Ezetimibe is effective in the treatment of persistent hyperlipidemia of renal allograft recipients.

INTRODUCTION: Ezetimibe is a hypolipidemic agent acting via inhibition of cholesterol absorption from the small intestine. The effectiveness and safety of long-term administration of ezetimibe was evaluated in renal allograft recipients with persistent hyperlipidemia. PATIENTS AND METHODS: 67 renal allograft recipients with post-transplantation hyperlipidemia resistant to statins were included in the study; 11 were treated with ezetimibe (10 mg/day) alone and 56 with ezetimibe and statin. The effectiveness of ezetimibe was assessed by determination of total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and triglycerides (TR). Its safety was determined by liver enzymes (ALT, AST), LDH, CPK, serum creatinine and blood levels of immunosuppressive drugs (cyclosporine, tacrolimus, everolimus, sirolimus) over the follow-up period of 18±6 months. RESULTS: A significant reduction of TC and LDL-C blood levels by 25% and 34% respectively, was observed during the first month of treatment with ezetimibe (p<0.001). This reduction was maintained for the whole period of ezetimibe administration. Renal function remained stable over the follow-up period, while no changes of the blood levels of immunosuppressive drugs were observed. Liver enzymes, LDH and CPK remained normal in all patients except for one diabetic patient who developed rhabdomyolysis. Apart from gastrointestinal symptoms in 2 patients, no other side effects were observed. CONCLUSION: Combination of ezetimibe with statins represents an effective and safe regimen for treatment of persistent hyperlipidemia in renal allograft recipients.

Microchimerism in peripheral blood and urine in renal transplant recipients: preliminary results.

The role of microchimerism in peripheral blood and urine of renal transplant recipients remains a matter of debate, depending on the sensitivity of the methods used for detection. We studied 17 female renal transplant recipients who had received renal allografts from male donors. Polymerase chain reaction (PCR) was applied to blood and urine for the microsatellite markers D1S80, DYZ1, TH01, and kalphai SE33. Detection of DYZ1 that is present only on the Y chromosome was considered proof for microchimerism. No microchimerism was detected in peripheral blood, whereas it could be detected in the urine of 8/17 (48%) patients. There were no differences between patients with and without microchimerism regarding patient age, dialysis vintage, immunosuppression, time post-transplantation, and allograft function as measured using serum creatinine, creatinine clearance, and proteinuria. Two patients in each group showed chronic allograft dysfunction. These findings raise questions regarding the role of microchimerism in renal transplantation.

Impedance cardiography derived cardiac output in hemodialysis patients: a study of reproducibility and comparison with echocardiography.

BACKGROUND: Hemodialysis patients experience a variety of hemodynamic abnormalities that contribute to cardiovascular disease mortality which is the leading cause of death in these patients. Impedance cardiography has been utilized in order to monitor cardiac hemodynamics with lower cost and inconvenience, but it has not been appropriately validated in the hemodialysis population. AIM: We repeatedly used impedance cardiography to assess short- (48 hours) and long-term (15 days) reproducibility of cardiac output measurements and we compared baseline impedance cardiography measurements with echocardiographic measurements. PATIENTS AND METHODS: We studied 109 stable hemodialysis patients, aged 59.70 +/- 11.97 years being on hemodialysis for 67.59 +/- 40.15 months, on a non-dialysis day. Cardiac output was obtained with the BioZ impedance cardiography system (Cardiodynamics, San Diego, Ca, USA). Baseline echocardiography was performed using a Hewlett-Packard Sonos 2500 (Andover, Mass., USA). RESULTS: The values of impedance cardiography derived cardiac output were 5.28 +/- 0.79, 5.27 +/- 0.75 and 5.25 +/- 0.74 l/min at baseline (107 patients), 48 hours (107 patients) and 15 days (98 patients) respectively, showing high reproducibility. Bland and Altman analysis estimated that bias at 48 hours and at 15 days were: -0.013 (95% confidence intervals = -0.045 to 0.019) and 0.028, (95% confidence intervals = -0.044 to 0.101), respectively. In addition baseline impedance cardiography derived cardiac output was significantly correlated with the echocardiographic derived cardiac output (r = 0.9, p < 0.0001). CONCLUSION: Impedance cardiography is a simple non invasive technique for cardiac output estimation in hemodialysis patients which has high reproducibility when performed under controlled conditions, and is closely correlated with echocardiographic measurements of cardiac output.

Echinocytic transformation and aggregation of red cells in uremic patients.

Isolated rabbit lungs were perfused with washed and resuspended human red blood cells (RBCs) in the presence of drugs known to change the shape and deformability of RBCs. With sodium salicylate (0.5-2 g/l), which causes echinocytosis and increases RBC deformability, lung diffusing capacity for O2 (DLO2) increased by 21%. When chlorpromazine, which induces stomatocytosis and stiffens RBCs, was given (50 mg/l), DLO2 decreased by 18% under chlorpromazine. Comparative experiments with hemoglobin solutions did not reveal any effect of those two drugs either on DLO2 or on pulmonary arterial pressure, which indicates that the effects of sodium salicylate and chlorpromazine were due to changes in RBC shape and deformability. It is concluded that RBC shape and deformability affect pulmonary artery pressure and oxygen diffusing capacity, which may have an influence on oxygen transfer to tissue and hence be of clinical relevance.

Ammonia concentration in the renal veins in unilateral renal artery stenosis with hypertension.

We measured blood ammonia in pre-angioplasty samples from the renal veins, aorta and inferior vena cava of 15 patients with hypertension due to unilateral renal artery stenosis confirmed by arteriography. Patients with renal insufficiency or small kidneys were excluded. Mean ammonia values were microgram/dl: vein of affected kidney, 106.00 +/- 12.75; vein of unaffected kidney, 75.65 +/- 23.10; aorta 61.04 +/- 15.00; vena cava, 62.44 +/- 19.65. The value for the affected kidney was significantly higher than the other three values (p < 0.001). Mean +/- SD DTPA uptake (%) was 42.8 +/- 2.21 in the affected kidney and 56.53 +/- 3.64 in the unaffected kidney. This difference did not correlate significantly with that of the ammonia concentrations tau = -0.292).

Management of claudication and hypertension by stent implantation in a renal transplant recipient.

Graft artery stenosis is one of the main causes of hypertension in renal transplant recipients. We present a rare case of severe common iliac artery stenosis, proximal to the graft artery, that was the cause of accelerated hypertension and claudication in a male renal transplant recipient. After percutaneous balloon angioplasty combined with a Palmaz stent implantation, a dramatic improvement of hypertension and claudication was observed during a 10-month follow-up period.

Pre-HD dilution acidosis, without post-HD contraction alkalosis in uremic patients.

The aim of this study was to verify if the degree of pre-HD acidosis and its correction post-HD is related to body fluid expansion during the interdialytic period. Twelve uremic patients without major problems, with stable hematocrit, with regular and similar HD-session characteristics, but widely varying amounts of body fluid expansion in the interdialytic period were included. Blood samples were collected from arterial line pre- and post-HD, anaerobically in heparinized syringes, for determination of HCO3-, pH and PaCO2 (radiometer Copenhagen ABL 300 Acid-Base Laboratory), in two similar HD-sessions for each patient (12 patients, 24 HD-sessions). The percentage (%) of body weight gain in the interdialytic period was also estimated. For each patient, the mean value of parameters studied in the two HD-sessions was used for the evaluation of findings. According to mean values (+/-SD) of HCO3-, pH and PaCO2 Pre-HD (18.26+/-1.99 mmol/L, 7.31+/-0.03, 36.27+/-2.5 mmHg respectively) and post-HD (26.37+/-1.7, 7.43+/-0.03, 38.43+/-2.10 respectively) patients are acidotic pre-HD and slightly alkalemic post-HD. Correlation between the percentage (%) of interdialytic body weight gain (IBWG) and the values of HCO3-, pH and PaCO2, Pre-HD (r=-0.814, p<0.001; r=-0.931, p<0.001; r=0, 100 NS; respectively) and post-HD (r=-0.958, p<0.001; r=-0.937, p<0.001; r=-0.504 NS; respectively) indicates a significant and negative relationship of IBWG% with HCO3- and pH pre- and post-HD, but not with PCO2. In conclusion, the negative relationship of IBWG% with HCO3- and pH pre- and post-HD indicates that the body fluid expansion during the interdialytic period contributes to a dilutional acidosis pre-HD, but not to a contraction alkalosis post-HD, by the elimination of fluid during the HD-session.

A cross-over study of a new low molecular weight heparin (Logiparin) in hemodialysis.

The safety and effectiveness of a low molecular weight heparin (LMWH) of 4500 +/- 1500 Daltons were evaluated in eight hemodialysis (HD) patients, in comparison with unfractionated heparin (UFH). In phase A of the study 3000 +/- 500 anti-factor Xa (AFXa) IU of LMWH were administered in bolus for the three consecutive HD sessions of a week. In phase B, 10000 +/- 2500 IU of UFH were administered to the same patients for the same time. Were observed no significant differences in hematocrit (Ht), platelets (Pt), fibronogen (FG) and prothrombin time (PT). Whole blood activated coagulation time (WBACT) was more prolonged with LMWH, 24 and 48 hours (start of next session) after administration (p < 0.05), and less prolonged at 5, 60, 120, 180, 240 min compared to UFH (p < 0.001). The activated partial thromboplastin time (APTT) and AFXa activity were more prolonged with UFH at 60 and 240 min (p < 0.001). The clinical effectiveness of the two preparations was similar as judged by thrombus formation and compression time. In conclusion, the present study found no real differences between LMWH and UFH, except for prolongation of WBACT 24 and 48 hours after the administration of LWMH. This probably indicates a cumulative effect of the LMWH and needs further investigation.

Telemedicine technology and applications for home hemodialysis.

Home hemodialysis (HD) for the treatment of patients with end-stage renal disease (ESRD) was first put into practice about 30 years ago. In this paper we describe the application of telematics monitoring services (TMS) for supporting patients who need home or satellite HD (SHD). For the clinical trials two modified HD machines were located in the renal unit and a central control station (UNIX workstation with multimedia PC-terminal) was located in another room of the hospital. Bi-directional communication between modified HD machines and central control station was managed via ISDN (Integrated Services Digital Network) links. Using these HD-machines 150 HD sessions were performed in nine patients over a period of five months. This system enabled on-line remote supervision of the HD machine-related functions (air in the blood, leak of blood, low conductivity etc.) and the clinical condition of patients through measurement of blood pressure (BP), pulse rate, PO2 (pulse oxymetry) and electrocardiogram (ECG) from the central control station (CCS). The user checked the type of alarm/warning, its appearance on HD machines and multimedia terminal units (MTU), the action of the protective system and the appearance of consultative messages from CCS on the remote terminal unit RTU. According to the data collected, the disturbances of HD machine function were visible and audible in the CCS and the user messages were always observed on the RTU. No unusual dialysis-associated complications were observed, all data and alarms/warnings were transmitted correctly and patients had adequate HD treatment.

Is hypertension a manifestation of the nutcracker phenomenon/syndrome? Case report and brief review of the literature.

Hypertension has been rarely reported in patients with the nutcracker phenomenon/syndrome. We describe a young male adult where a computed tomography angiography provided evidence of left renal vein dilatation, probably due to its compression through the angle between the aorta and the superior mesenteric artery, during the evaluation for secondary hypertension. As there were no other signs for secondary hypertension, we proceeded with a venography of the inferior vena cava and the renal veins that revealed mild anatomical findings compatible with the so called nutcracker phenomenon/syndrome. Blood levels of renin and aldosterone and renocaval pressure gradient from these sites were between normal limits. As there were coexisting anatomical and clinical findings (hypertension), nutcracker syndrome might have been claimed. However, no causal links could be established and these findings should be considered only as a coincidence.

Phosphorus metabolism in chronic kidney disease.

The knowledge about the exact mechanisms involved in phosphorus homeostasis and the evolution of secondary hyperparathyroidism in chronic kidney disease (CKD) has improved during the last years. The discovery of Fibroblast Growth Factor 23 (FGF23) has revolutionized our understanding about the links between mineral metabolism, vitamin D and parathyroid hormone (PTH). FGF23 serum levels increase early in CKD before the increase of serum phosphorus or the decrease of vitamin D and there is parathyroid resistance to FGF23 in advanced CKD. Increased levels of serum phosphorus have been related in epidemiological studies with adverse outcomes in patients with CKD, diabetes, coronary artery disease, or even normal adults. In patients with CKD stage 3 or 4, low phosphorus diets have been related with adverse outcomes due to the risk of malnutrition and there are limited data regarding the role of phosphate binders in these patients. Recent studies suggest that increased serum FGF23 levels are associated with mortality, left ventricular hypertrophy and progression of CKD independently of serum phosphorus levels. There is an ongoing debate about the "normal" or "desirable" levels of serum phosphorus in CKD and a new role of FGF23 as a marker of the disturbances of mineral metabolism in CKD is emerging.

Antiplatelet effects of prasugrel vs. double clopidogrel in patients on hemodialysis and with high on-treatment platelet reactivity.

BACKGROUND: High on-treatment platelet reactivity (HTPR) is frequent in patients on hemodialysis (HD) receiving clopidrogel. OBJECTIVES: The primary aim of this study was to determine the antiplatelet effects of prasugrel vs. high-dose clopidogrel in patients on HD with HTPR. PATIENTS/METHODS: We performed a prospective, single-center, single-blind, investigator-initiated, randomized, crossover study to compare platelet inhibition by prasugrel 10 mg day(-1) with that by high-dose 150 mg day(-1) clopidogrel in 21 patients on chronic HD with HTPR. Platelet function was assessed with the VerifyNow assay, and genotyping was performed for CYP2C19*2 carriage. RESULTS: The primary endpoint of platelet reactivity (PR, measured in P2Y12 reaction units [PRU]) was lower in patients receiving prasugrel (least squares [LS] estimate 156.6, 95% confidence interval [CI] 132.2-181.1) than in those receiving high-dose clopidogrel (LS 279.9, 95% CI 255.4-304.3), P < 0.001). The LS mean differences between the two treatments were - 113.4 PRU (95% CI - 152.9 to - 73.8, P < 0.001) and - 163.8 PRU (95% CI - 218.1 to - 109.2, P < 0.001) in non-carriers and carriers of at least one CYP2C19*2 allele, respectively. HTPR rates were lower for prasugrel than clopidogrel, in all patients (19% vs. 85.7%, P < 0.001) and in non-carriers (25.7% vs. 80%, P = 0.003). All carriers continued to show HTPR while receiving high-dose clopidogrel, but none showed it while receiving prasugrel. CONCLUSIONS: In HD patients exhibiting HTPR following standard clopidogrel treatment, prasugrel 10 mg day(-1) is significantly more efficient than doubling the clopidogrel dosage in achieving adequate platelet inhibition. Neither effect seems to be influenced by carriage of the loss-of-function CYP2C19*2 allele.

Relationship between interdialytic weight gain and acid-base status in hemodialysis by bicarbonate.

The aim of this study was to determine the relationship between interdialytic weight gain and acid-base balance pre- and posthemodialysis in uremic patients undergoing hemodialysis with a high bicarbonate dialysate (39 mmol/L). To this end we studied 8 stable uremic patients on regular hemodialysis thrice weekly who had stable hematocrit values for at least 3 months, similar clinical characteristics including dry weight but widely varying interdialytic weight gain. Arterial line blood samples were collected anaerobically in heparinized syringes pre- and posthemodialysis in 4 consecutive hemodialysis sessions for the determination of pH, Paco2, and HCO3. Prehemodialysis values (mean +/- SD) were pH = 7.34 +/- 0.03, Paco2 = 36.43 +/- 1.4, and Hco3 = 20.1 +/- 1.55. Posthemodialysis values were pH= 7.47 +/- 0.02, Paco2 = 38.72 +/- 2.0, and HCO3 = 27.73 +/- 1.72. In other words, patients were moderately acidemic prior to and moderately alkalemic after the hemodialysis session. Of note, a significant negative correlation was revealed between the interdialytic weight gain and the values of prehemodialysis blood pH (r = -0.721, p < 0.001) and HCO3 (r = -0.836, p < 0.001) and posthemodialysis pH (r = -0.533, p < 0.001), Paco2 (r = -0.623, p < 0.001) and HCO3 (r = -0.815, p < 0.001), suggesting an important role of the interdialytic weight gain on acid-base equilibrium of uremic patients undergoing hemodialysis. Thus, patients with high interdialytic weight gains may require higher bicarbonate concentrations to achieve normal acid-base status whereas patients with low interdialyic weight gains may require lower bicarbonate concentrations to prevent alkalemia at the end of dialysis.

Arteriovenous difference of blood ammonia in uremic patients under hemodialysis.

In this study the ammonia concentration was determined in arterial and venous blood samples pre- and posthemodialysis (HD) in 18 uremic patients and in 18 health subjects (controls). The mean values (+/- SD) of ammonia in the arterial blood of uremic patients pre-HD were 98.32 +/- 26.55; post-HD, 63.18 +/- 17.09; and in control group patients, 72.37 +/- 10.09 micrograms/dl. In venous blood they were pre-HD, 71.70 +/- 20.68; post-HD, 58.05 +/- 16.73; and in control patients, 74.46 +/- 12.0 micrograms/dl. According to our findings, the ammonia concentration in the arterial blood of uremic patients pre-HD exceeds the normal limits and is significantly higher (p < 0.001) than that post-HD and that of control patients. The ammonia contents of venous blood pre- and post-HD ranges were within normal values, but the post-HD range was significantly lower than the pre-HD range (p < 0.05) and the control range (p < 0.01). Comparison between ammonia levels from arterial and venous blood showed significant and positive arteriovenous differences pre-HD (p < 0.001), which disappeared post-HD and were not observed in the control patients. In conclusion, uremic patients under HD present pre-HD high levels of ammonia in arterial blood with a significantly positive arteriovenous difference. In contrast, the post-HD ammonia levels in arterial and venous blood are decreased, and the arteriovenous difference is not significant.

Relation between echinocytosis and erythrocyte calcium content in hemodialyzed uremic patients.

A rise in intracellular calcium concentration in erythrocytes has multiple effects on these cells. The purpose of this study was to determine the changes of calcium content in red blood cells (RBCs) and of echinocyte percentages in uremic patients during hemodialysis sessions. In 30 uremic patients under hemodialysis, the calcium content of RBCs and echinocyte percentages were determined in 3 blood samples collected at 0 min hemodialysis (prehemodialysis), 45 min hemodialysis, and 240 min hemodialysis (end hemodialysis) for a 4 h hemodialysis session. Calcium content of RBCs and echinocytes were also determined in 22 normal subjects (controls). The findings of the present study were that the mean values (+/-SD) of calcium content of RBCs in patients at 0 min hemodialysis, 45 min hemodialysis, and 240 min hemodialysis were 2.00 +/- 1.0, 2.66 +/- 0.87, and 1.62 +/- 0.66 microg/ml respectively and 0.65 +/- 0.07 microg/ml in controls. These values show that the calcium content of RBCs in uremic patients at 0 min hemodialysis, 45 min hemodialysis, and 240 hemodialysis was significantly higher than in controls (p < 0.0001), and that RBC calcium content at 45 min hemodialysis was significantly higher in comparison to that at 0 min hemodialysis (p < 0.001) and to that at 240 min hemodialysis (p < 0.0001), while that at 240 min hemodialysis was significantly lower than at 0 min hemodialysis (p < 0.05). The mean values (+/-SD) of echinocyte percentages in patients at 0 min hemodialysis, 45 min hemodialysis, and 240 hemodialysis were 11.93 +/- 6.18, 17.23 +/- 4.1, and 7.96 +/- 5.67% respectively, and in controls ranged from 0 to 1%. The values in uremic patients show a transient increase of echinocyte percentages at 45 min hemodialysis, which is significant in comparison to that at 0 min hemodialysis (p < 0.001) and to that at 240 min hemodialysis (p < 0.0001). Echinocyte percentages at 240 min hemodialysis were significantly lower to those at 0 min hemodialysis (p < 0.001). Correlation between calcium content of erythrocytes and echinocyte percentages shows a significantly positive relationship at 45 min hemodialysis (r = 0.368, p < 0.05) but no significant relationship at 0 min hemodialysis and 240 min hemodialysis. In conclusion, uremic patients under hemodialysis present with high calcium content in erythrocytes and abnormal erythrocytes like echinocytes. A rapid and transient increase of erythrocyte calcium is also accompanied by transient elevation of echinocytes in the first hour of hemodialysis (45 min hemodialysis), which returns after hemodialysis to lower than prehemodialysis levels.

Alterations in echinocyte transformation and erythrocyte sedimentation rate during hemodialysis.

In 18 uremic patients under regular hemodialysis (HD) with bicarbonate dialysate, the echinocytes and erythrocyte sedimentation rates (ESR) were determined in 4 blood samples collected from the arterial line at 0, 45, 120, and 240 min (end-HD) in one HD session by a bioincompatible dialyzer and in another by a biocompatible one. In the HD session by a bioincompatible dialyzer, the mean values (+/- SEM) of echinocytes (%) at 0, 45, 120, and 240 min were 8.89 +/- 1.15, 20.77 +/- 2.35, 7.39 +/- 1.1, 5.27 +/- 0.66 and of ESR (mm/h) were 65.00 +/- 6.26, 47.05 +/- 3.89, 66.72 +/- 6.00, 68.44 +/- 5.92, respectively. According to these findings, echinocytes show a transient significant increase at 45 min HD in comparison to those at 0 (p < 0.001), 120 (p < 0.001), and 240 (p < 0.001) min while ESR shows a transient significant decrease at 45 min HD compared with the rates at 0 (p < 0.05), 120 (p < 0.05) and 240 (p < 0.01) min. In the HD sessions with the biocompatible dialyzer, the mean values (+/- SEM) of echinocytes at the aforementioned 4 time points were 8.55 +/- 1.10, 17.05 +/- 2.40, 17.05 +/- 1.19, and 5.11 +/- 0.75%, and the ESR values were 60.89 +/- 6.08, 44.33 +/- 4.18, 62.94 +/- 6.55, and 65.61 +/- 6.13 mm/h, respectively. These values also show a transient significant increase of echinocytes at 45 min HD in comparison with those at 0 (p < 0.01), 120 (p < 0.01), and 240 (p < 0.001) min, with a parallel transient decrease of ESR at 45 min HD as compared to the ones at 0 (p < 0.05), 120 (p < 0.05), and 240 (p < 0.05) min. Although the echinocytosis at 45 min HD was more prominent in HD by the bioincompatible than by the biocompatible dialyzer, the comparison between these values indicates no significant difference in the echinocytes or the ESR. In conclusion, uremic patients receiving HD exhibit echinocytes, the percentage of which shows a transient increase at 45 min HD that returns to about baseline at 120 min HD. In parallel with the changes in echinocytes, the ESR shows an inverse change at 45 min HD which returns to baseline at 120 min HD.