BACKGROUND AND AIMS:The adipocyte-derived adiponectin (APN) has potent insulin-sensitizing and anti-inflammatory properties. The adipose tissue is known to be the main source for APN in the circulation, but sites and mechanisms which remove APN from blood are still unknown in humans. METHODS AND RESULTS:We reviewed APN data obtained in previous studies in which the inter-organ exchange of amino acids and cytokines was measured in our laboratory. Results for kidney and splanchnic arterio-venous differences of APN were available for 5 subjects (age 57 ± 7 years, mean eGFR 79 ± 4 ml/min 1.73 m2). Both the liver and renal vein concentrations of total APN were lower than in the artery (by ∼32 and 20 %, respectively p < 0.05) indicating removal from blood; a similar trend (liver and renal vein level lower than the arterial by ∼22 and 15 %, respectively, p = NS) was observed for high molecular weight (HMW) APN. CONCLUSIONS:The present study identifies the splanchnic organs and the kidney as major sites for APN removal from blood in humans. Our data provide new understanding of kidney APN metabolism and suggests that reduced handling by the human kidney is a major factor to increase circulating APN in renal disease.

Cellular senescence has emerged as an important driver of aging and age-related disease in the kidney. The activity of β-galactosidase at pH 6 (SA-β-Gal) is a classic maker of senescence in cellular biology; however, the predictive role of kidney tissue SA-β-Gal on eGFR loss in chronic kidney disease (CKD) is still not understood. We retrospectively studied the expression of SA-β-Gal in kidney biopsies obtained in a cohort [n = 22] of incident patients who were followed up for 3 years as standard of care. SA-β-Gal staining was approximately fourfold higher in the tubular compartment of patients with CKD vs. controls [26.0 ± 9 vs. 7.4 ± 6% positive tubuli in patients vs. controls; p < 0.025]. Tubular expressions of SA-β-Gal, but not proteinuria, at the time of biopsy correlated with eGFR loss at the follow up; moreover, SA-β-Gal expression in more than 30% of kidney tubules was associated with fast progressive kidney disease. In conclusion, our study shows that SA-β-Gal is upregulated in the kidney tubular compartment of adult patients affected by CKD and suggests that tubular SA-β-Gal is associated with accelerated loss of renal function.

Sites and mechanisms regulating the supply of homocysteine (Hcy) to the circulation are unexplored in humans. We studied the exchange of Hcy across the forearm in CKD patients (n = 17, eGFR 20 +/- 2 ml/min), in hemodialysis (HD)-treated patients (n = 14) and controls (n = 9). Arterial Hcy was similar to 2.5 folds increased in CKD and HD patients (p < 0.05-0.03 vs. controls). Both in controls and in patients Hcy levels in the deep forearm vein were consistently greater (+similar to 7%, p < 0.05-0.01) than the corresponding arterial levels, indicating the occurrence of Hcy release from muscle. The release of Hcy from the forearm was similar among groups. In all groups arterial Hcy varied with its release from muscle (p < 0.03-0.02), suggesting that muscle plays an important role on plasma Hcy levels. Forearm Hcy release was inversely related to folate plasma level in all study groups but neither to vitamin B12 and IL-6 levels nor to muscle protein net balance. These data indicate that the release of Hcy from peripheral tissue metabolism plays a major role in influencing its Hcy plasma levels in humans and patients with CKD, and that folate is a major determinant of Hcy release.

The use of tacrolimus (Tac) may be involved in the development of new-onset diabetes after transplantation (NODAT) in a dose-related manner. This study aimed to evaluate the effects of a standard twice-daily formulation of Tac (TacBID) vs. the once-daily slow-release formulation (TacOD) on the basal insulin resistance indexes (Homa and McAuley), and related metabolic parameters, in a cohort of kidney transplant patients. We retrospectively evaluated 20 stable renal transplant recipients who were switched from TacBID to TacOD. Blood levels of Tac were analyzed at one-month intervals from 6 months before to 8 months after conversion. Moreover, Homa and McAuley indexes, C-peptide, insulin, HbA1c, uric acid, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol serum levels and their associations with Tac levels were evaluated. We observed a significant decrease in Tac exposure (8.5 ± 2 ng/mL, CV 0.23 vs. 6.1 ± 1.9 ng/mL, CV 0.31, TacBID vs. TacOD periods, p < 0.001) and no significant changes in Homa (1.42 ± 0.4 vs. 1.8 ± 0.7, p > 0.05) and McAuley indexes (7.12 ± 1 vs. 7.58 ± 1.4, p > 0.05). Similarly, blood levels of glucose, insulin, HbA1c, lipids, and uric acid were unchanged between the two periods, while C-peptide resulted significantly lower after conversion to TacOD. These data suggest that in kidney transplant recipients, reduced Tac exposure has no significant effects on basal insulin sensitivity indexes and metabolic parameters.

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney trans-plant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 +/- 1.6 mL/min/1.73 m(2)) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 +/- 2.2 mL/min/1.73 m(2) ) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 +/- 2.2 vs 48.0 +/- 2.7 mL/min/1.73 m(2) in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia. In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in with

Abstract Background and Aims Skeletal muscle is a highly adaptive tissue, however even small imbalances between protein synthesis and degradation can lead to substantial protein loss. Althought proteolysis plays a major role in the development of cachexia in CKD (chronic kidney disease), the responses of muscle protein metabolism to malnutrition had not been completely elucidated. We evaluated retrospectively the results of kinetic studies of protein turnover estimated by the forearm perfusion method associated with H2phenylalanine kinetic, obtained in CKD patients and controls in the last 25 years. Method We analyzed 59 forearm H2phenylalanine kinetic studies obtained in 14 controls (C) (M 11, F 3) and 45 patients with CKD, of whom 15 (M 10, F 5) were on conservative treatment (CKD stage IV-V), 16 (M 14, F 2) under maintenance hemodialysis (HD), 14 (M 12, F 2) in peritoneal dialysis (DP); all subjects were on non-restricted protein/calorie (0.8-1.1 g/kg and 28-32 kcal/kg, respectively) diets. Ten (M 9, F 1) HD patients had Protein Energy Wasting. Acidosis was corrected in all patients (HCO3 24.2±1.9 mmol/L) and studies were performed in the post-absorptive overnight fasted state at rest. Results Overall, Muscle protein synthesis and degradation were similar (p=NS) in patients and controls. Protein net balance was reduced in patients with PD and those with CKD Stage IV-V (p <0.003 - p <0.014) indicating a reduced catabolic state and nitrogen conservation. However PEW HD patients showed reduced rates of protein synthesis and degradation (p <0.048 and p <0.04 respectively). In addition the efficiency of muscle protein turnover, a parameter expressing muscle's ability to reuse amino acids derived from degradation into protein synthesis, was significantly reduced in HD PEW patients vs. controls (55.5 vs. 61.2 %, p <0.018, respectively) and vs. not malnourished patients in conservative treatment (70.1 % p <0.0025) or in PD (74.6 % p <0.005). Conclusion In CKD patients, in absence of acidosis, muscle is able to increase the efficiency of protein metabolism for the maintenance of nitrogen balance. However, in PEW patients, combined alterations of protein synthesis and degradation proceed together to a reduced efficiency of amino acids recycled into protein synthesis and contribute to maintaining wasting. These data also suggest that calorie/protein requirements of CKD patients with PEW may be higher than currently theorized.

Background: Chronic kidney disease (CKD) reduces both Klotho expression and its shedding into circulation, an effect that accelerates progression and cardiovascular complications. However, the mechanisms that regulate Klotho release by the human kidney are still unknown. Methods: We measured plasma Klotho across the kidney, splanchnic organs and lung in 22 patients (71 +/- 2 years, estimated glomerular filtration rate [eGFR] 60 +/- 5.4 mL/min 1.73 m(2)) during elective diagnostic cardiac catheterizations. Results: Although the Klotho average renal vein concentrations were remarkably higher (by similar to 9%) than arterial values, the kidney removed Klotho (or was at zero balance) in 7 subjects, indicating that the kidney contribution to systemic Klotho is not constant. Klotho fractional enrichment across the kidney was inversely related to plasma sodium (r = 0.43, p = 0.045) and acid uric acid levels (r = 0.38, p = 0.084) and directly, to renal oxygen extraction (r = 0.56, p = 0.006). In multivariate analysis, renal oxygen extraction was the only predictor of the enrichment of Klotho across the kidney, suggesting the dependence of renal Klotho release on tubular hypoxia or oxidative metabolism. Klotho balance was neutral across the lung. In patients with eGFR <60 mL/min, Klotho was also removed by splanchnic organs (single pass fractional extraction similar to 11%). Conclusions: The present study identifies kidney oxygen uptake as a predictor of Klotho release, and splanchnic organs as a site for Klotho removal. This study provides new understanding of kidney Klotho release and suggests that modulating kidney oxygen metabolism could increase Klotho delivery, as an option to slow disease progression and blunt organ damage. (C) 2019 The Author(s) Published by S. Karger AG, Basel

Wasting is observed in a large percentage of patients receiving peritoneal dialysis (PD) and it is associated with functional impairment and worse outcome. In this article, we review the current state of our knowledge regarding the effects of PD on protein metabolism and their possible interactions with the uremia-induced and comorbidity-induced alterations in protein metabolism. Available evidence shows that glucose-based PD induces a new state in muscle protein dynamics which is characterized by decreased turnover rates and a reduced efficiency of protein turnover, a condition which may be harmful in stress conditions, when nutrient intake is diminished or during superimposed catabolic illnesses. The effects of PD on protein turnover may overlap with the effects of aging and comorbidities to promote net catabolism. There is a need to develop more effective treatments to enhance the nutritional and functional status of PD patients. New approaches include the use of icodextrin to maintain extracellular volume, amino acids/keto acidscontaining supplements combined with physical exercise, vitamin D, myostatin antagonism, and ghrelin agonism for malnourished patients refractory to standard nutritional therapy.

Introduction: Early studies have shown that patients with chronic kidney disease (CKD) are able to maintain nitrogen balance despite significantly lower protein intake, but how and to what extent muscle protein metabolism adapts to a low-protein diet (LPD) or to a supplemented very LPD (sVLPD) is still unexplored. Methods: We studied muscle protein turnover by the forearm perfusion method associated with the kinetics of 2H-phenylalanine in patients with CKD: (i) in a parallel study in subjects randomized to usual diet (1.1 g protein/kg, n = 5) or LPD (0.55 g protein/kg, n = 6) (Protocol 1); (ii) in a crossover, self-controlled study in subjects on a 0.55 g/kg LPD followed by a sVLPD (0.45 g/kg thorn amino/ketoacids 0.1 g/kg, n = 6) (Protocol 2). Results: As compared with a 1.1 g/kg containing diet, a 0.55 g/kg LPD induced the following: (i) a 17% to 40% decrease in muscle protein degradation and net protein balance, respectively, (ii) no change in muscle protein synthesis, (iii) a slight (by approximately 7%, P < 0.06) decrease in whole-body protein degradation, and (iv) an increase in the efficiency of muscle protein turnover. As compared with an LPD, an sVLPD induced the following: (i) no change in muscle protein degradation, and (ii) an approximately 50% decrease in the negative net protein balance, and an increase in the efficiency of muscle protein turnover. Conclusion: The results of these studies indicate that in patients with CKD the adaptation of muscle protein metabolism to restrained protein intake can be obtained via combined responses of protein degradation and the efficiency of recycling of amino acids deriving from protein breakdown.

Cancer affects sexuality in multiple and cumulative ways. Fifty per cent of cancer patients and survivors have sexual difficulties secondary to cancer and its treatment. Loss of sexual desire, erectile dysfunction (ED) and dyspareunia are the most prevalent sexual dysfunctions. Even if cancer cured, sexual problems tend to worsen over time and become chronic if not prevented or immediately treated. Millions of patients and survivors need clear information, screening and prompt intervention on predictable sexual consequences of cancer treatment. This work highlights the OncoSexology Clinic experience in a major Portuguese oncology center. Description of the OncoSexology Clinic created in 2009: mission, organization, professional team and main groups of patients. Before starting the outpatient clinic, this group had carried out an intensive and inclusive program of education and training in Sexual Medicine and OncoSexology basics: teaching other nurses and doctors to feel more comfortable talking with patients about sex and screening expected sexual problems in each step and type of disease.

A changing paradigm of treatment of kidney transplant recipients is a new, wider approach to immunosuppression, which should take into account both antiviral and anticancer effects, in addition to cardiovascular protection. Recent observations suggest that the early introduction of mammalian target of rapamycin inhibitors (mTORi) in association with low dose CNI may offer many of these effects. The present manuscript summarizes benefits and contraindications of combinations with mTORi in kidney transplant immunosuppressive strategies.

BackgroundInflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up‐regulates pro‐inflammatory cytokines is unknown. Toll‐like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro‐inflammatory cytokine.MethodsTLR4, phospho‐p65, phospho‐ikBα, tumour necrosis factor (TNF)‐α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT–PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT–PCR) and TLR‐driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.ResultsCKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB‐regulated gene TNF‐α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF‐α and down‐regulated pAkt. These effects were prevented by blockade of TLR4.ConclusionsCKD promotes muscle inflammation through an up‐regulation of TLR4, which may activate downward inflammatory signals such as TNF‐α and NFkB‐regulated genes.

Fibroblast growth factor-23 (FGF-23) accumulates in blood of patients with chronic kidney disease (CKD) and is associated both with cardiovascular complications and disease progression. However, our knowledge of the sites and mechanisms that regulate plasma FGF-23 is still incomplete. We measured plasma intact FGF-23 across the kidney, splanchnic organs, and lung in 11 patients [estimated glomerular filtration rate (eGFR) 60 ± 6 ml/min] during elective diagnostic cardiac catheterizations. In these patients FGF-23 was removed by the kidney, with a fractional extraction (FE) of ∼22%. The FE of FGF-23 across the kidney was similar to that of creatinine (∼17%, P = NS). In addition, the FGF-23 FE by the kidney was significantly directly related to eGFR (r = 0.709 P = 0.018) and to kidney creatinine FE (r = 0.736 P = 0.013) but only as a trend to plasma phosphate levels (r = 0.55, P = 0.18). There was no difference in FGF-23 levels in blood perfusing splanchnic organs and cardiopulmonary bed. However, the arterial-venous difference of FGF-23 across the lung was directly related to FGF-23 pulmonary artery levels, suggesting that the lung, and possibly the heart, participate in the homeostasis of plasma FGF-23 when its systemic levels are increased. Our data show that the human kidney is the only site for FGF-23 removal from blood and suggest that FGF-23 is predominantly removed by glomerular filtration. The kidney ability to remove FGF-23 from the circulation likely accounts for the early increase in blood of FGF-23 in patients with CKD.

An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass in patients with chronic kidney disease (CKD). We tested whether insulin resistance extends to protein metabolism using the forearm perfusion method with arterial insulin infusion in 7 patients with CKD and metabolic acidosis (bicarbonate 19mmol/l) and 7 control individuals. Forearm glucose balance and protein turnover (2H-phenylalanine kinetics) were measured basally and in response to insulin infused at different rates for 2 h to increase local forearm plasma insulin concentration by approximately 20 and 50 mu U/ml. In response to insulin, forearm glucose uptake was significantly increased to a lesser extent (-40%) in patients with CKD than controls. In addition, whereas in the controls net muscle protein balance and protein degradation were decreased by both insulin infusion rates, in patients with CKD net protein balance and protein degradation were sensitive to the high (0.035 mU/kg per min) but not the low (0.01mU/kg per min) insulin infusion. Besides blunting muscle glucose uptake, CKD and acidosis interfere with the normal suppression of protein degradation in response to a moderate rise in plasma insulin. Thus, alteration of protein metabolism by insulin may lead to changes in body tissue composition which may become clinically evident in conditions characterized by low insulinemia.

Context. In 2009, the Sun and the Earth passed through the equatorial plane of Jupiter and therefore the orbital planes of its main satellites. It was the equinox on Jupiter. This occurrence made mutual occultations and eclipses between the satellites possible. Experience has shown that the observations of such events provide accurate astrometric data able to bring new information on the dynamics of the Galilean satellites. Observations are made under the form of photometric measurements, but need to be made through the organization of a worldwide observation campaign maximizing the number and the quality of the data obtained.

PEW is associated with muscle dysfunction and excess mortality in ESRD patients. However the mechanisms causing wasting have been scarcely studied in humans. In addition, to what extent the microinflammatory state associated with uremia affects the individual determinants of protein turnover has not been specifically studied so far. In the present study, we measured protein synthesis (PS) and degradation (PD) (2H-phe kinetics) and oxygen (O2) uptake across the forearm in 58 subjects. Forearm protein turnover was studied in patients with CKD stage IV (n=16-unresticted diet- and n= 13 under low protein diets), in hemodialysis-treated patients with ESRD (n=17, of whom 10 were protein-calorie wasted), and in 12 controls (C). Amino acids were determined by an amino acid analyzer, while phenylalanine isotopic enrichments by GC/MS. Blood flow across the forearm was determined by strain-gauge plethysmography. Data are given in nmol/min. 100 ml forearm.

Studies in animals have shown that uremia interacts with IRS signaling, leading to defective AKT phosphorylation, and that this process may lead to caspase activation and accelerated proteolysis. In a previous study, we observed that apoptotic loss of myonuclei is enhanced in CKD-Stage 5 patients and that this finding couples with defective AKT phosphorylation, suggesting that altered insulin signalling is responsible for defective regeneration of muscle myofiber. In this study we evaluated the occurrence of cell loss by apoptosis, as well as of changes in myostatin gene expression and MAPK-related cellular signaling in muscle biopsies of patients with advanced CKD.