[Effects of dose of erythropoiesis stimulating agents on cardiovascular outcomes, quality of life and costs of haemodialysis. the clinical evaluation of the DOSe of erythropoietins (C.E. DOSE) Trial]. / Effetti della dose degli agenti stimolanti l'eritropoiesi su esiti cardio-cerebrovascolari, qualità di vita e costi in emodialisi.

BACKGROUND: Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested. METHODS: We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).

[Health care based on patients' needs]. / Costruire una Sanita' che parta dalle esigenze dei malati.

Survival is not enough. We need to build a health system starting from patients' needs without wasting the resources of our grandchildren and great-grandchildren. We have to switch from curative to preventive medicine by firing managers who think they can resolve all problems by cutting expenditures. We need to educate a new cadre of managers able to govern by centering the system on the patients. Managers should consider health care as an asset and should reinforce clinical research. Such a program has been recently adopted in France.

[Health-related quality of life in patients with chronic kidney disease]. / Qualita' della vita nei nefropatici.

Assessment of quality of life in patients with different degrees of chronic kidney disease is an important issue because of its impact on clinical decisions and financial resource management in the health-care system. The aim of this study was to assess whether a generic instrument like the SF-36 questionnaire is able to discriminate three different populations of patients with different degrees of renal disease (pre-ESRD, ESRD, TxR). Five hundred sixty-three patients from 12 Italian nephrology units completed the SF-36 scales by themselves. The results from these samples were compared with those from the general population. Univariate analysis and multivariate regression were used. The generic SF-36 questionnaire proved to be a powerful instrument to discriminate populations with different degrees of chronic renal failure. The quality of life of patients on dialysis is significantly worse than that of the normal population and other patients with less severe renal function impairment.

[Nocturnal hemodialysis: an alternative treatment for a better quality of life]. / Emodialisi notturna: un trattamento alternativo per una migliore qualità della vita.

The interest of investigators in intensified dialysis regimens has been growing in recent years, especially since the HEMO Study Group showed that a higher dose of thrice-weekly hemodialysis fails to reduce mortality and morbidity but improves clinical outcomes. Alternative hemodialysis strategies including short daily hemodialysis (SDHD), long hemodialysis (LHD) and nocturnal daily hemodialysis (NDHD) have been developed in the hope to improve patients' outcomes. A growing number of investigators are studying patients on alternative dialysis regimens and most publications in this field have reported significant improvements in clinical outcomes including left ventricular hypertrophy, blood pressure control, anemia, calcium-phosphate metabolism, and fluid and electrolyte balance; all of these parameters can be considered as indirect signs of improvement in quality of life. However, the strength of these results is often limited by shortcomings in study design. Indeed, in most of these studies an adequate control group is missing, the patient groups are not properly matched, and the number of patients enrolled is small. Similarly, most studies have evaluated the effects of NDHD and/or nocturnal LHD on health-related quality of life (HRQoL) by questionnaire administration. Even though better results might be achieved with nocturnal hemodialysis, no conclusive data exist to prove statistically significant differences in HRQoL between conventional and intensive hemodialysis. In conclusion, all of these novel dialysis strategies offer reliable opportunities for uremic patients, but further trials are needed to determine whether alternative hemodialysis can reduce morbidity and mortality in this high-risk population of patients.

Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial.

Microalbuminuria is a strong, consistent and independent risk factor for cardiovascular and renal disease in patients with diabetes and/or hypertension and in the general population. Several randomized trials have shown the efficacy of inhibiting the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) to prevent cardiovascular events and the progression of kidney disease. These 2 classes of drugs are equally effective for renal outcomes in patients with diabetic nephropathy, but only ACEIs have been found to significantly impact the risk of all-cause mortality, predominantly cardiovascular, in patients with diabetic nephropathy. Studies on the cardiorenal efficacy of combined therapy with ACEIs and ARBs in individuals with microalbuminuria or macroalbuminuria and other cardiovascular risk factors have been inconclusive. The Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) study aims to address existing questions in this setting. This is a phase III, randomized, comparative, pragmatic trial with prospective randomized open blinded endpoint (PROBE) design. It will evaluate the comparative efficacy of combined therapy with ACEIs and ARBs versus monotherapy with either ACEIs or ARBs in improving cardiovascular and renal outcomes in microalbuminuric or macroalbuminuric individuals at cardiorenal risk. The study will enroll 2,100 patients, selected in a network of internal medicine, diabetology or nephrology outpatient clinics. Patients will be randomly allocated to ACEIs, ARBs or their combination. The study has been approved and funded by the Agenzia Italiana del Farmaco (A.I.F.A.) within the 2005 funding plan for independent research on drugs.

[Angiotensin converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in microalbuminuric patients with one or more cardiovascular risk factors. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes randomized trial (LIRICO).]. / ACE-inibizione, antagonismo recettoriale e terapia combinata in soggetti microalbuminurici con fattori di rischio cardiovascolare. Protocollo dello studio randomizzato multicentrico ''Long-term impact of RAS inhibition on cardiorenal outcomes-LIRICO".

Angiotensin converting enzyme inhibitors (ACE-i) and angiotensin II receptor blockers (ARB) are considered to be equally effective for patients with diabetic kidney disease, while only ACE-i have been shown to determine a significant reduction in the risk of all-cause mortality, predominantly cardiovascular, in these patients. Studies on the cardio-renal efficacy of combined therapy with ACE-i and ARB are not available or not conclusive, in a population with cardiovascular risk with micro- or macroalbuminuria. In this paper, we present the protocol of a randomized controlled clinical trial that will address the question. The LIRICO (Long-term Impact of RAS Inhibition on Cardiorenal Outcomes) study will evaluate the comparative efficacy for cardiovascular and renal outcomes of combined therapy with ACE-i and ARB versus monotherapy with ACE-i or ARB in micro/macroalbuminuric individuals at cardio-renal risk. The study will enrol 2100 patients allocated to monotherapy with ACE-i, ARB or combined treatment with ACE-i + ARB. The LIRICO study is a randomized comparative trial, with PROBE (Prospective Randomized Open Blinded End-Point) design. The study has been approved and funded by the Agenzia Italiana del Farmaco (AIFA) within the 2005 funding plan for independent research on drugs. Availability of funding for this study provides, for the first time in our Country, an opportunity to organize a collaborative national network of nephrology, internal medicine and diabetology outpatient clinics to develop a large multicentre trial collaboration. The results of this trial will establish the optimal therapy for micro/macroalbuminuric individuals with cardiovascular and renal risk.

[Allergic rhinitis: A challenge diagnosis]. / La rinite allergica: una diagnosi non semplice.

AIM: The allergic rhinitis represents one of the ten major causes of ambulatory check-up. The incidence is between 10% to 25% in the general population and, in Italy, is approximately present in 10% of children and 20% of adolescents. The diagnosis of this disease is related to family anamnesis and the presence of several signs and typical symptoms. Regarding the tests used to detect this disease, cutaneous specific IgE (skin prick test) is used as cute reactivity expression. Using nasal specific IgE dosage we analyzed patients affected by rhinitis and its relationship between positive test, gender and age, the relationship between positive test and disease and the better response to diagnosis between the 2 tests performed (i.e., skin prick test and nasal specific IgE). METHODS: We analyzed 125 subjects enrolled consecutively, age range 48-216 months (median 144 months) that performed skin prick test and nasal specific IgE. RESULTS: Looking at the overall subjects, 51 subjects were positive to skin prick test and nasal specific IgE, 23 subjects were positive to skin prick test, 31 subjects were positive to nasal specific IgE, 20 subjects were negative to both tests. Regarding the relationship between tests positive and symptoms we did not find any significant correlation. CONCLUSIONS: Our data suggests that rhinitis diagnosis is quite difficult to perform and the test used to detect this disease needs to be more accurate and precise. Family anamnesis and clinical signs are fundamental in the diagnosis of allergic rhinitis.

[Acute biocompatibility of hemodiafiltration with endogenous reinfusion (HFR)]. / Emodiafiltrazione con reinfusione endogena (HFR): profilo di biocompatibilità in acuto.

PURPOSE: In order to reduce the hemodialysis (HD)-induced pro-inflammatory activity we need to use a biocompatible dialysis membrane, avoid backfiltration and possibly use adsorbents. Hemodiafiltration reinfusion (HFR) is a new on-line hemodiafiltration (HDF) technique combining these aspects. This study aimed to evaluate the biocompatibility of the single dialysis session comparing standard HD and HFR. METHODS: Eighteen patients on chronic HD were enrolled in five Centers. Patients underwent one standard and two HFR study sessions; in each session we evaluated leukocyte activation at 0, 5, 15, 60 and 240 min; and interleukin-6 (IL-6), C-reactive protein (CRP) and IL-1 receptor antagonist (IL-1Ra) levels at 0, 60 and 240 min. RESULTS: Leukocyte activation was similar in HD and HFR, while the post-dialysis IL-6 increase was lower with HFR; CRP levels were stable during HFR, but increased after HD, and IL-1Ra did not demonstrate any difference. CONCLUSIONS: These preliminary data show that HFR still has a better biocompatibility in the single dialysis session.

Why do we need outcomes research in end stage renal disease?

Despite effective therapeutic strategies to slow or arrest the progression of chronic renal diseases, the number of patients entering renal replacement programs is increasing, with a dramatic burden in terms of morbidity, mortality and resource consumption. While in the past the attention was mainly devoted to the improvement of dialysis care, it has recently been argued that the timing and quality of care before dialysis is started may significantly affect the prognosis. Problems of transfer of research results, together with differences in physicians' attitudes and beliefs as well as in structural and organisational aspects make pre-end-stage renal disease (ESRD) care extremely heterogeneous. This lack of uniformity in medical practice has stimulated extensive inquiry into the relation between the use of clinical services and their end results--the outcomes. Outcomes research investigates medical effectiveness, meaning how well prevailing treatments work in different clinical practice settings. It is thus an important tool to help patients, providers and purchasers to make sound decisions, based on a deeper knowledge of how different choices affect the patient's life. By using a broad array of outcome measures, this research serves to evaluate the effectiveness of complex health care strategies from the different points of view of patients, providers and purchasers, reconciling their needs. Starting from these premises, initiatives aimed to evaluate the avoidability of ESRD morbidity and mortality are urgently needed. To this purpose, the care delivered to ESRD patients and its impact on clinical variables, quality of life and resource consumption need to be longitudinally monitored. Outcomes research thus represents a unique opportunity to increase our knowledge on pre-ESRD care and to identify those strategies more likely to reduce the unwanted outcomes related to the initiation of dialytic treatment.

Effect of coexistent diseases on survival of patients undergoing dialysis.

A cohort retrospective study was used to analyze the effect of comorbidity on survival of end-stage renal disease (ESRD) patients undergoing dialysis. The authors analyzed the survival of 255 patients (144 men, 111 women; median age 54 years; range 8-81 years) followed at the District Hemodialysis Unit in Foggia, Italy, over a 15 year period (median follow-up 30 months; range 1-190 months). Two subscales assessing the overall severity of the identified coexistent diseases and overall physical impairment, and a composite four level index of coexistent diseases (ICED) were assembled using information recorded at the time of admission. The Cox proportional hazard model was applied to evaluate the association of various patient characteristics with the probability of death. Mortality risk was associated with patient age (RR = 3.4 for patients aged 42-61; RR = 4.8 for patients older than age 61 compared with patients younger than age 42), initial condition leading to renal failure (RR = 3.1 for diabetes compared with primary renal disease) and ICED (RR = 3.0 for patients with uncontrolled coexistent disease or severe impairment compared with patients with no coexistent disease and no or mild impairment). Gender and type of dialysis were not associated with mortality risk. It was concluded that, as is the case with other chronic conditions, co-morbidity is a powerful independent prognostic factor in determining the mortality of ESRD patients.

Influence of phosphatidylcholine on ultrafiltration and solute transfer in CAPD patients.

Fifteen patients (mean age 59.9 +/- 16.1 years) treated by CAPD for a mean of 21.6 +/- 14 months, underwent peritoneal clearances before and after 15 days of intraperitoneal phosphatidylcholine (PC) treatment (50 mg/L). No difference was observed in urea, creatinine, uric acid, and reverse dextrose clearances. A statistically significant increase in phosphate clearances (4 and 6 hr dwell times) (1.36%) and a reduction in drainage volume (2 hr dwell time) (1.36%) were observed after treatment. Urine output and percent dextrose reabsorption were unchanged. The ultrafiltration (UF) showed a tendency to increase, which lasted for 15 days after discontinuation of treatment. This tendency allowed the patients to reduce, during the same period, the amount of hypertonic solution (23.8 L vs. 21.3 L) required. The tendency to increase UF over time deserves further study.

Follow-up of reverse dextrose clearances in patients undergoing CAPD.

Three hundred eighty-eight sequential reverse dextrose clearances (RDC) have been performed in 61 unselected patients (12 of whom were diabetics), whose mean age was 54 years (30-79). They were treated for a mean time of 23 +/- 12 months (0-60); the total observation time was 1,440 months. One hundred forty-two episodes of peritonitis were registered, producing a peritonitis incidence of 1 episode per 10.2 patient months. The RDC values are significantly inversely related to dwell-time and show a tendency to increase over time; they never, however, reach statistical significance. Age of patients, episodes of peritonitis and primary renal disease (diabetes) had no influence. It is important to underline the significant inverse relationship between ultrafiltration and residual diuresis. Unknown mechanisms regulate this relationship.

Peritoneal clearances. Long-term study.

To investigate if age of patients, time on CAPD, episodes of peritonitis, or systemic illness (diabetes) may affect the permeability of the peritoneal membrane to small solutes, 51 patients (eight diabetic) 57.2 +/- 9.4 years of age undergoing long-term CAPD were enrolled in a prospective study of peritoneal clearances (PC), started in January 1982. The studies were repeated, when possible, every 6 months after peritonitis episodes. The results were divided according to osmolality of solutions and dwell time. The age of patients had no influence on results. Significantly positive correlations were found between PC (1.36%) of creatinine, uric acid, phosphate, and time on CAPD. Uric acid PC (3.86%) correlated directly with time on CAPD. The PC in diabetic and nondiabetic patients were similar. Patients who had more than three episodes of peritonitis showed PC similar to those observed in patients who had less than three episodes, despite a longer time on CAPD. The stability of PC in patients undergoing long-term peritoneal dialysis suggests that CAPD may permit effective dialysis over many years.

Ionized calcium/total calcium ratio during biofiltration.

The transmembrane transfer of calcium during hemodialysis is related to many factors (calcium gradient, plasma volume flow, plasma concentration of phosphate). During biofiltration the high ultrafiltration rate reduces the net transfer of calcium from dialysate to patient. Prolonged metabolic alkalosis occurs during biofiltration, lowering the ionized calcium/total calcium ratio. These two factors may stimulate PTH secretion, with negative long-term effects in dialysis bone disease.

Puglia cooperative study on biofiltration.

Biofiltration (BF) was performed on 60 patients from 12 dialytic centers in Puglia. The protocol was 9-10.5 hours a week with 1.2 m2 PAN dialyzers. A dialysate with 140 Na+, 2-2.5 K+, 3.5-4 Ca++, 38 mEq/l acetate was used in 49 patients; the acetate was replaced by bicarbonate (35-40 mEq/l) in 11 patients. The same patients were treated for 1 year with standard acetate dialysis (49 patients) and standard bicarbonate dialysis (11 patients). The two protocols were compared on the basis of the clinical state, BUN and serum creatinine, acid-base balance, PTH, anemia, and nerve conduction velocity (NCV). Favourable effects were achieved in 55 patients. Four patients left the program because of progressive hyperhydration. BUN and serum creatinine levels showed a moderate, but insignificant increase. PTH, anemia and NCV did not worsen. BF gave better correction of metabolic acidosis in the patients undergoing acetate dialysis.

[Serum concentration of T3, T4, FT3, FT4, TSH during cycloergometer muscular exercise]. / Concentrazioni sieriche di T3, T4, FT3, FT4, TSH durante esercizio muscolare al cicloergometro.

The serum concentrations of total and free thyroid hormones and of TSH have been determined in 10 trained subjects before, during and after exercise on a bicycle ergometer. The concentrations of T4 and FT4 increase during the muscular exercise and reduce 30 minutes after the end of work; the decrease is statistically meaningful for the T4. The concentrations of TSH and T3 reduce 30 minutes after the end of work on a bicycle ergometer. The serum concentration of FT3 and of hematocrit doesn't presents any statistically meaningful variation during and after the muscular exercise. The results achieved in our work are in support of the hypothesis that the physic and intense exercise would involve the thyroid gland exalting its activity.

[Intravenous glucose tolerance test during muscular exercise]. / Prova di tolleranza al glucosio per via intravenosa durante esercizio muscolare.

We have valued in 8 individuals subjected to muscular moderate work the degree of use of glucose in the body tissues, measured by means of K-Conard, and the role that holds the insulin hormone in this particular condition. The IVGTT was carried out in 8 individuals, at first, in condition of relax. In the same individuals, the day after, the IVGTT was carried out after 5 minutes from the beginning of muscular work to cycloergometer set a 50 watts for a term of 30 minutes. The study demonstrates that, during the muscular moderate work, we have an improvement, statistically significant, of the use of glucose, measured by means of K-Conard (t = 2.42; P less than 0.05). Then, it demonstrates that the muscular moderate work has not any influence on plasmatic concentrations of insulin.