Imaging of haemodialysis-associated amyloidosis with 123I-serum amyloid P component.

Long-term haemodialysis is frequently complicated by amyloid deposition in which the fibrils consist of beta 2-microglobulin. Dialysis-related amyloid disease causes extensive morbidity and has been associated with deaths in some cases. All amyloid deposits contain amyloid P component that is derived from the normal circulating protein, serum amyloid P component (SAP). We have used scintigraphic imaging after injection of 123I-labelled SAP to assess the distribution of amyloidosis in 38 patients receiving long-term haemodialysis for end-stage renal failure. There was focal localisation of tracer at all sites where histological examination confirmed amyloid deposition. Splenic uptake was seen in 12 patients, indicating splenic amyloidosis, but there was no evidence of other visceral involvement. 6 control subjects who had been dialysed for under 1.5 years showed no localisation of tracer, nor was there any uptake of 123I-labelled human serum albumin in 3 long-term dialysis patients with histologically confirmed amyloidosis and positive 123I-SAP images. Negative scans were also obtained in 5 patients who had been transplanted 0.8-2.4 years previously, despite past evidence of dialysis arthropathy (5) and histologically proven amyloidosis (4). 123I-SAP scintigraphy may be helpful as a non-invasive method for both the diagnosis and monitoring of dialysis-associated amyloidosis.

Total parathyroidectomy alone or with autograft for renal hyperparathyroidism?

Seventy-six patients underwent parathyroidectomy for renal hyperparathyroidism. There were 10 subtotal parathyroidectomies, 49 total parathyroidectomies with implantation of part of one gland as an autograft, nine total parathyroidectomies with no autograft, and eight patients in whom only three parathyroid glands were found. In 34 dialysis patients who underwent total parathyroidectomy with an autograft there was a high rate of recurrent hyperparathyroidism after 6 years in those remaining on dialysis. Fifty per cent had asymptomatic recurrent hyperparathyroidism and 30 per cent required partial autograft excision for symptomatic hyperparathyroidism. In contrast, recurrent hyperparathyroidism was rare in renal transplant recipients with good renal function. This favourable outcome did not depend upon whether parathyroid surgery was performed before or after transplantation, or on the type of parathyroidectomy. Total parathyroidectomy without an autograft was performed in nine dialysis patients without any short-term adverse effects, and with clinical and pathological improvement in bone disease. In summary, the results of surgery for renal hyperparathyroidism were excellent in patients who received a successful renal transplant. However, there was a high incidence of recurrent hyperparathyroidism in patients who remained on long-term dialysis. Total parathyroidectomy without an autograft may be the treatment of choice in patients unlikely to receive a renal transplant.

Joint and systemic distribution of dialysis amyloid.

Deposition of beta 2-microglobulin amyloid in the joints of dialysis patients is common and begins early in the course of treatment, but its pathogenic significance in the production of dialysis arthropathy is uncertain. The joints (hip, knee, shoulder, elbow, wrist, cervical and lumbar spine, sacroiliac joint) and systemic tissues of 19 autopsied patients who had undergone haemodialysis for between 6 and 231 months were examined histopathologically for the presence of beta 2-microglobulin amyloid; it was present in all joints examined, including those unassociated with radiological changes and those of patients who had been on haemodialysis alone for only 24 months. Osteoarticular beta 2-microglobulin amyloid deposits were also found in patients who had been treated mainly by continuous ambulatory peritoneal dialysis. Systemic amyloid deposition was only seen in patients who had been haemodialysed for more than 13 years and consisted of sparse tiny deposits in blood vessel walls.

Stepwise correction of anaemia by subcutaneous administration of human recombinant erythropoietin in patients with chronic renal failure maintained by continuous ambulatory peritoneal dialysis.

Sixteen anaemic CAPD patients (Hb less than 9 g/dl) were treated with thrice-weekly subcutaneous recombinant erythropoietin, epoetin-alfa. The dose was adjusted to induce a stepwise increase in haemoglobin. Fourteen patients reached a first target haemoglobin of 11.0-11.5 g/dl and eight of these a second of 13.0-13.5 g/dl, but one could not be maintained at this level. Failure to reach or maintain the second target in nine subjects was accounted for by incomplete responses associated with infection in one, extreme shortening of red-cell survival in another, and was unexplained in one subject. These three received the maximum dose studied of 450 IU/kg per week. Six other subjects were withdrawn from the study for reasons unrelated to treatment with erythropoietin. The median dose required to maintain the haemoglobin at 11.0-11.5 g/dl was 75 IU/kg per week and at 13.0-13.5 g/dl was 150 IU/kg per week. Quality of life, assessed in 12 patients at haemoglobin 11.0-11.5 g/dl, showed significant improvement in energy, and at 13.0-13.5 g/dl improvements in sleep and emotional wellbeing became significant. Twelve subjects required either institution of, or an increase in, treatment for hypertension. The thrice-weekly subcutaneous doses of erythropoietin were well tolerated and were a convenient and effective treatment for anaemia in patients on CAPD.

A comparison between intraperitoneal ciprofloxacin and intraperitoneal vancomycin and gentamicin in the treatment of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD).

In a prospective, randomized, controlled trial in 40 patients, intraperitoneal ciprofloxacin was shown to be as effective as the currently recommended regimen of intraperitoneal vancomycin and gentamicin for the treatment of CAPD peritonitis. There was one treatment failure in the ciprofloxacin arm and four in the comparative arm. A single drug regimen is preferred by patients. The intraperitoneal route of administration of ciprofloxacin therapy has advantages over the oral route.

Subcutaneous administration of recombinant human erythropoietin to subjects on continuous ambulatory peritoneal dialysis: an erythrokinetic assessment.

Erythrokinetic studies were performed in subjects on continuous ambulatory peritoneal dialysis, during a trial examining the effectiveness of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) in correcting the anaemia associated with end stage renal disease. 15 subjects (mean haemoglobin concentration 6.9 g/dl, SD 1.1) entered the study, and during treatment 9 were restudied at a haemoglobin concentration of 11-11.5 g/dl and six underwent a third study at haemoglobin 13-13.5 g/dl. By adjusting the dose of r-HuEPO, a stepwise increase in haemoglobin concentration was achieved, and this was accompanied by increases in total red cell volume and erythron transferrin uptake. Plasma volume decreased as red cell volume increased, leaving total blood volume essentially unchanged. Red cell survival, modestly reduced before treatment (mean 64, range 44-96 d, n = 6) tended to increase during treatment and when subjects were retested at a haemoglobin concentration of 13-13.5 g/dl (after 38-62 weeks treatment), the mean increase in red cell survival was 20 d (95% confidence interval 1-39 d). Thus subcutaneous r-HuEPO is effective in correcting the anaemia of end stage renal disease when administered thrice weekly to subjects on continuous ambulatory peritoneal dialysis. It produces an increase in haemoglobin concentration primarily by expanding the erythron, and may have a secondary effect, seen after several months of treatment, of increasing red cell survival.

The Oxford-Manchester study of dialysis patients. Age, risk factors and treatment method in relation to quality of life.

A retrospective study of 159 patients who started Haemodialysis (HD) or Continuous Ambulatory Peritoneal Dialysis (CAPD), between 1981 and 1984 was carried out in two UK Renal Units. An extension of the study was carried out in one unit during 1985, gathering data on 30 patients aged greater than 65. The aim was to assess whether age, medical or social risk factors, or treatment method, affected perceived quality of life. Assessment was by standardised self-report questionnaire. The overall life satisfaction, measured on Cantril's ladder scale, showed no significant difference between dialysis patients and a normal population. On a quality of life semantic differential scale CAPD patients scored significantly better than HD patients. Satisfaction with sexual relationships showed marked deterioration in all age groups, but this did not seem to affect reported satisfaction with marriage. Those aged greater than 65 scored significantly better than younger patients on dialysis stress scales, and were generally more satisfied with life. When the study population was sub-divided into four groups, by age (less than or greater than 60) and presence or absence of additional factors, were seen to be those least satisfied with life on several different assessment scales.

The quality of life of dialysis patients treated with recombinant human erythropoietin.

In June 1986, eight haemodialysis patients, seven male, one female, entered a pilot trial of recombinant human erythropoietin (EPO) at the Churchill Hospital Renal Unit. Six patients completed the Nottingham Health Profile (NHP) before starting EPO therapy, in order to assess quality of life, and were retested when haemoglobin level reached 120 g/l. A further test was given at one year. Statistically significant improvements were seen in the areas of Energy and Emotional Wellbeing. In the subsequent UK trial, involving previously transfusion dependent patients from nine centres, the pre and post treatment NHP scores of a further 18 patients have been assessed. Highly significant improvements were found in Energy, Physical Mobility (p less than 0.005) and in Emotional Wellbeing (p less than 0.002). Improvements which did not reach significance were found in the areas of Sleep, Social Isolation and Pain problems. An increase in appetite, and less sensitivity to cold were noted by over one third of patients. Problems with Employment, Looking after the Home, and Relationships were greatly reduced. We conclude that early findings show EPO treatment to improve not only the haemoglobin levels, but also the quality of life of haemodialysis patients with the anaemia of end stage renal failure.

Subcutaneous deposition of beta 2-microglobulin amyloid in a long-term haemodialysis patient.

Subcutaneous deposition of beta 2-microglobulin (beta 2-M) amyloid is an uncommon finding in uraemic patients on long-term haemodialysis. A 60-year-old female on haemodialysis for 16 years developed a subcutaneous haematoma 2 years prior to death. At necropsy the lesion contained numerous deposits of beta 2-M amyloid as well as evidence of old haemorrhage, fibrous repair, dystrophic calcification and calcium oxalate crystal deposition. Highly sulphated glycosaminoglycans were present in the amyloid deposits. beta 2-M amyloid deposits were also present in the hip joint, cervical and lumbar spine, and in small blood vessels of the heart, liver, and lung. The possible role of trauma and tissue glycosaminoglycans changes in the formation of subcutaneous amyloid tumours is discussed.

The ventilatory response to lowering potassium with dextrose and insulin in subjects with hyperkalaemia.

Arterial plasma potassium concentration ([ K+]a) is increased during exercise. This change is sufficient to excite arterial chemoreceptors and stimulate ventilation (VE) in the anaesthetized cat. Moreover, changes in [K+]a and VE are highly correlated during exercise, however the contribution that [K+]a makes to the control of breathing in man is not yet known. Four otherwise relatively healthy male hyperkalaemic renal patients had their VE measured before, during and after an intravenous infusion of dextrose and insulin to lower their [K+]a. Thirty-six minutes after the infusion began [K+]a had been reduced by ca. 2 mM. Ventilation was virtually unchanged throughout the experiment. These results suggest that [K+]a does not significantly affect VE in this group of subjects. The assumptions that would need to be made to extrapolate this conclusion to the general population are discussed.

Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics.

Studies were directed to characterization of the anaemia of renal failure of 11 patients on haemodialysis and determination of the way in which it is corrected by human erythropoietin derived from recombinant DNA expressed in Chinese hamster ovary cells (r-HuEPO) administered intravenously. Erythrokinetics before treatment showed that total red cell mass was below normal and that both erythron transferrin uptake and red cell survival were modestly reduced; treatment increased both total red cell mass and erythron transferrin uptake but did not change red cell survival in previously untransfused patients. When BFU-e and CFU-e from patient bone marrow were cultured in autologous serum we found no evidence for inhibitors of erythroid progenitor maturation in patient serum compared with normal. Erythroid expansion in response to r-HuEPO was not limited by the availability of iron, iron requirements for new red cell formation being met from stores (if adequate) or from oral iron supplements. In pharmacokinetic studies the plasma clearance of r-HuEPO could be expressed by a three-parameter exponential curve with T1/2 range of 2.3 to 7.3 h. T1/2 after the first dose of r-HuEPO was not significantly different from that after 14 to 54 weeks treatment when the erythron had expanded to a new steady state. Erythron transferrin uptake before treatment was related to endogenous production of erythropoietin estimated from the plasma clearance of the first dose of r-HuEPO administered intravenously. This finding suggested that the availability of erythropoietin was the main factor limiting expansion of the erythron. This conclusion was supported by the continuity of the relationship during the response to treatment.

Late renal failure due to prostatic outflow obstruction: a preventable disease.

Nineteen patients presenting with late renal failure due to prostatic outflow obstruction (mean age 68.7 years; mean serum creatinine concentration 1158 mumol/l) were identified from the admission records of two renal units. As late renal failure secondary to prostatic enlargement is preventable case records were analysed retrospectively in an attempt to identify aspects of management in which preventive efforts might be of value. Delays in referral were common, with a mean of 2.8 years between the onset of prostatic symptoms and time of referral, six patients being referred who had had symptoms for more than three years. Four of five patients who had had a prostatectomy were known to be in renal failure at the time of operation but were not referred until 2-13 years later, when prostatic symptoms had recurred and there was evidence of progressive nephropathy with dilatation of the upper urinary tract. Two patients died on admission and eight (47% of survivors) required long term dialysis, most patients (80%) requiring some dialysis support during the initial period. These findings suggest that progressive nephropathy caused by prostatic outflow obstruction might, in part, be averted by more adequate screening of renal function in men with untreated prostatism and closer follow up of patients with uraemia at the time of prostatectomy.

Erythroid progenitor cell kinetics in chronic haemodialysis patients responding to treatment with recombinant human erythropoietin.

The response of bone marrow and peripheral blood erythroid progenitors to human recombinant erythropoietin (rHuEPO) was studied in nine haemodialysed renal failure patients receiving this hormone for the correction of their anaemia. The haematocrit rose in all patients in response to thrice weekly injections of escalating rHuEPO doses (12-192 IU/kg). Both the numbers of CUF-e and BFU-e and their proliferative state in the bone marrow as well as BFU-e numbers in the peripheral blood were estimated before treatment and again after correction of the anaemia, at 16 h following an intravenous dose of rHuEPO. Following treatment bone marrow BFU-e numbers fell to a mean of 24.5% (P less than 0.01) of the pre-treatment values although there was no significant change in CFU-e or circulating BFU-e numbers. The mitotic rate (percentage S-phase cells) estimated by tritiated thymidine suicide rose from 45.2% to 68.4% (P less than 0.05) in the case of CFU-e and from 16.4% to 45.1% (P less than 0.05) for BFU-e following treatment with rHuEPO thus indicating in-vivo sensitivity of both the primitive as well as the mature erythroid progenitors to the hormone. The fall in BFU-e numbers in the bone marrow after several months of treatment may be due to a loss of cells from this progenitor pool by maturation that is uncompensated by replacement from the pluripotential stem cell compartment.

Systemic amyloidosis of beta 2-microglobulin type: a complication of long-term haemodialysis.

A patient receiving long-term haemodialysis developed systemic amyloidosis, which was shown immunohistochemically to be of beta 2-microglobulin type, a previously unrecognised form of systemic amyloidosis. Histologically, the amyloid deposits were closely associated with foci of acute and granulomatous inflammation and vasculitis, although it was not clear if the amyloid deposits directly caused the inflammatory process, or if amyloid was deposited preferentially in areas of inflammation of uncertain aetiology.

Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis.

Ten patients with end-stage renal failure and anaemia (mean haemoglobin 6.1 g/dl, range 4.6-8.8 g/dl) on thrice-weekly haemodialysis were treated with human erythropoietin derived from recombinant DNA (rHuEPO). This was given as an intravenous bolus after each dialysis in rising doses within the range 3-192 IU/kg. All patients showed increases in reticulocyte numbers and haemoglobin concentration and after the first week of treatment none of the four previously transfusion-dependent patients needed further transfusions. In nine patients treated for 12 weeks haemoglobin rose to a mean of 10.3 g/dl, range 9.5 to 12.8 g/dl. Thereafter the dose of erythropoietin was adjusted to avoid a further rise in haemoglobin. During treatment one patient had an episode of hypertensive encephalopathy and two had clotting in their arteriovenous fistulas (complete in one). rHuEPO is an effective treatment for the anaemia of end-stage renal failure but longer-term observations are needed on the consequences of increasing the haematocrit.