Cardiac risk assessment: when and who? [Retrospectroscope].

Think about the above lines taken from the Old Testament: At 130 years of age, Adam begat a son and at 800 he kept going, quitting this earthly life at 930. These numbers surpass by far the limits our current experience teaches us, however, perhaps a life span into the hundreds of years is ? What if, in the future, science were to do away with disease? What then would cause people to die: accidents, killings, wars? How old would old age be? Aging has always been a hot topic for research (with considerable quackery, too). For example, animals with a slow metabolism tend to live longer than those with a fast metabolism. Compare the average life span of a mouse with that of a turtle. Apparently, meditators are able to slow their metabolism down [1].

[Use of oral hypoglycemic agents in patients with chronic kidney failure]. / Farmaci ipoglicemizzanti orali nei pazienti con insufficienza renale cronica.

Type 2 diabetes mellitus is one of the most common disease worldwide. Diabetes mellitus is expected to affect over 380 million people by 2025 and one third of these patients will develop chronic kidney disease (CKD). There are many categories of hypoglycemic agents available for treatment of type 2 diabetes mellitus: sulphounilureas, glinides, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, and the new brand incretines. In nephropatic patients with CKD stage I-II, any hypoglycemic agent can be used: the choice must be linked to a careful evaluation of potential risk and benefit. In CKD stage III to V, conversely, some drugs are not recommended while other agents can be used with dose reduction due to risk of hypoglycemia. In these patients the early use of insulin may be indicated. The target of this review is to evaluate evidences about the possible use of hypoglycemic agents in patients affected by diabetes and CKD stage III-V.

[Reduced nitric oxide bioavailability in chronic renal failure: a new factor of progression?]. / Ridotta biodisponibilità di ossido nitrico nell'insufficienza renale cronica: un nuovo fattore di progressione?

Nitric oxide (NO) is a gaseous free radical and an important molecular mediator of many physiologic processes in virtually every organ. NO is produced from L-arginine by nitric oxide synthase (NOS). This enzyme is expressed as 3 isoforms, all of which have been isolated from the kidney: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). At present it is very difficult to measure authentic nitric oxide in vivo; a way to circumvent the difficulties is to study the effects of NOS stimulation and subsequent nitric oxide release directly by measurement of the resulting changes in vascular tone. In the kidney and vasculature, NO plays fundamental roles in the control of systemic and intrarenal hemodynamics, the tubuloglomerular feedback response, pressure natriuresis, release of sympathetic neurotransmitters and renin, and tubular solute and water transport. Chronic renal failure (CRF) is a state of NO deficiency secondary to decreased NO production and/or increased bioinactivation of NO by reactive oxygen species. The purpose of this review is to examine the functions of NO in the kidney, and to discuss the effects of NO deficiency in the progression of chronic kidney disease.

[Haemoglobin targets for chronic kidney disease: guideline from the Italian Society of Nephrology]. / Target ottimale di emoglobina per l'insufficienza renale cronica: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of optimal haemoglobin (Hb) target levels in chronic kidney disease (CKD), either for pre-dialysis, dialysis or renal transplanted patients, is presented. METHODS: SR of RCT and RCT on different Hb target levels in patients with CKD were identified, referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Four SR (19 RCT) were found addressing the point. Methodological quality of available trials was suboptimal. In CKD patients (non-dialysis patients) Hb targets of 11.3 g/dL should be preferred to Hb >13.5 g/dL (evidence from RCT). A Hb target of 11.0-11.5 g/dL should be preferred in CKD patients receiving dialysis treatment without significant cardiac disease, since no survival benefits has been showed with Hb >14 g/dL (evidence from RCT). The optimal Hb target in haemodialysis patients with severe cardiac disease should be 10.0-10.5 g/dL (evidence from SR). Increases in Hb target lev-els are associated with improved quality of life, although this was mainly noticed in observational studies and in few RCT often relying on unvalidated quality of life assessment scales. CONCLUSION: In CKD patients current available evidence supports the hypothesis that optimal Hb targets should be low to subnormal.

Platelet-leukocyte interactions in hemodialysis patients: culprit or bystander?

The formation of circulating platelet-leukocyte complexes has been observed in a variety of conditions and may be pathophysiologically significant. Platelet-leukocyte interactions in fact facilitate metabolic cooperation and mutual activation, which may be of relevance in many biological processes including inflammation, atherogenesis and hemostasis. During hemodialysis procedure, the series of reactions that can occur upon blood contact with the foreign membrane surface may involve a variety of changes affecting almost every cellular and plasmatic component of the blood. This article reviews the evidence for abnormal interactions between circulating platelets and leukocytes in uremic patients undergoing maintenance hemodialysis and the pathophysiologic implications which may stem from such interactions.

[Census 2004 of the Italian renal and dialysis units--Abruzzo-Lazio-Marche-Molise-Umbria]. / Censimento 2004 dei Centri di Nefrologia e Dialisi Italiani. Abruzzo-Lazio-Marche-Molise-Umbria.

The Italian Society of Nephrology (SIN) promoted a national survey in order to collect detailed information from all Italian renal and dialysis units. This is the second paper, following the first one which focused on three northwestern regions, aim-ing to present the results of the survey. In this paper, data from the central regions (Abruzzo, Lazio, Marche, Molise and Umbria) are reported. The most relevant findings in the five regions were: A) epidemiology--prevalence of dialysis patients = 742, 781, 731, 814, 768 per million population (pmp); prevalence of transplanted patients = 162, 153, 296, 134, 304 pmp; incidence of dialysis patients = 175, 179, 184, 143, 162; gross mortality of dialysis patients = 12.3, 11.8, 15.9, 13.4, 14.0%; distribution of vascular access in prevalent dialysis patients: arteriovenous fistula = 90, 87, 82, 94, 80%, central venous catheter = 7, 10, 15, 4, 17%; vascular graft = 3, 3 ,3, 2, 3%. B) Structural resources--number of hospital beds = 52, 43, 39, 62, 44; dialysis places = 205, 260, 203, 301, 226. C) Personal resources--renal physicians = 50, 78, 47, 53, 47 pmp; renal nurses = 162, 172, 180, 224, 245 pmp; each renal physician takes care of 15, 10, 16, 15, 17 dialysis patients and each renal nurse cares of 4.6, 4.6, 4.1, 3.6, 3.1 dialysis patients. D) Activity--admission to hospital= 2334, 1689, 2652, 1255, 1377 pmp; renal biopsies = 59, 84, 97, 19, 80 pmp. Despite the differences we find among the regions, most indexes are similar and show a satisfactory level of renal care provided in the central regions examined.

Management of hypertension in chronic kidney disease: the Italian multicentric study.

BACKGROUND: Guidelines have indicated the achievement of blood pressure target (BP <130/80 mmHg) as a priority in the conservative treatment of chronic kidney disease (CKD), but the current implementation of these recommendations in clinical practice is unknown. METHODS: We assessed control rates, treatment and clinical correlates of hypertension in 1201 adult non-dialyzed CKD patients followed up by a nephrologist for at least 6 months. RESULTS: Estimated glomerular filtration rate (GFR) was 32 (SD 15) mL/min/1.73 m2. BP target was not achieved in 88% of patients (95% confidence interval (95% CI): 86-90%). In 84% of patients, BP levels were also above the target at the first visit to the nephrology unit 4.5 yrs previously. The risk of not achieving BP target during the nephro-logy follow-up was associated with older age (odds ratio (OR): 1.24, 95% CI 1.06-1.45, p=0.008), diabetes (OR: 2.25, 95% CI 1.20-4.20, p=0.011), and the duration of hypertension (OR: 1.13, 95% CI 1.02-1.24, p=0.016). Among patients with uncontrolled BP, about 70% received multidrug antihypertensive therapy including renin-angiotensin system (RAS) inhibitors; conversely, diuretic treatment was prescribed in a minority of patients (37%), and at insufficient doses in half the cases, despite the insufficient implementation of a low salt diet (18%). CONCLUSIONS: BP target was not reached in most CKD patients routinely seen in the renal clinics. The main barrier to guideline implementation is possibly the inadequate treatment of extracellular volume expansion despite the large prevalence of factors, such as older age and diabetes, which further enhance the intrinsic BP salt sensitivity of CKD.

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.

[Angiodysplasia of the small bowel: a possible cause of anemia even in mild chronic renal failure]. / Angiodisplasia dell'intestino tenue: una possibile causa di anemizzazione nell'IRC anche di grado lieve.

BACKGROUND: Gastroenteric angiodysplasia (AD) is a vascular lesion characterized by vascular ectasias to the submucous sheath of the gastrointestinal tract. Lesions can be flat or raised, isolated or grouped and can break or ulcerate causing acute hemorrhage or, more commonly, chronic bleeding. CASE-REPORT: We describe a 65-year-old patient with a 3-yr history of chronic renal failure (CRF), who gradually developed anemia (hemoglobin (Hb) 10 g/dl) without any episodes of clinically relevant bleeding or any exposure to bleeding risk factors. Blood pressure (BP) was normal and renal function was stable (serum creatinine (Cr) 1.9 mg/dl). Routine laboratory tests showed a slight reduction in serum iron and transferrin saturation and a slightly elevated absolute reticulocyte count. These findings were associated with a positive occult gastrointestinal blood test and raised the clinical suspicion of chronic gastrointestinal blood loss. Oesophagogastro-duodenoscopy and colonoscopy demonstrated an absence of significant lesions, suggesting the need to investigate for a lesion localized in the small intestine. Capsular endoscopy, a recently developed endoscopic technique, particularly suited for small bowel pathology, was performed, and demonstrated the presence of an angiodysplasic lesion, located in the jejunum. CONCLUSIONS: Our case report supports the necessity for a complete clinical and laboratory evaluation of the possible causes of anemia superimposed on relative erythropoietin deficiency in CRF patients. When gastrointestinal blood loss is suspected, the entire gastroenteric tract should be examined to search for the bleeding sites. Our report also demonstrates that AD could be responsible for gastrointestinal bleeding even in mild CRF and not only, as usually reported, in end-stage renal disease (ESRD). Capsular endoscopy offers the unique possibility to determine the bleeding site in the small intestine and appears as an effective diagnostic procedure in CRF patients.

Prevention of peritoneal sclerosis: a new proposal to substitute glucose with carnitine dialysis solution (biocompatibility testing in vitro and in rabbits).

AIM: Commercial glucose peritoneal dialysis solutions expose the peritoneum to hyperosmolar glucose containing variable amounts of non-enzymic breakdown products of glucose. These solutions are toxic for the peritoneum. The aim of the present study is to compare in vitro and in vivo characteristics of a new dialysis solution containing carnitine, a naturally occurring compound, as substitute of glucose. MATERIAL AND METHODS: We compared in vitro and in the rabbit a new peritoneal dialysis solution containing carnitine, with two standard bicarbonate glucose peritoneal dialysis solutions and a solution containing icodextrin. RESULTS: In vitro and in vivo the solution containing carnitine seems to be more biocompatible than standard glucose solutions and those containing icodextrin. CONCLUSIONS: In our study the peritoneal dialysis solution containing carnitine seems to prevent the mesothelial changes observed with solutions containing glucose. Since carnitine has been extensively studied and seems to be well tolerated by hemodialysis patients, even at high doses for long periods, clinical trials in humans may be planned in the near future.

[Italian Registry of Dialysis and Transplantation: 1996-2001 experience]. / Registro Italiano Dialisi e Trapianto. Esperienza 1996-2001.

The Italian Registry of Dialysis and Transplantation (RIDT) was born in 1996 under the aegis of the Italian Society of Nephrology, and it is organized as a federation of regional registries. This study aimed to completely revise the epidemiological data collected during the first 5 yrs (1996-2001) of RIDT activity to evaluate the trends of the main epidemiological features. During this period, regional registries were not always able to assure complete and exhaustive information according to RIDT requirements, owing to different levels of organization and functioning. To avoid any possible error in data analysis, information inadequately assessed was refused. The incidence of end-stage renal disease (ESRD) patients on renal replacement therapy (RRT) in Italy has increased from 114 pmp in 1996 to 139 pmp in 2001, that means an increase of 3.5%/yr, corresponding to 5718 patients during 1996 and 8000 patients during 2001. Primary renal diseases (according to the EDTA) in incident ESRD patients are vascular and diabetic nephropathy. Main dialysis modality in incident patients was hemodialysis (HD) (85%), while peritoneal dialysis (PD) was only 15%; pre-emptive transplantation was a very unusual modality. The prevalence of ESRD patients at 31 December was 693 pmp in 1996 and 827 pmp in 2001; among dialysis patients, the corresponding rates were 575 pmp and 657 pmp, respectively. Consequently, the number of dialyzed patients increased, respectively, from 28892 to 37919. The prevalent dialysis modality was bicarbonate dialysis in 74% of cases, followed by hemodiafiltration (HDF) in 15%, continuous ambulatory peritoneal dialysis (CAPD) in 7% and APD in 3%. The gross mortality rate in dialyzed patients was stable during this period, at approximately 14%, the main causes of death being cardiovascular diseases and cachexia.

Increased platelet phosphatidylserine exposure and caspase activation in chronic uremia.

Platelet activation is associated with exposure of the aminophospholipid phosphatidylserine (PS) to the outer hemi-leaflet of the plasma membrane bilayer, which seems to be involved in the coagulation process. Because platelet activation may occur in patients suffering from chronic uremia, which is frequently associated with a thrombophilic tendency, we studied whether uremic platelets show an increased propensity to expose PS on the outer membrane leaflet and whether this process is linked with important functional and molecular changes. Flow cytometric percentage of annexin V-positive platelets, a measure of PS externalization, was significantly elevated (P < 0.001) in uremic patients when compared to normal controls under both unstimulated and agonist-stimulated conditions. Uremic platelet procoagulant activity, as measured by thrombin generation, was more than twice as high (4.13 +/- 0.3 micro mL(-1)) as that found in normal controls (1.86 +/- 0.2 micro mL(-1)). Two independent assays showed that the enzymatic activity of caspase-3, a protease involved in the loss of membrane PS asymmetry, was significantly greater in the platelets of uremic subjects than in those of healthy controls. PS exposure in agonist-stimulated platelets was markedly reduced by inhibition of caspase-3 activity but was not affected by inhibition of calpain activity. These results support the view that the thrombophilic susceptibility of uremic patients may be partly ascribed to increased PS exposure to the outer membrane leaflet of platelets. This process seems to be causally linked to an increase in caspase-3 activity, particularly during platelet activation.

[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.

Cell activation and cellular-cellular interactions during hemodialysis: effect of dialyzer membrane.

During hemodialysis (HD), circulating blood cells can be activated and also engage in dynamic interplay. These phenomena may be important factors behind dialysis membrane bio(in)compatibility. In the present prospective cross-over study, we have used flow cytometry to evaluate the influence of different dialysis membranes on the activation of circulating blood cells (leukocytes, platelets) and their dynamic interactions (formation of circulating platelet-leukocyte and platelet-erythrocyte aggregates) during in vivo HD. Each patient (n = 10) was treated with dialyzers containing membranes of cellulose diacetate, polysulfone and ethylenevinylalcohol (EVAL) in a randomized order. Upregulation of adhesion receptor expression (CD15s, CD11b/CD18) occurred mainly with the cellulosic membrane, though an increase in CD11b/CD18 circulating on neutrophils was also found with both synthetic membranes. Circulating activated platelets (P-selectin/CD63-positive platelets) increased during HD sessions with cellulose diacetate and polysulfone. An increased formation of platelet-neutrophil aggregates was found at 15 and 30 min during dialysis with cellulose diacetate and polysulfone but not with EVAL. Platelet-erythrocyte aggregates also increased with cellulose diacetate and at 15 min with polysulfone as well. Generally in concomitance with the increase in platelet-neutrophil coaggregates, there was an increased hydrogen peroxide production by neutrophils. The results of this study indicate that cellular mechanisms can be activated during HD largely depending on the membrane material, EVAL causing less reactivity than the other two membranes. It appears that each dialysis membrane has multiple and different characteristics that may contribute to interactions with blood components. Our results also indicate that derivatizing cellulose (cellulose diacetate) may be a useful way to improve the biocompatibility of the cellulose polymer and that there may be great variability in the biocompatibility profile of synthetic membranes, dialysis with polysulfone being in general associated with a higher degree of cell activation than EVAL membrane.

Platelet activation and platelet-erythrocyte aggregates in end-stage renal disease patients on hemodialysis.

Activated platelets may engage in dynamic interplay with other blood cells. We examined the evidence for platelet activation and the formation of platelet-erythrocyte aggregates in chronic hemodialysis patients. Circulating activated platelets (P-selectin/CD63-positive platelets) were higher than normal controls (p < 0.001) and further increased during hemodialysis sessions, the increase being higher when patients were dialyzed with cellulosic than with synthetic membranes. We found direct evidence of uremic platelet-erythrocyte adherence in vitro and increased levels of circulating platelet-erythrocyte aggregates in dialysis patients, which represents a new observation in uremia. Platelet-erythrocyte aggregates were subject to further increase during hemodialysis, and again higher levels were found with cellulosic than synthetic membranes. This phenomenon was reproduced in vitro by both ADP and PAF, but not by either complement factor C3a or by heparin concentrations corresponding to those used for clinical hemodialysis. We conclude that platelet-erythrocyte aggregates occur in hemodialysis patients probably owing to a primary platelet activation mechanism.

Involvement of phosphatidylserine exposure in the recognition and phagocytosis of uremic erythrocytes.

Cell surface-exposed phosphatidylserine (PS) represents a signal for macrophage recognition and cell phagocytosis. This study examines PS exposure and susceptibility to erythrocyte phagocytosis in patients with chronic uremia in an attempt to assess the possible pathogenic mechanism behind cell removal in a condition associated with shortened erythrocyte life. Both PS-expressing erythrocytes and erythrophagocytosis (human monocyte-derived macrophages ingesting one or more erythrocytes) were significantly increased in uremic patients compared with healthy controls. Phagocytosed uremic erythrocytes appeared intact, suggesting they were identified before lysis through some surface change recognized by the macrophages. The degree of phagocytosis was markedly greater for PS-positive than PS-negative fluorescence-activated cell sorter (FACS)-sorted uremic erythrocytes. A significant correlation (r = 0.655) was found between the percentage of PS-expressing red blood cells (RBCs) and the percentage of phagocytosing macrophages in uremic patients. Reconstitution experiments showed the ability of uremic plasma to promote both PS exposure and erythrophagocytosis, the latter without direct interaction with the macrophage population. Phagocytosis of uremic erythrocytes was strongly inhibited when the macrophages were preincubated with glycerophosphorylserine (GPS), a structural derivative of PS, but this was not the case with the equivalent derivative of phosphatidylethanolamine, glycerophosphorylethanolamine. This inhibition appeared to be specific because GPS failed to inhibit the phagocytosis of opsonized uremic erythrocytes that occurs through an Fc receptor-mediated pathway. These findings suggest that a PS-recognition mechanism may promote the susceptibility of uremic RBCs to phagocytosis and thus be involved in the shortened erythrocyte life span of uremia.