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Preview: Nephrology Dialysis Transplantation - current issue

Nephrology Dialysis Transplantation Current Issue





Published: Sat, 09 Sep 2017 00:00:00 GMT

Last Build Date: Sat, 09 Sep 2017 11:48:56 GMT

 



Announcements

2017-09-09

News from ERA-EDTA:









Opponent’s comments

2017-09-09

Dr Szpirt and Dr Schwartz review the scarce data on high-volume (HV) plasma exchange (PE), which is defined as an exchange volume of up to 15% of the ideal body weight [14] and come to the conclusion that there is currently no evidence to support the introduction of HV PE exchange into routine clinical practice of aphereses. We could not agree more! Yet we remain proponents of high doses (exchange volumes) in TPE, thus adhering to the current recommendations. The two eminent clinical scientists perform many hundreds of treatments per year in their respective institutions and ‘usually exchange 1–1.5 plasma volume per PE session’. Not surprisingly, there is no gap between the guidelines, for which Dr Schwartz is a lead author [6], and clinical practice at their institutions.



Catheter-based renal denervation and renal function: no evidence of harm but is there a hope of nephroprotection?

2017-07-31

Catheter-based renal denervation (RDN) was introduced into clinical practice in 2009 [1] and immediately generated great hope and enthusiasm for the effective treatment of refractory hypertension as spectacular reductions of both systolic and diastolic blood pressure (BP) were achieved [2, 3]. It is important to stress that this invasive method was frequently performed in patients with compromised kidney function (where the use of contrast media is especially dangerous for kidney function) and was routinely done not by nephrologists (who were often not even present in the team during the work-up of the eligibility of patients for RDN), but by invasive cardiologists or radiologists. This is one of the reasons why kidney function was not systematically assessed before or after RDN in many randomized clinical trials (RCTs). The goals of such studies were usually to reduce BP, and several RCTs or observational studies in several centres were able to achieve this aim [4]. However, in some relatively small studies, other potential benefits of RDN were used as the treatment target, namely reduction of the clinical symptoms of sleep apnoea [5], improvement of blood glucose level [6], or a reduction of left ventricular hypertrophy [7] or atrial fibrillation [8]. In a few studies, RDN was performed in patients with chronic kidney disease (CKD) and significant reduction of the slope of kidney function deterioration or proteinuria was demonstrated [9]. Such an effect of RDN was, to some extent, expected as hyperactivity of the sympathetic nervous system is present in all patients with CKD and unquestionably participates in both the pathogenesis of elevated BP and the progression of CKD into end-stage kidney disease. There are several BP-dependent and BP-independent mechanisms by which hyperactivity of the sympathetic nervous system participates in the pathogenesis of CKD [10, 11]. It has already been documented that pharmacological treatment with drugs that decrease the activity of the sympathetic nervous system is effective in the reduction of progression of CKD in both experimental models [12] and clinical situations [13].



Incidence of hyperglycemia and diabetes and association with electrolyte abnormalities in pediatric solid organ transplant recipients

2017-07-27

Abstract
Background. Posttransplant hyperglycemia is an important predictor of new-onset diabetes after transplantation, and both are associated with significant morbidity and mortality. Precise estimates of posttransplant hyperglycemia and diabetes in children are unknown. Low magnesium and potassium levels may also lead to diabetes after transplantation, with limited evidence in children.Methods. We conducted a cohort study of 451 pediatric solid organ transplant recipients to determine the incidence of hyperglycemia and diabetes, and the association of cations with both endpoints. Hyperglycemia was defined as random blood glucose levels ≥11.1 mmol/L on two occasions after 14 days of transplant not requiring further treatment. Diabetes was defined using the American Diabetes Association Criteria. For magnesium and potassium, time-fixed, time-varying and rolling average Cox proportional hazards models were fitted to evaluate the association with hyperglycemia and diabetes.Results. Among 451 children, 67 (14.8%) developed hyperglycemia and 27 (6%) progressed to diabetes at a median of 52 days (interquartile range 22–422) from transplant. Multi-organ recipients had a 9-fold [hazard ratio (HR) 8.9; 95% confidence interval (CI) 3.2–25.2] and lung recipients had a 4.5-fold (HR 4.5; 95% CI 1.8–11.1) higher risk for hyperglycemia and diabetes, respectively, compared with kidney transplant recipients. Both magnesium and potassium had modest or no association with the development of hyperglycemia and diabetes.Conclusions. Hyperglycemia and diabetes occur in 15 and 6% children, respectively, and develop early posttransplant with lung or multi-organ transplant recipients at the highest risk. Hypomagnesemia and hypokalemia do not confer significantly greater risk for hyperglycemia or diabetes in children.



Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study

2017-07-11

Nephrol Dial Transplant 2017; 32 (5): 870-879. doi: 10.1093/ndt/gfw042



Completeness of reporting of adverse events in trials of maintenance immunosuppression in kidney transplantation: a systematic review

2017-07-11

Abstract
Background. Decision-making regarding immunosuppression after transplantation relies on robust evidence on the benefits and harms of available drugs. We aimed to evaluate the reporting of adverse events (AEs) in trials of maintenance immunosuppression in kidney transplantation.Methods. We conducted a systematic review of published randomized controlled trials of maintenance immunosuppression following kidney transplantation in the Cochrane Kidney and Transplant Register (January 2003–December 2015). Appraisal against the 23-item harms extension of the Consolidated Standards of Reporting Trials statement was conducted.Results. Of 233 trials, 163 (69%) reported at least one AE. Only 17 (10%) provided definitions or justified the AEs, 13 (8%) described methods and 27 (17%) measured severity. Forty AE types were reported, with gastrointestinal being the most common [116 (71%)]. The frequency of reporting did not reflect known drug side-effect profiles. For example, of 90 calcineurin inhibitor trials, only 22% reported tremors, 3% paresthesia and none anxiety, aggression or mood swings. Trials that reported at least one adverse effect were more likely to be industry funded {adjusted odds ratio [OR] 7.6 [95% confidence interval (CI) 3.4–17.1]}, multicenter [OR 5.9 (95% CI 1.7–18.7)] and with follow-up time <24 months [OR 3.7 (95% CI 1.4–10.2)].Conclusions. AEs in kidney transplant immunosuppression trials appear to be selectively reported and may be unreliable for clinical decisions. Adherence to the Consolidated Standards of Reporting Trials harms extension should be mandatory to ensure transparent reporting of AEs that are important to patients and clinicians.



Pro: High dose of therapeutic plasma exchange—mind the gap!

2017-07-09

Abstract
‘Mind the gap’ is a recorded warning phrase used in the London Tube since 1969. The following article is meant to be a warning of an increasing knowing–doing gap in routine practice of therapeutic plasma exchange (TPE), a treatment method that is used more and more throughout the world. The American Society of Apheresis recommendations, including the most recent ones from 2016, suggest using a TPE volume of 1.0–1.5 times the actual calculated plasma volume of the patient. There are only a few exceptions to that rule, such as the recommnded exchange volume in vasculitis or mushroom poisoning. The published literature suggests that in routine clinical practice in many institutions in several countries the exchanged volume might in fact be lower than recommended by the guidelines. In the following article we argue for a high dose of exchanged plasma volume, yet sketch different scenarios on how this time-averaged high dose can be delivered in various ways depending on the underlying disease, refuting a one-size-fits-all strategy that might facilitate the procedure but may result in ‘underpheresis’ in many patients. Further, the objectives underlying the use of smaller exchange volumes, especially the gap between the cost of blood products and the reimbursement of TPE are discussed. Lastly, the knowing–guiding gap is described, which can only be overcome by collecting high-quality data and conducting prospective clinical trials in the field of TPE.



Con: High-volume plasma exchange application in nephrology and beyond

2017-07-09

Abstract
The rationale behind the use of plasma exchange (PE) includes the removal of autoantibodies and other plasma constituents, such as cytokines, complement components, neutrophil extracellular traps, and microparticles, and the substitution of missing plasma factors. The more established indications are associated with the beneficial effects of PE of reducing the plasma levels of pathogenic agents, although the efficiency of this process decreases during the course of the procedure as the substituted replacement fluid dilutes the patient’s original plasma. Thus, removal can be more effective by repeating sessions rather than continuing so-called high-volume PE. The kinetics of PE efficiency have been extensively investigated and exchange between body compartments of substances to be removed is of considerable importance.



Renal safety of catheter-based renal denervation: systematic review and meta-analysis

2017-07-08

Abstract
Background: Catheter-based renal denervation (RDN) is a possible treatment to lower blood pressure. The invasive nature of RDN and the use of contrast agents raise concerns about potential consequent kidney damage. Our objective was to determine the change in renal function after RDN by performing a systematic review on hypertensive patients treated with RDN.Methods: A systematic search was performed in the Embase and MEDLINE databases to identify studies reporting on the effects of catheter-based RDN on renal outcome. Studies published between January 2009 and May 2016, irrespective of study design, device used or indication for treatment were included. We performed random effects meta-analyses on the change in estimated glomerular filtration rate (eGFR), serum creatinine, serum cystatin C and albumin:creatinine ratio after RDN. We only extracted and meta-analysed data from patients treated with RDN.Results: From 1034 citations, 52 studies (38 cohort studies, 4 non-randomized comparative studies and 10 randomized controlled trials) reporting on 56 RDN cohorts were included in meta-analyses and another 14 studies in a qualitative review. Of these 56 cohorts, 48 were specifically eligible for determining the change in eGFR after RDN, totaling 2381 patients. There was no statistically significant change in eGFR after a mean follow-up time of 9.1 ± 7.0 months [0.64 mL/min/1.73 m2 (95% confidence interval −0.47 to 1.76), P = 0.26]. The pooled mean change in serum creatinine and the results of the qualitative review further supported these findings.Conclusions: Based on meta-analyses of 52 studies and a qualitative review of an additional 14 studies, reporting on 2898 patients in total, we conclude that renal function does not significantly change up to at least 9 months after RDN.



Moderator’s view: High-volume plasma exchange: pro, con and consensus

2017-07-03

Abstract
I have been asked to comment on the pro and con opinions regarding high-volume plasma exchange. The authors of both positions have provided cogent arguments and a reasonable approach to choosing the exchange volume for any given therapeutic plasma exchange. The major issue of relevance in this discussion is the nature of the toxins targeted for removal. These parameters include molecular weight, the apparent volume of distribution, the degree of protein binding, the biologic and chemical half-life, and the severity and rapidity of its toxicity.



O-linked β- N -acetylglucosamine modification of proteins is essential for foot process maturation and survival in podocytes

2017-02-27

Abstract
Background. O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development.Methods. O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogty/− and TM-Podo-Ogty/−, respectively) and analyzed their renal phenotypes.Results. Podo-Ogty/− mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogty/− mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogty/− mice. In contrast to Podo-Ogty/− mice, the induced TM-Podo-Ogty/− mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogty/− mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogty/− mice were prevented by Bis-T-23 treatment.Conclusions. O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.



Characterizing the early inflammatory contribution of the donor kidney following reperfusion

2017-02-27

Abstract
Background. Donor kidneys contain a large reservoir of passenger leucocytes that contribute to acute rejection via direct alloantigen presentation and pro-inflammatory cytokine secretion. However, the early contribution of these cells following revascularization has not previously been described. We performed a secondary, high-volume preservation flush following cold storage to characterize the inflammatory contribution of the donor kidney upon reperfusion.Methods. Porcine kidneys were retrieved using a protocol analogous to current UK clinical practice. Following 2 h of cold static preservation, kidneys underwent a secondary flush with Ringer’s solution. The venous effluent was collected and leucocytes phenotyped via flow cytometry. Inflammatory mediators, including cytokines and cell-free DNA, were then assessed to determine the inflammatory contribution of the donor kidney.Results. Upon reperfusion, a significant population of donor-derived CD45+ leucocytes mobilized from the renal vasculature via the renal vein [mean 4.738 × 108  (SD 1.348 × 108)]. Within this population, T cells were dominant, representing >60% of the leucocyte repertoire. Granulocytes, monocytes and natural killer cells were also identified, but in comparatively lower numbers. Significant concentrations of cytokines and cell-free DNA were also eluted upon reperfusion.Conclusions. The donor kidney contains a significant immune load that rapidly mobilizes following reperfusion. Performing a secondary preservation flush prior to implantation may reduce this inflammatory burden via diversion of donor leucocytes and inflammatory mediators from entry into the recipient circulation. This may modulate direct presentation and reduce the inflammatory contribution of the donor kidney following transplantation.



Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial

2017-02-27

Abstract
Background. The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration.Methods. FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400–600 µg/L) or lower (100–200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period.Results. The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups.Conclusions. These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD.



Alterations in urinary collagen peptides in lupus nephritis subjects correlate with renal dysfunction and renal histopathology

2017-02-23

Abstract
Background. The excessive accumulation of extracellular matrix (ECM) in the renal tubulointerstitium is a key component of chronic renal damage in lupus nephritis (LN) and a critical determinant of the disease progression to renal failure. Detection of fibrosis requires renal biopsy and is therefore limited by high risks associated with an invasive procedure. This study explores whether a unique LN urinary peptidome can be identified and whether LN-specific alteration reflects the underlying fibrogenic process of altered ECM turnover.Method. Urinary peptides were analyzed for 36 LN and 35 nonrenal systemic lupus erythematosus (SLE) subjects and 58 healthy volunteers (HVs).Results. In total, 70 collagen and 230 noncollagen peptides were significantly changed between LN and nonrenal SLE and between LN and HV and defined as ‘LN peptides’; 14 proteases associated with observed LN collagen peptides were identified and activities in 9 proteases were significantly different between LN and nonrenal SLE; 28 collagen peptides were correlated with at least one parameter of clinical renal dysfunction or histolopathology.Conclusion. Urinary peptidomic alterations likely reflect pathogenic pathways involving ECM turnover in LN kidneys and potentially could be developed as biomarkers to monitor renal disease progression.



Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats

2017-02-23

Abstract
Background. Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH.Methods. 5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co-treated with FGF23 and calcitriol.Results. In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth.Conclusions. Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy.



Predicting 6-month mortality risk of patients commencing dialysis treatment for end-stage kidney disease

2017-01-10

Abstract
Background. There is evidence that end-stage kidney disease patients who are older or with more comorbidity may have a poor trade-off between benefits of dialysis and potential harms. We aimed to develop a tool for predicting patient mortality in the early stages of receiving dialysis.Methods. In 23 658 patients aged 15+ years commencing dialysis between 2000 and 2009 in Australia and New Zealand a point score tool was developed to predict 6-month mortality based on a logistic regression analysis of factors available at dialysis initiation. Temporal validation used 2009–11 data from Australia and New Zealand. External validation used the UK Renal Registry.Results. Within 6 months of commencing dialysis 6.1% of patients had died. A small group (4.7%) of patients had a high predicted mortality risk (>20%), as predicted by the point score tool. Predictive variables were: older age, underweight, chronic lung disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease (particularly for patients <60 years of age), late referral to nephrologist care and underlying cause of renal disease. The new point score tool outperformed existing models, and had an area under the receiver operating characteristic curve of 0.755 on temporal validation with acceptable calibration and 0.713 on external validation with poor calibration.Conclusion. Our point score tool for predicting 6-month mortality in patients at dialysis commencement has sufficient prognostic accuracy to use in Australia and New Zealand for prognosis and identification of high risk patients who may be given appropriate supportive care. Use in other countries requires further study.



Prognostic value of bone- and vascular-derived molecular biomarkers in hemodialysis and renal transplant patients: a systematic review and meta-analysis

2016-12-26

Abstract
Background. Patients undergoing hemodialysis and kidney graft recipients are high-risk populations for cardiovascular and all-cause mortality. Fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), RANK ligand, osteopontin (OPN), Klotho protein and bone morphogenetic protein-7 (BMP-7) are bone- and vascular-derived molecular biomarkers that have been shown to be associated with cardiovascular surrogate end points; however, currently available data on the prognostic value of these biomarkers is inconsistent. The aim of the present study was to conduct a systematic review and meta-analysis in order to summarize the available evidence on the association of molecular biomarkers with mortality in individuals undergoing hemodialysis and renal transplant patients.Methods. Two databases (MEDLINE and Embase) were systematically searched. Studies were eligible if the association of biomarker and mortality was reported as time-to-event data [hazard Ratio (HR)] or as effect size with a fixed time of follow-up [odds Ratio (OR)]. Abstracted HRs were converted onto a standard scale of effect and combined using a random effects model.Results. From a total of 1170 studies identified in initial searches, 21 met the inclusion criteria. In hemodialysis patients, comparing the lower third with the upper third of baseline FGF23 distribution, pooled HRs (95% confidence intervals) were 1.94 (1.47, 2.56) for all-cause mortality and 2.4 (1.64, 3.51) for cardiovascular mortality. For the same comparison of baseline OPG distribution, pooled HRs were 1.8 (0.95, 3.39) for all-cause mortality and 2.53 (1.29, 4.94) for cardiovascular mortality. Reported risk estimates of RANK ligand, OPN, Klotho protein and BMP-7 were not suitable for pooling; however, only Klotho protein was significantly related to mortality. For kidney graft recipients, four studies that investigated the relationship of FGF23 and OPG with mortality were identified, all of which reported a significant association.Conclusions. In hemodialysis patients, FGF23 is a predictor of all-cause and cardiovascular mortality, whereas the predictive value of OPG is restricted to cardiovascular mortality. Further studies are needed in order to gain insight into the prognostic value of these biomarkers in renal transplant recipients.



Neutrophil-dependent pentraxin-3 and reactive oxygen species production modulate endothelial dysfunction in haemodialysis patients

2016-12-03

Abstract
Background. The aim of this study was to investigate neutrophil activation and its role in long pentraxin-3 (PTX3) release and oxidative stress generation during haemodialysis (HD) and to correlate neutrophil PTX3 and oxidant expression with endothelial dysfunction.Methods. Forty-seven uraemic patients on stable HD, 12 healthy subjects and 15 patients with congestive heart failure (New York Heart Association classes III and IV) were enrolled. Neutrophil PTX3 protein expression was evaluated by confocal microscopy. l-selectin expression, intracellular PTX3 localization and reactive oxygen species (ROS) generation in human neutrophils were measured by flow cytometry. NADPH-dependent superoxide generation was investigated by chemiluminescence. PTX3 plasma concentrations were measured by ELISA. Endothelial dysfunction was studied by flow-mediated dilation (FMD).Results. The low baseline levels of FMD significantly improved after HD, but worsened by 24 h. A significant up-regulation of PTX3 protein expression, localized within secondary granules, was detected in neutrophils isolated at 30 and 240 min of HD, along with an increase in l-selectin expression. The up-regulation in intracellular PTX3 in neutrophils was associated with a significant increase in PTX3 plasma concentrations at 240 min. HD increased ROS production and NADPH oxidase activity in neutrophils. In a univariate analysis, pre-treatment with FMD was inversely correlated with PTX3 expression and ROS generation in neutrophils. In a multivariate analysis, both circulating pre-HD PTX3 and intracellular ROS generation by neutrophils were independent predictors of abnormal FMD.Conclusions. Neutrophil overexpression of PTX3 is associated with ROS overproduction and endothelial dysfunction and may represent an emerging marker of vascular damage progression in HD patients.



Association of body weight changes with mortality in incident hemodialysis patients

2016-10-27

Abstract
Background. Incident hemodialysis patients may experience rapid weight loss in the first few months of starting dialysis. However, trends in weight changes over time and their associations with survival have not yet been characterized in this population.Methods. In a large contemporary US cohort of 58 106 patients who initiated hemodialysis during 1 January 2007–31 December 2011 and survived the first year of dialysis, we observed trends in weight changes during the first year of treatment and then examined the association of post-dialysis weight changes with all-cause mortality.Results. Patients' post-dialysis weights rapidly decreased and reached a nadir at the 5th month of dialysis with an average decline of 2% from baseline, whereas obese patients (body mass index ≥30 kg/m2) did not reach a nadir and lost ∼3.8% of their weight by the 12th month. Compared with the reference group (−2 to 2% changes in weight), the death hazard ratios (HRs) of patients with −6 to −2% and greater than or equal to −6% weight loss during the first 5 months were 1.08 (95% confidence interval, 1.02–1.14) and 1.14 (1.07–1.22), respectively. Moreover, the death HRs with 2–6% and ≥6% weight gain during the 5th to 12th months were 0.91 (0.85–0.97) and 0.92 (0.86–0.99), respectively.Conclusions. In patients who survive the first year of hemodialysis, a decline in post-dialysis weight is observed and reaches a nadir at the 5th month. An incrementally larger weight loss during the first 12 months is associated with higher death risk, whereas weight gain is associated with greater survival during the 5th to 12th month but not in the first 5 months of dialysis therapy.



Fibroblast growth factor 23 actions in inflammation: a key factor in CKD outcomes

2016-09-22

Abstract
During chronic kidney disease (CKD), bone mineral metabolism is disturbed owing in part to the endogenous hormone fibroblast growth factor 23 (FGF23). Elevated FGF23 levels are seen in CKD patients. Current research has demonstrated that FGF23 directly modulates the immune response and host defense to bacterial infections. FGF23 also impairs the activation and recruitment of neutrophils, which are the main immune effector cells required for host defense against bacterial infections. In addition, while FGF23 levels reduce leukocyte recruitment and functions, inflammatory conditions may also—in a reverse fashion—contribute to elevated FGF23 levels in the circulation. In this context, altered hypoxia inducible factor 1α signaling and iron metabolism may contribute to intact FGF23 (iFGF23) production. This review examines evidence on the role of FGF23 in inflammation, immune cell function and recruitment as well as the regulation of FGF23 during inflammation and the clinical implications of this process for the immune system in individuals with CKD. Clinical observations and laboratory investigations indicate an important role of FGF23 in directly modulating leukocyte activation and recruitment behavior with consequences on host defense against bacterial infections. This novel observation may in part explain the increased infectious risk among patients with CKD. However, studies of FGF23 neutralization also revealed increased mortality after sustained administration over several weeks in rats. Thus, therapeutic interventions targeting FGF23 must be carefully evaluated.



Suicide and chronic kidney disease: a case-control study

2016-09-16

Abstract
Background. The association of chronic kidney disease (CKD) and dialysis with suicide is not well established. The objectives of this study were to assess the association of suicide with CKD and dialysis and investigate whether differences exist between dialysis modalities or the durations of dialysis.Methods. Data were obtained from the Taiwan National Health Insurance Research Database. A total of 51 642 patients who died from suicide between 2000 and 2012 and 206 568 living control patients matched by age, gender and residency area were examined. Known risk factors included sociodemographic characteristics, physical comorbidities and psychiatric disorders, which were controlled for as covariates in the analysis. The crude odds ratios (ORs) and adjusted ORs (aORs) for various risk factors were obtained using conditional logistic regression.Results. After potential confounders were controlled for, CKD was significantly associated with an increased risk of suicide [aOR = 1.25, 95% confidence interval (CI) = 1.17–1.34]. End-stage renal disease patients on haemodialysis (HD) had an increased risk of suicide compared with controls (aOR = 3.35, 95% CI = 3.02–3.72). Moreover, patients who initially underwent dialysis within 0–3 months had a significantly increased risk of suicide (aOR = 20.26, 95% CI = 15.99–25.67).Conclusions. CKD and HD are positively associated with suicide. Suicide is preventable; therefore, assessing mental and physical disorders is essential and recommended to all physicians, particularly those treating patients in the early phase of HD.



A urinary proteome-based classifier for the early detection of decline in glomerular filtration

2016-07-07

Abstract
Background. Chronic kidney disease (CKD) progression is currently assessed by a decline in estimated glomerular filtration rate (eGFR) and/or an increase in urinary albumin excretion (UAE). However, these markers are considered either to be late-stage markers or to have low sensitivity or specificity. In this study, we investigated the performance of the urinary proteome-based classifier CKD273, compared with UAE, in a number of different narrow ranges of CKD severity, with each range separated by an eGFR of 10 mL/min/1.73 m2.Methods. A total of 2672 patients with different CKD stages were included in the study. Of these, 394 individuals displayed a decline in eGFR of >5 mL/min/1.73 m2/year (progressors) and the remaining individuals were considered non-progressors. For all samples, UAE values and CKD273 classification scores were obtained. To assess UAE values and CKD273 scores at different disease stages, the cohort was divided according to baseline eGFRs of ≥80, 70–79, 60–69, 50–59, 40–49, 30–39 and <29 mL/min/1.73 m2. In addition, areas under the curve for CKD273 and UAE were calculated.Results. In early stage CKD, the urinary proteome-based classifier performed significantly better than UAE in detecting progressors. In contrast, UAE performed better in patients with late-stage CKD. No significant difference in performance was found between CKD273 and UAE in patients with moderately reduced renal function.Conclusions. These results suggest that urinary peptides, as combined in the CKD273 classifier, allow the detection of progressive CKD at early stages, a point where therapeutic intervention is more likely to be effective. However, late-stage disease, where irreversible damage of the kidney is already present, is better detected by UAE.



Metabolic risk factors in nondiabetic adolescents with glomerular hyperfiltration

2016-06-16

Abstract
Background. In adults, glomerular hyperfiltration is associated with abnormalities related to metabolic syndrome (MetS). We investigated if glomerular hyperfiltration was associated with metabolic abnormalities in US adolescents without diabetes.Methods. We analyzed data from the National Health and Nutrition Examination Survey, a nationally representative sample of US adolescents ages 12–17 years. Estimated glomerular filtration rate (eGFR) was determined using the bedside Schwartz equation; adolescents with hyperfiltration (eGFR >120 mL/min/1.73 m2) were compared to those with normal eGFR (90–120 mL/min/1.73 m2). We calculated mean levels of factors related to MetS, insulin resistance and diabetes risk, adjusting for age, race/ethnicity, sex, socioeconomic status, and BMI z-score.Results. Overall, 11.8% of US adolescents had hyperfiltration [95% confidence interval (CI) 10.6–13.0]. Hyperfiltration prevalence varied by race (20.2% in Hispanics versus 9.8% non-Hispanic whites and 7.4% non-Hispanic blacks; P< 0.001). Compared to those with normal eGFR, adolescents with hyperfiltration had higher adjusted mean levels of triglyceride (83 versus 77 mg/dL; P = 0.05), fasting insulin (15.1 versus 12.9; P< 0.001) and homeostatic model assessment of insulin resistance (3.52 versus 3.01; P = 0.001). These differences persisted after adjusting for BMI z-score. Adolescents with hyperfiltration had increased odds for hypertriglyceridemia [odds ratio 1.58 (95% CI 1.11–2.23)]. These relationships varied by racial/ethnic group.Conclusions. Glomerular hyperfiltration is associated with hypertriglyceridemia and increased insulin resistance independent of BMI z-score in a nationally representative sample of US adolescents. Hispanic adolescents are more likely to have hyperfiltration than other racial/ethnic groups. These findings could have significance in evaluations of renal function and MetS in adolescents to identify related risks and target interventions.



End-of-life care for people with chronic kidney disease: cause of death, place of death and hospital costs

2016-05-20

Abstract
Background. End-of-life care for people with chronic kidney disease (CKD) has been identified as an area of great clinical need internationally. We estimate causes and place of death and cost of hospital care for people with CKD in England in the final 3 years of life.Methods. Hospital Episode Statistics data were linked to Office for National Statistics mortality data to identify all patients in England aged ≥18 years who died 1 April 2006–31 March 2010, and had a record of hospital care after 1 April 2003 (the study group). The underlying cause and place of death were examined in Office for National Statistics data, for patients without and with CKD (identified by International Classification of Diseases version 10 codes N18, I12 and I13). Costs of hospital admissions and outpatient attendances were estimated using National Health Service Reference Cost data. Associations between CKD and hospital costs, and between place of death and hospital costs in those with CKD, were examined using multivariate regressions.Results. There were 1 602 105 people in the study group. Of these, 13.2% were recorded as having CKD. The proportion of deaths at home was 10.7% in people with CKD and 17.2% in the age- and gender-matched non-CKD group. Regression analysis suggests that CKD was associated with an increase in hospital costs of £3380 in the last 12 months of life, holding constant place of death, comorbidities and other variables. For the CKD group, home death was associated with a reduction in hospital costs of £2811 in the 12 months before death. The most commonly recorded cause of death in people with CKD was heart disease. CKD was not mentioned on the death certificate in two-thirds of deaths in people with the condition.Conclusions. People with CKD are less likely to die at home than those without CKD. The condition is associated with increased hospital costs at the end of life regardless of place of death. Home death in CKD is associated with a substantial reduction in hospital costs at the end of life.