LMWH-saline prime, a bolus of 3000-4000 anti-factor Xa units (aXa U) and an infusion of 750 aXa U/h. Plasma concentrations of the LMWH were slightly less than those of UFH for the first hour of dialysis (0.87 aXa U/ml vs 0.99 IU/ml) but were very similar by the end of the infusion (0.96 vs 1.00) and slightly greater at the end of dialysis, an hour later (0.85 vs 0.69). All haemodialysis sessions were completed uneventfully, with infrequent wispy clot deposits in the drip chamber. The mean frequency of clot deposition was slightly higher with the LMWH (0.20 vs 0.15). Fibrin generation was almost fully suppressed: plasma concentrations of fibrinopeptide A were slightly greater during dialysis with the LMWH (3.31-3.98 vs 2.29-2.75 pmol/ml) but were almost identical by the end of dialysis (5.62 vs 5.49 pmol/ml). The mean 'venous' compression time at the end of dialysis was significantly shorter with the LMWH than with UFH (8.45 min vs 11.12 min). We conclude that the LMWH is effective and safe in repeated use for haemodialysis. It prevents fibrin generation and clot formation to a similar degree as UFH. The shorter venous compression time of the LMWH may reflect a reduced haemorrhagic risk.

A low molecular weight heparin ("fragmin") for routine hemodialysis: a crossover trial comparing three dose regimens with a standard regimen of commercial unfractionated heparin.

In 20 hemodialysis patients using mainly flat plate dialyzers, we have conducted a controlled randomized crossover trial of three dose regimens of a low molecular weight heparin (LMWH), "Fragmin" (Kabi 2165), in comparison with a standard dose regimen of commercial unfractionated heparin (UFH) that had previously been shown to provide effective anticoagulation. The aim of the present study was to find the lowest dosage regimen of the LMWH which would be as effective as the standard UFH regimen. The UFH regimen comprised a prime with heparinized saline, an initial intravenous bolus of 5,000 international units (IU) and an infusion of 1,500 IU/h. The three LMWH regimens comprised a LMWH-saline prime, an infusion of 750 anti-factor Xa (aXa) U/h and three different bolus doses: 1) LMWH-low: 3,000 aXa U. 2) LMWH-medium: 4,000 aXa U. 3) LMWH-high: 5,000 aXa U. With the UFH regimen, plasma heparin levels of around 1.0 IU/ml were maintained during the heparin infusion, declining to 0.71 IU/ml an hour after the infusion was terminated. The LMWH-medium regimen produced very similar plasma aXa levels. The LMWH-high regimen also produced similar plasma aXa levels: therefore, it had no advantage over the LMWH-medium regimen. The LMWH-low regimen produced significantly lower levels than the other regimens during the heparin infusion (0.81-0.85 aXa U/ml, p less than 0.025). Dialysis proceeded uneventfully at all times and plasma levels of fibrinopeptide A (FPA) were suppressed well with all 4 regimens (2.77-5.74 pmol/ml) but tended to rise after the infusion was switched off (5.52-8.45 pmol/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Cryptococcosis complicating continuous ambulatory peritoneal dialysis.

We report a case of invasive cryptococcosis complicating continuous ambulatory peritoneal dialysis and its successful treatment. This form of infection has not been previously described.

Is hypercapnia necessary for the ventilatory response to exercise in man?

1. Continuous recordings of arterial pH, ventilation, airway CO2 and heart rate were made during rest and during 3-4 min periods of rhythmic leg exercise in four renal patients with arteriovenous shunts. 2. The patients were anaemic (haemoglobin 6.5-9.0 g/dl) but had a normal ventilatory response to exercise as judged by the ratio of the change in ventilation to the change in CO2 production. 3. Breath-by-breath oscillations in arterial pH disappeared for the majority of the exercise period in each patient. 4. Changes in mean arterial pH and end-tidal CO2 tension with exercise were inconsistent between subjects but consistent within a given subject. On average, mean arterial pH rose by 0.011 pH unit. Changes in end-tidal CO2 tension reflected changes in mean pHa by falling on average by 1 mmHg (0.13 kPa). 5. Hypercapnia and acidaemia were not found to be necessary for the ventilatory response to moderate exercise.

The anticoagulant effect of heparinoid Org 10172 during haemodialysis: an objective assessment.

The heparinoid of natural origin Org 10172 has anti-factor Xa activity but minimal anti-thrombin activity, and little effect upon broad spectrum assays such as the KCCT in vitro. Its anticoagulant effects have been compared to those of commercial heparin in 7 patients undergoing haemodialysis for chronic renal failure. Commercial heparin was administered in a dose (5,000 iu bolus + 1,500 iu/hour continuous iv infusion) previously shown to inhibit fibrin formation during haemodialysis. This produced mean anti-factor Xa levels in plasma between 0.7-1.0 iu/ml and largely suppressed fibrin formation for 5 h dialysis measured as mean FPA levels in plasma. Administration of Org 10172 as a bolus of 1,350 anti-factor Xa u or 2,000-2,400 anti-factor Xa u produced plasma anti-factor Xa levels of less than 0.5 u/ml and allowed fibrin clot and FPA generation during dialysis. Org 10172 administered as a bolus dose of 4,000-4,800 anti-factor Xa u produced mean anti-factor Xa levels of greater than 0.5 u/ml, allowed dialysis of 6 patients for 5 h and appreciably suppressed FPA generation during dialysis, with little effect on the KCCT. It is concluded that the anti-factor Xa activity of Org 10172 may reflect its ability to inhibit fibrin during dialysis and that single bolus injection of Org 10172 may be a useful alternative method of achieving anticoagulation.

On the evaluation of heparin and low molecular weight heparin in haemodialysis for chronic renal failure.

Anticoagulation during haemodialysis for chronic renal failure can be assessed by measurement of plasma fibrinopeptide A (FPA) levels as an objective method of monitoring the initial step in fibrin formation, in conjunction with visual inspection of the dialyser circuit for fibrin clot deposition. Employing this approach, unfractionated commercial heparin administered as an intravenous bolus followed by an intravenous maintenance dose (5,000 IU + 1,500 IU/h) was found to suppress almost completely fibrin formation and deposition during prolonged dialysis. Comparison of a low molecular weight heparin, Kabi 2165, revealed that it can inhibit fibrin formation in the extracorporeal circulation, that this property is largely reflected in its anti-factor Xa activity in plasma, and that a useful and effective dose of Kabi 2165 for haemodialysis may be 4,000 anti-factor Xa U intravenous bolus + 750 anti-factor Xa U/h intravenous maintenance infusion. This dose only minimally alters the KCCT and corresponds to approximately 60% of that of unfractionated heparin, which may be important in the long-term use of heparin in these patients.

Haemodialysis with low MW heparin: dosage requirements for the elimination of extracorporeal fibrin formation.

We have performed a dose ranging study of a low MW heparin, Kabi 2165, during haemodialysis in humans (n = 16) and compared it to a dose of unfractionated commercial heparin that has already been shown to inhibit fibrin formation. Low MW heparin administered as 5000 or 10,000 anti-factor Xa units, s.c., half an hour prior to the initiation of dialysis was unable to prevent fibrin formation in the dialyser circuit. A single bolus injection of 5000 anti-factor Xa units of low MW heparin given i.v. inhibited fibrin formation, as determined by FPA generation, for up to 4 h and permitted dialysis for 6 h. Such a bolus injection may be useful for short frequent dialyses. Infusion of low MW heparin in the same dosage regimen as unfractionated heparin, 5000 anti-factor Xa units bolus plus 1500 anti-factor Xa units/h, resulted in a progressive rise in heparin, caused by its longer half-life of elimination from the circulation, and almost completely suppressed both FPA generation and fibrin clot formation for 6 h dialysis. From these studies we calculate that infusion of this low MW heparin at a dose of approximately 4000 anti-factor Xa units bolus plus 750 anti-factor Xa units/h should be a useful regimen that will be effective in suppressing fibrin formation during prolonged dialysis, and the plasma anti-factor Xa level of low MW heparin may reflect its ability to inhibit fibrin formation, although exactly comparable anti-factor Xa levels of unfractionated commercial heparin and low MW heparins may not have identical inhibitory effects.

Spleen size in chronic renal failure.

To investigate the cause of clinically detectable splenomegaly, which is common in patients receiving regular haemodialysis, splenic volume was assessed by isotopic scanning using intravenously injected technetium-99m microspheres in 34 controls and 149 patients with chronic renal failure. Of the patients, 16 had never received dialysis, 10 were undergoing continuous peritoneal dialysis, 94 were undergoing regular haemodialysis, and 29 had undergone successful renal transplantation more than nine months previously. Mean splenic volume was increased only in the patients who were receiving haemodialysis. Splenic enlargement was probably not due to iron overload as it occurred in all patients who had received haemodialysis, 14 of whom had not received intravenous iron. No patient had had hepatitis. Splenic enlargement was probably related to the process of haemodialysis itself and may have been due either to red cell damage produced by haemodialysis or to an immunological reaction induced by a component of haemodialysis, possibly ethylene oxide.

Dialysis encephalopathy: precipitating factors and improvement in prognosis.

The course of typical dialysis encephalopathy (D.E.) in 12 patients is described. Five patients are still alive from 31 to 57 months after the onset of the disease. Their mental state has improved, but 3 have severe, residual paraplegia. Improvement was associated with the presence of a well functioning renal transplant or dialysis with deionized water. Only one case has developed since deionization of water containing more than 50/micrograms/l of aluminium has been routine. The patients' histories suggest that immobilization, surgery, administration of corticosteroids and hypophosphatemia, all of which induce a negative calcium balance, may release aluminium or another toxic substance from bone and precipitate the onset of D.E.