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Background: Urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) have been used separately to provide information about cardiovascular risk. We analyzed whether UAE and eGFR used together provide complementary information. Methods: We analyzed UAE, eGFR, cardiovascular risk factors, and incidence of cardiovascular disease in 1665men and women of the Gubbio Population Study (aged 45-64 years). We designated UAE in the highest decile as high (18.6 μg/min in men and15.7 μg/min in women) and eGFR in the lowest decile as low (64.20 mL/min/1.73m2 in men and 57.90 mL/min/1.73 m2 in women). Results: Kidney dysfunction defined using both markers was more frequent than using 1 marker (UAE alone or eGFR alone) (P.001) because high UAE and low eGFR clustered in different individuals and were weakly associated with each other (P=.12). The hazard ratio (HR) for incident cardiovascular disease was elevated for both markers, independently of each other (HR for high UAE, 2.15; 95% confidence interval [CI], 1.33-3.49; HR for low eGFR, 2.14; 95% CI, 1.32-3.48). Kidney dysfunction defined by both markers predicted cardiovascular disease independently of sex, age, hypertension, hypercholesterolemia, smoking, diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity (HR, 1.50; 95% CI, 1.05-2.14). The discriminant power of dysfunction defined by both markers was statistically significant (area under the receiver operating characteristic curve, 0.569 [P=.02]) and slightly higher than what was found with 1 marker of diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity. Conclusions: High UAE and low eGFR provide complementary information in defining kidney dysfunction because they cluster in different individuals. Concomitant evaluation of both markers should be considered to adequately assess kidney dysfunction and cardiovascular risk.

Starting November 1973, peritoneal dialyses have been performed 7 days a week on a group of 18 patients, 11 of whom still on the program. A short daily dialysis technique at a dialysate flow of 2.5 L/hour was used. This group of patients has undergone 9,724 dialyses, 86.8% of which at home.A group of 4 patients had to be switched to hemodialysis. During the last 16 months a total of 5,670 short daily dialyses have been performed, 97.4% of which at home.Another group of 6 patients has undergone Continuous Ambulatory Peritoneal Dialysis (CAPD) for 24 hours daily with 10-liter dialysate containing 3-4.25 g/100 ml dextrose. A total of 967 dialyses have been performed. Peritonitis occurred in 7 instances, and 2 patients had to be switched to hemodialysis.In summary, daily dialysis with either schedule reveals itself suitable for home program and requires a much smaller financial effort from the community. The data presented indicate that CAPD constitutes the most physiological approach to the problem of waste ...

Sleeping disorders are very common in patients with chronic kidney disease on dialysis (CKD5D) and are an emerging risk factor able to predict mortality. Parathyroid hormone (PTH) although considered a pivotal uremic toxin has rarely been associated with sleep disorders in uremia. In a study from our laboratory PTH concentrations failed to distinguish patients with sleep disorders from those without. In a study performed by Chou et al a 97% prevalence of insomnia was found in patients undergoing hemodialysis requiring parathyroidectomy. Surgery reduced PTH and increased sleeping hours within 3 months. The aim of this study was to study the effects of parathyroidectomy on the sleep disorders of insomniacs on maintenance hemodialysis. The study was performed in 16 insomniac patients on maintenance hemodialysis who successfully underwent surgery with autotransplantation of autologous parathyroid tissue (40 mg) under the skin of the forearm. Patients (5 F and 11 M) were studied from 1 month before surgery to 1 year after. Sleep disorders were assessed by means of a 27-item questionnaire--Sleep Disorder questionnaire (SDQ)--that identified sleeping disorders according to Diagnostic and Statistical Manual of Mental Disorders - IV Edition (DSM-IV) criteria. The Charlson Comorbidity Index (CCI) was also measured along with systolic and diastolic blood pressure, Hb, PTH, Ca, P. A 95.5% prevalence of sleep disorders was found pre operatively. Patients slept 4.90+/-1.2 hours, Ca averaged 10.09+/-0.54 mg/dL, Phosphate 5.5+/-1.93, CCI 9.8+/-1.1, PTH 1498+/-498 ng/mL. After 1 year follow-up 2 out 16 patients had normal sleep, 6 out 16 patients had subclinical sleep disorders and 8 remained insomniacs (p=0.008, Mc Nemar Test for paired data, insomniacs vs. no disturbance + subclinical disorders). Sleeping hours increased up to 6.0+/-1.24 (p

Hydrogen sulfide (H(2)S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H(2)S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H(2)S production. We have recently studied H(2)S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Hydrogen sulfide (H2S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H2S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H2S production. We have recently studied H2S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients. Copyright © 2011 S. Karger AG, Basel.

On July 1, 1751, the royal Parisian printer Le Breton published the first volume of the Encyclopédie of Diderot and d'Alembert, a rational dictionary, in folio and in alphabetical order, sold by subscription. The whole work was completed in 1780 (a total of 35 volumes, of which 12 were of illustrations, 4 of supplements and 2 of indices). In 1782 it was followed by the Encyclopédie méthodique, printed by Panckoucke, which ended in 1832 with volume number 166. The frontispiece of the first volume, designed by Charles-Nicolas Cochin Jr. and engraved by Benoît-Louis Prévost showed the columns of an Ionic temple where the Truth appears between Reason and Philosophy. Reason is shown trying to break the veil of Truth, and Philosophy trying to embellish it. Below are the philosophers, their eyes fixed on Truth. Theology is on his knees with his back facing Truth, and seems to receive light from the top. The subsequent chain of figures depicts Memory, Ancient History, Modern History, Geometry, Astronomy and Physics. Below are Optics, Botany, Chemistry and Agriculture. On the bottom line one finds the representatives of arts and professions derived from science. In a 42-page preface ("Discours préliminaire") d'Alembert discussed the path to new knowledge as one "based on what we receive through senses. Ideas depend on senses." The medical collaborators were, or became, famous. Medicine was considered to be rooted in experiment, in patients and in measurements. Functions started to be described with numbers. It was the birth of determinism which was later reinforced by Magendie and Claude Bernard. Albrecht Haller, president of the Academy of Science at Göttingen, as well as a member of all European academies, wrote seminal entries. New accurate definitions appeared for life, disease, death, infections, plague, epidemics, hygiene, fevers and edema. Semiology, the study of signs, became the visible explanation of deranged function, diagnosis and prognosis.

Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function. © 2009 Wiley Periodicals, Inc.

Immobilization-induced bone loss is usually greater in the epiphyses than in the diaphyses. The larger fraction of trabecular bone in the epiphyses than in the diaphyses offers an intuitive explanation to account for this phenomenon. However, recent evidence contradicts this notion and suggests that immobilization-induced bone loss from the distal tibia epiphysis is mainly from the cortical compartment. The aim of this study was to establish whether this pattern of bone loss was a general rule during immobilization. We monitored various skeletal sites with different tissue composition during 5 weeks of immobilization. Ten healthy male volunteers with mean age of 24.3 years (SD 2.6 years) underwent strict horizontal bed rest. Bone scans were obtained during baseline data collection, at the end of bed rest and after 14 days of recovery by peripheral Quantitative Computed Tomography (pQCT). Sectional images were obtained from the distal tibia epiphysis (at 4% of the tibia's length), from the diaphysis (at 38%), from the proximal metaphysis (at 93%) and from the proximal epiphysis (at 98%), as well as from the distal femur epiphysis (at 4% of the femur's length) and from the patella. Relative bone losses were largest at the patella, where they amounted to − 3.2% (SD 1.8%, p < 0.001) of the baseline values, and smallest at the tibia diaphysis, where they amounted to − 0.7% (SD 1.0%, p = 0.019). The relative losses were generally larger from cortical than from trabecular compartments (p = 0.004), and whilst all skeletal sites depicted such cortical losses, substantial trabecular losses were found only from the proximal tibia epiphysis. Results confirm that the differential losses from the various skeletal sites cannot be explained on the basis of trabecular vs. cortical tissue composition differences, but that endocortical circumference can account for the different amounts of bone loss in the tibia. The present study therefore supports the suggestion of the subendocortical layer as a transitional zone, which can readily be transformed into trabecular bone in response to immobilization. The latter will lead to cortical thinning, a factor that has been associated with the risk of fracture and with osteoarthritis.

Background: Female gender is associated with high erythropoietin (EPO) resistance in end-stage renal disease. The aim of our study was to investigate the roles of age and menstrual status in this relationship. Methods: Cross-sectional analysis of registry data for 3,224 hemodialysis adults treated with EPO. Data collection included gender, age, weight, height, dialytic age, hemoglobin, EPO dose, and, for women with ages 25–44 only, also information on menstrual status and iron homeostasis. EPO resistance index (ERI) was calculated as EPO dose per kilogram BW/hemoglobin. Results: Men and women had not significantly different hemoglobin and significantly different EPO dose per kilogram weight (women vs. men, +18.2%, p < 0.001). Thus, ERI was higher in women than in men (+19.5%, p < 0.001). The gender-associated difference in ERI linearly decreased along age groups: +30.9% for ages 25–44, +23.2% for ages 45–64, and +14.2% for ages 65–84 (p < 0.05 for interaction between age and gender-associated difference in ERI). Within the subgroup of women with ages 25–44, women with menses in comparison to women without had 44.6% higher ERI (p < 0.01) due to combination of lower hemoglobin (p < 0.05) with higher EPO dose (p < 0.001). Women with menses had also lower serum iron, transferrin saturation, and serum ferritin (p < 0.001). Conclusion: The gender-associated difference in ERI is lower with increasing patients’ age. The large difference between young men and women is due to women with menses who have iron deficiency more frequently than women without periods.

Plasma proteins containing damaged L-isoaspartyl residues are increased in uremia: Implications for mechanism.BackgroundSeveral alterations of protein structure and function have been reported in uremia. Impairment of a transmethylation-dependent protein repair mechanism possibly related to a derangement in homocysteine metabolism is also present in this condition, causing erythrocyte membrane protein damage. Homocysteine may affect proteins via the accumulation of its parent compound S-adenosylhomocysteine (AdoHcy), a powerful in vivo methyltransferase inhibitor. However, since plasma homocysteine is mostly protein bound, a direct influence on protein structures cannot be ruled out. We measured the levels of L-isoaspartyl residues in plasma proteins of uremic patients on hemodialysis. These damaged residues are markers of molecular age, which accumulate when transmethylation-dependent protein repair is inhibited and/or protein instability is increased.MethodsL-isoaspartyl residues in plasma proteins were quantitated using human recombinant protein carboxyl methyl transferase (PCMT). Plasma concentrations of homocysteine metabolites were also measured under different experimental conditions in hemodialysis patients.ResultsThe concentration of damaged plasma proteins was increased almost twofold compared to control (controls 147.83 ± 17.75, uremics 282.80 ± 26.40 pmol of incorporated methyl groups/mg protein, P < 0.003). The major protein involved comigrated with serum albumin. Although hyperhomocysteinemia caused a redistribution of thiols bound to plasma proteins, this mechanism did not significantly contribute to the increase in isoaspartyl residues. The S-adenosylmethionine (AdoMet)/AdoHcy concentration ratio, an indicator of the flux of methyl group transfer, was altered. This ratio was partially corrected by folate treatment (0.385 ± 0.046 vs. 0.682 ± 0.115, P < 0.01), but protein L-isoaspartate content was not.ConclusionsPlasma protein damage, as determined by protein L-isoaspartyl content, is increased in uremia. This alteration is to be ascribed to an increased protein structural instability, rather than the effect of hyperhomocysteinemia.

The loop of Henle (LOH) reabsorbs approximately 15% of filtered HCO 3 - via a luminal Na+-H+ exchanger and H+ATPase. During acute metabolic alkalosis (AMA) induced by i.v. HCO 3 - infusion, we have observed previously inhibition of LOH net HCO 3 - reabsorption {Mathematical expression}, which contributes to urinary elimination of the HCO 3 - load and correction of the systemic alkalosis. To determine whether the activities of the Na+-H+ exchanger and/or H+-ATPase are reduced during AMA, two inhibitors believed to be sufficiently specific for each transporter were delivered by in vivo LOH microperfusion during AMA. AMA reduced LOH {Mathematical expression} from 205.0±0.8 to 96.2±11.8 pmol · min-1 (P

The paper deals with the use of estimated glomerular filtration rate (eGFR) as marker of low kidney function in the population. Data were collected on serum creatinine, other laboratory indices, blood pressure, and medical history in a population sample of 2083 men and 2491 women aged between 18-95 years. Estimated GFR was calculated by the equation of Modification Diet in Renal Disease study. Disorders included in the analysis were hypertension, cardiovascular disease, high serum uric acid, high serum phosphorus/low serum calcium, anemia, and high serum potassium. Prevalence of low eGFR (eGFR60 mL/min per 1.73 m2) increased with age: from1% for ages 18-24 to30% for agesor =75, P0.001. On the basis of these data, prevalence of low eGFR in the adult Italian population was 5.7% for men (n=1.3 million, 95%CI = 1.1/1.5) and 6.2% for women (n=1.5 million, 95%CI = 1.3/1.8). Disorders associated with kidney dysfunction were two or more in the majority of persons with low eGFR and were more frequent with lower eGFR (p0.001). Previous diagnosis of kidney disease was reported by less than 5% in people with low eGFR and was progressively higher with higher serum creatinine or with number of associated disorders (p0.03). Hypertension tended to be more frequently treated but not more frequently controlled in people with low eGFR. Data support the use of eGFR to identify people with or at risk of low kidney function. Awareness of kidney disease is low in people with low eGFR unless serum creatinine is very high or they have many associated disorders.

The effect of an acute protein load (2 g kg‐1bodyweight [BW]) was studied in nine type 1 diabetic children. Patients were maintained on two different dietary regimens. In study one, patients were on a high protein diet providing from 2.7 to 1.8 g of protein/kg of BW per day. In study two, patients were reevaluated after three weeks of a diet providing from 1.0 to 1.2 g kg‐1 of BW per day of protein. In study one (High Protein Diet), we failed to observe any rise in GFR and RPF following the protein meal (137 ± 21 basal vs. 110±14 and 472±93 basal vs. 494±93 ml/1.73 m2 of SA min‐1 at 60 min. This is in contrast with results from seven age matched controls consuming a free diet, which showed a significant rise in both GFR and RPF. In study two (low protein diet), basal GFR was significantly reduced. However after the protein load, both GFR (92±11 vs. 126±18 ml/1.73 m2 of SA min‐1) and RPF (467±83 vs. 705±102 ml/1±73 m2 min‐1) rose significantly (P

Tri-iodothyronine (T3), even when administered for short time and at low doses, induces a large increase in the isotonic fluid reabsorption (Jv) in proximal tubules of thyroidectomized rats (TX). In order to investigate the role of the Na−K-ATPase in this process, we measured the Na−K-ATPase activity in early proximal convoluted tubules (S1) and proximal straight tubules (S2) microdissected from TX rats and rats treated with low doses of T3 (10 μg/kg body wt), either for 3 days (TX+3T3) or for 7 days (TX+7T3). In both segments no changes in Na−K-ATPase activity were found in TX+3T3 rats versus TX rats, while an increase was registered in TX+7T3 rats. Using micropuncture techniques, Jv measured on the same tubular segments increased by 68% in TX+3T3 rats versus TX. Thus, no correlation between Jv and Na−K-ATPase activity measured in vitro could be detected after short term treatment of TX rats with T3. Na−K-ATPase activity in vivo is also regulated by the potassium permeability of the membrane, which might be altered by tri-iodothyronine. This hypothesis was tested by perfusing intraluminally and peritubularly proximal tubules of TX rats with the K ionophore, valinomycin (1 μg/ml). In the dual perfusion experiments valinomycin elicited 40% of the action induced on Jv by 3 days treatment with T3. On the other hand, no further increase in Jv was recorded when valinomycin was applied in TX rats pretreated with T3. Taken together, the in vivo and in vitro experiments suggest that low doses of T3 administered for short time to TX rats do not affect Na−K-ATPase activity directly, but stimulate the in vivo activity indirectly by an increase in the k permeability of proximal tubular cell membranes. This latter effect would explain the increase in Jv through an increase in the driving force for sodium entry into the cell. © 1985, Springer-Verlag. All rights reserved.

Relation of urinary albumin excretion to coronary heart disease and low renal function: Role of blood pressure.BackgroundPrevious studies report that urinary albumin excretion is associated with coronary heart disease (CHD). The present epidemiologic study investigated if (1) blood pressure status affects the association of urinary albumin excretion with CHD; and (2) urinary albumin excretion is associated with low renal function also.MethodsThe cross-sectional association was analyzed of overnight urinary albumin excretion with prevalence of CHD (myocardial infarction and/or ischemia as defined by standard electrocardiogram) and low renal function (overnight creatinine clearance

Cross-sectional and prospective data on urinary calcium and urinary stone disease.BackgroundUrinary calcium is considered a risk factor for urinary stone disease (USD), although prospective data are missing. This epidemiologic study investigates cross-sectionally and longitudinally the relation of urinary calcium excretion to USD.MethodsIn the Gubbio Population Study, data on USD were collected by questionnaire during medical examinations from 1989 to 1992 (baseline) and telephone interviews in 1997 to 1998 (follow-up). Baseline data collection included overnight urinary calcium excretion and use of medications. Study cohort was made of 1458 men and 1799 women, age 25 to 74 years, and not on treatment with diuretics at baseline. USD was diagnosed by: excretion of stone(s), and/or radiographic or ultrasonic evidence, and/or surgical or endoscopic removal of stone(s).ResultsAt baseline, urinary calcium excretion was higher in persons with than without USD (215 and 182 μmol/hour, P < 0.001) and related to USD prevalence independent of gender, age, and other variables (P < 0.001). Among persons without USD at baseline, baseline urinary calcium excretion was higher in persons with than without incident USD at follow-up (202 and 181 μmol/hour, P = 0.034) and related to incident USD independent of gender, age, and other variables. A difference of 100 μmol/hour (about 1 SD) in urinary calcium excretion related to a difference in USD risk of 1.32 for prevalence and 1.21 for incidence (95% CI = 1.15/1.52 and 1.01/1.45, respectively) in multivariate analyses controlled for gender, age, body mass index, parental history of USD, urinary excretion of urea, sodium, and potassium.ConclusionCross-sectional and prospective data show that urinary calcium excretion is a risk factor for USD.