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Background: The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial., Methods: Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial ( n  = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake., Results: Overall, 96% and 81.8% of participants ( n  = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups ( P  > 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P  = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P  < 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS ( P  < 0.05)., Conclusion: HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group., Competing Interests: G.R. reports research grants and travel sponsorship from Danone Research, Otsuka, and Sanofi. D.W.J. has received consultancy fees, research grants, speaker's honoraria, and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca, Bayer, and AWAK, speaker's honoraria from ONO and Boehringer Ingelheim & Lilly, and travel sponsorships from ONO and Amgen., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Sodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)]., Methods: In all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia., Results: Significant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate., Conclusions: SZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD., Methods: Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs)., Results: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup., Conclusions: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Clinical practice guidelines provide both local and global recommendations for the use of iron therapy in the management of anaemia in patients with chronic kidney disease. However, physicians must interpret and adapt these guidelines to meet the specific needs of their individual patients. The recommendations must also be considered in the context of findings from more recently published clinical trials and observational studies.

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., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The optimal iron therapy regimen in patients with non-dialysis-dependent chronic kidney disease (CKD) is unknown., Methods: Ferinject® assessment in patients with Iron deficiency anaemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD) was a 56-week, open-label, multicentre, prospective and randomized study of 626 patients with non-dialysis-dependent CKD, anaemia and iron deficiency not receiving erythropoiesis-stimulating agents (ESAs). Patients were randomized (1:1:2) to intravenous (IV) ferric carboxymaltose (FCM), targeting a higher (400-600 µg/L) or lower (100-200 µg/L) ferritin or oral iron therapy. The primary end point was time to initiation of other anaemia management (ESA, other iron therapy or blood transfusion) or haemoglobin (Hb) trigger of two consecutive values <10 g/dL during Weeks 8-52., Results: The primary end point occurred in 36 patients (23.5%), 49 patients (32.2%) and 98 patients (31.8%) in the high-ferritin FCM, low-ferritin FCM and oral iron groups, respectively [hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.44-0.95; P = 0.026 for high-ferritin FCM versus oral iron]. The increase in Hb was greater with high-ferritin FCM versus oral iron (P = 0.014) and a greater proportion of patients achieved an Hb increase ≥1 g/dL with high-ferritin FCM versus oral iron (HR: 2.04; 95% CI: 1.52-2.72; P < 0.001). Rates of adverse events and serious adverse events were similar in all groups., Conclusions: Compared with oral iron, IV FCM targeting a ferritin of 400-600 µg/L quickly reached and maintained Hb level, and delayed and/or reduced the need for other anaemia management including ESAs. Within the limitations of this trial, no renal toxicity was observed, with no difference in cardiovascular or infectious events., Clinicaltrialsgov Number: NCT00994318., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Rigorous data are sparse concerning the optimal route of administration and dosing strategy for iron therapy with or without concomitant erythropoiesis-stimulating agent (ESA) therapy for the management of iron deficiency anaemia in patients with non-dialysis dependent chronic kidney disease (ND-CKD)., Methods: FIND-CKD was a 56-week, open-label, multicentre, prospective, randomized three-arm study (NCT00994318) of 626 patients with ND-CKD and iron deficiency anaemia randomized to (i) intravenous (IV) ferric carboxymaltose (FCM) at an initial dose of 1000 mg iron with subsequent dosing as necessary to target a serum ferritin level of 400-600 µg/L (ii) IV FCM at an initial dose of 200 mg with subsequent dosing as necessary to target serum ferritin 100-200 µg/L or (iii) oral ferrous sulphate 200 mg iron/day. The primary end point was time to initiation of other anaemia management (ESA therapy, iron therapy other than study drug or blood transfusion) or a haemoglobin (Hb) trigger (two consecutive Hb values <10 g/dL without an increase of ≥ 0.5 g/dL)., Results: The background, rationale and study design of the trial are presented here. The study has been completed and results are expected in late 2013., Discussion: FIND-CKD was the longest randomized trial of IV iron therapy to date. Its findings will address several unanswered questions regarding iron therapy to treat iron deficiency anaemia in patients with ND-CKD. It was also the first randomized trial to utilize both a high and low serum ferritin target range to adjust IV iron dosing, and the first not to employ Hb response as its primary end point.

Background: No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients., Methods: Patients were randomized (1:1) to receive either 1.2 μg/kg C.E.R.A. Q4W or darbepoetin alfa QW/Q2W during a 20-week correction period and an 8-week evaluation period. Two primary end points were assessed: the haemoglobin (Hb) response rate and the change in average Hb concentration between baseline and evaluation., Results: The Hb response rate for C.E.R.A. was 94.1%, significantly higher than the protocol-specified 60% response rate [95% confidence interval (CI): 89.1, 97.3; P < 0.0001] and comparable with darbepoetin alfa (93.5%; 95% CI: 88.4, 96.8; P < 0.0001). C.E.R.A. Q4W was non-inferior to darbepoetin alfa QW/Q2W, with similar mean Hb changes from baseline of 1.62 g/dL and 1.66 g/dL, respectively. Patients receiving C.E.R.A. showed a steady rise in Hb, with fewer patients above the target range during the first 8 weeks compared with darbepoetin alfa [39 patients (25.8%) versus 72 patients (47.7%); P < 0.0001]. Adverse event rates were comparable between the treatment groups., Conclusion: C.E.R.A. Q4W successfully corrects anaemia and maintains stable Hb levels within the recommended target range in non-dialysis CKD patients.

Following renal transplantation, hypercalcaemia is frequently caused by persisting hyperparathyroidism. Unregulated extrarenal 1,25-dihydroxyvitamin D (1,25(OH)(2)D) synthesis, which is well recognized as a cause of hypercalcaemia in granulomatous diseases, may also occur after kidney transplantation. This mechanism is also likely to be responsible for hypercalcaemia reported during treatment of cytomegalovirus and associated with acute symptomatic pneumocystis jivorecii pneumonia (PCP). Hypercalcaemia as a prodromal feature of indolent PCP has not been described. We report a renal transplant recipient who developed hypercalcaemia 30 months post-transplant due to extrarenal production of 1,25(OH)(2)D. Two months later, PCP was diagnosed and hypercalcaemia resolved after initiation of treatment.

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 m(2), 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.

Background: An optimal haemoglobin (Hb) response to erythropoietin requires elevated iron indices in dialysis patients; however, it is unknown if the same applies in chronic kidney disease (CKD)., Methods: One hundred patients [CKD Stages 3-5, Hb >or= 110 g/L, iron replete, erythropoietin-stimulating agent (ESA)-naive, 47% diabetic, median age 69.5 years] were block-randomized in an open-label study to receive up to 200 mg intravenous iron sucrose (Group A, n = 52) bimonthly or oral iron sulphate (Group B) to maintain raised and normal iron indices (respectively) over 12 months. The primary endpoint was the change in Hb concentration at 12 months or at termination after at least 6 months of treatment., Results: Eighty-five patients reached the primary endpoint (43, Group A; 42, Group B). Initial Hb was 119 +/- 7 vs 116 +/- 12 g/L (mean +/- standard deviation); ferritin 122 (71-176), median (inter-quartile range), vs 90 microg/L (58-150); transferrin saturation (TSat) 22 (18-26) vs 21% (15-24); and creatinine 240 (195-313) vs 230 micromol/L (184-352). Ferritin and TSat differed by month 2 [157 (103-220) vs 96 microg/L (73-162), P = 0.003] and month 6 [25 (20-31) vs 21% (17-27), P = 0.02], respectively. At study end, Hb did not differ between groups (121 +/- 10 vs 117 +/- 13 g/L). Ferritin was 362 (310-458) vs 125 microg/L (84-190), P < 0.001; TSat 30 (23-34) vs 21% (18-24), P < 0.001; and creatinine 229 (188-326) vs 272 micromol/L (195-413), P = NS. For patients (Groups A and B, n = 27 in each group) whose creatinine regression slope increased (indicating worsening function), the fall in Hb over 12 months also did not differ between groups despite adequate separation in iron indices. Serious adverse events overall did not differ between groups., Conclusions: Elevated iron indices did not increase Hb synthesis in ESA-naive, iron replete, pre-dialysis patients with Hb >110 g/L.

Background: Numerous studies have assessed the accuracy of equations estimating glomerular filtration rate (eGFR) from serum creatinine in individuals with chronic kidney disease (CKD) in cross-sectional studies. Limited literature exists, however, on the consistency of performance of these equations in longitudinal studies as renal function declines., Methods: Radionucleotide-measured GFR from 155 predialysis patients with stage 3-5 CKD was compared with eGFR derived from four equations [6-variable Modification of Diet in Renal Disease (6-MDRD), 4-variable MDRD (4-MDRD), Cockcroft-Gault (CG) and Cockcroft-Gault equations corrected for body surface area (CGC)] at baseline, 12 and 24 months. Bias (difference between eGFR and measured GFR) was used as a measure of performance. Restricted Maximum Likelihood (REML) models were used to identify variables potentially affecting the performance of estimating equations across time., Results: Mean measured GFR (+/-SD) at baseline, 12 and 24 months was 25.9 +/- 10.7, 23.1 +/- 10.6 and 20.3 +/- 10.1 mL/min/1.73 m(2), respectively. There was a statistically significant negative association between bias and GFR for all four estimates (range: -0.76 to -0.71, P < 0.001 for all), indicating worsening underestimation and overestimation at higher and lower GFR, respectively. This negative association significantly reduced over the 24 months (P < 0.001); however, this was largely due to persistent underestimation of eGFR from individuals with GFR >50 mL/min/1.73 m(2). For those with a baseline GFR <50 mL/min/1.73 m(2), the change in bias for any of the four equations over 24 months was

It is hypothesized that anaemia contributes to the progression of renal disease via hypoxia and oxidative stress. These effects may stimulate the production of extracellular matrix by fibroblasts, increasing interstitial fibrosis and leading to tubular destruction. Recombinant human erythropoietin (r-HuEPO, epoetin) has antioxidative and anti-apoptotic properties, though these effects have yet to be demonstrated in renal cells. In theory, epoetin treatment might slow the progression of renal failure, not only by correcting anaemia but also via direct effects on tubular and vascular cell survival. Alternative hypotheses suggest, however, that epoetin could have negative effects on the kidney because of its vasoconstrictive action, which is independent of haemoglobin levels. Retrospective and prospective clinical studies clearly show that epoetin does not accelerate progression of renal disease, provided that blood pressure is well controlled. Some studies suggest that epoetin slows the progression of renal failure, although this remains a controversial issue, as all these studies have methodological limitations. Larger randomized controlled trials and meta-analysis of the existing trials are required to establish whether treatment of anaemia with epoetin can indeed slow the progression of renal disease.

Erythropoietin therapy for uraemic anaemia is associated with a high rate of hypertensive and thrombotic complications. The mechanism is unknown, but a change in cellular calcium control may be relevant to changes in blood pressure and thrombosis. Platelets were utilized as a model of vascular smooth muscle cells. The effects of erythropoietin therapy on platelet cellular calcium, assessed by fura-2, were measured in 25 patients receiving renal replacement therapy during a 6-month treatment period. Three patients failed to reach a target haemoglobin and were excluded from the analysis. Blood pressure increased in 11 of the remaining 22 subjects, eight requiring an increase in antihypertensive medication. There were no differences in cellular calcium control between the group in whom blood pressure rose and patients with stable blood pressure. Overall there was a fall of 24% in resting cytosolic calcium (baseline 69.2 +/- 5.1 to 52.5 +/- 3.0 nmol/l, P < 0.05) after 3 months of erythropoietin therapy. There was no change in the thrombin-stimulated peak response in the presence of extracellular calcium during therapy, although thrombin-stimulated intracellular release also fell at 3 months (baseline 769 +/- 61 versus 3 months 559 +/- 49 nmol/l, P < 0.01). This study suggests that intracellular free calcium control within platelets improves in response to erythropoietin therapy. However these changes appear not to be related to the development of hypertension.

Although the haemostatic defects that occur in uraemia are complex, a major factor is the anaemia of renal failure. This may now be corrected by recombinant human erythropoietin (rHuEpo) therapy rather than by repeated blood transfusion. Platelet reactivity to shear stress and collagen was measured using non-anticoagulated blood to study the effect of erythropoietin or blood transfusion on platelet function. Twenty dialysis patients were commenced on 25-50 U/kg rHuEpo twice weekly. The dose was adjusted after 3 months to maintain target Hb 10-10.5 g/dl. A further 15 patients were studied before and 10-12 days after receiving blood transfusion. Baseline platelet reactivity was subnormal in both groups versus control (P < 0.0001). In the rHuEpo group, a significant increase in platelet reactivity was observed at 2 months (P < 0.005) which disappeared at 3 months. This was not related to the increase in Hb (7.3 +/- 0.3 to 10.2 +/- 0.3 g/dl, P < 0.0001). There was no change in platelet reactivity after transfusion, despite an increase in Hb (6.2 +/- 0.2 to 8.8 +/- 0.2 g/dl, P < 0.0001) similar to that occurring in the rHuEpo group. We conclude that after rHuEpo therapy but not after transfusion a transient increase in platelet reactivity occurs which is dissociated from changes in platelet and red cell numbers.