Showing papers in "Nephrology Dialysis Transplantation in 2011"

Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury

Abstract: Background Several studies demonstrated that mesenchymal stem cells (MSCs) reverse acute kidney injury (AKI) by a paracrine mechanism rather than by MSC transdifferentiation. We recently demonstrated that microvesicles (MVs) released from MSCs may account for this paracrine mechanism by a horizontal transfer of messenger RNA and microRNA. Methods MVs isolated from MSCs were injected intravenously in rats (30 μg/rat) immediately after monolateral nephrectomy and renal artery and vein occlusion for 45 min. To evaluate the MV effects on AKI induced by ischaemia-reperfusion injury (IRI), the animals were divided into different groups: normal rats (n = 4), sham-operated rats (n = 6), IRI rats (n = 6), IRI + MV rats (n = 6), and IRI + RNase-MV rats (n = 6), and all animals were sacrificed at Day 2 after the operation. To evaluate the chronic kidney damage consequent to IRI, the rats were divided into different groups: sham-operated rats (n = 6) and IRI rats (n = 6), IRI + MV rats (n = 6), and all animal were sacrificed 6 months after the operation. Results We found that a single administration of MVs, immediately after IRI, protects rats from AKI by inhibiting apoptosis and stimulating tubular epithelial cell proliferation. The MVs also significantly reduced the impairment of renal function. Pretreatment of MVs with RNase to inactivate their RNA cargo abrogated these protective effects. Moreover, MVs by reducing the acute injury also protected from later chronic kidney disease. Conclusion MVs released from MSCs protect from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. This suggest that MVs could be exploited as a potential new therapeutic approach.

The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis

Abstract: Background. This prospective, randomized, controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone. Methods. Eligible subjects were on hemodialysis for ≥3 months with parathyroid hormone (PTH) >300 pg/mL or PTH 150–300 pg/mL with calcium–phosphorus product >50 mg 2 /dL 2 while receiving vitamin D. All subjects received calcium-based phosphate binders. Coronary artery calcification (CAC) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography. Subjects with Agatston CAC scores ≥30 were randomized to cinacalcet (30–180 mg/day) plus low-dose calcitriol or vitamin D analog (≤2 μg paricalcitol equivalent/dialysis), or flexible vitamin D therapy. The primary end point was percentage change in Agatston CAC score from baseline to Week 52. Results. Median (P10, P90) Agatston CAC scores increased 24% (−22%, 119%) in the cinacalcet group and 31% (−9%, 179%) in the flexible vitamin D group (P = 0.073). Corresponding changes in volume CAC scores were 22% (−12%, 105%) and 30% (−6%, 133%; P = 0.009). Increases in calcification scores were consistently less in the aorta, aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols, and the differences between groups were significant at the aortic valve. Conclusions. In hemodialysis patients with moderate to severe secondary hyperparathyroidism, cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification.

The incidence of primary glomerulonephritis worldwide: a systematic review of the literature

Abstract: Background. Little is known about the worldwide variation in incidence of primary glomerulonephritis (GN). The objective of this review was to critically appraise studies of incidence published in 1980-2010 so that an overall view of trends of these diseases can be found. This would provide important information for determining changes in rates and understanding variations between countries. Methods. All relevant papers found through searches of Medline, Embase and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. Results. This review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada, Australasia and the Middle East. Rates for the individual types of disease were found to be in adults, 0.2/100 000/year for membrano-proliferative GN, 0.2/100 000/year for mesangio-proliferative GN, 0.6/100 000/year for minimal change disease, 0.8/100 000/year for focal segmental glomerulosclerosis, 1.2/100 000/year for membranous nephropathy and 2.5/100 000/year for IgA nephropathy. Rates were lower in children at around 0.1/100 000/year with the exception of minimal change disease where incidence was reported to be 2.0/100 000/year in Caucasian children with higher rates in Arabian children (9.2/100 000/year) and Asian children (6.2-15.6/100 000/year). Conclusions. This study found that incidence rates of primary GN vary between 0.2/100 000/year and 2.5/100 000/ year. The incidence of IgA nephropathy is at least 2.5/100 000/year in adults; this disease can exist subclinically and is therefore only detected by chance in some patients. In addition, referral policies for diagnostic biopsy vary between countries. This will affect the incidence rates found.

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

Abstract: Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; 2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern ( 1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. Conclusion. Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease

Abstract: Background. Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients. Methods. This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months. Results. Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model. Conclusions. In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.

Survival of elderly patients with stage 5 CKD: comparison of conservative management and renal replacement therapy

Abstract: © The Author 2010. Published by Oxford University Press on behalf of the ERA-EDTA. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

Diabesity: an overview of a rising epidemic

Abstract: ‘Diabesity’ is the term for diabetes occurring in the context of obesity. In this review, we will overview the latest epidemiological data available describing the rising prevalence, health impact and economic impact of diabesity. We will also outline the measures required to slowdown this newly evolving epidemic. The global prevalence of diabetes in 2010 was 284 million people worldwide constituting around 6.4% of the world population, which is higher than was projected in earlier studies. Furthermore, the projections for 2030 show the prevalence to reach 439 million individuals comprising ~7.7% of the world population. The burden of diabetes on the world economy has been rising steadily in the last decade to reach $376 billion in 2010 and is expected to reach $490 billion in 2030. Diabesity represents a substantial economic burden as reflected by diabetes and obesity consuming 14 and 5.7% of the USA’s total health expenditure, respectively, representing the highest known expenditure on diabesity worldwide. When costs associated with being overweight were also included, the upper limit of obesity expenditure rises to 9.1% of the USA’s total healthcare expenditure. The highest recorded expenditure on diabetes alone was in Saudi Arabia consuming 21% of the country’s total health expenditure, with no data available about the health expenditure on obesity. The health impact of diabesity is substantial to include long-term diabetic complications, reduction in health-related functioning, reduction of quality of life and reduced overall life expectancy. Long-term complications include myocardial infarction, cerebrovascular stroke and end-stage renal disease. Also recent advances have found that there is an association between chronic stress, depression and sleeping troubles to both diabetes and obesity. This century is the unprecedented diabetogenic era in human history. It is thus urgent to take steps including screening, prevention and early management in an attempt to control this evolving epidemic of diabesity.

An immunofluorescence test for phospholipase-A2-receptor antibodies and its clinical usefulness in patients with membranous glomerulonephritis

Abstract: Background. The recent finding that phospholipaseA2-receptor antibodies (PLA2R-AB) may play a role in the development of primary membranous glomerulonephritis (MGN) offers the opportunity to measure a marker to help diagnose, classify and eventually monitor the course of patients with MGN. Methods. We developed an immunofluorescence test, which allows the easy and specific analysis of the presence of PLA2R-AB in serum. The usefulness of this test was studied in 153 healthy blood donors, 90 patients with non-membranous glomerular injuries, 17 patients with a secondary form of MGN and 100 patients with biopsyproven primary MGN. In addition, in five patients with biopsy-proven MGN, PLA2R-AB levels were monitored prospectively for up to 18 months following a single dose of rituximab (RTX) (375 mg/m 2 body surface). Results. PLA2R-AB were not found in healthy controls or patients with glomerular lesions other than biopsy-proven primary MGN. Fifty-two patients with primary MGN (52%) were positive for PLA2R-AB. The levels ranged from 1:10 to 1:3200. In patients who had MGN and were treated with RTX the fall in PLA2R-AB levels was followed by a decrease in proteinuria, whereas an increase in PLA2R-AB levels was associated with an increase in proteinuria. Conclusions. These studies show that the new test allows the monitoring of PLA2R-AB levels in patients with MGN and may help in making therapeutic decisions for these patients.

Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial

Abstract: Background. Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks.However,datafromrandomizedtrials comparing citrate anticoagulation with systemic heparinization are very limited. Methods. One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients’ acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. Results. Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients’ high mortality was not influenced by the mode of anticoagulation. Conclusions. Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor

The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression

Abstract: The fundamental insights into uraemic toxicity have evolved little since publication of the classical monograph by Cushny nearly a century ago [1]. Organic metabolites are still thought to substantially contribute to uremia (albeit urea might not be the culprit), yet evidence unequivocally demonstrating toxicity of any single uraemic constituent is lacking [2]. To advance research in uraemic toxicity, the European Toxin work group (EUTox) developed a classification of uraemic blood constituents according to characteristics that affect their removal during dialysis [3]. Besides small water-soluble molecules (e.g. urea and creatinine) and peptides/proteins (e.g. β2-microglobulin), they identified a group of solutes that circulate in equilibrium between free solute versus bound to carrier proteins. Tight protein binding severely limits solute clearances by dialysis [4]. Intriguingly, a substantial number of these so-called proteinbound uraemic retention solutes originate from protein fermentation in the large intestine, including p-cresyl sulfate and indoxyl sulfate [5]. Recently, several groups demonstrated direct associations between p-cresol, mainly reflecting p-cresyl sulfate, and overall mortality and cardiovascular disease in end-stage renal disease [6,7] and in chronic kidney disease (CKD) [8,9]. Likewise, direct associations between indoxyl sulfate and overall mortality and cardiovascular disease were reported [10]. While indoxyl sulfate and p-cresyl sulfate are frequently thought of as independent uraemic retention solutes, they share common ground. First, as mentioned before, p-cresyl sulfate and indoxyl sulfate both originate from bacterial protein fermentation in the large intestine. Colonic microbiota degrade tryptophan to indole. Further hydroxylation results in 3-hydroxy-indole, the majority of which is sulfonated to indoxyl sulfate. In parallel, fermentation of tyrosine results in p-cresol and ultimately p-cresyl sulfate [11]. Recently, we reported on sulfate conjugation of p-cresol in CKD [12,13]. Second, most p-cresyl sulfate and indoxyl sulfate circulates noncovalently bound to albumin and competes for the same albumin-binding sites (Sudlow site II) [14] (Figure 1). Indoxyl sulfate and p-cresyl sulfate are interchangeable marker molecules to study behaviour of protein-bound solutes during dialysis [15]. In this issue of Nephrology Dialysis Transplantation, Wu et al. demonstrate that serum indoxyl sulfate is associated with progression of CKD, confirming previous findings. Niwa et al. f irst advanced the hypothesis that accumulation of indoxyl sulfate accelerates glomerular sclerosis and progression of kidney disease [16,17]. Animal and small-scale human studies on CKD patients suggested retardation of CKD progression by adsorption of indole in the large intestine [18,19]. Intriguingly, Wu et al. equally demonstrate that p-cresyl sulfate is associated with CKD progression. Does this indicate that indoxyl sulfate and p-cresyl sulfate be considered equally valid markers for CKD progression? This illustrates one of the key problems we are faced with when investigating uremia. One of the hallmarks of uraemic retention solutes is that they all move more or less in the same direction. When glomerular filtration rate falls, concentrations of the uraemic retention solutes we measure, and most likely a host of solutes that we are not aware of, all rise. Indeed, in the current study, Wu et al. observed a moderate correlation between indoxyl sulfate and estimated glomerular filtration rate (eGFR) (r −0.72, P < 0.001), between p-cresyl sulfate and eGFR (r −0.64, P < 0.001) and between indoxyl sulfate and p-cresyl sulfate (r 0.66, P < 0.001). From a statistical point of view, if nominally related measures actually quantify the same phenomenon, then they are redundant, i.e. collinear. This might lead us to conclude that indoxyl sulfate and p-cresyl sulfate are plain markers of kidney function. The strongpoint of the study by Wu et al. is that they went to great length to correct for residual confounding, including by correction for related protein-bound uraemic retention solutes. They thus demonstrate that, while indoxyl sulfate is independently associated with CKD progression, this association is lost after correction for p-

Organ donation, transplantation and religion

Abstract: Religious concerns may be an important reason why patients decline listing for a renal transplant. These issues may be equally, or even more, important when live donation is discussed. There is good reason to believe that religious concerns play a significant role much more often than clinicians and transplant teams believe. The issue is certainly further compounded by the fact that a few, if any, patients come forward with their religious concerns, not least because issue of transplantation is new to them anyway and because they meet with transplant teams whom they do not know. Health professionals, on the other hand, may wish to avoid this sensitive issue altogether or may lack knowledge on religious issues pertaining to transplantation. Some may be entirely unaware. We encountered a case in clinic that revealed our remarkable lack of knowledge in this regard. Here, we aim to provide an overview on how the different religions view transplantation and organ donation, with an emphasis on practical points for health care professionals who are involved in transplant listing, organ donation and retrieval, and transplantation itself. Knowledge of these facts may provide a background to deal with these issues professionally and appropriately and to increase transplant numbers.

A population-based survey of Chronic REnal Disease In Turkey—the CREDIT study

Abstract: Background. Chronic kidney disease (CKD) is a growing health problem worldwide that leads to end-stage kidney failure and cardiovascular complications. We aimed to determine the prevalence of CKD in Turkey, and to evaluate relationships between CKD and cardiovascular risk factors in a population-based survey. Methods. Medical data were collected through home visits and interviews. Serum creatinine, blood glucose, total cholesterol, triglycerides, HDL, LDL and uric acid were determined from 12-h fasting blood samples, and spot urine tests were performed for subjects who gave consent to laboratory evaluation. Results. A total of 10 872 participants were included in the study. The final analysis was performed on 10 748 subjects (mean age 40.5 ± 16.3 years; 55.7% women) and excluded 124 pregnant women. A low glomerular filtration rate (GFR) (< 60 mL/min/1.73 m2) was present in 5.2% of the subjects who were evaluated for GFR, while microalbuminuria and macroalbuminuria were observed in 10.2% and 2% of the subjects, respectively. The presence of CKD was assessed in subjects who gave consent for urinary albumin excretion measurement (n = 8765). The overall prevalence of CKD was 15.7%; it was higher in women than men (18.4% vs. 12.8%, P < 0.001) and increased with increasing age of the subjects. The prevalence of hypertension (32.7% in the general population), diabetes (12.7%), dyslipidaemia (76.3%), obesity (20.1%) and metabolic syndrome (31.3%) was significantly higher in subjects with CKD than subjects without CKD (P < 0.001 for all). Conclusions. The prevalence of CKD in Turkey is 15.7%. Cardiovascular risk factors were significantly more prevalent in CKD patients.

Circulating microRNA expression is reduced in chronic kidney disease

Abstract: Background. MicroRNAs (miRNAs) are important regulators of gene expression, which have roles in renal development and disease. They exist in biological fluids including blood and urine and may have signalling roles and potential as disease biomarkers. Methods. We measured the levels of miRNAs in patients with different stages of chronic kidney failure including those receiving maintenance haemodialysis treatment. Results. In patients with severe chronic renal failure, circulating levels of total and specific miRNAs are reduced in comparison to patients with mild renal impairment or normal renal function. A strong correlation exists between detected circulating miRNAs and estimated glomerular filtration rate, and less strong correlations with other features of chronic kidney disease, such as anaemia and hyperparathyroidism. Conclusion. These findings have important implications for the use of circulating miRNAs as biomarkers in individuals with renal impairment and for the pathogenesis of uraemia.

Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy

Abstract: Background Transforming growth factor-β1 (TGF-β1) and the macrophage inhibitory factor receptor CD74 link the metabolic disorder with tissue injury in diabetic nephropathy. Fabry disease is an X-linked lysosomal glycosphingolipid storage disorder resulting from a deficient activity of α-galactosidase A that leads to proteinuric renal injury. However, the link between the metabolic abnormality and renal injury is poorly characterized. Globotriaosylsphingosine (lyso-Gb3) was recently identified as a bioactive molecule accumulating in Fabry disease. We hypothesized that lyso-Gb3 could modulate the release of secondary mediators of injury in glomerular podocytes and that recently described nephroprotective actions of vitamin D receptor activation in diabetic nephropathy may apply to lyso-Gb3. Methods Real time RT-PCR, ELISA and Western blot were used to study the biological activity of lyso-Gb3 in cultured human podocytes and potential modulation by vitamin D receptor activation. Results In human podocytes, lyso-Gb3 dose and time dependently increased the expression of TGF-β1, extracellular matrix proteins (fibronectin and type IV collagen) and CD74. TGF-β1 mediated lyso-Gb3 effects on extracellular matrix production. Vitamin D receptor activation with paricalcitol or calcitriol prevented the increase in TGF-β1, CD74 and extracellular matrix induced by lyso-Gb3. Conclusions Lyso-Gb3 may have a role in glomerular injury in Fabry disease by promoting the release of secondary mediators of glomerular injury common to diabetic nephropathy. These effects are prevented by paricalcitol, raising the issue of vitamin D receptor activation as potential adjunctive therapy in Fabry nephropathy.

Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study

Abstract: Background. para-Cresol, which is present in the blood mainly as p-cresyl sulphate, is a protein-bound uraemic toxin that is produced in the intestine by certain intestinal bacteria, and its production is affected by various intestinal environmental factors. Patients with end-stage renal disease who are undergoing haemodialysis (HD) often have defective bowel function leading to abnormal defecation. Since treatment with synbiotics (SYN), which are a combination of probiotics and prebiotics, is reported to improve bowel habit, we examined the effects of SYN on the serum p-cresol level in HD patients. Methods. Nine HD patients received SYN (Lactobacillus casei strain Shirota and Bifidobacterium breve strain Yakult as probiotics and galacto-oligosaccharides as prebiotics) three times a day for 2 weeks. The duration of the study was 4 weeks (2 weeks of pretreatment observation and 2 weeks of treatment). The subjects were asked to complete a questionnaire about their bowel habits (defecation frequency, stool quantity, stool form and ease of defecation) during the study period. Serum p-cresol levels before and after SYN treatment were determined. Results. According to the questionnaire conducted during the pretreatment observation period, HD patients with a high serum p-cresol level tended to have hard stools with difficulty in defecation. With SYN treatment, stool quantity increased significantly and hard, muddy or soft stools tended to be replaced by normal ones. The serum p-cresol level also decreased significantly. Conclusions. It was found that uraemic toxin, p-cresol, was associated with constipation and that SYN treatment resulted in normalization of bowel habits and a decrease of serum p-cresol levels in HD patients. Therefore, SYN treatment may be anticipated to reduce the toxic effect of p-cresol in HD patients.

A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis- dependent chronic kidney disease patients

Abstract: Background. Iron deficiency is a common cause of anaemia and hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in non-dialysis-dependent chronic kidney disease (ND-CKD) patients. Current intravenous iron agents cannot be administered in a single high dose because of adverse effects. Ferric carboxymaltose, a non-dextran parenteral iron preparation, can be rapidly administered in high doses. Methods. This open-label trial randomized 255 subjects with glomerular filtration rates ≤ 45 mL/min/1.73 m2, haemoglobin ≤ 11 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL, and stable ESA dose to either intravenous ferric carboxymaltose 1000 mg over 15 min (with up to two additional doses of 500 mg at 2-week intervals) or oral ferrous sulphate 325 mg thrice daily for a total of 195 mg elemental iron daily for 56 days. Results. In the modified intent-to-treat population, the proportion of subjects achieving a haemoglobin increase ≥ 1 g/dL at any time was 60.4% with ferric carboxymaltose and 34.7% with oral iron (P < 0.001). At Day 42, mean increase in haemoglobin was 0.95 ± 1.12 vs 0.50 ± 1.23 g/dL (P = 0.005), mean increase in ferritin was 432 ± 189 ng/mL vs 18 ± 45 ng/mL (P < 0.001) and mean increase in transferrin saturation was 13.6 ± 11.9% vs 6.1 ± 8.1% (P < 0.001). Treatment-related adverse events were significantly fewer with ferric carboxymaltose than with oral iron (2.7% and 26.2%, respectively; P < 0.0001). Conclusions. We conclude that 1000 mg ferric carboxymaltose can be rapidly administered, is more effective and is better tolerated than oral iron for treatment of iron deficiency in ND-CKD patients.

Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease

Abstract: Background. High levels of fibroblast growth factor 23 (FGF23) are associated with mortality and progression of chronic kidney disease (CKD). Reducing dietary phosphorus intake lowers FGF23 secretion in healthly individuals, but there is little data on its effects in patients with pre-dialysis CKD. Methods. Using a 2 × 2 factorial design, we randomly assigned 16 normophosphataemic CKD stage 3–4 patients to receive a 2-week treatment with either lanthanum carbonate 1000 mg three times daily or placebo, and to ingest a tightly controlled diet containing 750 or 1500 mg of dietary phosphorus daily. We analysed serial measurements of FGF23, parathyroid hormone, serum phosphate and calcium, and 24-h urinary phosphate and calcium excretion using repeated-measures analyses. Results. Compared with the 1500-mg phosphorus diet, patients assigned to the 750-mg diet had greater reduction in 24-h urinary phosphate excretion (66% vs. 29%; P < 0.0001). Lanthanum-treated patients experienced a significant reduction in 24-h urinary phosphate excretion compared with baseline (64%; P < 0.0001), but the difference compared with placebo did not reach significance (64% vs. 31%). Despite the significant reductions in 24-h urinary phosphate excretion, no group demonstrated a significant reduction in FGF23 levels; FGF23 levels actually increased significantly in the 1500-mg diet plus placebo group, suggesting dietary phosphorus loading. Conclusions. Although dietary phosphorus restriction and lanthanum lowered urinary phosphate excretion consistent with a rapid decrease in phosphorus absorption, inducing a reduction in FGF23 levels in CKD patients may require interventions with a longer duration than in healthy volunteers.

Patients' perspective of haemodialysis-associated symptoms

Abstract: Introduction. Patients often report symptoms during haemodialysis (HD). To better understand patients’ experience, we surveyed routine HD outpatients, to quantify the burden and duration of dialysis-associated symptoms. Methods. Five hundred and eight symptom questionnaires were returned from 550 HD outpatients (92.4%). The symptoms in relation to the HD session were analysed using a visual analogue score. Multivariate logistical regression analysis was used to identify characteristics associated with total symptom burden and time to recover following a HD session. Results. Fifty-four percent of the cohort were male, median age 64 years, 36% diabetic and median age unadjusted Charlson comorbidity score 3.0 (2–5). Fatigue (82%), intradialytic hypotension (76%), cramps (74%) and dizziness (63%) were the commonest symptoms reported, followed by headache (54%), pruritus (52%) and backache (51%), with fatigue occurring with a median frequency of 50% of dialysis sessions and intradialytic hypotension and cramps in 30%. Some 23% reported recovering from dialysis within minutes, 34% by the time they returned home, 16% by bed time, 24% the following morning and 3% just before the next dialysis session. Symptom burden was associated with female sex, younger age, longer duration of dialysis sessions, ethnicity and dialysis centre practice. The time taken to recover from dialysis varied from minutes to hours and was shorter for men and greater dialysis vintage but longer with increasing session time and those with increased intradialytic symptom burden. Conclusions. Despite advances in HD, intradialytic symptoms were frequently reported by our patients. There was substantial unexplained variation in symptom burden across centres, suggesting that clinical practice or policies may play a role in preventing the adverse effects of dialysis. Symptom burden was worse in women, patients of South Asian as opposed to African origin and also in those receiving a longer duration of dialysis. These patients may therefore benefit from a different approach to dialysis prescription.

Defining urine output criterion for acute kidney injury in critically ill patients

Abstract: Background. The widespread use of RIFLE and AKIN classification systems for acute kidney injury (AKI) diagnosis and staging has established the association between AKI severity and adverse outcomes. However, as a result of the difficulties in measuring and recording the urine output every hour, a few prospective studies have validated the urine output criterion as stated in these classification systems. We assessed hourly urine output in ICU patients using an automated and accurate device to determine if changes in urine flow and volume could be a sensitive marker of AKI. Additionally, we assessed various definitions of oliguria to determine whether measurement of urine output using a fixed 6-h interval that matches nurses’ shifts would be equivalent to the current standard for AKI diagnosis and staging. Methods. Hourly urine output was recorded continuously using a digital monitor in a medical ICU. Serum creatinine measurements were done at least once per 24 h. We assessed changes in urine output by four different definitions of oliguria. Patients with no AKI by either criterion were compared with patients diagnosed exclusively by the urine output criterion, exclusively by serum creatinine criterion and by both criteria. Results. Fifty-five percent of patients had an episode of oliguria during the ICU stay. There was no significant difference assessing urine output every hour or the total urine volume in a 6-h period for the detection of episodes of oliguria. Twenty-one patients (28%) were diagnosed as AKI using the serum creatinine criterion, whereas additional 24 (32%) were identified by the urine output criterion. Conclusions. Episodes of oliguria occur frequently in ICU patients and identify a higher percentage of AKI patients compared to serum creatinine criterion. Alterations in urine flow may be a sensitive marker of renal dysfunction and need to be validated in larger cohorts.

Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

Abstract: Background. The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin–angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury. Methods. Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription–polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Results. CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion. Conclusions. Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.

Cost-effectiveness analysis of renal replacement therapy in Austria.

Abstract: Background. Providing renal replacement therapy (RRT) for end-stage renal disease patients is resource intensive. Despite growing financial pressure in health care systems worldwide, cost-effectiveness studies of RRT modalities are scarce. Methods. We developed a Markov model of costs, quality of life and survival to compare three different assignment strategies to chronic RRT in Europe. Results. Mean annual treatment costs for haemodialysis were V43 600 during the first 12 months, V40 000 between 13 and 24 months and V40 600 beyond 25 months after initiation of treatment. Mean annual treatment costs for peritoneal dialysis were V25 900 during the first 12 months, V15 300 between 13 and 24 months and V20 500 beyond 25 months. Mean annual therapy costs for a kidney transplantation during the first 12 months were V50 900 from a living donor, V51 000 from a deceased donor, V17 200 between 13 and 24 months and V12 900 beyond 25 months after engraftment. Over the next 10 years in Austria with a population of 8 million people, increased assignment to peritoneal dialysis of 20% incident patients saved V26 million with a discount rate of 3% and gained 839 quality-adjusted life years (QALYs); additionally, increasing renal transplants to 10% from live donations saved V38 million discounted and gained 2242 QALYs. Conclusions. Live donor renal transplantation is cost effective and associated with increase in QALYs. Therefore, preemptive live kidney transplantation should be promoted from a fiscal as well as medical point of view.

When to start dialysis: updated guidance following publication of the Initiating Dialysis Early and Late (IDEAL) study

Abstract: This position statement is intended to be used in conjunction with the original 2002 European guideline on when to start dialysis [1]. The original guideline was based on a formal review of all evidence available at the time. The position statement considers mainly the results of the Initiating Dialysis Early and Late (IDEAL) study [2], but it also considers other relevant studies published since 2002. A formal literature review was not undertaken. The position statement has been prepared by a working group whose members were nominated by the European Renal Best Practice (ERBP) advisory board.

Suboptimal initiation of dialysis with and without early referral to a nephrologist

Abstract: Background. Our objective was to examine patients who initiate renal replacement therapy (RRT) at 10 representative Canadian centers, characterize their initiation as inpatient or outpatient and describe their initial type of dialysis access, duration of pre-dialysis care and clinical status at the time of dialysis initiation. We also examined the impact of an optimal dialysis start (i.e. initiated as an outpatient with an arteriovenous fistula, arteriovenous graft or peritoneal dialysis catheter) on subsequent health outcomes. Methods. Charts of consecutive incident RRT patients were identified from 1 July to 31 December 2006. Information was collected until 6 months after the initiation or until death, transplant or transfer. Results. Three hundred and thirty-nine incident RRT patients were studied: 39.6% initiated as an inpatient; 54% started hemodialysis (HD) with a central venous catheter; 15.3% had 1 year. Optimal starts occurred in 39.5% of patients. For HD patients, optimal starts occurred in 19.8%. Suboptimal starts were noted in patients referred <12 months prior to end-stage renal disease (44%) and in patients referred earlier (56%). The composite end point of death, transfusion or subsequent hospitalization was significantly reduced with an optimal start [hazard ratio 0.47 (95% confidence interval 0.32–0.68), P ¼ 0.0001]. Conclusions. Suboptimal initiation of dialysis is common in patients referred early or late. The benefits of early referral are lost if dialysis is initiated suboptimally. There is a need to identify factors that lead to suboptimal initiation despite early referral.

Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease

Abstract: Background Abnormally low serum testosterone levels were recently associated with an increased mortality risk in male dialysis patients. However, the prevalence of testosterone deficiency in end-stage renal disease (ESRD) is not well defined. We hereby explore the prevalence and correlates of clinical testosterone deficiency in a large cohort of ESRD male patients. Methods Two hundred and sixty ESRD men [median age 59 (25th-75th percentile 48-67) years] were included. Testosterone concentration and testosterone deficiency ( Results Testosterone deficiency was present in 44% of the patients, while 33% showed testosterone insufficiency (10-14 nmol/L), and only 23% had normal testosterone values (>14 nmol/L). Testosterone was strongly and inversely correlated to inflammatory markers (CRP, IL-6 and fibrinogen), even after correction for age and sex hormone-binding globulin. In a crude spline curve, low testosterone concentrations were associated with worse outcome. A clinical condition of testosterone deficiency was independently associated with cardiovascular co-morbidity [odds ratio (OR) 2.51; 95% confidence interval (CI) 1.32-4.76] and death (OR 2.00; 95% CI 1.01-3.97) in logistic regression analyses. Conclusions Testosterone deficiency is a common finding among male ESRD patients, and it is independently associated with inflammation, cardiovascular co-morbidity and outcome. Future studies are needed to determine the potential adverse effects of male hypogonadism in ESRD and the possibility of improving risk profile, quality of life, and ultimately outcome with testosterone supplementation in these patients.

Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients

Abstract: Background. In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. Methods. Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. Results. No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline � 21.8% (interquartile range � 4.5, � 30%), P ¼ 0.025). No changes were observed in PTH. Conclusions. In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.

Quercetin reduces cisplatin nephrotoxicity in rats without compromising its anti-tumour activity

Abstract: Background Nephrotoxicity is the major limitation for the clinical use of cisplatin as an anti-tumoural drug. Our aim was to investigate the protective effect of quercetin on cisplatin nephrotoxicity in a rat tumour model in vivo and to examine the mechanisms of renal protection. Methods Breast adenocarcinoma (13762 Mat B-III) cells were inoculated subcutaneously in male Fischer rats and 7 days later, the rats were administered daily with quercetin [50 mg/kg/day, intraperitoneally (i.p.)] or vehicle. Four days after that, the rats were given a single dose of cisplatin (4 mg/kg, i.p.) or vehicle. Tumour growth and renal function were monitored throughout the experiment. Two or 6 days after cisplatin administration, the rats were killed and the kidneys and tumours were removed to examine renal function and toxicity markers in both tissues. Results In the kidney, cisplatin treatment induced: (i) a decrease in renal blood flow and glomerular filtration rate, (ii) tubular necrosis/apoptosis, (iii) increased lipid peroxidation and decreased endogenous antioxidant systems, (iv) increased expression of inflammation markers and (v) increased activity of the apoptosis executioner caspase-3. Cisplatin effectively reduced tumour size and weight. Conclusions Co-treatment with quercetin partially prevented all the renal effects of cisplatin, whereas it did not impair its anti-tumour activity. In conclusion, in a model of tumour-bearing rats, quercetin prevents the nephrotoxic effect of cisplatin without affecting its anti-tumour activity.

Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria

Abstract: Background. Primary hyperoxaluria (PH) is a rare genetic disease, in which high urinary oxalate (Uox) cause recurrent kidney stones and/or progressive nephrocalcinosis, often followed by early end-stage renal disease, as well as extremely high plasma oxalate, systemic oxalosis and premature death. Oxalobacter formigenes, an anaerobic oxalate degrading bacterium, naturally colonizes the colon of most humans. Orally administered O. formigenes (Oxabact) was found to significantly reduce urine and plasma oxalate. We aimed to evaluate its effect and safety in a randomized, double-blind, placebo-controlled multicenter study.Methods. Oral Oxabact was given to PH patients (> 5 years old, Uox > 1.0 mmol/1.73m(2)/day, glomerular filtration rate (GFR) > 50 mL/min) at nine PH referral sites worldwide. Primary endpoint was the change from baseline in Uox (mmol/1.73m(2)/day) after 24 weeks of treatment (> 20% reduction).Results. Of the 43 subjects randomized, 42 patients received either placebo (23 subjects) or Oxabact (19 subjects). The change in Uox was 160 mmol/mol, Oxabact -28%, placebo -6%; P < 0.082). No serious adverse events were reported.Conclusion. Oxabact was safe and well tolerated. However, as no significant change in Uox was seen, further studies to evaluate the efficacy of Oxabact treatment are needed.

Calcium, phosphorus, PTH and death rates in a large sample of dialysis patients from Latin America. The CORES Study

Abstract: Background. Mineral metabolism parameters may play a role in the survival of patients with chronic kidney disease (CKD).Methods. In the CORES Study, we analysed the association between calcium, phosphorus and PTH and mortality (all-cause and cardiovascular) in 16 173 haemodialysis (HD) patients over 18 years from six Latin American countries, who underwent haemodialysis up to 54 months. Unadjusted, case-mix-adjusted and time-dependent multivariable-adjusted hazard ratio (HR) of death were calculated for categories of serum albumin-corrected calcium (Ca Alb ), phosphorus and PTH using as ‘reference values’ the range in which the lowest death rate was observed. Age, gender, vitamin D treatment, diabetes, vintage, vascular access, weight, blood pressure and laboratory variables (serum albumin, haemoglobin, creatinine, ferritin and Kt/V) were used as confounding variables.Results. Low ( 10.5 mg/dL) Ca Alb increased the HR for all-cause mortality. Low ( 5.5 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Low phosphorus ( 500 and >300 pg/mL) PTH increased the HR for both all-cause and cardiovascular mortality. In addition, only phosphorus >6.0 mg/dL increased the HR for cardiovascular hospitalizations. No effect was observed with Ca Alb or PTH.Conclusions. In summary, in 16 173 HD patients, elevated and reduced serum levels of albumin-corrected calcium, phosphorus and PTH levels were associated with increments in all-cause mortality. Similar results were obtained when only cardiovascular mortality was analysed.

Prevalence of and risk factors for chronic kidney disease in rural Nicaragua

Abstract: Background. Mostly anecdotal reports describe a high prevalence of chronic kidney disease in northwestern Nicaragua, predominantly among younger men, resulting in substantial morbidity and mortality. The true prevalence, nature and aetiology of kidney disease in this region remain unknown. Methods. We performed a population-based prevalence study in Quezalguaque, Nicaragua to assess the frequency of estimated glomerular filtration rate (eGFR) <60 mL/ min/1.73 m 2 , and compared the prevalence of reduced eGFR in Quezalguaque with the USA using the NHANES 1999–2006 data. We also conducted an embedded case– control study in a subset of participants to assess kidney disease risk factors. Results. From 1882 eligible households, 771 individuals from 300 households participated in the prevalence study, 98 (13%) of whom had reduced eGFR. Reduced eGFR was more common among older participants, men and participants living at lower altitudes. Among 18–29-year-old participants, 2.6% had reduced eGFR, and among 30–41year-old participants, 7.4% had reduced eGFR; this compares with 0.2% and 0.8%, respectively, in NHANES. No individuals in these age groups were diabetic. Among cases, only 27% had dipstick proteinuria of 1+ or greater, compared with 7% of controls. Haematuria did not significantly differ between cases and controls (24% versus 18%). In age- and sex-adjusted models, hypertension and residence at lower altitude were independently associated with reduced eGFR, while occupational history was not associated with reduced eGFR. Conclusions. Kidney disease appears common in residents of Quezalguaque, Nicaragua, particularly in younger men, with features most consistent with tubulointerstitial disease. Further research is needed to elucidate the causes of kidney disease in this region.

Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study

Abstract: Background. Aminoglycosides (AG) cause acute kidney injury (AKI), but the incidence and severity distribution are unclear, particularly in non-critically ill children. We determined the incidence, severity and risk factors of AG-associated AKI and assessed for associations with longer hospitalization and higher costs. Methods. At Texas Children’s Hospital, we conducted a retrospective cohort study of children treated with AG for ≥ 5d ays in 2005, excluding children with admission primary renal diagnoses. AKI was defined by the paediatric Risk, Injury, Failure, Loss, End Stage Kidney Disease (pRIFLE) and Acute Kidney Injury Network (AKIN) definitions. Multiple logistic and linear regression analyses were used to assess independence of associations with outcomes. Results. Five hundred and fifty-seven children [mean±SD age=8.0±5.9years,286(51%)male,489(88%)gentamicin] were studied. The AKI rate was 33% and 20% by pRIFLE andAKINdefinitions,respectively.Longer treatment,higher baselineestimatedglomerularfiltrationrate,beingonamedicine (versus surgical) treatment service and prior AG treatment were independent risk factors for AKI development. AKIbypRIFLEorAKINwasindependentlyassociatedwith longer hospital stay and higher total hospital costs. The pRIFLE definition was more sensitive for AKI detection, but the AKIN definition was more strongly related to outcomes. Conclusions. AKI is common and associated with poorer outcomes in non-critically ill children treated with AG. Future research should attempt to understand how to best define AKI in the non-critical illness paediatric setting.