Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure

The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEPO) given SC was investigated in 20 patients aged 7-20 years at different stages of chronic renal failure. In a pilot study we confirmed the lower bioavailability of the drug in 2 children when given SC compared with the IV route (24% and 43%, respectively). Following administration of 4,000 units/m2, rHuEPO SC effective serum erythropoietin concentrations increased from a mean baseline level (+/- SD) of 23 +/- 13 units/l to a mean peak concentration of 265 +/- 123 units/l, which was reached after 14.3 +/- 9.4 h, followed by a slow decline until baseline values were attained at 72 h. Mean residence time was 30 +/- 9 h and mean elimination half-time 14.3 +/- 7 h. The single-dose kinetics of SC rHuEPO in children with different degrees of renal failure are comparable to those in adult patients. Possibly, the higher efficacy of SC rHuEPO in patients with renal anaemia compared with IV rHuEPO is related to its prolonged action

Incidence and outcome of encapsulating peritoneal sclerosis

Background: Studies report variation in the incidence and outcomes of encapsulating peritoneal sclerosis (EPS). This study reports the incidence and outcome of EPS cases in a national cohort of peritoneal dialysis (PD) patients. Methods: The incident cohort of adult patients who started PD between 1 January 2000 and 31 December 2007 in Scotland (n = 1238) was identified from the Scottish Renal Registry. All renal units in Scotland identified potential EPS cases diagnosed from 1 January 2000 to 31 December 2014, by which point all patients had a minimum of 7 years follow-up from start of PD. Results: By 31 December 2014, 35 EPS cases were diagnosed in the 1238 patient cohort: an overall incidence of 2.8%. The incidence for subgroups with longer PD duration rises exponentially: 1.1% by 1 year, 3.4% by 3 years, 8.8% at 4 years, 9.4% at 5 years and 22.2% by 7 years. Outcomes are poor with mortality of 57.1% by 1 year after diagnosis. Survival analysis demonstrates an initial above-average survival in patients who later develop EPS, which plummets to well below average after EPS diagnosis. Conclusions: The incidence of EPS is reassuringly low provided PD exposure is not prolonged and this supports ongoing use of PD. However, continuing PD beyond 3 years results in an exponential rise in the risk of developing EPS and deciding whether this risk is acceptable should be made on an individual patient basis

Narrative Review of Incremental Hemodialysis.

The prescription of hemodialysis (HD) in patients with incident end-stage kidney disease (ESKD) is fundamentally empirical. The abrupt transition from nondialysis chronic kidney disease (CKD) to thrice-weekly in-center HD of much the same dialysis intensity as in those with prevalent ESKD underappreciates the progressive nature of kidney disease whereby the decline in renal function has been gradual and ongoing-including at the time of HD initiation. Adjuvant pharmacologic treatment (i.e., diuretics, acid buffers, potassium binders), coupled with residual kidney function (RKF), can complement an initial HD regimen of lower intensity. Barriers to less intensive HD in incident ESKD include risk of inadequate clearance of uremic toxins due to variable and unexpected loss of RKF, lack of patient adherence to assessments of RKF or adjustment of HD intensity, increased burden for all stakeholders in the dialysis units, and negative financial repercussions. A stepped dialysis regimen with scheduled transition from time-delineated twice-weekly HD to thrice-weekly HD could represent an effective and safe strategy to standardize incremental HD in patients with CKD transitioning to early-stage ESKD. Patients' adherence and survival as well as other clinical outcomes should be rigorously evaluated in clinical trials before large-scale implementation of different incremental schedules of HD. This review discusses potential benefits of and barriers to alternative dialysis regimens in patients with incident ESKD, with emphasis on twice-weekly HD with pharmacologic therapy, and summarizes in-progress clinical trials of incremental HD schedules

Wars, disasters and kidneys

This paper summarizes the impact that wars had on the history of nephrology, both worldwide and in the Ghent Medical Faculty notably on the definition, research and clinical aspects of acute kidney injury. The paper briefly describes the role of 'trench nephritis' as observed both during World War I and II, supporting the hypothesis that many of the clinical cases could have been due to Hantavirus nephropathy. The lessons learned from the experience with crush syndrome first observed in World War II and subsequently investigated over many decades form the basis for the creation of the Renal Disaster Relief Task Force of the International Society of Nephrology. Over the last 15 years, this Task Force has successfully intervened both in the prevention and management of crush syndrome in numerous disaster situations like major earthquakes

p-Cresyl sulfate

If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden

HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in a variety of conditions including peritoneal dialysis (PD), post-surgery adhesions and peritoneal metastases. The acquisition of invasive and pro-fibrotic abilities by mesothelial cells (MCs) through induction of MMT, a cell-specific form of EMT, plays a main role in this process. Aim of this study was to evaluate possible effects of histone deacetylase (HDAC) inhibitors, key components of the epigenetic machinery, in counteracting MMT observed in MCs isolated from effluent of PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While the effect of other inhibitors was limited to a partial E-cadherin re-expression, MS-275, a HDAC1-3 inhibitor, promoted: (i) downregulation of mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation of epithelial markers (E-cadherin, Occludin), (iii) reacquisition of an epithelial-like morphology and (iv) marked reduction of cellular invasiveness. Results were confirmed by HDAC1 genetic silencing. Mechanistically, MS-275 causes: (i) increase of nuclear histone H3 acetylation (ii) rescue of the acetylation profile on E-cadherin promoter, (iii) Snail functional impairment. Overall, our study, pinpointing a role for HDAC1, revealed a new player in the regulation of peritoneal fibrosis, providing the rationale for future therapeutic opportunities

Effect of frequent hemodialysis on residual kidney function.

Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times-per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined

History of Dialysis in the UK: c.1950-1980

Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.First published by the Wellcome Trust Centre for the History of Medicine at UCL, 2009.©The Trustee of the Wellcome Trust, London, 2009.All volumes are freely available online at:www.history.qmul.ac.uk/research/modbiomed/wellcome_witnesses/Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Annotated and edited transcript of a Witness Seminar held on 26 February 2008. Introduction by Professor John Pickstone.Dialysis, the first technological substitution for organ function, is significant not only for the numbers of patients who have benefited. It contributed to the emergence of the field of medical ethics and the development of the nurse specialist, and transformed the relationship between physicians and patients by allowing patients to control their treatment. This seminar drew on participants’ recollections of dialysis from the early, practically experimental days after the Second World War, when resources for research were scant, until the 1980s when it had become an established treatment. Pioneers from the first UK dialysis units recalled the creation of the specialty of nephrology amid discouragement from renal physicians and the MRC, which felt that the artificial kidney was a gadget that would not last. International and interdisciplinary collaborations, and interactions between with industry and clinics in developing and utilising the specialist technology were emphasized. Patients, carers, nurses, technicians and doctors reminisced about their experiences of home dialysis, its complications and impact on family life, as well as the physical effects of surviving on long-term dialysis before transplantation became routine. The meeting was suggested and chaired by Dr John Turney and witnesses include Dr Rosemarie Baillod, Professor Christopher Blagg, Professor Stewart Cameron, Mr Eric Collins, Professor Robin Eady, Mrs Diana Garratt, Professor David Kerr, Professor Sir Netar Mallick, Dr Frank Marsh, Dr Jean Northover, Dr Chisholm Ogg, Dr Margaret Platts, Dr Stanley Rosen and Professor Stanley Shaldon. Two appendices contain reminiscences from Professor Kenneth Lowe and Sir Graham Bull. Crowther S M, Reynolds L A, Tansey E M. (eds) (2009) History of dialysis in the UK: c. 1950–2000, Wellcome Witnesses to Twentieth Century Medicine, vol. 37. London: The Wellcome Trust Centre for the History of Medicine at UCL. ISBN 978 085484 1226The Wellcome Trust Centre for the History of Medicine at UCL is funded by the Wellcome Trust, which is a registered charity, no. 210183

Human peritoneal mesothelial cell death induced by high-glucose hypertonic solution involves Ca2+ and Na+ ions and oxidative stress with the participation of PKC/NOX2 and PI3K/Akt pathways

Indexación: Web of Science; Scopus.Chronic peritoneal dialysis (PD) therapy is equally efficient as hemodialysis while providing greater patient comfort and mobility. Therefore, PD is the treatment of choice for several types of renal patients. During PD, a high-glucose hyperosmotic (HGH) solution is administered into the peritoneal cavity to generate an osmotic gradient that promotes water and solutes transport from peritoneal blood to the dialysis solution. Unfortunately, PD has been associated with a loss of peritoneal viability and function through the generation of a severe inflammatory state that induces human peritoneal mesothelial cell (HPMC) death. Despite this deleterious effect, the precise molecular mechanism of HPMC death as induced by HGH solutions is far from being understood. Therefore, the aim of this study was to explore the pathways involved in HGH solution-induced HPMC death. HGH-induced HPMC death included influxes of intracellular Ca2+ and Na+. Furthermore, HGH-induced HPMC death was inhibited by antioxidant and reducing agents. In line with this, HPMC death was induced solely by increased oxidative stress. In addition to this, the cPKC/NOX2 and PI3K/Akt intracellular signaling pathways also participated in HGH-induced HPMC death. The participation of PI3K/Akt intracellular is in agreement with previously shown in rat PMC apoptosis. These findings contribute toward fully elucidating the underlying molecular mechanism mediating peritoneal mesothelial cell death induced by high-glucose solutions during peritoneal dialysis.https://www.frontiersin.org/articles/10.3389/fphys.2017.00379/ful

Quality of life with conservative care compared with assisted peritoneal dialysis and haemodialysis

Background. There is little information about quality of life (QoL) for patients with end-stage kidney disease (ESKD) choosing conservative kidney management (CKM). The Frail and Elderly Patients on Dialysis (FEPOD) study demonstrated that frailty was associated with poorer QoL outcomes with little difference between dialysis modalities [assisted peritoneal dialysis (aPD) or haemodialysis (HD)]. We therefore extended the FEPOD study to include CKM patients with estimated glomerular filtration rate ⌉10 mL/min/1.73m2 (i.e. individuals with ESKD otherwise likely to be managed with dialysis). Methods. CKM patients were propensity matched to HD and aPD patients by age, gender, ethnicity, diabetes status and index of deprivation. QoL outcomes measured were Short Form-12 (SF12), Hospital Anxiety and Depression Scale depression score, symptom score, Illness Intrusiveness Rating Scale (IIRS) and Renal Treatment Satisfaction Questionnaire. Frailty was assessed using the Clinical Frailty Scale. Generalized linear modelling was used to assess the impact of treatment modality on QoL outcomes, adjusting for baseline characteristics. Results. In total, 84 (28 CKM, 28 HD and 28 PD) patients were included. Median age for the cohort was 82 (79-88) years. Compared with CKM, aPD was associated with higher SF12 physical component score (PCS) [Exp B (95% confidence interval)=1.20 (1.00-1.45), P<0.05] and lower symptom score [Exp B=0.62 (0.43-0.90), P=0.01]; depression score was lower in HD compared with CKM [Exp B=0.70 (0.52-0.92), P=0.01]. Worsening frailty was associated with higher depression scores [Exp B=2.59 (1.45-4.62), P<0.01], IIRS [Exp B=1.20 (1.12-1.28), P<0.01] and lower SF12 PCS [Exp B=0.87 (0.83-0.93), P<0.01]. Conclusion. Treatment by dialysis, both with aPD and HD, improved some QoL measures. Overall, aPD was equal to or slightly better than the other modalities in this elderly population. However, as in the primary FEPOD study, frailty was associated with worse QoL measures irrespective of CKD modality. These findings highlight the need for an individualized approach to the management of ESKD in older people.Peer reviewedFinal Published versio