Wireless capsule endoscopy in the diagnostic of small intestine angiodysplasia in chronic uremic patient.

Gastroenteric bleeding due to angiodysplasia (AD) is a relatively common occurrence in patients with end-stage renal failure. Gastric and colon angiodysplasic lesions can be easily revealed by endoscopic procedures, whereas lesions of the small intestine are more difficult to detect. Imaging modalities used in the diagnostic imaging algorithm for the detection of small-bowel AD, include non-invasive methods like enema-helical computer tomography,(99m)Tc-labelled red blood cell scintigraphy, and angiography, and invasive methods such as intraoperative enteroscopy. We report the cases of 3 hemodialysis patients with recurrent episodes of gastrointestinal bleeding, caused by small-bowel AD diagnosed by means of wireless-capsule endoscopy. In all cases, previous gastroscopy and colonoscopy were unrevealing. Wireless-capsule endoscopy consists in swallowing a capsule endoscope (11 mmx27 mm) which contains a miniature video camera, a light source, batteries, and a radio transmitter. Video images are transmitted by means of radio telemetry to aerials taped to the body that allow images to be captured. Moving images from a period as long as 6 h are stored on a portable recorder. Wireless-capsule endoscopy may prove valuable in the assessment of gastrointestinal bleeding in uremic patients with unrevealing results at gastroscopy and colonoscopy.

[On-line HFR and removal of uremic toxins inducing the loss of phospholipidic asymmetry of the erythrocyte membrane]. / HFR on-line e rimozione di tossine uremiche inducenti la perdita dell'asimmetria fosfolipidica della membrana eritrocitaria.

The phospholipids of the erythrocyte membrane are normally distributed asymmetrically in the double layer with the aminophospholipid phosphatidylserine (PS) present only on the inside of the membrane, since its exposure on the outside has numerous physiopathological consequences. In previous studies we have observed that solutes retained in uremia cause increased exposure of PS on the outer surfaces of the erythrocyte membrane and that this phenomenon may be involved in the uremic physiopathology, reducing erythrocyte survival and encouraging abnormal erythrocyte-endothelium interactions. The capability of the extracorporeal blood clearance treatment in removing the circulating uremic factors, responsible for the increased exposure of PS in red blood cells (RBC), was evaluated in 6 chronic uremic patients treated with haemodialysis (HD) or with on-line HFR in a random cross-over perspective study. The PS removal was evaluated indirectly by measuring the expression of PS in normal RBC incubated with uremic plasma obtained at various moments of the clearance session. The capability of the uremic plasma to expose PS on the RBC of healthy subjects (n-times increase compared to incubation of normal RBC with autologous plasma) was essentially unmodified during HD (3.3 +/- 0.2 pre HD; 3.3 +/- 0.1 after 2 hours; 3.1 +/- 0.2 at the end of the session) but was reduced during HFR (3.1 +/- 0.2 pre HD; 2.3 +/- 0.1 after 2 hours; 1.6 +/- 0.1 at the end of dialysis; p<0.001 at the end of dialysis vs pre and after 2 hours and p<0.001 vs HD at 2 hours and at the end of the session). The reduced capability of the uremic plasma obtained during the HFR session to expose PS in normal RBC, proves removal of the plasmatic uremic factors able to externalize the PS. To assess whether this removal effect is linked to the cartridge containing styrene resin used in the treatment with HFR, samples of ultrafiltrate were taken before and after the cartridge and its capability to express PS on normal RBC was measured. The absolute RBC values expressing PS (%) were (pre-cartridge vs post-cartridge) 8.6 +/- 0.3 vs 3.8 +/- 0.2 after 5 minutes from the start of the session; 3.9 +0.1 vs 1.6 +0.2 halfway through the session; 3.1 +/- 0.1 vs 1.3 +/- 0.66 at the end of the session (p<0.005 pre vs post at all times). Our results show that uremic compounds able to cause increased exposure of PS in RBC can be removed during on-line HFR, mainly thanks to the adsorption properties of the cartridge containing resin. This removal might be of benefit to uremic patients, improving the anaemic condition and reducing abnormal RBC-endothelium interactions which may contribute to endothelial disorder during uremia.

Biocompatibility and functional performance of a polyethylene glycol acid-grafted cellulosic membrane for hemodialysis.

In order to improve the biochemical reactivity of the cellulose polymer, which is mainly attributed to the presence of surface hydroxyl groups, derivatized cellulosic membranes have been engineered replacing or masking some or all of the hydroxyl groups in the manufacturing process of the membrane. The present study was set up to analyze both biocompatibility and functional performance of two different derivatized cellulosic membranes (cellulose diacetate; polyethylene glycol, PEG, acid-grafted cellulose) as compared to a synthetic membrane (polymethylmethacrylate, PMMA). Cellulose diacetate is prepared by substituting hydroxyl groups with acetyl groups; PEG cellulose is obtained by grafting PEG chains onto the cellulosic polymer with a smaller amount of substitution than cellulose diacetate. While the three dialyzers provided similar urea and creatinine removal, the dialyzer containing cellulose diacetate showed a reduced ability to remove 32-microglobulin compared to that containing PEG cellulose or PMMA. A transient reduction in leukocyte count was observed for both derivatized cellulosic membranes. The neutrophil and monocyte counts throughout the entire dialysis session showed a closer parallelism with the cellular expression of the adhesive receptor CD 15s (sialyl-Lewis x molecule) than with CD11b/CD18 expression. Platelet activation, as indicated by the percentage of cells expressing the activation markers CD62P (P-selectin) and CD63 (gp53), occurred with all membranes at 15 min of dialysis and also with PMMA at 30 min. An increased formation of platelet-neutrophil and platelet-monocyte coaggregates was found at 15 and 30 min during dialysis with cellulose diacetate and PMMA but not with PEG cellulose. Generally in concomitance with the increase in platelet-neutrophil coaggregates, an increased hydrogen peroxide production by neutrophils occurred. Our results indicate that derivatizing cellulose may represent a useful approach to improve the biocompatibility of the cellulose polymer, though some homeostatic reactions remain activated. Our results also indicate that there may be a great variability in the biocompatibility profile of derivatize cellulosic membranes which most likely stem from the different type of structural modification rather than from the degree of hydroxyl group replacement.

Leukocyte adhesion molecules and leukocyte-platelet interactions during hemodialysis: effects of different synthetic membranes.

Membranes made from synthetic polymers, in general, are considered as being biocompatible membranes and tend to be treated as a homogeneous group. However, all of these membranes have multiple and different characteristics that may contribute to interactions with blood components. As a consequence, the biocompatibility profile of synthetic membranes may vary. In the present cross-over study, we examined by flow cytometry the effects (expressed as % change from predialysis values) of three different synthetic polymers (polysulfone, PSF; polyacrylonitrile-co-sodium methallyl sulfonate, AN69; ethylenevinylalcohol, EVAL) on the expression of leukocyte adhesion molecules (CD11b/CD18, CD15s) and the interactions between leukocytes and platelets under conditions of routine clinical use. For neutrophils, a statistically significant difference was found in CD15s expression for EVAL as compared to AN69 (p<0.05) and in CD11b/CD18 expression for PSF as compared to both EVAL (p<0.01) and AN69 (p<0.05). No difference between membranes was found on the expression of such adhesive molecules on monocytes. Significant differences in platelet-neutrophil (but not in platelet-monocyte) coaggregate formation were observed between PSF and both EVAL (p<0.001) and AN69 (p<0.01). Reactive oxygen species production by neutrophil population during hemodialysis was significantly different between each pair of synthetic polymers (PSF vs EVAL, p<0.001; PSF vs AN69, p<0.001; AN69 vs EVAL, p<0.05). Our data demonstrate that in terms of leukocyte adhesion receptors and platelet-leukocyte interactions, the biocompatibility profile of the synthetic membranes polysulphone, AN69 and EVAL shows many similarities but also several significant differences. Our results support the concept that biocompatibility evaluation of each membrane should be based exclusively on data generated by that membrane in order to avoid errors based on assumptions about group characteristics.

Endoscopy as a tool for diagnosing and treating gastrointestinal angiodysplasia in haemodialysis patients.

Gastroenteric angiodysplasia is an important cause of haemorrhage in chronic renal failure patients. This paper reports on 2 patients on maintenance haemodialysis with upper gastrointestinal bleeding due to different manifestations of angiodysplasic lesions (sudden appearance of haematemesis and melaena in one case, progressive anaemia with apparent resistance to erythropoietin in the other case). Exploratory endoscope examination of the first digestive tract showed in both cases the presence of bleeding angiodysplasic lesions. Both patients were there and then submitted to surgical endoscopy, during which the bleeding angiodysplasic lesion was sclerosed with physiological salt solution plus adrenaline 1/10000 and 1% polydocanol. In one patient, bleeding occurred again ten days later, making renewed surgical endoscopy necessary. In the course of this an elastic ligature was made to the superangular angiodysplasia. A year later in both cases there were no direct or indirect signs of further bleeding; an endoscopic check-up showed the treated lesions to be sclerosed. Endoscopy offers the unique possibility of being used for both diagnostic and therapeutic purposes in a single session. In expert hands, endoscope therapy is effective and markedly reduces the risk of side effects.

Increased erythrocyte phosphatidylserine exposure in chronic renal failure.

The appearance of phosphatidylserine, an aminophospholipid normally confined to the inner monolayer, at the outer leaflet of red cell membrane may have several pathophysiologic implications. This study examines erythrocyte phosphatidylserine exposure in chronic renal failure (CRF) patients on conservative treatment or on dialysis, to assess possible alterations to phospholipid asymmetry in a condition associated with a state of deranged red cell function. A significant increase in phosphatidylserine-expressing erythrocytes was found in undialyzed patients with CRF (2.32%) and patients on hemodialysis (3.06%) and on peritoneal dialysis (2.14%) compared with control subjects (0.68%). In undialyzed CRF patients, a strong correlation (r = 0.903) was found between the percentage of phosphatidylserine-expressing red cells and the serum creatinine concentration. The increased exposure of phosphatidylserine in uremic erythrocytes may be due to inhibition of phosphatidylserine transport from the outer to the inner leaflet of plasma membrane and may promote an increased erythrophagocytosis. In reconstitution experiments, normal erythrocytes showed an increase in phosphatidylserine-expressing cells when incubated in uremic plasma (3.2% after 2 h versus 1.1% at beginning of incubation), whereas phosphatidylserine-positive uremic erythrocytes decreased when resuspended in normal plasma (2.03% after 2 h and 1.65% after 8 h versus 2.9% at beginning of incubation). Preliminary characterization of the putative uremic compound(s) indicates a molecular weight between 10,000 and 20,000, as well as heat instability. These findings show an impairment of erythrocyte membrane phospholipid asymmetry in CRF patients, regardless of the dialysis treatment. Such abnormality seems related to the uremic state and could contribute to the red cell pathology present in CRF.

Surface antigen expression and platelet neutrophil interactions in haemodialysis.

BACKGROUND: There is increasing evidence to show the clinical implications of membrane biocompatibility in haemodialysis therapy. METHODS: We conducted a cross-over clinical study examining the clinical biocompatibility profile of three derivatised cellulosic membranes obtained by means of different modifications to the cellulose polymer (haemophan, cellulose diacetate, benzyl cellulose) in comparison to the parent polymer (cuprophan) and a reference synthetic membrane (polysulfone). RESULTS: In terms of leukopenia production, derivatised cellulosic membranes were generally intermediate between cuprophan and polysulfone, haemophan being more marked than the other two membranes. Upregulation of CD11b/CD18 molecule on neutrophils was found with all membranes, to a greater extent with the dialyser containing cuprophan. The expression of CD11b/CD18 on monocytes was slightly affected with cuprophan only. The neutrophil and monocyte counts throughout the entire dialysis session showed a much better correlation with the cellular expression of sialyl-Lewis x (CD15s) molecule than with CD11b/CD18 expression. An increased formation of platelet-neutrophil coaggregates occurred at 15 and 30 min during dialysis with all membranes but benzyl cellulose, the increase with cuprophan being higher than with the other membranes. In concomitance with the increase in platelet-neutrophil coaggregation, an increased hydrogen peroxide production by neutrophils occurred, which proved to be significantly higher compared to the unchanged neutrophil hydrogen peroxide production during HD with benzyl cellulose. CONCLUSIONS: Our results demonstrate that derivatised cellulose is associated with a considerable improvement in the clinical biocompatibility profile. Derivatised cellulosic membranes show many similarities but also several significant differences which very likely stem from the different type of structural modification to the cellulose polymer rather than from the degree of hydroxyl group replacement.

Role of dyslipidemia in the progression of chronic renal disease.

The connection between lipids and the rate of progression of chronic renal disease was retrospectively examined in 70 patients who were divided into 2 groups according to their baseline creatinine clearance (CCr): Group 1 (Gp1) contained 30 patients with CCr 60-40 mL/min followed for 40.0 +/- 13.3 months; Group 2 (G2) contained 40 patients with CCr 39-15 mL/min followed for 39.0 +/- 18.2 months. The following parameters were considered: basal and final CCr proteinuria per unit of CCr (UProt/CCr); the difference between final and basal UProt/CCr (delta UProt/CCr); the change in CCr/month (delta CCr); baseline triglycerides (TG), total (TC), HDL (HDLC) and LDL (LDLC) cholesterol, Apo AI, Apo B, Lp(a). Besides in basal CCr the 2 groups significantly differed in the final CCr, final UProt/CCr, delta UProt/CCr, delta CCr. No differences were observed concerning lipid parameters except for Lp(a) (G1 14.8 +/- 13.6, G2 28.7 +/- 27.4 mg/dL; p < 0.05). Baseline TG (G1 184.1 +/- 61.3, G2 187.5 +/- 72.1 mg/dL) and Apo B (only G2 1.05 +/- 0.32 g/L) were significantly higher than normal subjects and the Apo AI/Apo B ratio (G1 1.42 +/- 0.43, G2 1.33 +/- 0.45) were significantly lower than in normal subjects. delta CCr, while inversely correlated in both groups with delta UProt/CCr (p < 0.01), only in G2 did it correlate directly with the Apo AI/Apo B ratio (p < 0.05) and inversely with Apo B and LDLC (p < 0.05). Although a correlation between Lp(a) and delta CCr was not found, 20/22 patients (3/5 G1, 17/17 G2) with a level > 30 mg% ran a progressive course. A natural progression of CRI, heralded by an increasing UProt, is highly frequent when baseline CCr is < 40 mL/min; only then lipids seem to add a burden to the renal damage.

Efficacy and tolerability of recombinant human erythropoietin treatment in pre-dialysis patients: results of a multicenter study.

Chronic renal failure is characterized by a normochromic normocytic anemia, the severity of which generally increases during progression toward uremia. The purpose of the study was to evaluate the efficacy and safety of recombinant human erythropoietin (rHu-EPO) given subcutaneously (s.c.), the dose required to reach and maintain Hb levels within 10 and 11 g% and its effects, if any, on the progression of chronic renal failure. Eighty-four pre-dialysis patients (46 F, 38M, age 61.7+/-13.9 years) with Hb levels between 6 and 9 g% and serum creatinine ranging from 3 to 9 mg/dl were treated with s.c. rHu-EPO (2000 U/twice weekly). After 6 weeks, if Hb increase was below 1 g%, 1000 U of s.c. rHu-EPO were added at each administration (3000 U twice weekly). Once the Hb target was reached (10-11 g%), the rHu-EPO weekly dose was halved and administration reduced to once weekly. The patients showed a significant rise in mean Hb values (p<0.001) after 3 months. Mean Hb values were as follows: 8.00+/-0.77 g% (pretreatment), 9.35+/-1.0 (3rd month), 10.06+/-1.04 (6th month), 10.25+/-0.62 g% (12th month). The mean rHu-EPO doses were 4000 U/w (start of the study), 3592+/-1685 U/w (6th month), 2840-/+1178 U/w (12th month). Renal function was evaluated by plotting the reciprocal of serum creatinine values vs time with a two period comparison: period A (retrospective-8 mo); period B (prospective-12 mo). The residual renal function was not impaired by rHu-EPO therapy. Meanwhile, no relevant modifications were observed in mean blood pressure values. Low doses of s.c. rHu-EPO were well tolerated, safe and effective; this therapeutic approach should therefore be considered for the improvement of anemia in pre-dialysis patients. A slow and gradual correction of anemia induces an improved sense of well being and a more active of life style.

N-3 polyunsaturated fatty acid supplementation in chronic progressive renal disease.

Chronic renal failure (CRF) may be accelerated by secondary lipid and immune abnormalities which could be antagonized by polyunsaturated fatty acid (PUFA). We examined 20 CRF patients on conservative treatment, randomized in two groups: G1 consisted of 10 control patients and G2 10 patients supplemented for 12 months with a 3.4 g daily dose of PUFA. In basal conditions and after 12 months the following parameters were checked: creatinine clearance (CCr), daily urinary protein excretion per unit of residual renal function (UProt/CCr), rate of progression of renal insufficiency (delta CCr); triglycerides (TG), total (TC), HDL (HDALC) and LDL (LDLC) cholesterol, apolipoproteins Apo Al, Apo B, lipoprotein(a) Lp(a); lymphocyte subpopulations; spontaneous (c) and stimulated (s) cytokines IL-1 beta, IL-2, tumor necrosis factors TNF-alpha secretion by peripheral mononuclear cells. The groups did not differ in their basal parameters, which did not change in G1 during follow-up. In G2 the following parameters, initially higher than normal significantly decreased after 12 months: TG (2.9 +/- 0.45 to 2.6 +/- 0.3 mmol/l p < 0.005), Apo B (1.40 +/- 0.37 to 1.22 +/- 0.36 g/l, p < 0.05), c TNF-alpha (1008.1 +/- 534.9 to 726.8 +/- 458.7 pg/ml, p < 0.05). Spontaneous (c) IL-1 beta (216.7 +/- 116.2 to 150.5 +/- 107.8 pg/ml, p < 0.05), c IL-2 (124.5 +/- 43.8 to 101.6 +/- 25.8 pg/ml, p < 0.05), and s TNF-alpha (2456.4 +/- 908.3 to 1632.2 +/- 497.1 pg/ml, p < 0.005) also decreased, although already within the normal range at baseline. G2 patients experienced a steady monthly reduction of CCr whereas it rose progressively in G1 (p < 0.05), with a simultaneous increase in UProt/CCr (p < 0.05). PUFA are beneficial on the lipid and immune abnormalities secondary to CRF and may also have a useful effect on the progression of chronic renal damage.

Effects of subcutaneous recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis.

The use of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of renal anemia, but the dose regimens, the optimal frequency, and the effects on other target organs like the central nervous systems (CNS) are still under discussion. We designed a prospective, ongoing study with 10 stable continuous ambulatory peritoneal dialysis (CAPD) patients (6 males, 4 females; mean age 64.4 +/- 7.8 years), with a pretreatment hemoglobin (Hb) < 7.0 g% and requiring regular blood transfusions. Seven patients were treated with 4000 U rHuEPO once weekly (Eritrogen, Boehringer Mannheim), 2 patients received 4000 U every 5 and 8 days, and the last one 4000 U every 10 days. The target hematocrit was 33% and Hb 10.0 g%. The CNS activity was recorded as visual (VEP), brainstem (BAER), and somatosensory (SEP)-evoked potentials. The mean Hb concentration increased from 6.9 +/- 1.2 g% to 10.3 +/- 1.6 g% (p < 0.001) over 8 weeks. There were no significant changes in urea, creatinine, and potassium levels, and urine output. rHuEPO induced a decrease in latency of P100 VEP, in the four main components of BAER, and in the P27-N35 intertime of SEP. Parallel to the improvement of red cell indices, patients experienced a dramatic improvement in well-being. The subcutaneous administration of a single vial of rHuEPO is safe, convenient, and inexpensive in CAPD. The role of rHuEPO treatment in improving the electrophysiological brain function in uremic and anemic patients remains to be studied and may not necessarily be based on improved cerebral oxygenation.

Effects of uremia and dialysis on brain electrophysiology after recombinant erythropoietin treatment.

Quantitative electrophysiologic assessments are sensitive and useful indices of clinical state, and they are valuable in evaluating brain electrical activity before and after recombinant human erythropoietin (r-HuEPO) treatment. To study the hypothesis that, theoretically, anemia might be a cause of brain dysfunction in uremia, the authors assessed 18 patients (10 men and 8 women) on hemodialysis (RDT, age range, 35-58 years) before treatment (T1), and after 12 weeks (T2) and 24 weeks (T3) of r-HuEPO treatment, utilizing the following electrophysiologic tests: visual evoked potentials (VEP), brainstem auditory evoked responses (BAER), and somatosensory evoked potentials (SEP). The r-HuEPO was injected subcutaneously two times a week after RDT to produce hematocrit (Hct) levels of 30-35%. This drug induced a decrement of latency in P100 VEP (134.2 +/- 7.9 msec in T1 versus 116.5 +/- 6.9 msec in T2, p < 0.001, and versus 107.6 +/- 5.7 msec in T3, p < 0.005) and in the four main components of BAER. The most significant SEP changes were P27-N35 from peroneal nerve (p < 0.01), as an augmentation of SEP amplitude. Correction of anemia with r-HuEPO leads to a significant improvement in brain function in patients on RDT. The increased Hct level leads to enhanced brain oxygen delivery, directly improving brain metabolism. When the Hct rises, cerebral blood flow falls from high levels to normal, decreasing delivery of uremic "toxins" to the brain. The decrease in cerebral blood flow may decrease intracranial pressure and, in this way, may exert its beneficial effects by a rheologic pathway.

Clinical effects of recombinant human erythropoietin in hemodialysis patients. Results of the "Abruzzo" Multicenter Trial.

Anemia in regular dialysis treatment (RDT) patients is primarily due to a deficiency in renal-derived recombinant human erythropoietin (EPO). The aim of this study was to evaluate the results of a multicenter trial in 81 end-stage renal disease (ESRD) patients on RDT. An "open" study was conducted over 2 years; starting dose of r-HuEPO was 50 IU/kg/three times weekly i.v. and eventually was increased in steps of 25 Ul/kg/dialysis until 300 Ul/kg/week. Mean weekly dose per patient was 15 Ul/kg, with mean Hb increase of 27.5%. Mean hematocrit (Hct) levels increased in these patients from 22.9 +/- 2.5 to 31.7 +/- 2.8 (p less than 0.001) after 2 years of therapy. Both spontaneous and evoked potentials improved. The response to r-HuEPO is dose dependent; hypertension and hyperkalemia are the most common side effects, but they are easily controlled. Central nervous system function before and after treatment is improved, and seems consistent with an enhancement of patients' quality of life.