Patiromer Decreases Serum Potassium and Phosphate Levels in Patients on Hemodialysis

Background: Persistent hyperkalemia (serum potassium (K) ≥5.5 mEq/l) is a common condition in hemodialysis (HD) patients, is associated with increased mortality, and treatment options are limited. The effect of patiromer, a gastrointestinal K binder, on serum K was examined in HD patients. Methods: Six hyperkalemic HD patients (5 anuric) were admitted to clinical research units for 15 days (1 pretreatment week and 1 patiromer treatment week) and they received a controlled diet with identical meals on corresponding days of pretreatment and treatment weeks. Phosphate (P) binders were discontinued on admission. Patiromer, 12.6 g daily (divided 4.2 g TID with meals), was started on the Monday morning following the last pretreatment week blood sampling. Serum and 24-hour stool samples were collected daily. Results: Mean ± SE serum K decreased (maximum change per corresponding day, 0.6 ± 0.2 mEq/l, p = 0.009) and fecal K increased 58% on patiromer compared with the pretreatment week. During the pretreatment week, 69.0, 47.6, and 11.9% of patients' serum K values were ≥5.5, ≥6.0, and ≥6.5 mEq/l, respectively. This was reduced to 38.1% (p = 0.009), 11.9% (p < 0.001), and 2.4% (p = 0.2) on patiromer. Following P binder discontinuation, the long interdialytic interval mean ± SE serum P numerically increased from 5.8 ± 0.4 to 7.0 ± 0.5 mg/dl (p = 0.06). On patiromer, P decreased from 7.0 ± 0.5 to 6.2 ± 0.5 mg/dl (p = 0.04). While on patiromer, fecal P numerically increased by 112 ± 72 mg/day (17%; p = 0.1792; range -148 to 344 mg/day). No patient discontinued patiromer because of adverse events (AEs); none had serious AEs. Conclusions: In 6 hyperkalemic HD patients, patiromer decreased serum K and P levels and increased fecal K

Elevated Vitamin D Receptor Levels in Genetic Hypercalciuric Stone-Forming Rats Are Associated With Downregulation of Snail

Patients with idiopathic hypercalciuria (IH) and genetic hypercalciuric stone-forming (GHS) rats, an animal model of IH, are both characterized by normal serum Ca, hypercalciuria, Ca nephrolithiasis, reduced renal Ca reabsorption, and increased bone resorption. Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels are elevated or normal in IH and are normal in GHS rats. In GHS rats, vitamin D receptor (VDR) protein levels are elevated in intestinal, kidney, and bone cells, and in IH, peripheral blood monocyte VDR levels are high. The high VDR is thought to amplify the target-tissue actions of normal circulating 1,25(OH)2D levels to increase Ca transport. The aim of this study was to elucidate the molecular mechanisms whereby Snail may contribute to the high VDR levels in GHS rats. In the study, Snail gene expression and protein levels were lower in GHS rat tissues and inversely correlated with VDR gene expression and protein levels in intestine and kidney cells. In human kidney and colon cell lines, ChIP assays revealed endogenous Snail binding close to specific E-box sequences within the human VDR promoter region, whereas only one E-box specifically bound Snail in the rat promoter. Snail binding to rat VDR promoter E-box regions was reduced in GHS compared with normal control intestine and was accompanied by hyperacetylation of histone H3. These results provide evidence that elevated VDR in GHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H3. © 2010 American Society for Bone and Mineral Research

Epigenetic Regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA Methylation and Histone Modification.

Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D3(1,25(OH)2D3) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study, BMP2 expression is suppressed by the VDR-1,25(OH)2D3 complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD rat and in UMR-106 cell line. We used chromatin immunoprecipitation (ChIP) assays to identify VDR binding to only one of several potential binding sites within the BMP2 promoter regions. This negative region also mediates suppressor reporter gene activity. The molecular mechanisms underlying the down-regulation of BMP2 by 1,25(OH)2D3 were studied in vitro in BMSCs and UMR-106 cells using the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA). Both DAC and TSA activate BMP2 expression in combination with 1,25(OH)2D3. Bisulfite DNA pyrosequencing reveals 1,25(OH)2D3 to completely hypermethylate a single CpG site in the same BMP2 promoter region identified by the ChIP and reporter gene assays. ChIP assays also show that 1,25(OH)2D3 can increase the repressive histone mark H3K9me2 and reduce the acetylation of histone H3 at the same BMP2 promoter region. Taken together, our results indicate that 1,25(OH)2D3 binding to VDR down-regulates BMP2 gene expression in BMSCs and osteoblast-like UMR-106 cells by binding to the BMP2 promoter region. The mechanism of this 1,25(OH)2D3-induced transcriptional repression of BMP2 involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH)2D3represses bone formation through down-regulating BMP2 expression both in vivo and in vitro

Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115921/1/ejhf402_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115921/2/ejhf402.pd

Long‐term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin‐converting enzymes/angiotensin receptor blockers: results from AMETHYST‐DN

AimsChronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin‐converting enzyme inhibitor (ACE‐I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium‐free, non‐absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer’s long‐term safety and efficacy in HF patients from AMETHYST‐DN.Methods and resultsPatients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0–5.5 mmol/L (mild) or >5.5–88%) and moderate (≥73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer‐related adverse event was hypomagnesaemia (8.6%).ConclusionsIn patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE‐I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145406/1/ehf212292.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145406/2/ehf212292_am.pd

Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism

Importance Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease. Objective To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis. Design, Setting, and Participants Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014. Interventions Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks. Main Outcomes and Measures The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower. Results The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety

Effects of SNF472, a Novel Inhibitor of Hydroxyapatite Crystallization in Patients Receiving Hemodialysis - Subgroup Analyses of the CALIPSO Trial

Coronary artery calcium (CAC) is highly prevalent and linked with poor outcomes in patients receiving maintenance hemodialysis, and its reduction may improve patient prognosis. SNF472, a selective inhibitor of hydroxyapatite crystallization, slows CAC progression in patients receiving maintenance hemodialysis. In this analysis, we assessed the efficacy of SNF472 in prespecified patient subgroups. In a randomized clinical trial SNF472 300 mg, SNF472 600 mg, or placebo were infused thrice weekly in 91, 92, and 91 patients receiving maintenance hemodialysis and with CAC at baseline, respectively. In prespecified subanalyses, the percent change in CAC volume score (CACvs) from baseline to week 52 in modified intention-to-treat (mITT) and per-protocol (PP) populations was calculated in the following subgroups: age, sex, diabetes mellitus, dialysis vintage, prior atherosclerotic cardiovascular disease, baseline use of non-calcium and calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, and statins. In the main trial, SNF472 significantly reduced CACvs progression compared with placebo (11% versus 20% mITT analyses; P = 0.016; 8% vs. 24% PP analyses; P < 0.001). Treatment differences for CACvs progression were similar across all subgroups, and all interaction P values were non-significant in mITT and PP analyses. SNF472 treatment for 52 weeks reduced CACvs progression compared with placebo in a broad range of patients receiving maintenance hemodialysis. Future studies will determine the impact of SNF472 on cardiovascular events in this population

Trial design and baseline characteristics of CaLIPSO : a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification

The objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants. Adult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100-3500 U were enrolled. Patients were stratified by Agatston score (100-1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session. Overall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315-1435), 1728 U (625-4978) and 103 U (31-262), respectively, and the median (25th-75th percentile) calcium volume scores at baseline were 666 (310-1234), 1418 (536-4052) and 107 (38-278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline. The CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve