Giancarlo Bilancio

Bone loss in the lower leg during 35 days of bed rest is predominantly from the cortical compartment

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 tibias 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 femurs 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.

Serum uric acid and eGFR_CKDEPI differently predict long-term cardiovascular events and all causes of deaths in a residential cohort.

OBJECTIVES Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort. MATERIAL AND METHODS Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2). RESULTS Significant (p<0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05>p<0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC>0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04). CONCLUSION SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

Protein intake and kidney function in the middle-age population: contrast between cross-sectional and longitudinal data

BACKGROUND Protein intake is considered a determinant of glomerular filtration rate (GFR). Urinary urea is an objective marker of protein intake. The population-based study investigated, cross-sectionally and longitudinally, the association of protein intake with GFR, indexed by estimated GFR (eGFR). METHODS Data were collected on overnight urinary urea, serum creatinine (S-cr), eGFR and other variables in 1522 men and women aged 45-64 years who participated in the Gubbio study (baseline). S-Cr, eGFR and other variables were re-assessed in 1144 of the 1425 survivors after 12-year follow-up. RESULTS At baseline, mean ± SD was 84.0 ± 11.4 mL/min × 1.73 m(2) for eGFR calculated by CKD-Epi equation and 1.34 ± 0.57 g/day per kg of ideal weight for protein intake assessed by measurements of overnight urine excretion of urea nitrogen. Cross-sectional analyses of baseline data indicated a positive correlation of protein intake with eGFR (R = 0.180, P < 0.001). In multi-variable regression, 1 g/day higher protein intake related to 4.7 mL/min × 1.73 m(2) higher eGFR [95% confidence interval (CI) = 3.7/5.7]. At follow-up, mean ± SD of 12-year eGFR change was -11.6 ± 9.0 mL/min × 1.73 m(2). Baseline protein intake correlated with more negative eGFR change (R = -0.251, P < 0.001). In multi-variable regression, 1 g/day higher protein intake related to -4.1 mL/min × 1.73 m(2) more negative eGFR change (95% CI = -5.1/-3.1) and to 1.78 risk for incidence of eGFR < 60 mL/min × 1.73 m(2) (95% CI = 1.15/2.78). CONCLUSIONS In middle-aged adults, high protein intake is associated cross-sectionally with higher GFR but longitudinally with greater GFR decline over time.

Parallel-Group 8-Week Study on Chlorthalidone Effects in Hypertensives With Low Kidney Function

Short-term effects of chlorthalidone are unknown in low kidney function. The effects of 8-week treatment with 25-mg chlorthalidone on the top of ongoing treatment were compared between control hypertensives and low kidney function hypertensives as assessed by estimated glomerular filtration rate <60 mL/min×1.73 m2. Screening period consisted of 2 visits for patient selection and pretreatment laboratory evaluations (baseline). Inclusion criteria were uncontrolled hypertension on nondiuretic antihypertensive treatment. Exclusion criteria were chlorthalidone contraindications, refused consent, treatment with >3 antihypertensive drugs, severe hypertension, severe comorbidities, unreliable estimated glomerular filtration rate. Treatment period consisted of 5 visits (weeks 1, 2, 4, 6, and 8). Post-treatment laboratory evaluations were performed 3 to 4 days before week-8 visit. The 2 groups differed for baseline estimated glomerular filtration rate (low kidney function and control: n=60 and 60; mean, 39 and 76; range, 15–59 and 60–104) but not for sex, age, and baseline blood pressure. Week-8 blood pressure changes were a decrease in both groups (low kidney function and control: systolic pressure, −20 and −23; 95% confidence interval, −22/−18 and −26/−19; diastolic pressure, −9 and −10, −11/−7, and −13/−8) without significant between-group differences. Incidence of adverse events was similar in the 2 groups (15.0% and 16.7%). Baseline estimated glomerular filtration rate did not predict blood pressure changes and adverse events in either groups (P>0.6). In both groups, post-treatment changes were a decrease for estimated glomerular filtration rate and serum potassium, an increase for serum uric acid (P<0.01). Data show that short-term chlorthalidone effects were not reduced in hypertensives with low kidney function.

New onset of constipation during long-term physical inactivity: a proof-of-concept study on the immobility-induced bowel changes.

Background The pathophysiological mechanisms underlining constipation are incompletely understood, but prolonged bed rest is commonly considered a relevant determinant. Aims Our primary aim was to study the effect of long-term physical inactivity on determining a new onset of constipation. Secondary aim were the evaluation of changes in stool frequency, bowel function and symptoms induced by this prolonged physical inactivity. Methods Ten healthy men underwent a 7-day run-in followed by 35-day study of experimentally-controlled bed rest. The study was sponsored by the Italian Space Agency. The onset of constipation was evaluated according to Rome III criteria for functional constipation. Abdominal bloating, flatulence, pain and urgency were assessed by a 100mm Visual Analog Scales and bowel function by adjectival scales (Bristol Stool Form Scale, ease of passage of stool and sense of incomplete evacuation). Daily measurements of bowel movements was summarized on a weekly score. Pre and post bed rest Quality of Life (SF-36), general health (Goldberg’s General Health) and depression mood (Zung scale) questionnaires were administered. Results New onset of functional constipation fulfilling Rome III criteria was found in 60% (6/10) of participants (p=0.03). The score of flatulence significantly increased whilst the stool frequency significantly decreased during the week-by-week comparisons period (repeated-measures ANOVA, p=0.02 and p=0.001, respectively). Stool consistency and bowel symptoms were not influenced by prolonged physical inactivity. In addition, no significant changes were observed in general health, in mood state and in quality of life at the end of bed rest Conclusions Our results provide evidence that prolonged physical inactivity is relevant etiology in functional constipation in healthy individuals. The common clinical suggestion of early mobilization in bedridden patients is supported as well.

A longitudinal study of sleep disorders in early-stage chronic kidney disease.

Few studies have addressed the problem of sleep disturbances in patients with early-stage chronic kidney disease (CKD). A total of 220 patients newly diagnosed with CKD and 220 patients newly diagnosed with chronic hepatitis C were studied within 1 month from the diagnosis. They were evaluated by using the Charlson Comorbidity Index, the Pittsburgh Sleep Quality Index, and the Beck Depression Inventory. Patients with CKD were followed up for 4 years. Sleep disturbances affected 59.5% of patients with chronic hepatitis C and 84.6% of patients with CKD. Sleeping disorders that were severe and peculiar in early CKD improved significantly over time. Beck Depression Inventory disclosed significant depression, which was ameliorated over time. Charlson Comorbidity Index was constant over time. Logistic regression analysis failed to detect significant correlations for putative factors emerging from studies in hemodialyzed patients, with the exception of depression.

A population-based approach for the definition of chronic kidney disease: the CKD Prognosis Consortium.

INTRODUCTION The Kidney Disease: Improving Global Outcomes (KDIGO) foundation promoted the establishment of the Chronic Kidney Disease (CKD) Prognosis Consortium to meta-analyze the association of estimated glomerular filtration rate (eGFR) and albuminuria with incidence of various outcomes in samples of general populations from all over the world. METHODS Variables in meta-analysis included eGFR by the Modification of Diet in Renal Disease (MDRD) Study equation, the urinary albumin to creatinine ratio (uACR) as index of albuminuria, together with proteinuria at dipstick urinalysis and classical markers of cardiovascular risk. Overall, 105,872 participants had uACR measurements, and 1,128,310 participants had dipstick measurements. RESULTS The association with mortality was continuous over the whole range of uACR/proteinuria and J-shaped for eGFR which was associated with an excess risk for values <75 and ≥120 ml/min per 1.73 m². Results were similar for the association of eGFR or uACR/proteinuria with renal failure. The associations of eGFR and uACR/proteinuria with death or renal failure were independent of each other. Findings were consistent across population samples from North America, Asia, Oceania and Europe, as well as in individuals with age <65 years and individuals with age ≥65 years. CONCLUSIONS Data support the threshold of 60 ml/min for CKD definition but suggest that eGFR in the range 60-74 ml/min could represent the early stages of CKD. This first set of results of the CKD Prognosis Consortium represents an important step in the evidence-based definition of CKD. Conclusions should be reevaluated with eGFR calculation by equations less biased for normal-high eGFR.

The high prevalence of alexithymia in hemodialyzed patients with secondary hyperparathyroidism unsuppressed by medical therapy is cured by parathyroidectomy.

There are scanty data available on alexithymia in patients with end-stage renal disease, which point to an independent association with depression and social support. This study was devised to investigate the prevalence of alexithymia and sleep disorders in patients maintenance hemodialysis with insuppressible secondary hyperparathyroidism, who need parathyroidectomy (PTX), because previous data from our laboratories as well as those of others showed that this patient-group are the worst sleepers among hemodialysis patients with end-stage renal disease. A total of 40 patients needing PTX were enrolled and studied before the surgery. As for the control group, 80 patients on maintenance hemodialysis not needing PTX were enrolled. We measured alexithymia with the Toronto Alexithymia Score (TAS-20), sleep disorders with the Pittsburgh Sleep Quality Index (PSQI), and depression with Beck Depression Inventory (BDI), intact parathyroid hormone (iPTH), calcium, phosphate, use of antihypertensives, systolic and diastolic blood pressure, hemoglobin concentration, and albumin concentration. Patients needing PTX in comparison with those not needing PTX had significantly higher iPTH, calcium, and phosphate; they also had significantly higher systolic and diastolic blood pressure. They were more significantly alexithymic (P < .001), had more severe sleep disorders (P < .001), and were more depressed (P < .043). In multivariate analysis, BDI correlated significantly with iPTH concentration (r = 0.505, P < .001). A reduction of TAS-20 occurred after PTX which correlated with the number of patients on antihypertensive drugs, PSQI, BDI, hemoglobin concentration in the univariate and multivariate analysis. When TAS-20 and PSQI were adjusted for BDI (using analysis of variance) there was still a significant difference of TAS-20 and PSQI between patients needing PTX and not needing PTX (P < .001). This study confirms the high prevalence of sleep disorders in patients with unsuppressed secondary hyperparathyroidism and discloses a high prevalence of Alexithymia which is ameliorated by PTX. However, the correlation of Alexithymia with sleep disorders does not depend on depression.

Population-based dose–response curve of glomerular filtration rate to dietary protein intake

BACKGROUND Kidney function measured as estimated glomerular filtration rate (eGFR) is a risk factor for mortality and severe diseases. Protein intake up-regulates kidney function. The dose-response curve of eGFR over protein intake is unknown. Urinary urea nitrogen is an objective index of protein intake. METHODS The study cross-sectionally analysed the relation between overnight urinary urea nitrogen ((on)U-ureaN) and eGFR with and without control for other variables in 4106 adults of the Gubbio population. Analyses were done for serum creatinine (S-cr) also to investigate the independency of results from eGFR calculation. RESULTS Higher (on)U-ureaN associated with higher eGFR, and lower S-cr independently of sex and age (simple and partial correlation coefficients >0.100, P < 0.001). Analyses by (on)U-ureaN decile indicated sigmoid curves of eGFR and S-cr over (on)U-ureaN with trend to flatness in the lowest 20% and the highest 20% of (on)U-ureaN (<5.19 and >10.12 mg/h, respectively). Multi-variable spline regression indicated that the relation of eGFR over (on)U-ureaN was non-significant for (on)U-ureaN <5.19 mg/h (coefficient = +0.27, 95% CI = -0.31/+0.84, P = 0.364), positive for (on)U-ureaN in the range 5.19-10.12 mg/h (coefficients = 1.35-1.64, lower 95% CI ≥ +0.48, P ≤ 0.002), and non-significant for (on)U-ureaN >10.12 mg/h (coefficient = +0.05, 95% CI = -0.06/ +0.16, P = 0.394). eGFR differed by ≈8 mL/min × 1.73 m(2) between the lowest and highest 20% of (on)U-ureaN distribution. CONCLUSIONS Higher protein intake relates to higher eGFR. The relation is sigmoid with eGFR up-regulation for (on)U-ureaN >5.19 mg/h, a threshold approximately corresponding to the recommended daily allowance for protein intake (0.8 g/day per kg of ideal weight).

Effects of bed-rest on urea and creatinine: correlation with changes in fat-free mass.

Background Bed-rest experiments are designed for investigation on catabolic effects of hypokinetic conditions and/or for microgravity simulation in on-ground aerospace research. Bed-rest effects include a reduction in fat-free mass and muscle mass. Urea and creatinine are catabolites of endogenous protein and of muscular energetic metabolism which are excreted mainly by the kidney. The study investigated on urea, creatinine, and kidney function during bed-rest. Methods Twenty healthy young men underwent a 7-day adaptation period (day-6 to day-0) and a 35-day bed-rest experiment (day1 to day35) during normocaloric diet. Urine were collected from day-3 to day0 (baseline) and from day1 to day35. Blood samples and anthropometrical data were collected at day0 (baseline) and bed-rest days 7, 14, 21, 28, and 35. Results Bed-rest reduced plasma volume, weight, fat-free mass, and muscle mass (P<0.001). During bed-rest there was a transient increase in plasma and urinary urea, a decrease in plasma creatinine, and no change in urinary creatinine. The overall integral of changes from day0 to day35 was on average +101.7 mg/dL for plasma urea (95%CI = +43.4/+159.9), +82.2 g/24 h for urinary urea (95%CI = +55.8/+108.7), −2.5 mg/dL for plasma creatinine (95%CI = −3.1/−1.9). Bed-rest reduced plasma cistatyn C also, which was used as mass-independent marker of glomerular filtration rate (−13.1%, P<0.05). Correlations with final reduction in fat-free mass and muscle mass were significant for the overall integral of changes in urinary urea from day0 to day35 (R = 0.706, P<0.001) and for early changes in urinary urea and plasma urea from day0 to day7 (R = 0.566, P = 0.009 and R = 0.715, P<0.001, respectively). Conclusions Study results shows that urea is a marker of catabolic conditions secondary to hypokinetic conditions.