[Renal dysfunction as a marker of cardiovascular risk]. / La disfunsione renale come marcatore di rischio cardiovascolare.

The evaluation of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) is suggested for the assessment of cardiovascular risk. It is unclear whether UAE and eGFR provide complementary information. UAE, eGFR, cardiovascular risk factors, and the incidence of cardiovascular disease were analyzed in 45- to 64-year-old individuals involved in the Gubbio study. UAE in the highest decile was defined as high (microng/min: > or = 18.6 in men and > or = 15.7 in women), eGFR in the lowest decile as low (mL/min/1.73 m(2): <64.2 in men and <57.9 in women). Kidney dysfunction was more frequent when defined by both markers than when defined by one marker only (UAE or eGFR) because high UAE and low eGFR tended to cluster in different individuals. The hazard ratio (HR) for incident cardiovascular disease was 1.85 in individuals with high UAE only (95%CI 1.04-3.25), 1.84 in individuals with low eGFR only (95%CI 1.04-3.26), and 5.93 in individuals with high UAE and low eGFR (95%CI 2.58-13.61). Concomitant evaluation of UAE and eGFR should be considered to adequately assess kidney dysfunction and cardiovascular risk.

[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.

[Survival is not enough: improving quality of life]. / Sopravvivere non basta--migliorare la qualità della vita.

We need a new health care system that is based on patients' needs. The present cadre of health managers who acquired power by cutting expenditures must be removed from office. We need to educate a new cadre of health managers who are 1) convinced that safeguarding health does not use up the resources of the next generations; 2) capable of switching the system from curative to preventive medicine; and 3) able to reinforce clinical research. Such principles have been recently adopted by the French President Sarkozy in devising the national health care program.

[Early detection of chronic kidney disease: epidemiological data on renal dysfunction]. / L'identificazione precoce della nefropatia cronica: dati epidemiologici sulla disfunzione renale.

Estimated glomerular filtration rate (eGFR) and urinary albumin (U-Alb) have been suggested as indicators for the early identification of persons with kidney dysfunction. The Gubbio Study collected data on serum creatinine, UAlb, other laboratory indices, blood pressure, and medical history in a population sample of 4574 adults (2083 men and 2491 women, age range 18- 95 years). The study included analyses on six disorders which are commonly associated with kidney disease (hypertension, cardiovascular disease, anemia, high serum uric acid, high serum phosphorus/low serum calcium, and high serum potassium). Low eGFR (<60 mL/min per 1.73 m2) was found in 6.6% of men and 6.2% of women. Low eGFR prevalence varied largely with age (from <1% at 18-24 years up to > 30% at > or =75 years in both sexes, p<0.001). On the basis of these data, it was estimated that the prevalence of low eGFR in the whole Italian population could be 1.3 million among men (95%CI 1.1/1.5) and 1.5 million among women (95%CI 1.3/1.8). Data available only for age 45-64 indicate that 6.4% of men and 3.0% of women have high U-Alb (> or =20 microg/min) in the presence of non-low eGFR. Low eGFR was associated with at least two disorders potentially due to kidney disease in the majority of persons but was rarely associated with a previous diagnosis of kidney disease (<5% of cases). These data support the use of eGFR for the screening of people with or at risk of developing kidney disease. Awareness of kidney disease is very low in the Italian population.

Prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients--the Campania Dialysis Registry.

BACKGROUND: This study investigated prevalence and correlates of anemia and uncontrolled anemia in chronic hemodialysis patients. METHODS: A cross-sectional analysis was performed on registry data for 2,746 chronic (>6 months) hemodialysis patients aged 25-84. Data collection included years of dialysis, hours of dialysis/wk, disease causing hemodialysis, body mass index (BMI), erythropoietin (EPO) treatment, hemoglobin, markers of viral hepatitis, serum albumin, calcium, and phosphorus. RESULTS: Prevalence was 88.7% for anemia (hemoglobin <11 g/100 mL and EPO treatment at any Hb level), 39.4% for uncontrolled anemia (hemoglobin<11 g/100 mL). Gender, years of dialysis, hereditary cystic kidney disease (HCKD), and low BMI (<24 kg/m2) were independent correlates of anemia (P<0.001). Gender, HCKD, low BMI, serum albumin and calcium were independent correlates of uncontrolled anemia (P<0.05). An interaction was found between age (not correlated with anemia and uncontrolled anemia) and the association of gender with uncontrolled anemia (P<0.05). EPO doses were higher in patients with high prevalence of uncontrolled anemia than in patients with low prevalence (i.e., women vs men, other diseases vs HCKD, low vs not-low BMI, P<0.01). Gender, years of dialysis, HCKD, BMI, serum albumin, and calcium were independent correlates of the hemoglobin/EPO dose ratio in patients on EPO treatment (P<0.05). CONCLUSION: Anemia and uncontrolled anemia are more frequent in hemodialysis patients with shortterm dialysis, diseases other than HCKD, low BMI, and female gender. Gender effect was lower in elderly patients. Uncontrolled anemia was also associated with low serum albumin and calcium, suggesting that these parameters are indices of EPO resistance.

Nonisothermal reactors for the production of pure water from peritoneal dialysis waste waters.

The diffusion of peritoneal dialysis (PD) at home is somewhat restricted by the difficulty of transport and storage of a large amount of dialytic solutions. This problem is exacerbated in the case of hemodialysis. With the aim of producing pure water to be used in preparing the solution for peritoneal dialysis, or for hemodialysis in general, as one example, we purified the spent dialysate solution from PD. Experiments were carried out with 24 dialysate solutions taken from 8 patients. Pure water was obtained by means of a thermodialysis process in a hollow fiber reactor operating under nonisothermal conditions. Results show that the yield of the nonisothermal process is dependent on the temperature difference applied across the hydrophobic membranes. The production of pure water per square meter of membrane and per hour was equal to 0.55 or 1.2 or 2.0 liters, with a temperature difference of 11 degrees C or 21 degrees C or 28 degrees C, respectively. These results encourage the use of the thermodialysis process in the production of pure water for clinical uses.

[Hyperhomocysteinemia in chronic renal failure.]. / L'iperomocisteinemia nell'insufficienza renale cronica: aspetti clinici, nutrizionali e tossicità.

Chronic renal failure (CRF) is frequently associated with increased plasma levels of homocysteine (Hcy), an amino acid that can be considered a new uremic toxin according to recent evidence. Studies on Hcy described first homocystinuria, an inherited disease characterized by high plasma Hcy levels and premature cardiovascular disease, resulting in high mortal-ity rates. Hyperhomocysteinemia was then shown to be associated with cardiovascular events both in the general population and in CRF patients. Hcy is a sulfur amino acid derived from dietary methionine, an essential amino acid. Methionine is condensed with ATP to form S-adenosylmethionine (AdoMet), the universal methyl donor in transmethylation reactions. The AdoMet demethylated product is S-adenosylhomocysteine (AdoHcy), which is the direct precursor of Hcy in vivo. Hcy is toxic for the endothelium, it enhances vascular smooth muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis. Several mechanisms have been discussed to explain Hcy toxicity. Hcy levels increase as renal function declines and progresses to ESRD; the causes of hyperhomocysteinemia are still unclear. Studies in humans show that renal metabolic extraction depends on renal plasma flow; in addition, an alteration of the extrarenal metabolic clearance, depending on uremic toxins, may occur. Among the consequences of hyperhomocysteinemia in renal failure are: impaired protein methylation, with altered protein repair processes; DNA hypomethylation, with an alteration in the allelic expression of genes regulated through methylation; and protein homocysteinylation. Further, this review is dealing with the 'reverse epidemiology' issue, outlining also the main Hcy-lowering strategies.

Low glomerular filtration in the population: prevalence, associated disorders, and awareness.

Estimated glomerular filtration rate (eGFR) was used for analysis of kidney disease prevalence in the United States. The study investigated on prevalence, associated disorders, and kidney disease awareness in an Italian population sample. Data were collected on serum creatinine, other laboratory indices, blood pressure, and medical history in the Gubbio Population Study (n=4574, both sexes, ages 18-95 years). Analyses were carried out on eGFR (equation of Modification Diet in Renal Disease study), disorders potentially secondary to kidney dysfunction (hypertension, high serum uric acid, high serum phosphorus/low serum calcium, high serum potassium, cardiovascular disease, anemia), and kidney disease awareness. The prevalence of eGFR <60 ml/min x 1.73 m(2) increased with age in both sexes (from <1% for ages 18-24 years to >30% for ages > or =75 years, P<0.001). In the group with eGFR <60 ml/min x 1.73 m(2), number of disorders secondary to kidney dysfunction was > or =2 in the majority of persons, was higher than in persons with eGFR > or =60 ml/min x 1.73 m(2) (P<0.001), and was inversely related to eGFR (P<0.001). The prevalence of reported kidney disease was 3.3% in the group with eGFR <60 ml/min x 1.73 m(2) and directly related to serum creatinine and number of disorders secondary to kidney dysfunction (P<0.001). Low kidney function is frequent in the older population and is associated with disorders typical of kidney disease. Persons with low kidney function are rarely aware of kidney disease unless of very high serum creatinine or presence of many disorders typical of kidney disease.

Sevelamer worsens metabolic acidosis in hemodialysis patients.

BACKGROUND: Sevelamer hydrochloride, a major phosphate binder for patients on maintenance hemodialysis (MHD) is associated with reduced serum bicarbonate concentration due to hydrochloric acid release in the gut and to the binding of short chain fatty acids in the large intestine. Since metabolic acidosis can be deleterious, a study was devised to compare the time course of serum bicarbonate concentration during treatment with sevelamer hydrochloride or calcium carbonate. METHODS: Sixteen well nourished patients on MHD who were in excellent clinical conditions and achieving target levels for blood pressure (BP) and hemoglobin (Hb), while on a protein intake of 1.1g/kg body weight (bw), were enrolled in the study. After a 2-week washout period, the patients were divided into two groups, each consisting of eight patients, and randomized either to 24 weeks of sevelamer followed by 24 weeks of calcium carbonate (group A) or to 24 weeks of calcium carbonate followed by 24 weeks of sevelamer (group B). Protein intake, n-protein catabolic rate (nPCR), serum concentrations of calcium, phosphate, calcium x phosphate (Ca x P) product, bicarbonate, intact parathyroid hormone (iPTH) and albumin were monitored. Time course changes in serum bicarbonate concentrations in relation to short and long dialytic intervals (48 vs. 72 hr) were also investigated. RESULTS: Both sevelamer and calcium carbonate effectively controlled serum phosphate and the Ca x P product. During calcium carbonate treatment plasma phosphate concentrations were significantly below those of patients on sevelamer. Plasma bicarbonate concentration fell within target DOQI values during calcium carbonate administration both in group A and in group B, a goal which was not achieved under sevelamer administration. After a long dialytic interval in patients on sevelamer, serum bicarbonate concentration averaged 17.3 +/- 1.1 mEq/L, whereas it averaged 21.1 +/- 0.7 mEq/L in patients on calcium carbonate (p<0.01). Finally, a 24-week sevelamer administration caused a statistically significant (p<0.05) reduction (0.8 g/dL) in serum albumin concentration, without affecting iPTH. Taken together, these results indicate that sevelamer worsens metabolic acidosis, which needs to be corrected.

Acid-base balance in heart failure.

In end-stage heart failure, various acid-base disorders can be discovered due to the renal loss of hydrogen ions and hydrogen ion movements into cells, the reduction of the effective circulating volume, hypoxemia and renal failure. This justifies the occurrence of metabolic alkalosis, metabolic acidosis, respiratory alkalosis, as well as respiratory acidosis alone or in combination. Several studies have been published on the acid-base state in heart failure. In a 1951 study, Squires et al analyzed the distribution of body fluid in congestive heart failure by taking into consideration the abnormalities in serum electrolyte concentration and in acid-base equilibrium. A recent study by Milionis et al, analyzed 86 patients with congestive heart failure receiving conventional treatment; the majority of these patients exhibited hypokalemia, hyponatremia, hypocalcemia and hypophosphatemia. Disorders in acid-base balance were noted in 37.2% of patients. In a recent study, 70 patients with severe congestive heart failure before heart transplantation showed high-normal pH, slightly reduced pCO 2 and a slight loss of hydrogen ions. After heart transplantation, stability of blood pH and hydrogen ion concentrations was found. In contrast, bicarbonate and pCO 2 increased significantly. The data led us to formulate the diagnosis of a mixed acid-base disorder that includes respiratory alkalosis and metabolic alkalosis before heart transplantation. In heart failure, the presence of acid-base imbalance associated with the activation of mechanisms that lead to salt and water retention reveals evidence concerning the pivotal role of the kidney in determining the outcome of these patients.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

[Urinary albumin excretion and coronary artery disease]. / Albumina urinaria e malattia coronarica nella popolazione di età 45-64 anni.

The moderate elevation in urinary albumin excretion defined as microalbuminuria is common in the population and associated with cardiovascular (CV) risk factors. Microalbuminuria prevalence is low in the absence of CV risk factors and progressively increases with the number of the individual's CV risk factors. The main correlate of microalbuminuria is blood pressure (BP). The relationship between BP and microalbuminuria is continuous and graded since the prevalence of microalbuminuria increases with the severity of hypertension. Among hypertensives receiving treatment, BP control is associated with a low prevalence of microalbuminuria. Therefore, BP appears as a determinant of microalbuminuria rather than a mere correlate. For hypercholesterolemia, smoking and diabetes, the data are less strong, but point to an independent positive association with microalbuminuria. Altogether, data indicate that microalbuminuria in the population reflects the presence of CV risk factors. Data concerning microalbuminuria and coronary heart disease (CHD) support this idea. There is a continuous and graded relationship between urinary albumin excretion and CHD prevalence. High urinary albumin excretion is a likely sign of vascular damage existing both at renal and cardiac levels and induced by one or more uncontrolled CV risk factors.

[Promoting clinical research]. / Promuovere la ricerca clinica.

Although the development of science as any human activity is basic and practical at the same time, clinical science did not develop with the same pace of basic science. There is a need to support clinical science by granting independence, by enrolling young physician scientists, by giving them appropriate mentoring and economic support.

Increased plasma protein homocysteinylation in hemodialysis patients.

Hyperhomocysteinemia, an independent cardiovascular risk factor, is present in the majority of hemodialysis patients. Among the postulated mechanisms of toxicity, protein homocysteinylation is potentially able to cause significant alterations in protein function. Protein homocysteinylation occurs through various mechanisms, among which is the post-translational acylation of free amino groups (protein-N-homocysteinylation, mediated by homocysteine (Hcy) thiolactone). Another type of protein homocysteinylation occurs through the formation of a covalent -S-S- bond, found primarily with cysteine residues (protein-S-homocysteinylation). Scant data are available in the literature regarding the extent to which alterations in protein homocysteinylation are present in uremic patients on hemodialysis, and the effects of folate treatment are not known. Protein homocysteinylation was measured in a group of hemodialysis patients (n=28) compared to controls (n=14), with a new method combining protein reduction, gel filtration and Hcy derivatization. Chemical hydrolysis was performed, followed by high-pressure liquid chromatography separation. The effects of folate treatment on protein homocysteinylation, as well as in vitro binding characteristics were evaluated. Plasma Hcy, protein-N-homocysteinylation and protein-S-homocysteinylation were significantly higher in patients vs controls. Plasma Hcy and protein-S-homocysteinylation were significantly correlated. After 2 months of oral folate treatment, protein-N-homocysteinylation was normalized, and protein-S-homocysteinylation was significantly reduced. Studies on albumin-binding capacity after in vitro homocysteinylation show that homocysteinylated albumin is significantly altered at the diazepam-binding site. In conclusion, increased protein homocysteinylation is present in hemodialysis patients, with possible consequences in terms of protein function. This alteration can be partially reversed after folate treatment.

Paradox of circulating advanced glycation end product concentrations in patients with congestive heart failure and after heart transplantation.

OBJECTIVES: To analyse circulating concentrations of advanced glycation end products (AGEs) in patients with severe congestive heart failure (CHF) and after heart transplantation; to identify the potential contribution of kidney function to plasma AGE concentrations; and to determine whether AGE concentrations and parameters of oxidative stress are interrelated. METHODS AND RESULTS: Circulating N(epsilon)-(carboxymethyl)lysine (CML) and AGE associated fluorescence (AGE-Fl), lipid peroxidation, and glomerular filtration rate (GFR) were measured in a cross sectional study of 22 patients with advanced CHF, 30 heart transplant recipients, and 20 healthy controls. Compared with the controls, the CHF patients had decreased CML (mean (SEM) 467.8 (20.0) ng/ml v 369.3 (22.3) ng/ml, p < 0.01), AGE-Fl (mean (SEM) 302.2 (13.3) arbitrary units v 204.9 (15.7) arbitrary units, p < 0.01), and GFR (p < 0.01). CML was positively related to decreased total protein and serum albumin and negatively to body mass index (p < 0.01). In contrast, in the heart transplant group, impaired GFR was associated with a notable rise of both CML (mean (SEM) 876.1 (53.1) ng/ml, p < 0.01) and AGE-Fl (mean (SEM) 385.6 (26.1) arbitrary units, p < 0.01). A positive relation between CML and serum albumin (r = 0.394, p < 0.05) and lipofuscin (r = 0.651, p < 0.01) was found. CONCLUSIONS: The contrasting concentration of CML and AGE-Fl between patients with CHF and after heart transplantation in the presence of decreased GFR and oxidative stress are explained by lowered plasma proteins in CHF and higher concentrations in heart transplant recipients. In heart transplant recipients, in addition to myocardial inflammatory processes, immunosuppression may be important for enhanced formation of AGEs.

Homocysteine and oxidative stress.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (ischemic disease, such as stroke and myocardial infarction, and arterial and venous thrombotic events) in the general population. We can assume that the association is causal, based on the example of homocystinuria, and on the evidence put forward by several basic science and epidemiological studies; however, the results of large intervention trials, which will grant further support to this hypothesis, are not yet available. In addition, the mechanisms underlying this relationship, and also explaining the several toxic effects of homocysteine, related or not to cardiovascular disease, are unclear. Oxidation is one of the most favored postulated mechanisms; others are nitrosylation, acylation, and hypomethylation. Regarding the relative importance of these mechanisms, each of these hold pros and cons, and these are weighed in order to propose a balance of evidence.

[Microalbuminuria in nondiabetic adults]. / La microalbuminuria in adulti non diabetici.

This paper deals with the clinical relevance of moderate increase in urinary albumin excretion, commonly known as microalbuminuria, in non-diabetic adults. Presently there are several definitions of microalbuminuria. When measuring excretion rates, microalbuminuria is defined by thresholds of 30 mg/day or 20 g/min with urine collections shorter than 24 hours whereas macroalbuminuria is defined by rates higher than 300 mg/day or micro 200 g/min, respectively. Clinical and epidemiological data indicate the presence of a correlation between blood pressure and microalbuminuria. Microalbuminuria is progressively more frequent with higher blood pressure (systolic or diastolic) also in non-hypertensive persons. Antihypertensive drugs lower urinary albumin excretion, the effect is modest or absent for dihydropyridinic calcium-channel blockers, strong for inhibitors of the renin-angiotensin system. In addition to blood pressure, other factors directly related to urinary excretion of albumin are cigarette smoking, blood lipids, body mass and dietary protein. In non-diabetics, microalbuminuria anticipates lethal and non-lethal cardiovascular events. This correlation can also be observed in the range of urinary albumin excretion below the thresholds that define microalbuminuria. Present data are not consistent on the possible correlation between microalbuminuria and renal function in non-diabetics.

Relation of urinary urea to blood pressure: interaction with urinary sodium.

A previous study reported that urinary markers of protein intake are inversely related to blood pressure via unknown mechanisms. In man and rats, protein intake affects renal function and increases renal sodium excretion. The present study investigates the relation between markers of protein intake and blood pressure and the possible role of sodium in this relation. Blood pressure status, overnight urinary urea as index of protein intake, urinary and plasma sodium, and other variables were measured in a population sample of 3705 men and women, aged 25-74 years, without high plasma creatinine. Urinary urea was inversely related to blood pressure and hypertension: in multivariate analyses, 6.5 mmol/h higher urinary urea (about one s.d. in men and women) was related to 4.25 mm Hg lower systolic blood pressure (95% confidence interval = 1.34-8.49), and to 0.65 lower risk of hypertension (95% CI 0.34-0.87). An interaction was found between overnight urinary sodium and the relation of urinary urea to blood pressure: the relation was significant only in persons with overnight urinary sodium above the median. Urinary urea was significantly and inversely also related to plasma sodium. Data confirm an inverse relation to blood pressure of protein intake as measured by urinary urea. The possibility of sodium-related mechanisms is supported by the interaction of urinary sodium with the relation and by the inverse association of urinary urea with plasma sodium. The hypothesis is made that high protein intake could counteract sodium-dependent blood pressure rise via stimulation of renal sodium excretion.