Assessment of erythropoiesis following renal transplantation

Abstract: Ten patients, who received cadaveric kidneys, were followed for 24 wk with serial measurements of serum erythropoietin (S-Epo), transferrin receptor (S-TfR) and iron variables. The mean pretransplant creatinine clearance was 8.2 (range 0–22) ml/min and the mean haemoglobin (Hb) level was 99±18.6 (range 66–124) g/l. Nine patients demonstrated a gradual increase in S-Epo levels, which reached a peak, and was accompanied by a parallel increase in S-TfR levels with a median lag period of 3 wk between both peaks. Hb correction followed the S-TfR peak after a second lag period (median 7 wk). Elevated S-Epo and S-TfR did not result in correction of anaemia in 1 patient due to impaired graft function. Within 4 months, S-Epo levels reached the normal range while TfR levels were higher than normal. Follow-up of iron status demonstrated the development of iron deficiency in 5 patients, which was corrected spontaneously. Improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow, as detected by increasing S-TfR levels, subsequent to a S-Epo peak. This expansion precedes Hb normalization. A nonuraemic environment is probably a prerequisite for the correction of anaemia but not for the increase in S-Epo or S-TfR levels. Iron deficiency may occur after transplantation due to an increase in iron utilization.     

Persistence of gastric hypoacidity in uraemic patients after renal transplantation

To evaluate the effect of renal transplantation on the frequent gastric hypoacidity encountered among uraemic patients, 84 patients (19 with chronic renal failure receiving dietary treatment, 29 receiving regular dialysis treatment, and 36 with a well-functioning renal transplant) were studied for their gastric acid secretory capacity. The mean duration of preoperative dialysis treatment of the dialysed patients was 13.7 months, and the mean length of postoperative follow-up study of the transplant patients was 10.1 months. The mean gastric acid secretory capacity of all three subgroups of renal patients was similar, and all these means fell within the reported reference interval of healthy controls. Gastric hypoacidity was observed in 26% of the non-dialysed and in 17% of the dialysed patients but also in 28% of the patients with a well-functioning renal graft. Thus uraemia seems to result in gastric hypoacidity, which tends to persist for over 10 months after normalization of renal function through transplantation.     

Cancer risk in patients on dialysis and after renal transplantation

The increased risk of cancer in patients who have had kidney transplants has mainly been attributed to immunosuppressive therapy; however, the prior period of uraemia and dialysis has also been postulated as a cofactor. We analysed cancer risk retrospectively in a cohort of 4178 patients undergoing renal replacement therapy, of whom 3592 were treated with dialysis alone and 1821 later had transplants. We found that excess cancer risk in such patients occurred after transplantation and not during dialysis.     

Long-term dialysis and renal transplantation in lymphatic leukemia.

With increasing experience and skill with renal transplantation and dialysis, many disorders that were previously thought to contraindicate these procedures are no longer regarded as contraindications. We have previously reported that transplantation can successfully be performed in patients who have had malignant diseases if they seem to be cured after approximately 12 months. Although incurable malignancies have usually been regarded as absolute contraindications, successful dialysis and transplantation have been achieved in a patient with chronic lymphatic leukemia.     

The anemia of chronic renal failure and chronic diseases: in vitro studies of erythropoiesis.

The presence of a serum factor in chronic renal failure (CRF) which inhibits erythropoietin-stimulated erythropoiesis was studied, using a technique in which dog marrow cells were stimulated to produce heme in the presence of human serum. In the total series comparing 27 normal sera with 52 CRF sera, less heme was synthesized when the system contained CRF sera (total series, p = 0.0001). There was no evidence of inhibition of heme synthesis by serum from 12 patients with the anemia of chronic diseases (CD). Mixing experiments with normal and CRF sera suggested that this defect in CRF serum was not due to lack of a factor necessary for heme synthesis. Addition of urea, creatinine, and guanidinosuccinic acid to normal serum did not impair its ability to support erythropoiesis in this system. These data demonstrated that serum from patients with CRF contains a material inhibiting erythropoiesis in vitro, We propose that the material is responsible, in part, for the clinically severe anemia seen in these patients.     

Effect of lovastatin on serum lipid profile in the treatment of dyslipoproteinaemia in uraemic patients on continuous ambulatory peritoneal dialysis

Background: Dyslipoproteinaemia is an important risk factor for cardiovascular disease in uraemic patients on continuous ambulatory peritoneal dialysis (CAPD). Lovastatin is an HMG Coenzyme A reductase inhibitor which is useful in treating non-uraemic patients with hypercholesterolaemia.
Aims: We conducted a single blind cross-over study versus placebo in 10 CAPD patients to examine the effect of lovastatin (20–40 mg) on the serum lipid profile and its safety in uraemic patients.
Methods: Treatment phases were of eight weeks' duration. Each four weeks' measurements were made of serum total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), VLDL-cholesterol (VLDL-C), Apolipoprotein Al & B (Apo Al & Apo B) and Lipoprotein (a). After eight weeks, lovastatin significantly reduced TC by 29% from 6.7 ± 0.3 (mean±S.E.M.) to 4.8±0.1 mmol/L, LDL-C by 41% from 4.6±0.3 to 2.7±0.1 mmol/L and Apo B by 32% from 116±7 to 78±3 mg/dl (p<0.01). HDL-C increased by 8% froml.2±0.1 to 1.3 ±0.2 mmol/L after eight weeks' therapy (p<0.05). TG decreased by 18% from 1.9 ±0.4 to 1.6 ±0.3 mmol/L (p< 0.05). There was no significant difference in changes of other lipid profiles between placebo and drug. No adverse effects of the drug were noted during treatment and the liver function and muscle enzymes were not significantly altered by either drug therapy or placebo.
Results: Lovastatin appears to be a safe and useful drug in effectively treating dyslipoproteinaemia in CAPD patients. (Aust NZ J Med 1993; 23: 252–257.)     

The effects of serine proteinase inhibitors on bone resorption in vitro

The aims of this study were to identify the role and sites of action of serine proteinases (SPs) in bone resorption, a process which involves a cascade of events, the central step of which is the removal of bone matrix by osteoclasts (OCs). This resorbing activity, however, is also determined by recruitment of new OCs to future resorption sites and removal of the osteoid layer by osteoblasts (OBs), which enables OCs to gain access to the underlying mineralized bone. The resorption systems we have studied consisted of (i) neonatal calvarial explants, (ii) isolated OCs cultured on ivory slices, (iii) mouse OBs cultured on either radiolabelled type I collagen films or bone-like matrix, (iv) bone marrow cultures to assess OC formation and (v) 17-day-old fetal mouse metatarsal bone rudiments to assess OC migration and fusion. Two separate SP inhibitors, aprotinin and alpha(2)-antiplasmin dose-dependently inhibited (45)Ca release from neonatal calvarial explants: aprotinin (10(-6) M) was the most effective SP inhibitor, producing a maximum inhibitory effect of 55.9%.Neither of the SP inhibitors influenced either OC formation or OC resorptive activity. In contrast, each SP inhibitor dose-dependently inhibited OB-mediated degradation of both type I collagen fibrils and non-mineralized bone matrix. In 17-day-old metatarsal explants aprotinin produced a 55% reduction in the migration of OCs from the periosteum to the mineralized matrix after 3 days in culture but after 6 days in culture aprotinin was without effect on OC migration. Primary mouse osteoblasts expressed mRNA for urokinase type plasminogen activator (uPA), tIssue type plasminogen activator (tPA), the type I receptor for uPA, plasminogen activator inhibitor types I and II and the broad spectrum serine proteinase inhibitor, protease nexin I. In situ hybridization demonstrated expression of tPA and uPA in osteoclasts disaggregated from 6-day-old mouse long bones. We propose that the regulation of these various enzyme systems within bone tIssue determines the sites where bone resorption will be initiated.     

Haemoglobin concentration and serum erythropoietin in renal dialysis and transplant patients

In patients with chronic renal failure the use of the relatively new dialysis technique of continuous ambulatory peritoneal dialysis (CAPD), unlike other forms of dialysis, is consistently associated with an increase in Hb concentration, but the mechanism remains obscure. We measured Hb, haematocrit, S-erythropoietin and Hb-oxygen affinity in 3 groups of patients with chronic renal failure. (1) Untreated patients starting on haemodialysis. (2) Patients on intermittent peritoneal dialysis changing to CAPD. (3) Patients from the above 2 groups receiving renal transplants. In addition, red cell mass, plasma volume and red cell survival were measured in (2), before starting CAPD and at 6 months. There were distinctly different patterns of change in Hb concentration, Hb-oxygen affinity and S-erythropoietin in the 3 groups of patients. The increase in Hb concentration with CAPD is due to both a fall in plasma volume and an increase in red cell mass, with an increase in red cell survival. There was no change in Hb-oxygen affinity or serum erythropoietin concentration. The improvement in red cell mass and survival may be related to increased clearances of substances with mol. wt.s between 500 and 5000 daltons which accumulate in renal failure (uraemic middle molecules).     

Treatment of chronic renal insufficiency in the diabetic by dialysis and transplantation

The number of diabetics with end stage renal disease (ESRD) is growing. The best treatment at the lowest cost possible should be offered to all diabetics if therapeutic facilities are available. Such a policy requires that all dialysis methods and transplantation should be available and that transfer from one method to another should always be allowable. Results observed among insulin and non insulin-dependent diabetics are improving steadily, even in the older age group. However they are inferior to those observed in non diabetic people of the same age. Adequate medical care, including excellent control of high blood pressure and good control of blood glucose levels should reduce the frequency of severe complications including cardiac, ocular and peripheral vascular lesions. In diabetic patients under forty years of age, renal transplantation using a kidney from a cadaver or a related donor should be the first choice. However, for most patients dialysis methods are required as the only treatment or while waiting for a transplant. Very encouraging results are obtained with both hemodialysis and peritoneal dialysis. If home dialysis is considered, continuous ambulatory peritoneal dialysis (CAPD) offers the opportunity to treat many insulin-dependent or non dependent diabetics at home even those in the high risk population because of age and/or cardio-vascular instability. CAPD offers excellent control of blood glucose levels using the intraperitoneal route to administer insulin. Results obtained are discussed from data in the literature and from a survey of 124 insulin-dependent diabetic cases with ESRD treated in the Department of Nephrology of the Hospital de La Pitié from 1973 to 1984.     

The management of renal scleroderma: experience with dialysis, nephrectomy and transplantation.

In 25 of 100 patients with scleroderma seen over a five year period irreversible renal failure developed; renal support was instituted in 17. Ten of 17 received peritoneal or hemodialysis, one survived. The remaining seven received hemodialysis plus nephrectomy; three survived. Two of these three underwent renal transplantation; one survived. This experience is presented to encourage improvement of these and other technics to increase the survival rate in the otherwise uniformly fatal renal failure associated with scleroderma (systemic sclerosis).     

Contamination of erythropoietin by endotoxin: in vivo and in vitro effects on murine erythropoiesis.

Endotoxin was detected in all erythropoietin preparations tested and was removed from four lots, without loss of erythropoietic activity, by adsorption with limulus amebocyte lysate. Comparison of adsorbed (endotoxin-depleted) and nonadsorbed (endotoxin-containing) erythropoietin preparations demonstrated significant inhibition of CFU-e and BFU-e in vitro by nonadsorbed erythropoietin at concentrations higher than 0.25 U/ml and 2.0 U/ml, respectively. CFU-e and BFU-e were inhibited significantly by readdition in vitro of 10(-5)-10(-3) mug of endotoxin per unit of limulus-adsorbed erythropoietin. Administration of saline or 6 U of nonadsorbed or adsorbed erythropoietin twice a day for 4 days of CF1 mice resulted in reticulocyte counts of 2.1%, 9.9%, and 15.9%, respectively. Nonadsorbed erythropoietin resulted in a 29% decrease in erythropoiesis, a 42% decrease in CFU-e, and a 16% increase in granulopoiesis in the marrow, whereas adsorbed erythropoietin caused a 28% increase in erythropoiesis, no significant change in CFU-e and a 19% decrease in granulopoiesis in the marrow. Both preparations resulted in marked increases in splenic erythropoiesis and granulopoiesis. The effects of adsorbed erythropoietin are similar to those produced following stimulation of hematopoiesis by endogenous erythropoietin. Hemopoietic changes induced by nonadsorbed erythropoietin in vivo and in vitro are affected substantially by contamination of the erythropoietin preparations with endotoxin.