Effect of enalapril on exaggerated erythropoietin response to phlebotomy in erythrocytosic renal transplant patients

Background: Exaggerated erythropoietin (EPO) response to phlebotomy regardless of the baseline EPO levels have been shown in patients with post-transplant erythrocytosis (PTE) and administration of angiotensin-converting enzyme inhibitors (ACE-I) seems to be effective in controlling PTE. However, the mechanism of this ACE-I induced reduction in haematocrit (Hct) is not well known. Although some authors have suggested that ACE-I may reduce EPO secretion, this is still controversial. The aim of the present study was to assess the effect of a single dose ACE-I on exaggerated EPO response to phlebotomy. Methods: In this study, we compared serum EPO and renin (PRA) levels of 100 PTE patients, 10 non-PTE patients and 10 healthy blood donors before and after phlebotomy. The effects of a single dose of ACE-1 (enalapril, 5 mg p.o.) in PTE patients were also evaluated in the second phlebotomy. Results: While the mean basal serum EPO level was significantly higher in the PTE group than the other two groups (<0.01), the mean basal PRA levels did not differ significantly between these groups. Serum EPO and PRA levels increased significantly after the phlebotomy (P<0.001) and exaggerated EPO response to phlebotomy was suppressed by single dose enalapril (P<0.001) in the PTE patients. Conclusion: The present study has shown that the renin-angiotensin system plays an important role in EP formation and the Hct lowering effect of the ACE-I is through reduction of EPO in PTE patients.     

Increased monocyte Fc-dependent chemiluminescence in renal transplant patients

A luminol-enhanced chemiluminescence (CL) assay was used to study the microbicidal potential of phagocytic cells and the opsonic properties of serum in renal transplant recipients. Thirty-four patients receiving maintenance immunosuppression with prednisone and either cyclosporine or azathioprine and 35 normal controls were studied. Polymorphonuclear leukocytes (PMN) and monocytes were stimulated at the Fc receptor with heat-aggregated IgG (HAIgG) or immunoglobulin-treated zymosan (ITZ), and at the C3b receptor with serum-treated zymosan. Serum opsonic activity was determined by incubating zymosan with normal or patient serum and stimulating the CL response of normal phagocytes. We found that the Fc and C3b-dependent CL of PMN, the C3b-dependent CL of monocytes, and the opsonic properties of serum were identical in transplant recipients and normal controls. In contrast, the Fc-dependent CL of monocytes in renal transplant patients was 3 times greater than normal when stimulated with either soluble (HAIgG) or particulate (ITZ) ligands. These data suggest that some components of the host immune system are not affected by maintenance immunosuppressive medication in renal transplant recipients. The mechanisms and significance of the increased Fc-receptor-dependent CL observed in monocytes of renal transplant patients remain to be determined.     

Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme

The response to erythropoietin (Epo) is dose dependent but,for various poorly understood reasons, variable. In a cross-sectionalstudy we determined the Epo requirement of 60 patients in adialysis population to identify those patients requiring a highdose of Epo, and ascertained the reasons for higher requirements,paying particular attention to the effect of previous transplantation.All 289 patients attending a single centre were surveyed. Ofthese, 164 were receiving renal replacement therapy by continuousambulatory peritoneal dialysis (CAPD) and 125 were on haemodia-lysis(HD). Patients on HD needed more Epo than those on CAPD (129.0±14.9U/kg/week versus 86.9±10.7 U/kg/week, P<0.05). However,this difference was accounted for by a subgroup of patientswho had a previously failed transplant. The Epo requirementin those patients on HD with a failed transplant was significantlygreater than those on HD who had never been transplanted (164.0±24.5 U/kg/week versus 96.6 ± 11.9 U/kg/week, P<0.05).The seven patients who retain their transplanted kidney hadthe highest Epo requirement of all (213.4±46.6 U/kg/week).These studies have shown that previous transplantation is asignificant determinant of Epo requirement upon return to dialysis.They also show that it is necessary to ‘correct’for the effect of previous transplantation when investigatinggenerally accepted determinants of Epo need. Interpretationof previously published studies needs to take account of this.     

Determining factors of the response to hyperhomocysteinemia treatment in renal transplant patients

Hyperhomocysteinemia (hyperHcy) is a risk factor for cardiovascular disease. The benefits of lowering homocysteinemia (Hcy) in renal transplant recipients through vitamin treatment are not clearly understood. The objective of this study was to establish the demographic, renal, Hcy metabolism, and microinflammation factors that determined the response to folic acid and vitamin B complex treatment in stable patients with renal transplants and hyperHcy. We studied 65 renal transplant patients with baseline hyperHcy. The mean baseline Hcy level of these patients was 22.5 micromol/L. Following treatment it fell to 14.5 micromol/L, an overall reduction of 35.5%. Forty-one patients (63%) were classified as responders; the remainder (37%), nonresponders. A bivariance analysis suggested the only significant differences between responding and nonresponding patients were the pre-treatment Hcy level and the renal function level.     

Increased vascular sensitivity to noradrenaline in hypertensive renal transplant recipients

We have studied several factors that may cause hypertension in renal transplant recipients. Cardiac output measurements suggest that hypertension is maintained by an increase in total peripheral resistance. Plasma noradrenaline concentration was significantly higher in both normotensive and hypertensive patients than in matched normal subjects. Plasma noradrenaline rose significantly in response to head-up tilt in normotensive, but not in hypertensive, patients. Resting plasma renin activity was significantly higher in both groups of patients than in normal subjects, but there was no relationship between plasma renin activity and blood pressure. Plasma renin activity did not change in response to head-up tilt or isoprenaline infusion in the patients. The rise in arterial pressure during noradrenaline infusion was significantly greater in hypertensive than in normotensive patients. Regression analysis showed a significant relationship between the combination of total exchangeable sodium and the rise in mean arterial pressure during noradrenaline infusion with resting mean arterial pressure.     

Endogenous erythropoietin levels and anemia in long-term renal transplant recipients

BACKGROUND/AIM: Although anemia is a common complication after renal transplantation (RT), data concerning endogenous erythropoietin (EPO) levels in long-term RT recipients are rare. The goal of this study was to evaluate the prevalence of anemia within 6 months to 5 years after RT and to assess the relationship between the serum concentrations of endogenous EPO, graft function and grade of improvement of anemia. METHODS: 140 patients who had undergone RT were included in the group: 89 males (63.6%) and 51 females (36.4%), with an average age 46.8 +/- 12.8 years. The serum concentrations of EPO and creatinine (Cr) were tested in all the individuals and the values of the red blood component of blood count, serum ferritin (SF), plasma iron concentration, plasma total iron-binding capacity (TIBC), transferrin saturation (TS), folic acid and vitamin B(12) levels in the serum were determined. A statistical analysis of the results was performed using the correlation analysis, Mann-Whitney U test and Duncan's multiple range test. RESULTS: Normal blood count values were found in 91 patients (65%), and a mild grade of anemia with a mean hemoglobin (Hb) 114.4 +/- 11.9 g/l was observed in 45 patients (32.1%), and 4 patients (2.9%) fulfilled the diagnostic criteria for post-transplantation erythrocytosis. Individuals with normal Hb values had a mean EPO serum concentration of 39.3 +/- 12.3 mU/ml (median 37.2) and the mean Cr was 133.8 +/- 36.9 micromol/l (median 122). Patients with anemia (Hb <120 g/l in females, Hb <130 g/l in males) had a mean EPO value of 47.0 +/- 26.6 mU/ml (median 36.0) and a mean Cr of 203.8 +/- 108.9 micromol/l (median 181). The difference in the Cr values was statistically significant (p < 0.0001), while the difference between the EPO concentrations was not significant. No relation of EPO serum concentration with regard to graft function was found in the analysis. A lack of storage iron (SF <10 microg/l in females, SF <22 microg/l in males) was found in 16 patients (11.4%), and a lack of functional iron (TS <20%) was found in 27 patients (19.3%). CONCLUSIONS: Theprevalence of anemia in patients after transplantation was 32.1%. The most common cause of anemia is insufficient graft function development. The achieved values of the red component of blood count have no relation to the endogenous EPO serum concentrations.     

Increased incidence of benign breast disease in female renal transplant patients receiving cyclosporin

Background : Unlike other cancers, breast cancer does not occur at increased frequency in renal transplant patients but fibroadenomata may be more common as a result of exposure to cyclosporin. In order to determine the incidence of benign breast disease in renal transplant patients at Monash Medical Centre, current female patients were studied. Methods : The study was divided into two parts: (i) a retrospective review of those who presented with clinically detectable breast lumps; and (ii) mammographic screening of current female transplant patients who had been transplanted for more than 1 year. Results : In the retrospective study there were 11 patients with 16 breast lumps among a total of 85 patients. All were confirmed by biopsy. The mean age at diagnosis of breast lumps was 41.5 years (range 25–70 years). The mean time to presentation was 3.5 years after transplantation. Nine out of 11 patients had benign breast disease including fibroadenoma (six patients), fibrocystic disease (two patients) and intraductal papillomatosis (one patient). Two patients had breast cancer. Five of the patients with fibroadenoma had multiple lumps and a recurrent course. All patients with fibroadenomata had received cyclosporin. In the second part, 54 patients were further screened. The mean duration of transplantation was 6.4 years (range 1.25–18.5 years). Eighty‐seven per cent of the patients had received cyclosporin, and 80% had a negative (normal) study. Seven of 54 had abnormalities including cysts and calcification, of whom two patients had fibroadenomata. Four patients had ‘dense mammograms’, all of whom received cyclosporin as a part of their immunosuppression. No breast cancer was detected during the study. Conclusion : The incidence of benign breast disease in the female transplant patients studied was far greater then the general population. The increase in fibroadenomata, in particular, may relate to the use of cyclosporin.     

Endotoxin-free dialysate improves response to erythropoietin in hemodialysis patients

BACKGROUND/AIMS: Inflammatory process induced by endotoxin is one of the causes of resistance to recombinant human erythropoietin (rHuEPO) in hemodialysis patients. Thus dialysate contaminated with endotoxin may diminish response to rHuEPO. We investigated whether dose of rHuEPO could be reduced with endotoxin-free ultrafiltered dialysate. METHODS: Twenty-seven chronic hemodialysis patients receiving rHuEPO were studied. The patients did not have known causes of anemia other than chronic renal failure. An endotoxin-cut polyethylene ultrafilter was installed into the dialysate fluid circuit. Hematocrit and dose of rHuEPO were monitored before and after installation. Dose of rHuEPO was adjusted to keep hematocrit at about 30%. Endotoxin concentration of dialysate was measured by commercial limulus test (Endospecy. RESULTS: After installation of ultrafilter, dialysate endotoxin concentration decreased from >100 to <1.0 endotoxin units/liter (EU/l). Dose of rHuEPO decreased from 90.0 U/kg/week (median) to 57.3 U/kg/week (p < 0.05) and hematocrit increased from 30.3% (median) to 32.2% (p = 0.03) after 5 months of installation of ultrafilter. The running cost of the ultrafilter corresponded to only 4% of the cost of spared rHuEPO. CONCLUSIONS: Ultrafiltered endotoxin-free dialysate caused significant reduction in dose of rHuEPO to keep target hematocrit level. Endotoxin-cut ultrafilter was beneficial to hemodialysis patients in medical and in economical aspects.     

Increased incidence of renal transplant arterial stenosis in children

We have found an increase from 10% to 16.4% in the incidence of clinically significant transplant arterial stenosis since the introduction of cyclosporin immunosuppression. During the same period there has been a coincidental increase in the use of donor kidneys harvested from children less than 6 years of age. In patients treated with cyclosporin these stenoses of the donor artery are not related to the surgical anastomosis, and have only rarely been associated with clinical or histological evidence of rejection, whereas those patients who have developed transplant arterial stenosis whilst receiving azathioprine have had a higher incidence of rejection. Regardless of immunosuppressive regimes, the use of small donor kidneys appears to be the most significant association with transplant arterial stenosis in our experience, and this finding has major implications for cadaveric renal transplantation in children.     

Pregnancy in renal transplant patients

Renal transplantation is compatible with pregnancy in women under permanent dialysis, and leads to no problems for the mother or the transplant. The seven pregnancies observed in the authors' center over the past fifteen years progressed satisfactorily. There were no rejections, no cases of renal failure. In two cases, however, there was an aggravation of hypertension with acute gravidic toxemia and spontaneous abortion. The effects on the fetus of immunosuppressive drugs are difficult to evaluate; the main risk is prematurity.     

Candidate biomarkers for erythropoietin response in end-stage renal disease

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is important clinically and economically. Escalation of dose may produce harm. Post hoc analyses of clinical trials showed that responsiveness could be predicted by hemoglobin response to a fixed dose escalation. This maneuver requires weeks to months. The study by Merchant et al. offers promise that peptidomic analyses of patient sera and mass spectrometry can identify biomarkers of both responsiveness and resistance to ESAs.     

Conversion to sirolimus in renal transplant patients with tumors

BACKGROUND: Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) is an option for renal transplant patients who develop a tumor. This strategy, however, may be associated with an increased risk of rejection. AIM: We sought to evaluate a series of renal transplant patients who underwent conversion from CNI to SRL because they developed a tumor during the posttransplant period. METHODS: This prospective study of 29 patients included 2 patients with skin cancer (1 melanoma and 1 squamous cell carcinoma) and 27 patients who developed other tumors: lung (n = 6), prostate (n = 4), lymphoma (n = 2), colon adenocarcinoma (n = 2), kidney (n = 2), Kaposi sarcoma (n = 2), urothelium (n = 1), parotid (n = 1), larynx (n = 1), gastric (n = 1), breast (n = 1), tongue (n = 1), liver (n = 1), xanthoastrocytoma (n = 1), and aggressive angiomyxoma of the perineum (n = 1). RESULTS: CNI were withdrawn in 28 patients and reduced in the remaining patient. Renal function was better when CNI were rapidly or abruptly suspended, with maintenance of cyclosporine (CsA) + SRL for more than 3 months being especially detrimental. Proteinuria worsened in patients whose preconversion levels were >0.5 g/d, particularly those treated with CsA. There was no episode of rejection. CONCLUSIONS: SRL is a promising option for the management of posttransplant tumors. The switch in immunosuppression should be undertaken quickly, especially in patients under treatment with CsA.     

Low-dose subcutaneous erythropoietin corrects the anaemia of renal transplant failure.

Although erythropoietin (Epo) is known to correct anaemia in dialysis and pre-dialysis patients, there is limited experience with its use in immunosuppressed patients suffering from chronic renal graft dysfunction. We report the results of a pilot study of Epo in seven patients with failing grafts and normocytic normochromic anaemia attributable to renal failure. All entering patients had controlled blood pressure and serum ferritin greater than 100 micrograms/l. Three patients were taking triple immunotherapy (prednisone/azathioprine/cyclosporin), two patients prednisone/azathioprine, and two patients CsA monotherapy. Study duration mean was 15 +/- 2 (SEM) weeks, and Epo was started at 4000 units subcutaneously (s.c.) once weekly, adjusted to achieve a target haemoglobin (Hb) of 100 g/l. Mean Hb at initiation was 68 +/- 5 g/l and significantly increased to 96 +/- 6 at end of follow-up, P less than 10(-4). All patients responded. Maintenance Epo dosage was 120 +/- 32 U/kg bodyweight/week, roughly 4000 units/week. There was no significant change in serum creatinine: pre-study 392 +/- 45 mumol/l; post-study 430 +/- 62 mumol/l. There were no complications but blood pressure did rise significantly: pre- 124 +/- 11/74 +/- 4 mmHg to post- 142 +/- 10/86 +/- 3, P less than 0.05 for systolic and diastolic. Low-dose s.c. Epo effectively corrects anaemia in graft failure despite azathioprine and/or CsA therapy, without obvious acceleration of graft failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased intestinal permeability during cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) infections in renal transplant recipients can affect the gastrointestinal tract, but significant clinical manifestations are seldom seen. We hypothesize that subclinical involvement of the gastrointestinal tract may be quite frequent during CMV infection. In order to study this, we measured intestinal permeability by calculating the urinary lactulose mannitol (LM) excretion ratio after oral administration of lactulose and mannitol (normal<0.030) in patients with symptomatic and asymptomatic CMV infection. A total of 111 patients were enrolled in the study, 104 of whom were tested on postoperative day (POD) 10. Twenty-nine patients developed CMV infection, 12 of whom could be studied with the permeability test (median POD 40). Another nine patients without CMV infection were also studied at day 40 and served as controls. The LM ratio increased significantly during CMV infection compared to measurements before active infection (median 0.060 vs. 0.030, P<0.01) and was significantly higher during the infection than in the control group (median 0.007, P<0.01). No correlation could be found between the LM ratio and viral load, humoral response to the virus, or symptomatology of infection. We conclude that an increased intestinal permeability is found in a substantial number of patients with an active, albeit asymptomatic, CMV infection after renal transplantation. Pathophysiological mechanisms and clinical implications remain speculative but will be subject to further study.