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Increased arterial hypertension represents a prevalent condition in peritoneal dialysis patients that is often related to volume expansion. Pulse pressure is a robust predictor of mortality in dialysis patients, but its association with mortality is unknown in peritoneal patients. We investigated the relationship between home pulse pressure and survival in 140 PD patients. During a mean follow-up of 35 months, 62 patients died, and 66 experienced the combined event death/CV events. In a crude COX regression analysis, a five-unit increase in HPP was associated with a 17% increase in the hazard ratio of mortality (HR: 1.17, 95% CI 1.08–1.26 p < 0.001). This result was confirmed in a multiple Cox model adjusted for age, gender, diabetes, systolic arterial pressure, and dialysis adequacy (HR: 1.31, 95% CI 1.12–1.52, p = 0.001). Similar results were obtained considering the combined event death–CV events as an outcome. Home pulse pressure represents, in part, arterial stiffness, and it is strongly related to all-cause mortality in peritoneal patients. In these high cardiovascular risk populations, it is important to maintain optimal blood pressure control, but it is fundamental to consider all the other cardiovascular risk indicators, such as pulse pressure. Home pulse pressure measurement is easy and feasible and can add important information for the identification and management of high-risk patients.

Background: In Europe, the number of elderly end-stage kidney disease patients is increasing. Few of those patients receive peritoneal dialysis (PD), as many cannot perform PD autonomously. Assisted PD programmes are available in most European countries, but the percentage of patients receiving assisted PD varies considerably. Hence, we assessed which factors are associated with the availability of an assisted PD programme at a centre level and whether the availability of this programme is associated with proportion of home dialysis patients. Methods: An online survey was sent to healthcare professionals of European nephrology units. After selecting one respondent per centre, the associations were explored by χ 2 tests and (ordinal) logistic regression. Results: In total, 609 respondents completed the survey. Subsequently, 288 respondents from individual centres were identified; 58% worked in a centre with an assisted PD programme. Factors associated with availability of an assisted PD programme were Western European and Scandinavian countries (OR: 5.73; 95% CI: 3.07–10.68), non-academic centres (OR: 2.01; 95% CI: 1.09–3.72) and centres with a dedicated team for education (OR: 2.87; 95% CI: 1.35–6.11). Most Eastern & Central European respondents reported that the proportion of incident and prevalent home dialysis patients was 30% for both incident and prevalent home dialysis patients. Availability of an assisted PD programme was associated with a higher incidence (cumulative OR: 1.91; 95% CI: 1.21–3.01) and prevalence (cumulative OR: 2.81; 95% CI: 1.76–4.47) of patients on home dialysis. Conclusions: Assisted PD was more commonly offered among non-academic centres with a dedicated team for education across Europe, especially among Western European and Scandinavian countries where higher incidence and prevalence of home dialysis patients was reported.

BACKGROUND Chronic Kidney Disease is a major public health issue, with about 13% of the general adult population and 30% of the elderly affected. Patients in the last stage of this disease have an almost uniquely high risk of death and cardiovascular events, with reduced adherence to therapy representing an additional risk factor for cardiovascular morbidity and mortality. Considering the wide spreading of mobile phones, a mobile app could educate patients in self-monitoring cardio-renal risk factors. OBJECTIVE To develop an integrated system to educate patients in self-monitoring cardio-renal risk factors. METHODS We developed an integrated system made by a server and an app, with the aim of improving self-monitoring of cardiovascular and renal risk factors and of improving adherence to therapy. RESULTS The SMIT-CKD APP allows the monitoring of cardio-renal risk factors and their transmission to the referring GP. Special reminders help drug administration. Via the SMIT-CKD Server, GPs can monitor the clinical status of their patients and adherence to therapy. During the test, 73% of subjects entered all the required data regularly and sent feedbacks of drug intake. Looking at the evaluation questionnaires, both the app and the server counterpart were well accepted by the users. CONCLUSIONS Our study demonstrated that a simple Mobile APP, created to self-monitor modifiable cardio-renal risk factor and adherence to therapy, is well tolerated by patients affected by Chronic Kidney Disease. Further studies are required to clarify if the use of this integrated system will have long-term effects on therapy adherence, and if self-monitoring of risk factors will improve clinical outcomes in this population. CLINICALTRIAL NA

Hyperkalemia is a potential life-threatening condition among chronic kidney disease (CKD) patients. Available estimates of the burden of this alteration in CKD are mainly derived from large administrative databases. Since K measurements in patients in these databases are often dictated by clinical reasons, longitudinal studies including pre-planned measurements of potassium independently of clinical complication/symptoms may produce more reliable estimates of the frequency and the risk factors underlying hyperkalemia in CKD patients. We estimated the prevalence and the incidence of hyperkalemia in a longitudinal study in 752 stages 2–5 CKD patients lasting 3 years and including up to seven pre-planned assessment of key biochemical measurements including K. At baseline, 203 out of 752 patients (27%) had serum K > 5.0 mM/L and 33% had acidosis (HCO3 ≤ 22 mmol/L). Among those without hyperkalemia at baseline (n = 549), 284 patients developed this alteration across the 3-year follow-up. The point prevalence of hyperkalemia rose from 27% (baseline) to 30% (last visit) (P = 0.001). In a multivariate model, hyperkalemia at baseline [odds ratio (OR):7.29, 95% CI 5.65–9.41, P

Introduction: Peritoneal dialysis (PD) remains underutilised and unplanned start of dialysis further diminishes the likelihood of patients starting on PD, although outcomes are equal to haemodialysis (HD). Methods: A survey was sent to members of EuroPD and regional societies presenting a case vignette of a 48-year-old woman not previously known to the nephrology department and who arrives at the emergency department with established end-stage kidney disease (unplanned start), asking which dialysis modality would most likely be chosen at their respective centre. We assessed associations between the modality choices for this case vignette and centre characteristics and PD-related practices. Results: Of 575 respondents, 32.8%, 32.2% and 35.0% indicated they would start unplanned PD, unplanned HD or unplanned HD with intention to educate patient on PD later, respectively. Likelihood for unplanned start of PD was only associated with quality of structure of the pre-dialysis program. Structure of pre-dialysis education program, PD program in general, likelihood to provide education on PD to unplanned starters, good collaboration with the PD access team and taking initiatives to enhance home-based therapies increased the likelihood unplanned patients would end up on PD. Conclusions: Well-structured pre-dialysis education on PD as a modality, good connections to dedicated PD catheter placement teams and additional initiatives to enhance home-based therapies are key to grow PD programs. Centres motivated to grow their PD programs seem to find solutions to do so.

Background and Aims Effective outpatient organization is essential in the management of patients with chronic kidney disease. Although peritoneal dialysis (PD) has many advantages it is still not popular. Method The aim of this study was to evaluate patient and center-related factors that affect the final choice of peritoneal dialysis (PD) versus hemodialysis (HD) in the Calabrian region (Italy). We analyzed 2 annual regional surveys performed by nephrologists (2017 and 2018) in incident dialysis patients. Collected factors included: early and late referral to the dialysis program, pre-dialysis participation in outpatient visits, first dialysis access [peritoneal catheter (PC), central venous catheter (CVC), arteriovenous fistula (AVF)], final dialysis treatment (HD or PD) and the care giver. Results The study sample included 296 incident patients (63% males) aged 66±15 years. Time to referral influenced the type of first dialysis access. Among patients with early referral, 35% initiated dialysis by a PC, 34% by AVF and 31% by CVC, while among those with late referral, only 5% started dialysis by a PC, 15% by AVF, and the majority (80%) by CVC (P Conclusion These data confirm that a more attentive and dedicated organization of the pre-dialysis outpatient program would contribute to a greater expansion of the peritoneal dialysis program.

Background and Aims The knowledge of the impact of peritoneal dialysis (PD) program in terms of hospitalization rate can provide solid guidance for nephrologists for management purpose. In a historical cohort of adult PD patients, we examined the hospitalization rates and causes of hospital admissions. Method One hundred ninety-one consecutive PD patients between January 1st 2000 to December 31st 2018 were enrolled. The maximum follow up was 194 months. Their mean age was 65±15 years, 110 were males, 56 had co-morbidities and 67 were diabetics. The median PD vintage was 35 months (interquartile range 20-63 months). Results During the follow-up, 163 out of 191 patients (85%) underwent hospital admission for a total of 356 hospitalizations [57 hospitalizations per 100-person-years]. The most frequent cause of admission was infection (20 hospitalizations per 100-person-years) mainly due to peritonitis (12 hospitalizations per 100-person-years) followed by cardiovascular diseases (17 hospitalizations per 100-person-years). Hospitalizations due to miscellaneous causes were 21 per 100-person-years. In the whole group, high NYHA score [Incidence Rate Ratio (IRR): 1.52, 95%CI 1.21-1.89, P65 years) (IRR 1.26, 95%CI 1.02-1.56, P=0.03) and were associated to all-cause hospitalizations. In an analysis by hospitalization type, the factors related to admission for infection diseases was malnutrition (IRR: 1.91, 95%CI 1.16-3.03, P=0.005) and high NYHA score (IRR: 1.52, 95%CI 1.03-2.22, P=0.02). As expected, hospitalizations due to cardiovascular causes were strongly related to older age (>65 years) (IRR 2.02, 95%CI 1.35-3.03, P Conclusion Analyzing the causes and the rate of hospitalization in PD patients allows more accurate management of these high risk category of patients and contributes to a more efficient organization of a renal department.

Background and Aims A 21 year old boy with a diagnosis of Autosomal Recessive Polycystic Kidney Disease and Caroli disease reached a final stage of chronic kidney disease (CKD) and started haemodialysis. Method After 3 years in haemodialysis he underwent a kidney transplant from a cadaveric donor. His transplanted kidney worked fairly well until the patients was 31 year old when he developed graft dysfunction (serum creatinine from 2.7 to 5 mg/dL in a very short period). There was a concomitant increase in serum phosphate levels (8.3 mg/dl) and iPTH that progressively increased to 1032 pg/ml despite a traditional therapy. Results At age 32, the patient returned to haemodialysis treatment thrice weekly with a concomitant a progressive worsening of hyperparathyroidism with bone pain . Cinacalcet at a dosage of 30 mg daily treatment was initiated, then it was increased to 120 mg daily without any benefit. Two years later, being the clinical situation without any improvement and being the patient scarcely compliant to the therapy and because a further enlargement of parathyroid glands was observed, a Parathyroidectomy (PTX) was advised. Nevertheless, PTX was not performed because of patient’s refusal. Furthermore, despite Erythropoietic Stimulating Agent (ESA) therapy, he developed severe anemia that required regular and frequent blood transfusions. iPTH increased to 4500 pg/ml [Fig.1] with a parallel rise in alkaline phosphatase >600 UI/L [Fig.2]. A Computed Tomography scan showed multiple bone-thickening lesions. He thus initiated Etelcalcetide 5 mg e.v. 3 times a week, after the HD session but without any benefit. The dosage was then increased to 7.5 mg but the patient gradually became frail and developed pancytopenia and low-grade fever. Hematological evaluation with bone marrow biopsy was performed in December 2019. Bone marrow histology showed severe fibrosis [Myelofibrosis (MF) grade 3] with normal bone marrow cytogenetics. Blood samples for mutations in JAK-2, CALR, and MPL and BCR-ABL rearrangement were negative. There was no evidence for a myeloproliferative neoplasm (MPN) or metastatic lesions. During the following months, while on a 7,5 mg dose of etalcalcetide, there was a gradual reduction in iPTH [Fig.1] and serum alkaline phosphatase [Fig.2], up to 500 pg/dl and 200 IU/L respectively. The patient developed asymptomatic, often severe, hypocalcemia which was managed with therapy. The patient’s clinical conditions gradually improved, anemia responded to lower doses of ESAs. A bone marrow biopsy was repeated after one year (December 2020) and it showed a reduction in fibrosis (MF grade varying from 1-2). Then etelcalcetide dosage was reduced while serum calcium and phosphate levels were in the normal limit. Conclusion Myelofibrosis secondary to renal osteodystrophy is an uncommon complication. It has been rarely reported and usually is associated with primary hyperparathyroidism. Marrow fibrosis and pancytopenia is related to the excessive iPTH that upregulates production of cytokines and paracrine factors in the bone marrow (IL-1a, IL-6, FNF-a, TGF–b, and platelet-derived growth factor) and it has an important stimulatory effect on fibroblast proliferation. It is known that surgical parathyroidectomy is associated with a reduction of bone marrow fibrosis in primary hyperparathyroidism. To our knowledge, this is probably the first case of tertiary hyperparathyroidism in which the effect of etelcalcetide is comparable to parathyroidectomy as far as on calcium-phosphate balance, and a significant improvement in bone marrow fibrosis and hemoglobin. In conclusion, etelcalcetide at least in this patient seems as effective as PTX on bone balance, bone marrow and anemia.

Chronic Kidney Disease is a major public health issue, with about 13% of the general adult population and 30% of the elderly affected. Patients in the last stage of this disease have an almost uniquely high risk of death and cardiovascular disease, probably because kidney and cardiovascular system share the same risk factors, such as hypertension, high blood glucose and body weight. Reduced adherence to therapy represents an additional risk factor for cardiovascular morbidity and mortality in renal patients. Considering the wide spreading of mobile phones, an app could be a possible solution to self-monitor cardiovascular risk factors and to improve adherence to therapyWe developed an integrated system made by a server and an app within the SMIT-CKD project, with the aim to improve self-monitoring of risk factors of both renal and cardiovascular disease and to improve adherence to therapy. The integrated system was tested with the help of 22 volunteers.The level of compliance with the use of the app and data entering was quite high, being “malfunctioning due to obsolete versions of the operative system” the main cause of scarce use. After 6 months of use, the percentage of regular intake of medications rose from 64 to 82%. User satisfaction was high, as both the server and the app obtained high scores in the questionnaires administered to general practitioners and patientsOur pilot study demonstrated that the use of a simple Mobile APP may improve adherence to therapy in patients affected by Chronic Kidney Disease. Further studies, specifically designed to test this app in a larger population, are required to clarify if the use of the SMIT-CKD integrated system will have long-term effects on therapy adherence, and if self-monitoring of risk factors will improve clinical outcomes in this population.

Background Sleep‐disordered breathing ( SDB ) is considered a strong risk factor for hypertension in the general population. This disturbance is common in end‐stage kidney disease patients on long‐term hemodialysis and improves early on after renal transplantation. Whether SDB may be a risk factor for hypertension in renal transplant patients is unclear. Methods and Results We investigated the long‐term evolution of simultaneous polysomnographic and 24‐hour ambulatory blood pressure (BP) monitoring recordings in a cohort of 221 renal transplant patients. Overall, 404 paired recordings were made over a median follow‐up of 35 months. A longitudinal data analysis was performed by the mixed linear model. The apnea‐hypopnea index increased from a median baseline value of 1.8 (interquartile range, 0.6–5.0) to a median final value of 3.6 (interquartile range, 1.7–10.4; P =0.009). Repeated categorical measurements of the apnea‐hypopnea index were directly associated with simultaneous 24‐hour, daytime, and nighttime systolic ambulatory BP monitoring (adjusted analyses; P ranging from 0.002–0.01). In a sensitivity analysis restricted to 139 patients with at least 2 visits, 24‐hour, daytime, and nighttime systolic BP significantly increased across visits ( P SDB (n=40), whereas the same BP metrics did not change in patients (n=99) with stable apnea‐hypopnea index. Conclusions In renal transplant patients, worsening SDB associates with a parallel increase in average 24‐hour, daytime, and nighttime systolic BP . These data are compatible with the hypothesis that the link between SDB and hypertension is causal in nature. Clinical trials are, however, needed to definitively test this hypothesis.

Background and Aims Mortality risk is very high in the dialysis population and the Charlson Comorbidities Index (CCI) is considered as an useful risk stratification tool in these patients. The purpose of this study was to examine the accuracy of CCI for predicting mortality in peritoneal dialysis (PD) patients and to compare the prognostic power of CCI with that of a risk prediction model jointly including a clinical score of malnutrition and the NYHA classes. Method We analyzed this problem in a series of 66 consecutive PD patients on follow-up in our unit. Their mean age was 69±14 years, 64% were male, 36% were diabetic. The median dialysis vintage was 39 months (Interquartile range 23-67 months). Results During follow-up period, 37 patients died. On univariate Cox regression analysis, CCI largely failed to predict mortality [Hazard ratio (HR): 1.08, 95% CI: 0.94-1.24, P=0.30) and this relationship did not improve (HR: 0.93, 95% CI: 0.79-1.08, P=0.32) also after data adjustment for malnutrition and NYHA classes. In the same model, malnutrition (HR: 1.98, 95% CI 1.20-3.27, P=0.007) and NYHA classes (HR: 3.15, 95% CI 1.67-5.94, P Conclusion In this study, CCI did not predict survival in PD patients whereas malnutrition and NYHA score displayed a relevant prognostic accuracy for death in the same patient-population. These results generate the hypothesis, to be confirmed in a larger PD population, that CCI solely for risk stratification is unwarranted in PD patients.

Paget bone disease (PDB) is often asymptomatic and incidentally diagnosed. It is a cause of osteoporosis and bone fragility and exposes patients to a high incidence of bone fractures. In Europe the prevalence varies according to the geographical area of origin, and increases with age. In patients with chronic renal disease, the prevalence is unknown and only few cases with PDB have been reported. We present a challenging case in an elderly patient with chronic kidney disease on peritoneal dialysis treatment. Our patients presented extremely high levels of alkaline phosphatase, suggesting a Paget bone disease. Secondary hyperparathyroidism was confirmed by the bone histological examination. The surprising biochemical and clinical response to active vitamin D confirms the well-known role on hyperparathyroidism and may indicate an additional role in the pathogenesis of Paget's disease.

Introduction The soluble receptor of urokinase plasminogen activator (suPAR) is an innate immunity/inflammation biomarker predicting cardiovascular (CV) and non-CV events in various conditions, including type 2 diabetic patients on dialysis. However, the relationship between suPAR and clinical outcomes in the hemodialysis population at large has not been tested. Methods We measured plasma suPAR levels (R&D enzyme-linked immunosorbent assay [ELISA]) in 1038 hemodialysis patients with a follow-up of 2.9 years (interquartile range = 1.7−4.2) who were enrolled in the PROGREDIRE study, a cohort study involving 35 dialysis units in 2 regions in Southern Italy. Results suPAR was strongly (P < 0.001) and independently related to female gender (β = −0.160), age (β = 0.216), dialysis vintage (β = 0.264), CV comorbidities (β = 0.105), alkaline phosphatase (β = 0.136), albumin (β = −0.147), and body mass index (BMI; β = 0.174) (all P < 0.006). In fully adjusted analyses, suPAR tertiles predicted the risk of all-cause mortality (third tertile vs. first tertile hazard ratio (HR) = 1.91, 95% confidence interval (CI) = 1.47 – 2.48, P < 0.001), CV mortality (HR = 1.47, 95% CI = 1.03–2.09, P = 0.03), and non-CV mortality (HR = 1.94, 95% CI = 1.28–2.93, P = 0.002); these relationships were not modified by diabetes or other risk factors. suPAR added only modest prognostic risk discrimination and reclassification power for these outcomes to parsimonious models based on simple clinical variables. Conclusion In conclusion, suPAR robustly predicted all-cause and both CV and non-CV mortality in a large unselected hemodialysis population. Intervention studies are needed to definitively test the hypothesis that suPAR is causally implicated in clinical outcomes in this population.

Etelcalcetide is a new calcimimetic indicated for the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients. Etelcalcetide efficacy in SHPT has been ascertained only in randomized controlled trials. This multicenter study was carried out in &ldquo, real world&rdquo, setting that is different from randomized controlled trials (RCTs) to (1) evaluate the effectiveness of etelcalcetide in SHPT, (2) to assess calcium, phosphorus, alkaline phosphatase changes, (3) to register gastrointestinal side effects. Data were collected from twenty-three dialysis units with n = 1190 patients on the charge. From this cohort, n = 168 (14%) patients were on treatment with etelcalcetide, and they were evaluated for statistics. A median weekly dose of etelcalcetide was 15 mg (7.5&ndash, 45 mg). Patients were either na&iuml, ve (33%) or switched from cinacalcet to obtain better control of SHPT with reduced side effects or pills burden. Serum parathyroid hormone (PTH) declined over time from a median value of 636 pg/mL to 357 pg/mL. The median time for responders (intact PTH (iPTH) range: two to nine times the upper normal limit) was 53 days, the percentage of responders increased (from baseline 27% to 63%) being similar in switched-patients and na&iuml, ve-patients. Few patients had symptomatic hypocalcemia requiring etelcalcetide withdrawal (four cases (3%) at 30-day control, two cases (2%) at 60-day, one case (1%) at 90-day control). Side effects with etelcalcetide were lower (3&ndash, 4%) than that registered during cinacalcet treatment (53%). Etelcalcetide is a new therapeutic option for SHPT with low side effects and pills burden. Etelcalcetide may improve adherence to therapy, avoiding unremitting SHP. It remains to be assessed whether etelcalcetide may reduce parathyroidectomy, vascular calcification, or mortality. Being etelcalcetide very potent in suppressing PTH levels, even in severe SHPT, future studies should evaluate the potential risk of more adynamic bone disease during long-term therapy.

Lung congestion and frank pulmonary edema are established complications of acute kidney injury (AKI) and early detection and monitoring of lung congestion may be useful for the clinical management of AKI patients.We compared standardized clinical criteria (including lung crackles and peripheral edema grading) and simultaneous chest ultrasound (US) to detect lung congestion in a series of 39 inpatients with AKI.At baseline, twelve patients (31%) were clinically euvolemic and twelve presented clear-cur cardiovascular congestion (31%) by clinical criteria. Fifteen patients (38%) were hypovolemic. The median number of US-B lines in patients with cardiovascular congestion was much higher (50, inter-quartile range 27-99) than in euvolemic (14, IQR 11-37) and hypovolemic patients (7, IQR 3-16, P 0.001). Remarkably, a substantial proportion of asymptomatic euvolemic (66%) and hypovolemic (46%) patients had lung congestion of moderate to severe degree ( 15 US-B lines) by lung US. Crackles severity and the number of US-B lines over time were inter-related (Spearman's ρ = 0.38, P 0.01) but the agreement (Cohen k statistics) between the two metrics was unsatisfactory. Forty-eight percent of patients had lung congestion of moderate to severe degree by lung US and this estimate by far exceeded that by clinical criteria (32%).This pilot study shows that chest US has potential for the detection of lung congestion at a pre-clinical stage in AKI. The results of this pilot study form the basis for a clinical trial testing the usefulness of this technique for guiding lung congestion treatment in patients with AKI.

Background Excessive sodium intake is a risk factor for hypertension, cardiovascular disease and the risk for kidney failure in chronic kidney disease (CKD) patients. Methods We tested the diagnostic performance and the feasibility of an inexpensive method based on urine chloride strips for self-monitoring sodium intake in a series of 72 CKD patients. Results Twenty-four hour urinary chloride as measured by the reactive strips and 24 h urinary sodium were interrelated (r=0.59, p100 mmol/24 h, i.e. the upper limit recommended by current CKD guidelines. The strip method had 75.5% sensitivity and 82.6% specificity to correctly classify patients with urine sodium >100 mmol/24 h. The positive and the negative predictive values were 90.2% and 61.3%, respectively. The overall accuracy (ROC curve analysis) of urine chloride self-measurement for the >100 mmol/24 h sodium threshold was 87% (95% CI: 77%–97%). The large majority of patients (97%) perceived the test as useful to help compliance with the prescribed dietary sodium and considered the test as simple and of immediate application (58%) or feasible but requiring attention (39%). Conclusions A simple and inexpensive test for urine chloride measurement has a fairly good performance for the diagnosis of excessive sodium intake. The test is feasible and it is perceived by CKD patients as helpful for enhancing compliance to the dietary sodium recommendations. The usefulness of this test for improving hypertension control in CKD patients will be tested in a clinical trial (Clinicaltrials.gov RF-2010-2314890).

Background Old patients with end-stage kidney disease (ESKD) represent an increasing segment of the ESKD population maintained on chronic dialysis treatment. Quality of life (QoL) is notoriously poor in ESKD but relationship between QoL and mortality has not been investigated in the old dialysis population. The objective of this study is to investigate the relationship between QoL and mortality in the old dialysis population. Methods Quality of Life was measured by the Rand- QoL Short Form 36 questionnaires in a multicentre, perspective cohort study including 253 very old patients (age ≥ 75 years) on chronic dialysis. Prognostic power of QoL was assessed applying C-statistics. Results In multivariate statistical models including a series of demographic and clinical variable physical function and general health maintained an independent relationship with survival (P ≤ 0.01). In analyses testing the prognostic value of these two SF36 components physical functioning was the component adding the highest explanatory power to standard demographic and clinical risk factors (+5.7%). Furthermore, the same parameter increased by 4.5% the discriminant power by the Harrell’s C Index, improved risk reclassification by the 20% (P = 0.003) and model calibration by the 83%. Conclusions In the very old dialysis population the physical function component of the SF36 is the QoL component holding the highest predictive power for mortality among the eight components of this instrument. As the discrimination power and risk reclassification ability by physical functioning is of degree relevant for clinical practice, such a measure has potential for refining prognosis and informing exercise programs in this population.

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Rationale & Objective Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. Study Design Phase 2, randomized, controlled, open-label, crossover trial. Setting & Participants Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. Intervention After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. Outcomes The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. Results Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. Limitations Short treatment duration, lower pretreatment proteinuria than expected. Conclusions 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. Funding Sanofi (Milan, Italy). Trial Registration Registered at ClinicalTrials.gov with study number NCT01968759.

BACKGROUND The prognostic relevance of health-related quality of life (HRQoL) has been scarcely studied in the dialysis population and the prognostic power for mortality of the HRQoL domains is unknown. METHODS We tested the prognostic value for mortality of the HRQoL domains included in the 36-item Short Form Health Survey (SF-36) by Cox's regression analysis and by state-of-the-art prognostic techniques {explained variation in mortality [R2], calibration, discrimination [Harrell's C], risk reclassification [Net Reclassification Index (NRI)], Integrated Discrimination Index [IDI]} in a cohort of 951 patients on chronic haemodialysis. RESULTS In multivariable Cox models, all but two domains (role limitation due to physical health and due to emotional problems) were independently related with mortality. Physical functioning was the domain adding the highest explanatory power (R2+5.3%) to a basic model including established risk factors for mortality in the dialysis population. The same domain improved risk calibration and showed the highest Harrell's C (+1.7%) and the highest reclassification power (categorical NRI + 8.7%, continuous NRI +46%, P ≤ 0.006) and the highest IDI (+3.4%, P

Summary Background and objectives Poorphysical performanceiscommoninpatients with kidneyfailureondialysis (CKD5D). Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical performance of CKD-5D patients has not been investigated in hemodialysis patients. Design, setting, participants, & measurements This study investigated the relationship between the physical functioning scale of the Kidney Disease Quality of Life Short Form and a validated ultrasonographic measure of lung water in a multicenter survey of 270 hemodialysis patients studied between 2009 and 2010. ResultsModerate to severe lung congestion by lung ultrasonography was observed in 156 (58%) patients; among these, 60 (38%) were asymptomatic (New York Heart Association [NYHA] class I). On univariate analysis, physical functioning was inversely associated with lung water in the whole group (r=20.22; P,0.001) and in the subgroup of asymptomatic patients (r=20.40; P=0.002). Age (r=20.45; P,0.001) and past cardiovascular events (r=20.22; P=0.002) were also inversely associated with physical functioning, whereas albumin (r=0.23;P,0.001) was directly associated with the same parameter. NYHA class correlated strongly with physical functioning (r=20.52; P,0.001). In a multiple regression analysis, both NYHA class and lung water maintained an independentassociationwithphysical functioning,whereasalbuminandbackgroundcardiovascularevents failed to independently relate with the same outcome. Conclusions Symptomatic and asymptomatic lung congestion is associated with poor physical functioning in hemodialysis patients. This association is independent of NYHA, suggesting that this measurement and NYHA may have complementary value to explain the variability in physical performance in hemodialysis patients. Clin J Am Soc Nephrol 8: 1343–1348, 2013. doi: 10.2215/CJN.11111012

Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function.This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 μg/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed.The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions.

Background. Chest ultrasound (US) is a non-invasive wellvalidated technique for estimating extravascular lung water (LW) in patients with heart diseases and in end-stage renal disease. We systematically applied this technique to the whole peritoneal dialysis (PD) population of five dialysis units. Methods. We studied the cross-sectional association between LW, echocardiographic parameters, clinical [pedal oedema, New York Heart Association (NYHA) class] and bioelectrical impedance analysis (BIA) markers of volume status in 88 PD patients. Results. Moderate to severe lung congestion was evident in 41 (46%) patients. Ejection fraction was the echocardiographic parameter with the strongest independent association with LW (r ¼� 0.40 P ¼ 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r ¼ 0.21 P ¼ 0.05). Among patients with severe lung congestion, only 27% had pedal oedema and the majority (57%) had no dyspnoea (NYHA Class I). Similarly, the prevalence of patients with BIA, evidence of volume excess was small (11%) and not significantly different (P ¼ 0.79) from that observed in patients with mild or no congestion (9%). Conclusions. In PD patients, LW by chest US reveals moderate to severe lung congestion in a significant proportion of asymptomatic patients. Intervention studies are necessary to prove the usefulness of chest US for optimizing the control of fluid excess in PD patients.

Background and methods. The endogenous inhibitor of nitric oxide synthase (NOs) asymmetrical dimethylarginine (ADMA) has been implicated as a possible modulator of inducible NOs during acute inflammation. We examined the evolution in the plasma concentration of ADMA measured at the clinical outset of acute inflammation and after its resolution in a series of 17 patients with acute bacterial infections. Results. During the acute phase of inflammation/ infection, patients displayed very high levels of C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin and nitrotyrosine. Simultaneous plasma ADMA concentration was similar to that in healthy subjects while symmetric dimethyl-arginine (SDMA) levels were substantially increased and directly related with creatinine. When infection resolved, ADMA rose from 0.62 � 0.23 to 0.80 � 0.18mmol/l (þ29%, P ¼ 0.01) while SDMA remained unmodified. ADMA changes were independent on concomitant risk factor changes and inversely related with baseline systolic and diastolic pressure. Changes in the ADMA/SDMA ratio were compatible with the hypothesis that inflammatory cytokines activate ADMA degradation. Conclusions. Resolution of acute inflammation is characterized by an increase in the plasma concentration of ADMA. The results imply that ADMA suppression may actually serve to stimulate NO synthesis or that in this situation plasma ADMA levels may not reflect the inhibitory potential of this methylarginine at the cellular level.

BACKGROUND High FGF23 and low α-Klotho levels associate with systemic inflammation and reduced nitric oxide (NO) bioavailability, but the dynamics of this relationship in patients with CKD has not been investigated. METHODS We sequentially measured serum intact FGF23 and carboxyl-terminal (iFGF23, cFGF23), the iFGF23/cFGF23 ratio, αKlotho, biomarkers of inflammation (hs-CRP, IL-6 and TNF-α) and sepsis (procalcitonin), nitrotyrosine (reflecting NO synthesis and oxidative stress), serum iron and ferritin and CKD-MBD biomarkers, PTH, 25(OH)VD, 1,25(OH)2 VD at peak of intercurrent sepsis and after complete resolution in a series of 17 patients with CKD. RESULTS At peak infection, biomarkers of inflammation/sepsis, ferritin and nitrotyrosine were all very high (all P < 0·01) and declined towards the normal range thereafter (P < 0·01). iFGF23 was 191 ± 10 pg/ml (geometric mean, SD) and doubled to 371 ± 8 pg/ml (P = 0·003) after the resolution of infection, while cFGF23 did not change (246 ± 5 pg/mL vs. 248 ± 5 pg/mL, P = 0·50). As a consequence, the iFGF23/cFGF23 ratio, an indicator of the proteolytic cleavage of the FGF23 molecule, was 0·78 ± 3·87 at peak infection and increased to 1·49 ± 3·00 after resolution of infection (P < 0·001). In contrast, serum α-Klotho levels were upregulated at peak infection (peak infection: 526 ± 4 pg/ml, postinfection: 447 ± 4 pg/ml, P = 0·001). The eGFR, PTH and vitamin D did not change significantly throughout. CONCLUSIONS Acute inflammation/sepsis suppresses the active form of FGF23 and activates α-Klotho, the latter effect being likely attributable to enhance proteolysis of FGF23 molecule. iFGF23 downregulation and α-Klotho upregulation during acute sepsis may participate into the counter-regulatory response to severe inflammation in CKD patients with sepsis.

♦ Background End-stage renal disease (ESRD) is a situation with a cardiovascular (CV) risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, in chronic kidney disease (CKD), nontraditional risk factors play an increasingly important role, being perhaps dominant in ESRD patients. ♦ Objective We review the role inflammation [C-reactive protein (CRP)], hyperhomocysteinemia, high plasma norepinephrine, and accumulation of the endogenous inhibitor of the nitric oxide synthase asymmetric dimethylarginine (ADMA) in the high all-cause and CV mortality of patients on continuous ambulatory peritoneal dialysis (CAPD). ♦ Results The association between CRP and clinical outcomes in patients on peritoneal dialysis (PD) was examined in six studies totaling 692 subjects. The largest of these studies in Caucasians indicates that the independent risk of CV events in patients in the top CRP quartile is about five times higher than in the bottom quartile. Seven prospective studies, including over 1000 hemodialysis and 176 CAPD patients, reported both positive and negative associations between homocysteine and mortality and/or CV events. Because homocysteine circulates bound to albumin, negative associations — rather than negating the vasculotoxicity of homocysteine — most likely reflect the very deleterious effects of malnutrition. Plasma norepinephrine is higher in CAPD than in hemodialysis patients, and multivariate analyses suggest the difference quantitatively entails a 16% higher risk of incident CV events. Likewise, ADMA is more elevated in CAPD patients and such an elevation corresponds to a 15% increase in risk. ♦ Conclusion Nontraditional risk factors are far more prevalent in ESRD patients than in the general population. ADMA and norepinephrine may play a greater role in CV risk in CAPD than in hemodialysis patients.

● Background: Cardiovascular (CV) calcifications constitute a strong risk marker, and recent studies in continuous ambulatory peritoneal dialysis patients have associated valvular calcifications to inflammation, mortality, and CV events. The prognostic value of cardiac valve calcifications and their relationship with left ventricular hypertrophy and background cardiovascular risk in hemodialysis patients is still unknown. Methods: The prognostic value of heart valve calcifications (detected by echocardiography) for all-cause and CV death was tested in a cohort of 202 hemodialysis (HD) patients. Results: Forty-seven patients had 1 or more calcified valves. Background CV complications were more frequent (P 0.001) and left ventricular hypertrophy was more severe (P < 0.001) in patients with calcified valves than in those without this alteration. During the follow-up period (44 23 months), 96 patients died, 66 patients (69%) of CV causes. Valve calcifications were significantly associated with all-cause (P 0.02) and CV mortality (P < 0.001). However, in statistical models adjusting for traditional and nontraditional CV risk factors and background CV complications and left ventricular mass index (LVMI), the relationship between calcified valves and incident all-cause and CV mortality was not significant. Conclusion: In HD patients, cardiac valve calcifications predict all-cause and CV mortality in unadjusted analyses, but these associations are not evident in models adjusting for background CV complications, LVMI, and other risk factors. Cardiac valve calcifications do not provide an independent contribution in the prediction of death and CV mortality. Am J Kidney Dis 43:479-484. © 2004 by the National Kidney Foundation, Inc.

Adiponectin is markedly increased in patients with nephrotic series of proteins spanning from TNF- and angiotensin- syndrome and is related to metabolic risk factors. ogen to plasminogen activator inhibitor type-1 and leptin. Background. Adiponectin (ADPN), the gene product of These proteins impinge upon important body functions apM1, is the most abundant secretory protein of the adipose ranging from inflammation, hematopoiesis, and immu- tissue in human plasma. Altered regulation (reduced synthesis) nomodulation, to sympathetic activity (1). Of particular of this substance may be relevant to endothelial dysfunction and cardiovascular complications in patients with ESRD. interest is the emerging hypothesis that disordered endo- Methods. We investigated the relationship between plasma crine function of the adipocyte may contribute to cardio- ADPN, glomerular filtration rate (GFR) (plasma iohexol clear- vascular disease (2), a concept supported by the observa- ance), and metabolic risk factors in 16 patients with nephrotic tion that high fat mass is associated to raised plasma syndrome, in 25 patients with chronic nephropathies without concentration of vasculotoxic cytokines, such as TNF, nephrotic syndrome, and in 31 healthy subjects. Results. Plasma ADPN was much higher (P 0.01) in pa- and to high circulating levels of leptin, which is a recog- tients with nephrotic syndrome (24.4 14.9 g/mL) than in nized sympathetic trigger and a predictor of cardiovascu- patients with chronic nephropathies without nephrotic syndrome lar events (3). Adiponectin (ADPN) is the most abundant (12.3 7.2 g/mL) and healthy subjects (5.9 2.6 g/mL). In adipose tissue protein in human plasma (4). ADPN is a the aggregate 24-hour, proteinuria (r 0.53, P 0.01) and particularly interesting compound because it may have serum cholesterol (r 0.53, P 0.01) were strong and direct correlates of plasma ADPN, while serum albumin correlated a protective influence on the cardiovascular system. In- inversely (r 0.46, P 0.01) with this protein. Proteinuria deed, it suppresses the attachment of monocytes to endo- appeared to be an important confounder of the relationship thelial cells and modulates the endothelial response to between ADPN and the GFR because in the whole patient inflammatory stimuli (5) The potential protective role population (with and without nephrotic syndrome), this rela- tionship emerged only after data adjustment for 24-hour pro- of adiponectin in human diseases is supported by the teinuria (partial r0.31, P 0.05), while no such relationship observation that plasma ADPN is low in patients with was demonstrable on crude data analysis (r 0.03, P 0.87). coronary artery disease (5) and in patients with type 2 Conclusions. ADPN is markedly increased in patients with diabetes mellitus (6). nephrotic syndrome, and proteinuria is strongly related to cir- Renal insufficiency is a notorious trigger of cardiovas- culating ADPN in patients with nephrotic and non-nephrotic renal diseases. The relationships between plasma ADPN, se- cular complications because, in this condition, endothe- rum cholesterol, and serum albumin suggest that this adipocyte lial dysfunction and atherosclerosis are almost universal. protein may serve to mitigate endothelial damage triggered by Preliminary observations in our laboratory indicated that dyslipidemia and other risk factors in patients with chronic ADPN is inversely related to creatinine clearance (7); renal diseases. this finding has been recently confirmed in a large survey in patients with dyslipidemia (8). Furthermore, we have also shown that ADPN is markedly increased in patients In the last decade substantial evidence has been ac- with ESRD (9). However, it is unknown whether the crued showing that the adipose tissue produces a large increase in plasma ADPN observed in patients with renal diseases depends purely on accumulation of this protein † Deceased. or represents a counter-regulatory response to the sev- eral metabolic and hemodynamic risk factors of renal

BACKGROUND Pruritus has a negative impact on quality of life (QoL) in dialysis patients. The reversibility of this symptom after renal transplantation and its impact upon QoL has scarcely been studied in these patients. METHODS Pruritus was evaluated by the Visual Analogue Scale (VAS), the Visual Rating Scale (VRS), and the Numerical Rating Scale (NRS) in 133 unselected renal transplant patients, 62 healthy subjects, and 29 hemodialysis patients. QoL was assessed by KDQOL-SF™ 1.3. The reversibility of pruritus was studied by applying retrospectively the VRS. RESULTS The prevalence of pruritus by the VRS was 62% in hemodialysis patients, 32% in renal transplant patients, and 11% in healthy subjects (P

Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 μg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (−75 pg/mL; 95% confidence interval, –90 to –60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5–36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the between-group difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3–3.1%) was significant ( P =0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD.

BACKGROUND Whether hypertension and left ventricular hypertrophy (LVH) are more prevalent in CAPD than in haemodialysis (HD) patients is still under discussion. METHODS To examine this problem we compared a group of 51 CAPD patients, with a group of 201 HD patients. The evaluation included the measurement of atrial natriuretic peptide (atrial natriuretic factor (ANF)), taken as indicator of volume status, and echocardiographic measurements. RESULTS CAPD patients were older, had been treated for a shorter time, and had lower serum albumin and phosphate than HD patients. Plasma ANF was higher (P

Purpose Decline in physical function is commonly observed in patients with kidney failure on dialysis. Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical functioning of these patients has not been investigated. Methods In 51 peritoneal dialysis (PD) patients, we investigated the cross-sectional association between the physical functioning scale of the Kidney Disease Quality of Life Short Form (KDQOL-SF: Rand Corporation, Santa Monica, CA, USA) and an ultrasonographic measure of lung water recently validated in dialysis patients. The relationship between physical functioning and lung water was also analyzed taking into account the severity of dyspnea measured using the New York Heart Association (NYHA) classification currently used to grade the severity of heart failure. Results Evidence of moderate-to-severe lung congestion was evident in 20 patients, and this alteration was asymptomatic (that is, NHYHA class I) in 11 patients (55%). On univariate analysis, physical functioning was inversely associated with lung water ( r = –0.48, p < 0.001), age ( r = –0.44, p = 0.001), previous cardiovascular events ( r = –0.46, p = 0.001), and fibrinogen ( r = –0.34, p = 0.02). Physical functioning was directly associated with blood pressure, the strongest association being with diastolic blood pressure ( r = 0.38, p = 0.006). The NYHA class correlated inversely with physical functioning ( r = –0.51, p < 0.001). In multiple regression analysis, only lung water and fibrinogen remained independent correlates of physical functioning. The NYHA class failed to maintain its independent association. Conclusions This cross-sectional study supports the hypothesis that symptomatic and asymptomatic lung congestion is a relevant factor in the poor physical functioning of patients on PD.

Background Pro-inflammatory cytokines play a key role in bone remodeling. Inflammation is highly prevalent in CKD-5D patients, but the relationship between pro-inflammatory cytokines and fractures in CKD-5D patients is unclear. We studied the relationship between inflammatory cytokines and incident bone fractures in a cohort of CKD-5D patients. Methods In 100 CKD-5D patients (66 on HD, 34 on CAPD; males:63, females:37; mean age: 61 ± 15; median dialysis vintage: 43 months) belonging to a single renal Unit, we measured at enrolment bone metabolic parameters (intact PTH, bone and total alkaline phosphatase, calcium, phosphate) and inflammatory cytokines (TNF-α, IL-6, CRP). Patients were followed-up until the first non traumatic fracture. Results During follow-up (median: 74 months; range 0.5 -84.0) 18 patients experienced fractures. On categorical analysis these patients compared to those without fractures had significantly higher intact PTH (median: 319 pg/ml IQ range: 95–741 vs 135 pg/ml IQ: 53–346; p = 0.04) and TNF-α levels (median: 12 pg/ml IQ: 6.4-13.4 vs 7.8 pg/ml IQ: 4.6-11; p = 0.02). Both TNF-α (HR for 5 pg/ml increase in TNF-α: 1.62 95% CI: 1.05-2.50; p = 0.03) and intact PTH (HR for 100 pg/ml increase in PTH: 1.15 95% CI: 1.04-1.27; p = 0.005) predicted bone fractures on univariate Cox’s regression analysis. In restricted (bivariate) models adjusting for previous fractures, age, sex and other risk factors both PTH and TNF-α maintained an independent association with incident fractures. Conclusions In our bivariate analyses TNF-α was significantly associated with incident fractures. Analyses in larger cohorts and with adequate number of events are needed to firmly establish the TNF α -fracture link emerged in the present study.

In mice, neuropeptide Y (NPY) decreases bone turnover by means of a parathyroid hormone-independent effect on osteoblast activity.Cross-sectional study.We studied the relationship between levels of NPY and biomarkers of osteoblast activity in 161 nondiabetic patients with end-stage renal disease (131 patients, hemodialysis; 30 patients, continuous ambulatory peritoneal dialysis).We performed an analysis of demographic and clinical variables associated with NPY as a dependent variable and a second analysis testing the association of NPY (as an independent variable) with markers of osteoblast activity.Peritoneal dialysis as treatment modality (beta = 0.37; P0.001) and longer duration of dialysis therapy (beta = 0.24; P0.01) were independently related to plasma NPY. NPY level was related inversely (P0.001) to serum alkaline phosphatase and bone alkaline phosphatase levels (P = 0.01). The NPY-alkaline phosphatase link was confirmed in a multiple regression analysis adjusting for a series of potential confounders, including parathyroid hormone. In a categorical analysis in which the study population was divided according to NPY quartiles, the proportion of patients with low alkaline phosphatase levels was lowest in the first 2 NPY quartiles (26%) and highest in NPY quartile 4 (80%; P0.001), and this association held true in a multiple logistic regression analysis, indicating that the risk of low alkaline phosphatase level increases in parallel with NPY level.The hypothesis generated by this cross-sectional study needs to be confirmed in cohort studies.The inverse relationships between levels of NPY and biomarkers of bone turnover support the hypothesis that NPY may be implicated in low bone turnover in dialysis patients by a central parathyroid-independent mechanism.

Background. Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied. Methods. We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free triiodothyronine (fT3) in a cohort of 41 CAPD patients (mean age, 66 years; M, 26; F, 15) without heart failure and inter-current illnesses. Results. CAPD patients had lower fT3 levels (2.7 � 0.8 pg/ml) than healthy subjects (3.7 � 1.0 pg/ml, P < 0.001) of similar age. Free T3 levels were directly related to those of serum albumin (r ¼ 0.52, P ¼ 0.001) and inversely to IL-6 (r ¼� 0.30, P ¼ 0.05) and CRP (r ¼� 0.54, P < 0.001). Age (r ¼� 0.61, P < 0.001), haemoglobin levels (r ¼ 0.32, P ¼ 0.05) and diastolic blood pressure (r ¼ 0.50, P ¼ 0.001) were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3. During the follow-up (2.8 � 1.7 years) 27 patients died. Plasma fT3 levels were lower in patients who died (2.5 � 0.8 pg/ml) compared with survivors (3.3 � 0.5 pg/ml P ¼ 0.001). In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors. Conclusions. The relationship between fT3, CRP and serum albumin suggests that inflammation– malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients.

Plasma fibrinogen (Fib) and calcium x phosphate product have emerged as cardiovascular (CV) event predictors in hemodialysis (HD) patients, but their role in peritoneal dialysis (PD) is less studied.We investigated whether Fib and calcium x phosphate product predict CV events in a prospective cohort study of 47 continuous ambulatory PD (CAPD) patients (mean follow-up 34.6 months).During the follow-up, 29 patients experienced CV events, which were fatal in 11 of them. Plasma Fib was markedly elevated in the entire population studied (median 612 mg/dL inter-quartile range (IQ): 566-718 mg/dL). On univariate analysis, Fib was higher (p=0.02) in those patients who had fatal or non-fatal CV events (median 654 mg/dL, IQ: 577-801) than in event-free patients (median 579 mg/dL, IQ: 532-629). Patients with incident CV events also tended to have higher calcium x phosphate product (51.6 +/- 12.8 vs. 43.8 +/- 13.9 mg2/dL2, p=0.06). On multivariate Cox's regression analyses, including traditional risk factors and history of previous CV events, Fib (hazard ratio (HR) associated with 100 mg/dL increase in plasma Fib 1.29 95% confidence interval (CI) 1.03-1.63 (p=0.03)) and calcium x phosphate product (HR associated with a 5 mg2/dL2 increase 1.25 95% CI 1.05-1.49 (p=0.01)) emerged as independent CV event predictors.Calcium x phosphate product and Fib are CV event predictors in CAPD patients.

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.

The adipose tissue cytokine leptin is suggested to interfere with bone turnover mechanisms because, in rats with leptin deficiency, intra-cerebroventricular administration of this cytokine causes a reduction in bone mass. We studied the relationship between plasma leptin and biochemical bone turnover indicators in 161 hemodialysis (HD) patients.Plasma leptin was sex-dependent, being significantly higher (p0.001 ) in female dialysis patients than in male dialysis patients, and it related directly to body mass index (BMI). In males, plasma leptin related inversely to serum intact parathyroid (PTH) (partial r= -0.34), serum PTH(1-84) (r= -0.36), carboxyterminal PTH (C-PTH) fragment (r= -0.31) and serum PTH(1-84)/C-PTH fragment ratio (r= -0.22), while no such relationships were found in females. Of 93 male dialysis patients, 44 had a serum intact PTH100 pg/mL and 14 had a serum PTH(1-84)/C-PTH fragment ratio1. In a multiple logistic regression analysis in males, for each 1 ng/mL increase in plasma leptin there was an 11% excess risk of serum intact PTH100 pg/mL (odds ratio (OR) 1.11, 95% confidence interval (95% CI): 1.02-1.20, p=0.01) and a similar OR was found when low bone turnover was defined based on a serum PTH(1-84)/C-PTH fragment ratio1 (p=0.01). In addition, plasma leptin related inversely to skeletal alkaline phosphatase and again this relationship was found in male but not in female dialysis patients.Our data support the theory that leptin reduces bone turnover in male dialysis patients. Whether this link underlies a noxious or a protective mechanism, i.e. if it can serve to limit high bone turnover due to hyperparathyroidism, remains to be established in prospective studies based on solid outcome measures like the risk of fractures.