Acute and chronic effects of therapeutic apheresis.

In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used.

Therapeutic apheresis in peripheral and retinal circulatory disorders.

In microcirculation disorders, the therapeutic apheresis seems to have two different effects. The first, achieved after only a few sessions, is acute, consisting of drastic reduction of blood viscosity and obtained with the use of low-density lipoprotein (LDL) apheresis, rheopheresis, or fibrinogen apheresis. The second effect is long term, or chronic, and needs to be evaluated after a long course of treatment. The mechanisms underlying the chronic effect are still objects of debate and take into account the pleiotropic effects of apheresis. However, it is likely that the acute effect of apheresis mainly influences the functional components of the vascular damage, and so the derived rheological benefit might last only for a short period. The chronic effect, on the contrary, by acting on the morphological alterations of the vascular walls, requires the apheresis treatment to be prolonged for a longer period or even cycles of treatment to be programmed.

[Effects of cascade filtration in combination with interferon and ribavirin in the treatment non responder chronic hepatitis C patients]. / La filtrazione a cascata nei pazienti HCV positivi.

In 40% of patients with chronic hepatitis C, standard therapy is unable to eradicate the virus. Since the response to pharmacological treatment depends on the initial viral load, there is a rationale for reducing this load by means of apheretic depletion of the C virus. The aim of this work was to administer cascade filtration (CF) to non responder patients affected by hepatitis C (pts) before resuming the pharmacological treatment. 10 pts underwent 12 sessions of CF, 3 per week (treated plasma volume/session: 3000 mL). After the first week, therapy with PEG-IFN (1.5 ug/Kg/week) plus Ribavirin (1200 mg/day) was added. The viral load was determined before and after each CF session, and at the 1st, 3rd and 6th month. The mean pre-apheresis viral load dropped from 2176275+/-3109997 U/mL at the first session to 1486726+/-2091975 U/mL by the fourth (p<0.001), and 347500+/-637428 U/mL before the last (p<0.001). The mean percentage reduction of the viral load went from a minimum of 29.5% to a maximum of 42%. Early viral response (EVR) was obtained in 70% of these patients as compared with only 10% in an age- and sex-matched control group consisting of 10 patients. Unfortunately, we did not get the same good results in terms of sustained viral response (SVR: 10% in apheretic patients vs 0% in the control group). Efficacious removal of HCV was obtained with CF. However, the successful reduction in the viral load achieved with apheresis in terms of EVR was not confirmed when we considered the SVR.

[CPFA (coupled plasma filtration absorption) treatment of septic shock. A retrospective study of nine patients]. / Trattamento con CPFA (coupled plasma filtration absorption) dello shock settico. Uno studio retrospettivo di 9 casi.

Coupled plasma filtration absorption (CPFA) can increase blood pressure in septic shock and reduce fever during and after treatment. It is not able to stop the activation of intravascular coagulation and does not reduce the need for dialysis or the overall mortality.

Endothelial progenitor cells in sudden sensorineural hearing loss.

CONCLUSIONS: Endothelial progenitor cells (EPCs) are a unique subtype of circulating cells with properties similar to those of embryonal angioblasts. They have the potential to proliferate and to differentiate into mature endothelial cells. EPCs are reduced in patients with vascular risk factors due to a decreased mobilization, an increased consumption at the site of damage or a reduced half-life. The results of this study confirm the existence of an endothelial dysfunction in patients with sudden sensorineural hearing loss (SSHL) and support the vascular involvement in the pathogenesis of the disease. OBJECTIVE: The aim of this study was to evaluate the concentration of EPCs in patients affected by SSHL. METHODS: Twenty-one patients affected by SSHL were evaluated. The number of EPCs was analyzed by flow cytometry analysis of peripheral blood CD34+KDR+CD133+ cells. RESULTS: Circulating levels of EPCs were significantly lower in SSHL patients compared with controls. In particular, CD34+KDR+ cells and CD34+CD133+KDR+ cells were significantly reduced (p < 0.05).

[Does rheopheresis reduce the cardiovascular risk?]. / La reoferesi riduce il rischio cardio-vascolare?

Rheopheresis comprises various types of apheresis procedures, namely double filtration plasmapheresis, LDL apheresis, and fibrinogen apheresis. These techniques are used to remove high molecular weight proteins from the circulation and have been shown to exert a protective effect on the vessel walls. The vascular protection can be attributed to pleiotropic mechanisms, especially from LDL apheresis, that safeguard against endothelial dysfunction by reducing the concentrations of proinflammatory and procoagulation factors. In addition, rheopheresis improves whole-blood viscosity, principally by reducing fibrinogen and lipoproteins, stimulates endothelium-mediated vasodilation, and has a positive effect on the hemorheological picture, improving perfusion in the microcirculation. All of this helps to correct the functional vessel alterations caused by aggression factors, and is translated into an extremely fast clinical response, only a few hours after the end of apheresis. Demonstrated efficacy has been obtained especially in the microcirculation, as has been observed in ischemic optic neuropathy, sudden hearing loss, and peripheral arterial disease. Although the short-term effects on the functional component of the vascular damage seem to be temporary, long-term effects on the morphological alterations have been shown. It is still not clear which of the many suggested actions, or others still to be confirmed (for instance a short-term increase in endothelial progenitor cells) constitutes the main vessel protective mechanism.

Effect of low-density lipoprotein apheresis on circulating endothelial progenitor cells in familial hypercholesterolemia.

BACKGROUND: Long-term treatment with low-density lipoprotein (LDL) apheresis (LA) has been shown to reduce the incidence of cardiovascular events in patients affected by familial hypercholesterolemia (FH). Data from experimental studies suggest that circulating endothelial progenitor cells (EPCs) can repair the vascular lesions caused by atherosclerosis. Since a reduction of these cells has been demonstrated to predict atherosclerosis progression, the aim of this study was to verify whether LA can increase the percentage of EPCs. METHODS: In 15 patients affected by FH periodically treated with LA, the percentage of EPCs was determined before and after performing LA, and compared with the values of 15 control subjects and 15 hypercholesterolemic patients treated with statins. RESULTS: Significant differences were found in FH patients between the pre-apheresis percentages of CD34+/KDR+, defined as EPCs by a wide consensus of opinion, and the values found 24 h after the procedures (0.00868 +/- 0.003 vs. 0.01009 +/- 0.002%, p < 0.005). Instead, the percentages of CD34+/KDR+/CD133+, considered as an immature subset of EPCs, remained substantially unchanged. However, a significant reduction in the percentage of EPCs was observed in both patient groups as compared to the controls, at all the assessment times. CONCLUSION: In the short-term LA seems to stimulate mobilization of CD34+/KDR+ cells. Hypercholesterolemic patients show a lower percentage of EPCs than controls. There were no differences in the EPCs percentages between the 2 patients groups, despite the fact that LDL cholesterol levels were higher in the group undergoing LA.

Cutaneous microcirculation is impaired in early autosomal dominant polycystic kidney disease.

BACKGROUND/AIMS: An endothelial dysfunction has been described in autosomal dominant polycystic kidney disease (ADPKD) before the development of hypertension and renal impairment. The aim of this work was to verify the existence of a microvascular reactivity in the early stages of ADPKD. METHODS: Fifteen ADPKD normotensive patients with normal renal function underwent laser Doppler examination of the cutaneous microcirculation in basal conditions and after the warm test, as well as evaluation of plasma concentrations of some endothelial activation parameters [total cholesterol and fractions, fibrinogen, von Willebrand factor, Lp(a)]. The results were compared with those in 15 healthy subjects, 15 essential hypertensive patients and 15 hypertensive ADPKD patients with normal renal function. RESULTS: Both basal and post-warm-test values were significantly lower in normotensive ADPKD subjects than controls (3.2 +/- 1 vs. 5.8 +/- 1.3 AU, p = 0.0001; 35.2 +/- 10.9 vs. 50.5 +/- 10.8 AU, p = 0.005, respectively). All evaluated parameters were within normal limits and comparable between normotensive ADPKD subjects and controls, except for LDL cholesterol (125 +/- 18 vs. 101 +/- 22 mg/dl, p = 0.01) and Lp(a), which was significantly higher in the ADPKD subjects (52.2 +/- 36 vs. 6.0 +/-4 mg/dl, p = 0.0006). CONCLUSION: Our study confirms the existence of a systemic microcirculation defect in ADPKD. The presence of high levels of Lp(a) could contribute to causing the high incidence of cardiovascular events in ADPKD.

Pleiotropic effects of LDL apheresis.

LDL apheresis (LA), a technique employed to remove atherogenic lipoproteins, has been shown to exert a protective function on the vessel walls. This effect can be attributed to pleiotropic mechanisms that safeguard against endothelial dysfunction by reducing the concentrations of pro-inflammatory and pro-coagulation markers. Besides these actions, LA improves whole blood viscosity and endothelium-mediated vasodilation, and has a positive effect on the hemorheological picture, improving perfusion in the microcirculation. Although the short term effects on the functional component of the vascular damage seem to be temporary, long term effects on the morphological alterations have also been shown. It is still not clear which of the many proposed actions, or others still to be discovered, is the principal vessel protective mechanism.

A case report of double filtration plasmapheresis in an acute episode of multiple sclerosis.

Plasma exchange has been proposed as support therapy in both acute and chronic forms of multiple sclerosis (MS). For the first time, we aimed to assess whether double filtration plasmapheresis (DFPP) could be clinically efficacious. We describe the case of a patient affected by MS who developed a severe crisis refractory to conventional steroids, and immunosuppressive and immunomodulating therapy. The patient underwent 12 sessions of DFPP. In each session 3000 mL of plasma was treated. Before and immediately after each session the routine laboratory parameters were assessed. Before the apheresis cycle and one month after the end of treatment, encephalic magnetic resonance imaging (MRI) was performed. A neurological examination and assessment of the extended disability status scale (EDSS) were made once each week from the beginning of treatment until one month after the end of the cycle. No therapy was administered during the course of the apheresis cycle, with the exception of a scaled dose of steroids, that was completely withdrawn half-way through the cycle. The immunoglobulin (Ig) G, IgA and IgM values declined from 465 +/- 104 mg/dL, 69 +/- 18 mg/dL, 34 +/- 16 mg/dL, respectively, pre-apheresis to 331 +/- 76 mg/dL, 42 +/- 5 mg/dL, 15 +/- 6 mg/dL, respectively, post-apheresis; C3 and C4 decreased from 105 +/- 27 mg/dL and 21 +/- 5 mg/dL to 75 +/- 9 mg/dL and 15 +/- 4 mg/dL, respectively; fibrinogen went from 228 +/- 72 mg/dL to 128 +/- 28 mg/dL. The EDSS dropped from a value of 6 before the cycle to 5.5 one month after the end of the treatment. As compared with the pretreatment conditions, post-apheresis MRI showed stabilization of the lesions already present, the reduction of one lesion and a complete absence of enhancement of all lesions. DFPP, adopted for the first time in MS, seems to foster a short-term improvement in both the clinical and magnetic resonance images during an acute MS episode.

Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in sudden hearing loss.

HYPOTHESIS: The aim of the present study was to evaluate the concentration of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in patients affected by sudden sensorineural hearing loss (SSHL). STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Patients affected by SSHL were evaluated. Inclusion criteria for this study were hearing loss of more than 30 dB hearing level affecting at least 3 contiguous frequencies, normal hearing on the contralateral ear, negative history of hearing loss or ear surgery in the affected ear, and magnetic resonance with gadolinium negative for VIII cranial nerve pathologic findings. INTERVENTION: Circulating levels of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule (VCAM) 1 were evaluated by means of enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The levels of adhesion molecules in SSHL patients were compared with those of a control group. RESULTS: Intercellular adhesion molecule 1 and VCAM-1 levels in sera of patients with SSHL were significantly higher than those of the matched control subjects (p < 0.001). Statistical analysis did not show significant differences between the 2 groups in terms of the known vascular risk factors such as total and fractionated cholesterol, triglycerides, fibrinogen, erythrocyte sedimentation rate smoking, and diabetes. CONCLUSION: The results of this study show that in SSHL patients, there is an increased expression of circulating adhesion molecules confirming the existence of an endothelial dysfunction and supporting the vascular involvement in the pathogenesis of the disease. The identification of high levels of adhesion molecules and of the endothelial dysfunction open the way to selective pharmacologic treatments able to correct the activation of endothelial cells.

Can a decreasing ultrafiltration profile affect the dialytic dose administered?

During hemodialysis, ultrafiltration (UF) seems to affect the dialytic dose because of convective removal of urea and contraction of its distribution volume. We aimed to assess whether the adoption of a decreasing UF profile could yield a different dialytic dose from that obtained with a constant UF mode. Ten patients were randomly assigned to undergo 12 sessions with a constant UF mode (phase A) followed by 12 sessions with a decreasing UF rate (phase B), or the reverse. Kt/V and urea reduction ratio (URR) were 1.77 +/- 0.26 and 70.02 +/- 8.26% in phase A vs. 1.81 +/- 0.36 and 71.02 +/- 6.48% in phase B, respectively, showing no significant difference. Measurement of the differences in volemic variations between the two phases showed a statistically significant difference at the second hour (P < 0.001, the volemic reduction being greater in phase B than A) and at the fourth hour (P < 0.001, being greater in phase A than B). In standard bicarbonate dialysis, the adoption of a decreasing UF profile rather than a constant one does not alter the efficiency of the dialytic treatment.

Does a reduction of adhesion molecules by LDL-apheresis have a role in the treatment of sudden hearing loss?

Sudden hearing loss (SHL) is a highly disabling affliction that can severely affect the subject's social and relational life. Although the etiology of the complaint is still debated, it is thought that microcirculation disturbances conditioned by an endothelial dysfunction might be the main pathogenetic mechanism. Adhesion molecules favoring interaction between leukocytes and endothelial cells are early markers of endothelial damage. In the present report, we describe a case of SHL that derived evident benefit from a single session of LDL/fibrinogen apheresis, with complete hearing recovery. In this patient, in addition to reducing LDL cholesterol and fibrinogen, the circulating adhesion molecules (sE-selectin, sVCAM-1 and sICAM-1), previously present in higher than normal concentrations, were reduced by the treatment.

LDL-apheresis accelerates the recovery of nonarteritic acute anterior ischemic optic neuropathy.

Nonarteritic acute anterior ischemic optic neuropathy (NAION) is a disabling disease which impairs visual function. It is presumed to result from disturbances of microcirculation in the anterior portion of the optic nerve head due to hemodynamic factors derived from excessive blood viscosity, or restriction of the vasal lumen in hypertensive, hypercholesterolemic, diabetic patients. We aimed to determine whether acute reduction of plasma fibrinogen and serum low-density lipoprotein (LDL) cholesterol is effective for treatment of NAION. We recruited 11 patients (7 females, 4 males) with a mean age of 57.2 +/- 19.6 years. All except one of them presented risk factors for atherosclerosis. The mean values of LDL-cholesterol and fibrinogen before treatment were 144 +/- 32 mg/dL and 341 +/- 80 mg/dL, respectively. All were treated with standard therapy (prednisone, salicylate, pentoxiphyllin) and underwent three sessions of LDL-apheresis (HELP system-B Braun) that can reduce plasma LDL-cholesterol and fibrinogen by more than 50% in a very short time. In all patients we observed a drastic reduction of LDL cholesterol and fibrinogen and a clear improvement in the visual functional data. In fact, mean values of corrected vision increased from 3.7/10 +/- 3/10 to 7.9/10 +/- 2.2/10 (P = 0.002) after the third session, while the scotomatous portion of the visual field regressed after the first session, and in 5 patients further regressed after the third session. This improvement had remained stable after 3 months. Thanks to it's effect of antagonizing hemorheologic disorders of the ocular microcirculation, fibrinogen/LDL-apheresis seems to be an efficacious treatment of NAION.

Asymptomatic microhematuria: an indication of hereditary hemorrhagic telangiectasia?

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Clinical manifestations include spontaneous and recurrent epistaxis, mucocutaneous telangiectases that bleed easily and arteriovenous malformations in many organs. Despite the anecdotal recommendations of some groups, to our knowledge information regarding the prevalence of microscopic hematuria (MH) in patients with HHT has not been reported to date. We evaluated the prevalence of MH in patients with HHT. MATERIALS AND METHODS: Between January 2002 and June 2003, 116 consecutive patients with HHT were studied, of whom 20 were excluded because of a possible false-positive MH bias. Therefore, 53 males and 43 females with a mean age +/- SD of 45.8 +/- 15.8 years who had HHT underwent urine dipstick testing for heme and microscopic urinary examination. A control group of 192 males and 148 females with a mean age of 46.5 +/- 14.2 years and no statistical age or sex differences without HHT who were hospitalized in the same period at the same medical unit for gastrointestinal disorders was compared to the HHT cohort. RESULTS: MH was detected in 45 of 96 patients with HHT (47%) compared to 41 of 340 controls (12%) (p <0.0005). None of the patients with HHT showed abnormal renal function, proteinuria, hypercalciuria or hyperuricosuria. MH was due to glomerular hematuria in 29 of 45 patients (65%), postglomerular hematuria in 13 (29%) and mixed hematuria in 3 (6%). No gross hematuria was detected. CONCLUSIONS: Our results show that MH is common in patients with HHT. This might indicate the possibility of weak urinary tract bleeding due to telangiectases and/or small arteriovenous fistulas, which are typical HHT lesions. Therefore, HHT should be considered among the causes of MH. Urinalysis should always be performed when there is severe anemia in HHT patients with HHT, particularly those without other apparent bleeding sites.

Renal vascular resistance and renin-angiotensin system in the pathogenesis of early hypertension in autosomal dominant polycystic kidney disease.

Activation of the renin-angiotensin system (RAS) has been proposed to increase renal vascular resistance (RVR) and to play a role in the development of hypertension in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to investigate the relationship among RVR, RAS and blood pressure (BP) profile in patients without renal impairment. Thirty-four ADPKD patients underwent ambulatory blood pressure monitoring (ABPM) over a 24-h period and were divided into two groups: 17 hypertensive (group A, day-systolic BP > or = 135 mmHg and/or day-diastolic BP > or = 85 mmHg) and 17 normotensive (group B, day-BP < 135/85 mmHg) patients. The two groups were comparable with respect to age, sex, and renal function. None of the patients assumed therapy. In all subjects the plasma renin activity (PRA) was measured, and the RVR was assessed by measuring resistivity indices (RI). RI was significantly higher in the hypertensive than in normotensive patients (0.67 +/- 0.05 vs. 0.62 +/- 0.03), while PRA was normal in all subjects, and showed no statistical difference between the two groups. Taking all the patients together (group A + group B), a significant positive correlation between RI and 24-h mean arterial pressure (MAP) was discovered, but no correlation was found between RI and PRA or between MAP and PRA. We conclude that in ADPKD patients without renal impairment the MAP values are strictly correlated with the RVR, but not with PRA. Thus factors other than RAS probably contribute to the increase of the RVR and to the early development of hypertension.