Effects of erythropoietin, angiotensin II, and angiotensin-converting enzyme inhibitor on erythroid precursors in patients with posttransplantation erythrocytosis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) have become the treatment of choice for posttransplantation erythrocytosis (PTE). Yet the pathogenesis of PTE and the mechanisms of action of ACEI remain unclear. Therefore, we studied the dose response to erythropoietin (Ep), angiotensin II (AII), and the ACEI enalaprilat on the in vitro proliferation of erythroid progenitors in patients with PTE and in controls. We also evaluated ACE polymorphism in the two groups. METHODS: Twelve patients with PTE and 12 renal transplant patients without PTE were studied. Erythroid burst-forming units (BFU-E) were isolated from peripheral blood using standard methods. Ep sensitivity was determined for four patients with PTE and three control patients, using 0-3 U/ml Ep. AII dose response was studied in four patients with PTE and five control patients, using AII concentrations of 0-1000 nM. The effect of enalaprilat was studied in eight patients with PTE and eight control patients, using drug concentrations of 0-10 ng/ml. ACE gene insertion/deletion polymorphism was determined by polymerase chain reaction. RESULTS: PTE patients showed a significant shift of the Ep response curve to the left compared with controls, with 50% maximal growth occurring at a lower Ep concentration (0.3 U/ml vs. 0.95 U/ml, P<0.025.) However, there was no difference in the number of BFU-E colonies between PTE patients and controls. AII added to the growth medium produced only minor stimulation in both groups. PTE patients showed significant inhibition of BFU-E growth with 10 ng/ml enalaprilat, but controls showed no inhibition of BFU-E growth with ACEI. There was no difference in ACE polymorphism between PTE and controls. CONCLUSIONS: Our data suggest that PTE is associated with increased erythroid progenitor sensitivity to Ep. The effect of ACEI to decrease hematocrit in patients with PTE may be due to inhibition of red cell precursor growth.     

Increased erythropoietin response to venesection in erythrocytosic renal transplant patients

Anaemia of end-stage chronic renal failure improves following successful kidney transplantation. However, erythrocytosis occurs in 6.8–17.3% of transplanted patients. Mechanism of post-transplant erythrocytosis (PTE) and its erythropoietin (Epo) dependence are still controversial. Firstly, we compared basal serum Epo levels of 10 PTE patients, 14 non-erythrocytosic renal transplant (non-PTE) patients and 12 healthy blood donors. Then we performed venesection in PTE patients and healthy blood donors and compared their Epo response to venesection 5 hours later. The mean basal serum Epo of 24.3 mU/ml was significantly higher in the PTE group than the 10.8 mU/ml in the non-PTE and 8.6 mU/ml in the healthy blood donor group (p<0.01). Epo levels in the non-PTE group did not differ significantly from those of healthy blood donors (p>0.05). Following venesection the mean serum Epo levels increased significantly in both groups, from 24.3 mU/ml to 67.7 mU/ml (p<0.001) in the PTE group and from 8.6 to 12.1 mU/ml (p<0.01) in the healthy blood donor group, but the increment in the PTE group was more marked. We conclude that PTE patients have elevated basal serum Epo levels and there is a feedback regulation of Epo secretion in these patients like in healthy blood donors, but in an exaggerated way.     

Serum Stem Cell Factor Level in Renal Transplant Recipients With Posttransplant Erythrocytosis

The etiology of posttransplant erythrocytosis (PTE) remains unclear, and the most frequently suggested causative factors are still a matter of controversy. We aimed to investigate serum‐soluble stem cell factor (sSCF) along with serum erythropoietin (EPO) levels in renal transplant recipients (RTRs) with PTE. Thirteen RTRs with PTE, 42 RTRs without PTE, and 42 healthy controls were included. Serum sSCF and EPO levels were determined using an enzyme‐linked immunosorbent assay kit. Expected and observed/expected EPO levels were calculated. Serum sSCF levels and observed/expected EPO were significantly higher in RTRs with PTE than both RTRs without PTE and controls. In RTRs with PTE, sSCF level was significantly correlated with hematocrit and observed/expected EPO, respectively. Significant correlation was also observed between hematocrit level and observed/expected EPO in RTRs with PTE. Increased sSCF level and inadequate suppression of EPO production seem to have a role in the pathogenesis of PTE.     

Factors predictive of post-transplant erythrocytosis.

Ninety-three patients with PTE (that is, hematocrit 51% or greater) were identified among 431 renal transplant recipients, an incidence of 21.6%. Thirty-eight patients underwent blood volume measurements, and 22 of these had high red cell volume and therefore were considered to have true PTE. To analyze factors predictive of erythrocytosis, a control group with normal hematocrit was randomly selected from our renal transplant population and compared with the 93 patients with PTE, and with the 22 who had true PTE. Using step-wise logistic regression analysis, we identified three variables that were consistent predictors of PTE. In order of significance, the serum creatinine value at the onset of PTE appears to most strongly predict the occurrence of PTE (P less than 0.0001). As creatinine value increases, the probability of PTE decreases. Next was immunosuppression, where double immunosuppressive therapy was associated with a greater probability of PTE than triple therapy (P less than 0.0001). The overall incidence of PTE in patients on double therapy was 34%, while that for those on triple therapy 10.4%. Last was duration of dialysis for which increasing values correspond to increasing probability of PTE (P = 0.004). Comparison of the serum erythropoietin (EPO) levels for patients and controls yielded a nonsignificant result (P = 0.2507 and P = 0.383 for all patients with PTE and true PTE, respectively), and therefore EPO levels were inappropriately elevated for the level of hematocrit in the PTE group. Only the number of rejections and duration of follow-up (r = -0.3507) were significantly correlated with EPO (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

In-vitro growth patterns of bone marrow erythroid progenitors from patients with post-renal transplant erythrocytosis

Background: Erythrocytosis is relatively common after renal transplantation and is associated with a higher risk of thromboembolism. Its aetiology is unclear and there is still debate about the most frequently suggested causes. The culture in vitro of erythroid progenitors is regarded as a useful tool for the differential diagnosis of patients with unclear erythrocytosis. We studied the growth in vitro of bone marrow erythroid progenitor from renal transplant patients with erythrocytosis and controls without erythrocytosis. Subjects and methods: Thirteen renal transplant patients with erythrocytosis and 12 normocythaemic renal transplant controls were studied. The clinical characteristics of these patients were evaluated and serum erythropoietin (Epo) and ferritin levels were determined. Bone marrow erythroid progenitors were cultured both with and without the addition of Epo to the medium. Results: Samples from six polycythaemic patients and seven controls did not grow spontaneously in the absence of exogenous Epo. Three cases of post-transplant erythrocytosis and five controls produced CFU-E, but not BFU-3. A few CFU-E and BFU-E grew spontaneously in samples from four polycythaemic patients but not in samples from the controls. Addition of 1 unit per millilitre Epo caused similar increases in the number of colonies in both polycythaemic patients and controls. Of the nine patients eligible for follow-up, all four with spontaneous growth of BFU-E had transient erythrocytosis and four of the five patients with no spontaneous growth or spontaneous growth of CFU-E only had persistent erythrocytosis requiring treatment with ACE inhibitors. Conclusions: Pathophysiology of post-transplant erythrocytes is heterogenous. In one-third of the patients, there was unexpected, spontaneous and transient growth of BFU-E which was not predictive of permanent erythrocytosis. The results of stem-cell studies suggest that in these cases erythrocytosis may be caused by defective regulation of erythroid progenitor proliferation, possibly due to particular cellular interactions or the effect of cyclosporin on erythropoiesis.     

Anemia due to losartan in hypertensive renal transplant recipients without posttransplant erythrocytosis

Losartan is a safe, effective long-term treatment for hypertension or posttransplant erythrocytosis (PTE) in renal transplant recipients. There were only a few studies in patients without PTE and their results were different. Starting from week 6 and continuing to the week 12 we observed a decrease in hemoglobin (Hb) and hematocrit (Hct) levels in patients without PTE. Anemia developed in 42.8% of the patients, and Hb levels increased after the withdrawal of losartan treatment. There was a significant decrease in Hct levels beginning from week 3 when compared with the control group. Our study suggests that losartan therapy can decrease Hb beyond its antihypertensive efficacy. Based on the capacity of losartan to decrease Hb and Hct, this drug should be carefully used in patients with preexistent anemia or low Hb levels.     

Captopril induces correction of postrenal transplant erythremia

Abstract. Kidney transplant patients may develop post-transplant erythremia (PTE), and in order to avoid thromboembolism venesection, anticoagulation and native kidney removal have been suggested. We propose captopril as an alternative therapy for PTE. Seven hypertensive PTE patients, aged 42 10 years with stable renal function, were investigated to exclude primary or secondary polycythemia. All patients manifested true erythrocytosis [red blood cells (RBC) mass > 20% of predicted level] with concomitant increases in hematocrit and hemoglobin levels. Captopril was introduced in gradually increasing doses up to 75 mg/day under careful monitoring of blood pressure and renal function. Weekly follow-up was arranged to evaluate drug efficacy. After captopril, a significant reduction with normalization of the RBC mass (42 4 vs 31 5 ml/kg; P < 0. 005) was observed. The RBC counts and hematocrit and hemoglobin levels also decreased. One patient had recurrent erythrocytosis after captopril withdrawal. Captopril may be a simple, effective, and non aggressive treatment for postrenal transplant erythremia.     

Influence of angiotensin-converting enzyme polymorphism gene, IGF-1, and other factors in the response rate of hematocrit to enalapril treatment in patients with posttransplant erythrocytosis

A significant relationship between hematocrit values and serum parameters such as the insulin like growth factor (IGF-1) and calcium was observed in patients with posttransplant erythrocytosis (PTE). Since angiotensin-converting enzyme inhibitors (ACEI) decrease hematocrit (Ht) levels in these patients, ACE genotype should play an important role. We designed this study to investigate whether ACE genotype or baseline concentrations of IGF-1, IGF-blood binding protein 3 (BP3), growth hormone (GH), or Ca influenced the response of Ht to ACEI treatment. Twenty-one kidney graft recipients with PTE were treated with enalapril (2.5 to 5 mg/d) for 1 year. IGF-1, BP3, GH, Ca, and Ht were determined before as well as 15, 30, 90, 180, and 365 days after enalapril treatment. ACE polymorphism was also determined. Enalapril treatment significantly decreased Ht levels. Only IGF-1 baseline levels showed a positive correlation to the decreased Ht (P < .025). ACE genotype as determined in 18 patients, showed no correlation with the response to enalapril. Patients with ACE genotype II showed a tendency to an earlier display of PTE. We conclude that low doses of enalapril decrease Ht levels in PTE patients; that PTE begins earlier in patients with II ACE genotype; and that only IGF-1 baseline levels influence the Ht decrease after treatment. These observations suggest that ACEI decrease the Ht via an inhibitory effect on IGF-1, which has a stimulary effect on erythropoiesis.     

Captopril induces correction of postrenal transplant erythremia

Kidney transplant patients may develop post-transplant erythremia (PTE), and in order to avoid thromboembolism venesection, anticoagulation and native kidney removal have been suggested. We propose captopril as an alternative therapy for PTE. Seven hypertensive PTE patients, aged 42±10 years with stable renal function, were investigated to exclude primary or secondary polycythemia. All patients manifested true erythrocytosis [red blood cells (RBC) mass>20% of predicted level] with concomitant increases in hematocrit and hemoglobin levels. Captopril was introduced in gradually increasing doses up to 75 mg/day under careful monitoring of blood pressure and renal function. Weekly follow-up was arranged to evaluate drug efficacy. After captopril, a significant reduction with normalization of the RBC mass (42±4 vs 31±5 ml/kg; P<0.005) was observed. The RBC counts and hematocrit and hemoglobin levels also decreased. One patient had recurrent erythrocytosis after captopril withdrawal. Captopril may be a simple, effective, and non aggressive treatment for postrenal transplant erythremia.     

Iron deficiency--an underrecognized problem in nonanemic and erythrocytic kidney transplant recipients: risks and effects of ACEI and of iron treatment

The state of iron deposits in long-term kidney graft recipients is not well-known. Angiotensin enzyme inhibitors (ACEIs) reduce hematocrit levels in patients with posttransplant erythrocytosis (PTE), but their action on iron deposits has not been sufficiently evaluated. We designed this study to investigate the prevalence of iron deficiency among patients without anemia, the efficacy of ACEI treatment and its influence on iron deposits, and the risks of iron treatment in patients with symptomatic iron deficiency but no anemia. One hundred thirty eight patients were included if they had a kidney transplant for more than a year, with good renal function, with no anemia, and with neither iron nor rHuEpo, ARA, or ACEI treatment. One hundred seventeen had a normal Ht (group 1) and 21 had PTE (group 2). Iron deficiency was found in 73 (62.4%) group 1 patients and in 10 (47%) group 2 patients. Two group 1 patients with symptoms of iron deficiency were treated with oral iron. Their symptoms disappeared, but one developed PTE. Enalapril treatment decreased Ht levels in PTE but not in control patients. Furthermore, this drug increased iron deposits in PTE and controls with a baseline iron deficiency. We conclude that there is a high prevalence of iron deficiency in long-term transplanted patients without anemia. Furthermore, iron treatment must be carefully administered because of the risk of PTE. Enalapril treatment decreased Ht levels in PTE but not in control patients and increased iron deposits in patients with baseline iron deficiency.     

Is Erythrocytosis More Common After Simultaneous Pancreas Kidney Transplantation? A Single-Center Experience

Post-transplant erythrocytosis (PTE) is reported in 8% to 22% of kidney transplant recipients. Few studies have evaluated the prevalence of PTE in simultaneous kidney–pancreas transplantation (SPKT). This study aimed to evaluate the prevalence of PTE in a cohort of SPKT and same-donor single kidney transplant patients and find predictive factors for erythrocytosis development. A single-center retrospective cohort study was performed with 65 SPKT recipients and 65 same-donor single kidney transplant patients. Post-transplant erythrocytosis was defined as a hematocrit persistently >51% without a known cause of erythrocytosis. The PTE prevalence was 23.1% and was more frequent in SPKT patients than in single donor patients (38.5% vs 7.7%; P < .001). The mean time for PTE development was 11.2 ± 13.3 months. In the multivariate model, SPKT was the only predictor for PTE development. De novo hypertension was more frequent in the PTE group (P = .002), but there was no difference in stroke and pancreatic or kidney thrombosis occurrence. Post-transplant erythrocytosis is more common after SPKT than after single kidney transplantation. De novo hypertension was more frequent in the erythrocytosis group, but allograft thrombosis rates.     

Post Transplant Erythrocytosis in Hypercalcemic Renal Transplant Recipients

In vitro data suggest that calcium plays an important role in normal and disordered erythropoiesis. The purpose of this study is to determine whether there is an association between serum calcium, various hormone levels, and the development of post transplant erythrocytosis (PTE). Data were collected on 283 patients who underwent renal transplantation between 1994 and 1998. The relationship between serum calcium and PTE development was tested using the chi-square test. Univariate and multivariable adjusted models were employed to determine predictors of maximum hematocrit. Selected patients underwent measurement of intact parathyroid hormone (PTH), 1,25-dihydroxy vitamin D, and erythropoietin (EPO). Seventy-three patients (26%) developed PTE. Post transplant erythrocytosis was more common in patients with hypercalcemia compared with patients with normal serum calcium (34% vs. 18%, p = 0.002). In multivariable analyses, serum calcium was a strong independent predictor of maximum hematocrit post transplant, even after adjustment for renal function. A serum calcium of >or=10.2 mg/dL was associated with greater than two-fold increased odds of PTE. There were no differences in hormone levels between subjects with hypercalcemia and PTE, subjects with PTE alone, and subjects with hypercalcemia alone. Hypercalcemia is associated with the development of PTE in renal transplant recipients.     

Posttransplant erythrocytosis

Posttransplant erythrocytosis (PTE) is defined as a persistently elevated hematocrit to a level greater than 51% after renal transplantation. It occurs in 10% to 15% of graft recipients and usually develops 8 to 24 months after engraftment. Spontaneous remission of established PTE is observed in one fourth of the patients within 2 years from onset, whereas in the remaining three fourths it persists for several years, only to remit after loss of renal function from rejection. Predisposing factors include male gender, retention of native kidneys, smoking, transplant renal artery stenosis, adequate erythropoiesis prior to transplantation, and rejection-free course with well-functioning renal graft. Just as in other forms of erythrocytosis, a substantial number (approximately 60%) of patients with PTE experience malaise, headache, plethora, lethargy, and dizziness. Thromboembolic events occur in 10% to 30% of the cases; 1% to 2% eventually die of associated complications. Posttransplant erythrocytosis results from the combined trophic effect of multiple and interrelated erythropoietic factors. Among them, endogenous erythropoietin appears to play the central role. Persistent erythropoietin secretion from the diseased and chronically ischemic native kidneys does not conform to the normal feedback regulation, thereby establishing a form of "tertiary hypererythropoietinemia." However, erythropoietin levels in most PTE patients still remain within the "normal range," indicating that erythrocytosis finally ensues by the contributory action of additional growth factors on erythroid progenitors, such as angiotensin II, androgens, and insulin-like growth factor 1 (IGF-1). Inactivation of the renin-angiotensin system (RAS) by an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II type 1 AT1 receptor blocker represents the most effective, safe, and well-tolerated therapeutic modality.     

Insulin-like growth factor I plays a role in regulating erythropoiesis in patients with end-stage renal disease and erythrocytosis

Erythroid progenitor growth, the serum hormones that regulate erythropoiesis, and the effect of patient's serum on the growth of normal erythroid progenitors were assessed in eight patients with end-stage renal disease (ESRD) and erythrocytosis. All patients were male and had been on maintenance dialysis, they had a hematocrit >50% and/or a red blood cell count >6 x 10(12)/L and an arterial oxygen saturation >95%. Four had acquired cystic disease of the kidney (ACDK), and four other non-ACDK patients did not have known causes of secondary erythrocytosis after appropriate investigations and long-term follow-up. The methylcellulose culture technique was used to assay the erythroid progenitor (BFU-E/CFU-E) growth. Serum erythropoietin (EPO) and insulin-like growth factor I (IGF-I) levels were measured by RIA. Paired experiments were performed to determine the effects of 10% sera from ESRD patients and control subjects on normal marrow CFU-E growth. The numbers of EPO-dependent BFU-E in marrow and/or blood of patients with ESRD and erythrocytosis were higher than those of normal controls. No EPO-independent erythroid colonies were found. Serum EPO levels were constantly normal in one patient and elevated in three patients with ACDK; for non-ACDK patients, EPO levels were normal or low in two patients and persistently increased in one, but fluctuated in the remaining one on serial assays. There was no correlation between serum EPO levels and hematocrit values. The serum IGF-I levels in patients with ESRD and erythrocytosis were significantly increased compared with normal subjects or ESRD patients with anemia. We found an inverse correlation between serum EPO and IGF-I levels. Sera from patients with ESRD and erythrocytosis exhibited a stimulating effect on normal marrow CFU-E growth. The stimulating effect of sera from patients who had a normal serum EPO level and an elevated IGF-I level could be partially blocked by anti-IGF-I. The present study suggests that IGF-I plays an important role in the regulation of erythropoiesis in patients with ESRD and erythrocytosis who did not have an increased EPO production.     

Effects of an angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitors on burst forming units-erythroid in chronic hemodialysis patients

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been reported to reduce the response to erythropoietin (EPO) administration in chronic hemodialysis patients, but the mechanism for this effect has not yet been clarified. To clarify the mechanism of ACE inhibitors- and angiotensin II type 1 (AT1) receptor antagonist-induced anemia in hemodialysis patients, we examined the effect of ACE inhibitors and AT1 receptor antagonist on burst-forming units-erythroid (BFU-E) in the peripheral blood of hemodialysis patients and healthy controls in vitro. METHODS: Peripheral blood mononuclear cells (PBMNCs) were isolated by gradient centrifugation from 10 patients on regular hemodialysis and 7 healthy control volunteers. A colony assay of hematopoietic progenitors was performed using the methylcellulose culture system. PBMNCs of 1 or 2 x 10(5) were plated in a medium containing EPO with various concentrations of ACE inhibitors or AT1 receptor antagonist and incubated for 14 days. Colonies of BFU-E were counted under an inverted microscope. RESULTS: The PBMNCs from the chronic hemodialysis patients formed fewer BFU-Es than those from healthy volunteers. AT1 receptor antagonist in both healthy volunteers and hemodialysis patients suppressed the number of BFU-Es. The ACE inhibitors produced a smaller effect than the AT1 receptor antagonist. CONCLUSION: AT1 receptor blockade can directly inhibit erythropoiesis in vitro.     

彩色多普勒超声在肾移植后红细胞增多症随访中的应用

对１５例肾移植后红细胞增多症病人和对照组病人行彩色Ｄｏｐｐｌｅｒ检查，分别测定其肾动脉管径、肾动脉和弓状动脉的血流速度及阻力指数，发现ＰＴＥ病人并不存在肾动脉狭窄，但直血流速度明显减慢，而阻力指数明显增高，另外，同步检查ＰＴＥ组与对照组的肾功能，并未发现显著性差异。     

Efficacy of Enalapril after ineffective theophylline treatment on erythrocytosis after renal transplantation

Erythrocytosis represents a common complication in renal allograft recipients. Traditional therapies including phlebotomy and bilateral native nephrectomies are cumbersome for both the clinical personnel and the patient. Recently, pharmacological agents such as angiotensin converting enzyme inhibitor and theophylline have been proposed as effective therapies for post-transplant erythrocytosis (PTE). We have treated a PTE patient successfully with enalapril without any side effects and renal dysfunction after theophylline treatment showed no improvement in PTE. A decline in Ht levels was independent of the changes in Epo levels during enalapril treatment. Although the mechanism underlying the beneficial effect of enalapril remains undetermined, enalapril is recommended for the initial treatment of PTE.     

Angiotensin-converting enzyme inhibition induces apoptosis in erythroid precursors and affects insulin-like growth factor-1 in posttransplantation erythrocytosis

A number of studies suggest that erythropoietin (Ep), angiotensin II, and insulin-like growth factor (IGF-1) are involved in the pathogenesis of posttransplantation erythrocytosis (PTE). Angiotensin-converting enzyme inhibitors (ACEI) are the treatment of choice in PTE, but their mechanism of action is unclear. It was shown previously that ACEI added directly to cultures of erythroid precursors from patients with PTE inhibit colony growth. In this report, the effect of ACEI on CD34+ erythroid precursor apoptosis was studied, as were hematocrit (Hct), Ep, IGF-1, and IGF-binding protein 3 (IGF-BP3) levels. Ten patients with PTE, 10 transplant control patients, and 7 normal control subjects were studied. Peripheral blood CD34+ cells were isolated, and apoptosis was assessed by annexin assay and DNA laddering before and during ACEI therapy. At the same time, Hct, Ep, IGF-1, and IGF-BP3 levels were measured. Baseline CD34+ cell number, CD34+ apoptosis, Ep, IGF-1, and IGF-BP3 levels were the same between PTE and transplant control subjects. ACEI therapy was associated with a striking increase in CD34+ cell apoptosis and a decrease in Hct in both groups. In contrast to control subjects, patients with PTE on ACEI showed a significant decrease in IGF-1 levels and a greater percentage decrease in Hct. In normal control subjects, ACEI therapy was associated with a fall in Hct but no change in CD34+ cell apoptosis. In PTE, ACEI-related increase in erythroid progenitor apoptosis may partially explain the ACEI-associated decrease in Hct. However, it is not clear that erythroid precursor apoptosis is related to changes in IGF-1 or IGF-BP3.     

The anemia of end-stage renal disease: hematopoietic progenitor cell response

Patients with the anemia of end-stage renal disease (ESRD) fail to display an appropriate compensatory increase in red cell production. In order to investigate the extent to which the impaired erythropoietic response is determined at the progenitor cell level, we determined the frequencies of marrow colony-forming cells in 11 anemic and 3 non-anemic, dialysis-dependent ESRD patients and 10 healthy individuals. In addition, we measured serum levels of erythropoietin (Epo) by radioimmunoassay. There were no significant differences (P greater than 0.1) between normal and ESRD groups in the frequencies of primitive or late erythroid (BFU-E and CFU-E, respectively), granulocyte-macrophage, and megakaryocyte progenitors, CFU-E/BFU-E ratios, or serum Epo levels. In contrast, 5 non-uremic patients with chronic anemia comparable in severity to the anemic ESRD patients had serum Epo levels and CFU-E/BFU-E ratios that were significantly increased (P less than 0.05 and P less than 0.001, respectively) in comparison to the normal controls and ESRD patients. Pre-dialysis serum and plasma from both ESRD groups were as supportive of autologous erythroid and non-erythroid colony growth in vitro as normal serum and plasma; inhibition was not observed. We conclude that the relative numbers of erythroid and non-erythroid progenitors and the majority of serum Epo levels are unchanged from normal in patients with the anemia of ESRD. However, their normal CFU-E/BFU-E ratio reflects an inadequate compensatory erythropoietic response due to their inability to appropriately increase Epo production in response to anemia. Inhibitors of autologous erythroid colony formation were not detected in ESRD serum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ramipril in post-renal transplant erythrocytosis

BACKGROUND: Posttransplant erythrocytosis (PTE; i.e., hematocrit [Ht] >=51%) may be responsible for cardiovascular events. Angiotensin-converting enzyme inhibitors (ACEIs) are increasingly employed in PTE treatment. Diverse ACEIs have been administered at variable doses and with erratic follow-up. In addition, guidelines recommend the administration of ACEIs as first-line therapy for PTE but do not give information on dosage. In this study the dose-response of a single ACEI was assessed, and patients were followed up for 1 year. The role of ACE gene polymorphism in both prevalence of PTE and successful response to ACEI therapy was also tested. METHODS: At study entry, blood chemistry and ACE-gene polymorphism were measured. ACEI (ramipril) was initiated at 1.25 mg/day; if Ht was still >=51%, ramipril was increased every 6 weeks to ensuing greater dosages. Scheduled dosages were 1.25, 2.5, 5.0, 7.5 and 10 mg/day. Blood chemistry was repeated every 6 weeks. Serum erythropoietin (EPO) concentration was assayed at the start and end of the study. Follow-up was extended for 1 year. RESULTS: PTE developed 12.6 +/- 16.0 months after transplantation in 40 out of 400 patients; 27 patients completed the study. Initial Ht was not correlated with any variable. Final Ht appeared normalized in 26 out of 27 patients. Mean dose (+/- SD) of ramipril was 4.6 +/- 3.6 mg. Mean time for correction of PTE was 135 days, and was not dependent on baseline Ht, hemoglobin or EPO. PTE relapsed in 4 patients. Prevalence of PTE and successful response to ramipril was not dependent on ACE-gene polymorphism. CONCLUSION: Ramipril was effective in PTE; low doses normalized Ht in most patients. No clinical characteristics or biochemical variables predicted the response to ramipril. PTE may relapse; thus long-term follow-up is mandatory.