N.G. De Santo

Homocysteine and oxidative stress

Summary. 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.

Effects of thyroid hormones on heart and kidney functions.

Thyroid hormones affect the functions of several organs including the heart and kidney. Using isolated left papillary muscles we have investigated the action of thyroid hormones on the mechanical and electrical properties of the heart. We found that pure hypothyroidism causes a depression in contractile and electrical parameters, but we noticed that superimposed hypoparathyroidism accounts for the marked prolongation in contractile kinetics and action potential duration. At kidney level we have shown that thyroid hormones affect proximal tubular sodium transport and this effect is only partially mediated by the action of thyroid hormones on Na-K-ATPase activity. Using the micropuncture technique, we hypothesized that the early effect of thyroid hormone action is on the potassium permeabilty of proximal tubular cell membrane. This latter effect would explain the increase in isotonic fluid reabsorption through an increase in the driving force for sodium. Finally, hypothyroid patients have a decrease in glomerular filtration rate and renal plasma flow that are completely reversed by thyroxine administration. On the other hand, hyperthyroid subjects exhibit a significant increase in both parameters.

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.

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 Nε-(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.

Berengario da Carpi

Berengario da Carpi was magister of anatomy and surgery at the University of Bologna from 1502 to 1527. Eustachio and Falloppia defined him as ‘the restaurator of anatomy’. He was a great surgeon, anatomist and physician of illustrious patients including Lorenzo II dei Medici, Giovanni dalle Bande Nere, Galeazzo Pallavicini, Cardinal Colonna, and Alessandro Soderini. He had strong links to the intellectuals of his time (Forni, Bonamici, Manuzio, Pomponazzi) as well as with the Medici family. He was respected by the Popes Julius II, Leo X and Clement VII. His main contributions are the Isogogae Breves, De Fractura calvae sive cranei, and the illustrated Commentaria on the Anatomy of Mondino de Liucci, a textbook utilized for more than 200 years, which Berengario aimed to restore to its initial text. The Commentaria constitutes the material for the last part of this paper which concludes with a personal translation of some passages on ‘The kidney’, where the author gives poignant examples of experimental ingenuity.

Effects of a Meat Meal on Renal Sodium Handling and Sodium Balance

Protein ingestion increases renal blood flow and glomerular filtration rate (GFR). This study investigated in healthy adults if the renal response to protein ingestion includes changes in urinary sodium (Na) excretion rate and Na balance. Renal clearance of Na and inulin (used as index of GFR) were measured in 25 healthy adults before (90 min) and after (180 min) a standard meal and, as control, before and after administration of water and Na-chloride (saline). The meal consisted of red lean meat (2 g protein/kg body weight); in control experiments, water and Na were given to match water and Na content of the meal. ANOVA for repeated measures, Student’s t-test, and linear regression were used for statistical analysis. GFR and urinary Na excretion increased over baseline after the meal (p < 0.001), not after saline. The post-meal natriuretic response was accounted for an early (0–90 min) increase in glomerular filtered load of Na (p < 0.001) and a late (90–180 min) reduction in tubular Na reabsorption (p < 0.02). Urine flow rate and plasma Na did not significantly change after the meal and in control experiments. Analysis of Na balance showed that post-meal Na excretion was significantly higher than baseline also after Na balance returned to pre-meal values. In healthy individuals, a meat meal stimulates natriuresis and causes a net decrease in Na balance. The renal natriuretic response to the meal appears secondary to the meal-induced changes in renal hemodynamics. The data are in keeping with the hypothesis that dietary protein intake affects also renal Na handling.

The renal hemodynamic response to an oral protein load is normal in IgA nephropathy

The study was devised to explore the effects of an acute oral protein load on renal hemodynamic response in patients with IgA nephropathy (IgAN). The study was performed in 10 proteinuric IgAN patients (800 +/- 300 mg/day) and in 20 healthy controls (matched by sex, age, BMI, BSA, plasma creatinine, plasma urea, urinary urea and protein intake). Blood pressure and creatinine clearance were nearly identical in the two groups. GFR and RPF, measured as the clearance of inulin and of p-aminohippurate (PAH) were studied before and after a meat meal which provided 2 g of protein/kg BW. Following the protein load, renal reserve, percent renal reserve and postmeal cumulative changes of GFR were not significantly different in IgAN and controls. Filtration fraction (FF) at baseline was significantly higher (p < 0.01) in IgAN than in controls (25.5 +/- 1.41 vs. 19 +/- 2%). Postmeal hyperemia and hyperfiltration did not affect FF in either group. Filtration capacity in IgAN was lower (p<0.02) than in controls (117 +/- 5.6 vs. 137.9 +/- 7.0 ml/min x 1.73 m2), whereas the percent of filtration capacity utilized at rest was identical in controls and in IgAN. Creatinine clearance overestimated GFR in IgAN. The data indicate that renal hemodynamic response to proteins in IgAN is normal.

The role of emeriti and retired professors in medicine

University professors, at least in Europe, are requested to retire at fixed ages, independent of their wishes or intellectual abilities. By contrast, in the USA, age alone cannot legally be a reason for imposing retirement. After retirement, in many universities some professors achieve the status of emeritus(a) which in some instances is an honorary title, but usually allows continued research and teaching. However, the nomination of emeritus(a) professors is not granted to everybody, and specific studies on these academic policies are still lacking and is the goal of this study. We conducted an international inquiry focusing on emeritus policy in 99 departments of medicine of 99 universities, in 20 countries of high, medium and low economy (Algeria, Australia, Brazil, Egypt, France, Germany, Greece, Italy, Malta, Libya, Poland, Romania, Slovak Republic, Slovenia, Switzerland, The Netherlands, Tunisia, Turkey, UK and USA). Specific questionnaires were sent to 63 active professors and 64 emeritus/retired professors. The response rate was 89.1%. The questionnaire asked about (i) facilities granted through emeritus status, (ii) the possibility of submitting applications for grant support and to receive donations, (iii) participation in teaching activities, e.g. providing tutorial activity, giving seminars and teaching in Masters’ and Ph.D. courses and (iv) about the possibility for …

Renal Reserve Is Normal in Patients with Dilative Cardiomyopathy Waiting for Heart Transplantation

Renal reserve was explored by means of an oral protein load (2 g/kg body weight) under the form of cooked red meat in a group of 9 patients with end-stage heart failure (ESHF), class III of the New York Heart Association receiving loop diuretics and angiotensin-converting enzyme (ACE) inhibitors, and in a group of 18 healthy controls (HC) matched for age, gender, and height under an identical dietary regimen providing 40 cal/kg per day, 1 g/kg body weight of protein per day, Na 120 mmol/day, and K 50 mmol/day. Baseline glomerular filtration rate averaged 109.5±9.89 ml/min×1.73 m2 in HC and 71.9±8.8 ml/min×1.73 m2 in ESHF. Renal plasma flow averaged 540±27 ml/min×1.73 m2 in HC and 235±47 ml/min×1.73 m2 in ESHF. The filtration fraction was significantly higher in ESHF (p<0.01). Renal reserve averaged 26.03±3.28 ml/min×1.73 m2 in HC and 27.2±7.12 ml/min×1.73 m2 (not significant). Renal reserve averaged 123.9±2.9% in HC and 137.3±6.68% in ESHF (not significant). The filtration capacity was significantly higher in HC (p<0.001). The data point to a normalcy of renal reserve in ESHF which may depend on the chronic use of ACE inhibitors.

Homocysteine and Chronic Renal Failure

Homocysteine, a sulfur amino acid, is an important methionine derivative, which has been implicated in the pathogenesis of atherothrombosis. Although only observational, epidemiological studies are available at present, the evidence of an association between hyperhomocysteinemia and increased cardiovascular risk is quite strong and this is confirmed also in a population of chronic renal failure patients. From a biochemical standpoint at least three mechanisms have been so far summoned in order to explain homocysteine toxicity including: oxidation, hypomethylation, and acylation. Proteins are believed to play a crucial role as homocysteine molecular targets. Interference with the functions of several of such macromolecules has been so far described being mediated by any of the above mechanisms. Vitamins may positively influence homocysteine metabolism, thus facilitating the metabolic clearance of this compound. Therefore they are presently considered as potential means for reducing plasma levels of this amino acid and preventing vascular occlusions in hyperhomocysteinemic patients. These compounds, with special regard to folate, are eligible for interventional clinical trials, from which the definitive answer on the role of homocysteine in atherothrombosis is expected.