Tenapanor for peritoneal dialysis patients with hyperphosphatemia: a phase 3 trial.

BACKGROUND: Tenapanor is a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporter. This is the first trial to assess the efficacy and safety of tenapanor in Japanese patients with hyperphosphatemia who are undergoing peritoneal dialysis. METHODS: This phase 3, open-label, multicenter, single-arm clinical trial targeted patients whose serum phosphorus was within 3.5-7.0 mg/dL with phosphate binders at screening. After phosphate binder washout, tenapanor was orally administered twice-daily, stepwise from 5 to 30 mg/dose for 16 weeks. The primary endpoint, mean change in serum phosphorus level, was evaluated at week 8. The 16-week treatment period was completed with tenapanor alone, and only one phosphate binder type was allowed for combined use after the primary endpoint. RESULTS: Of the 54 patients enrolled, 34 completed the study. At week 8, the primary endpoint, mean change in serum phosphorus level (last observation carried forward), was - 1.18 mg/dL (95% confidence interval: - 1.54, - 0.81 mg/dL) with tenapanor. From a baseline value of 7.65 mg/dL, serum phosphorus decreased to 6.14 and 5.44 mg/dL at weeks 8 and 16, respectively, and 46.3% and 76.5% of patients achieved serum phosphorus within 3.5-6.0 mg/dL at week 8 and week 16, respectively. The most common adverse event, diarrhea, occurred in 74.1% of patients; the severity of diarrhea was mild or moderate. Thus, the discontinuation percentage due to diarrhea was low at 5.6%. CONCLUSIONS: Administration of tenapanor resulted in a sufficient reduction in serum phosphorus level at week 8 and was considered safe and tolerable. TRIAL REGISTRATION: NCT04766385.

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans.

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

Anemia Management in Peritoneal Dialysis: Perspectives From the Asia Pacific Region.

Anemia is an important complication in patients with chronic kidney disease. Peritoneal dialysis (PD) is one of the most common modalities of kidney replacement therapy for patients with end-stage kidney disease. PD is particularly prevalent in the Asian Pacific region. Among the different countries and regions, including mainland China, Hong Kong, Japan, Malaysia, Singapore, South Korea, and Thailand, PD accounts for 2.8% to 74.6% of the dialysis population. In addition, 82% to 96% of the PD populations from these countries and regions are receiving erythropoiesis-stimulating agents (ESAs). Asian Pacific countries and regions follow the latest KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the initiation of treatment of anemia in PD patients. The types of ESAs commonly used include shorter-acting (epoetin alfa and beta) and longer-acting agents, including darbepoetin alfa or methoxy polyethylene glycol-epoetin beta. The most commonly used ESAs in Mainland China, Malaysia, Singapore, and Thailand are the shorter-acting agents, whereas in Hong Kong, Japan, and South Korea, longer-acting ESAs are most common. Oral iron therapy is still the most commonly used iron supplement. The route and dosage of iron administration in PD patients requires more research studies. With the introduction of oral hypoxia-inducible factor prolyl hydroxylase inhibitors into clinical use, the landscape of treatment of anemia in the PD population in the Asia Pacific region may change in the coming years.

Hyponatremia presenting with hourly fluctuating urine osmolality.

SUMMARY: The etiology of hyponatremia is assessed based on urine osmolality and sodium. We herein describe a 35-year-old Asian man with pulmonary tuberculosis and perforated duodenal ulcer who presented with hyponatremia with hourly fluctuating urine osmolality ranging from 100 to 600 mosmol/kg, which resembled urine osmolality observed in typical polydipsia and SIADH simultaneously. Further review revealed correlation of body temperature and urine osmolality. Since fever is a known non-osmotic stimulus of ADH secretion, we theorized that hyponatremia in this patient was due to transient ADH secretion due to fever. In our case, empiric exogenous glucocorticoid suppressed transient non-osmotic ADH secretion and urine osmolality showed highly variable concentrations. Transient ADH secretion-related hyponatremia may be underrecognized due to occasional empiric glucocorticoid administration in patients with critical illnesses. Repeatedly monitoring of urine chemistries and interpretation of urine chemistries with careful review of non-osmotic stimuli of ADH including fever is crucial in recognition of this etiology. LEARNING POINTS: Hourly fluctuations in urine osmolality can be observed in patients with fever, which is a non-osmotic stimulant of ADH secretion. Repeated monitoring of urine chemistries aids in the diagnosis of the etiology underlying hyponatremia, including fever, in patients with transient ADH secretion. Glucocorticoid administration suppresses ADH secretion and improves hyponatremia even in the absence of adrenal insufficiency; the etiology of hyponatremia should be determined carefully in these patients.

Oral Ferric Citrate Hydrate Associated With Less Oxidative Stress Than Intravenous Saccharated Ferric Oxide.

INTRODUCTION: A recent study suggested that orally dosed ferric citrate hydrate (FC) corrects renal anemia in patients on hemodialysis (HD), suggesting biological differences in effects of iron supplementation using different routes of administration. To address this issue, the present study compared oral FC with i.v. saccharated ferric oxide (FO) in stable HD patients. METHODS: Participants comprised 6 patients administered 3 consecutive protocols in the first HD session of the week in a fasting state: nothing given, as control (C); oral load of FC (480 mg iron), and 5 minutes of i.v. FO (40 mg iron). Iron dynamics in the body and biological impact on redox-inflammation status during the study (6 hours) were examined. RESULTS: Significant increases in serum iron and transferrin saturation were seen with both FC and FO. Regarding total iron-binding capacity as the sum of serum iron and unsaturated iron-binding capacity, no changes were found in FC, whereas significant increases were seen in FO (appearance of non-transferrin-binding iron [NTBI]), despite the lower serum iron levels in FO. Compared with C, increases were seen in serum myeloperoxidase (oxidative marker) with accompanying significant decreases in thioredoxin (antioxidant) in FO, whereas no changes were found in FC. CONCLUSION: Oral FC differs from i.v. FO in areas such as less NTBI generation and less induction of oxidative stress. The result indicates potential clinical benefits of oral FC in terms of iron supplementation for renal anemia in HD patients.

Rosuvastatin pretreatment suppresses distant organ injury following unilateral renal ischemia-reperfusion in hypertensive Dahl salt-sensitive rats.

AIM: Ischaemia-reperfusion (I/R) induces distant organ injury (DOI) via inflammation and oxidative stress. Statins have anti-inflammatory and anti-oxidant effects independent of their cholesterol-lowering properties. To clarify whether statins could suppress DOI, we investigated the effect of rosuvastatin (RO) on the contralateral kidney following unilateral renal I/R. METHODS: Dahl salt-sensitive rats (6 weeks old) were randomly divided into four groups: sham, sham with RO, I/R, and I/R with RO. All rats were fed a high-salt (8%) diet for 6 weeks. RO (10 mg/kg per day) was pre-administered by supplementation to the drinking water for 2 weeks before I/R. The rats then underwent unilateral renal I/R (ischemia for 45 min). Three days after I/R, laboratory data, histological changes and protein expression levels of the contralateral kidney were assessed. RESULTS: I/R significantly elevated serum creatinine and malondialdehyde levels and induced a significantly higher glomerular sclerosis index and tubular dilation area of the contralateral kidney, with about 2-fold infiltration of ED-1-positive cells. In the I/R group, protein expression of superoxide dismutase (SOD) of the contralateral kidney was reduced to about 50% of the sham group. RO-pretreatment significantly suppressed all of these changes following I/R. CONCLUSION: RO-pretreatment diminished contralateral kidney injury with the suppression of ED-1-positive cell infiltration and SOD reduction after I/R. RO appears to have a protective effect on DOI by its anti-inflammatory and anti-oxidant effects.

Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis.

OBJECTIVE: JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. This study investigated long-term safety and efficacy of JTT-751 for hyperphosphatemia in patients receiving hemodialysis. DESIGN AND METHODS: This was 52-week, phase 3, multicenter, open-label, dose titration, long-term study. All patients were receiving thrice-weekly hemodialysis for ≥3 months before the initiation of the study. JTT-751 was given at titrated doses between 1.5 and 6.0 g/day. MAIN OUTCOME MEASURES: Safety endpoints were adverse events and adverse drug reactions. Efficacy outcomes were the change in serum phosphate, corrected serum calcium, and intact parathyroid hormone. Changes in ferritin, transferrin saturation, and doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron formulations were additional outcomes. RESULTS: One hundred and eighty patients were included in the trial. Dose-titrated JTT-751 decreased mean serum phosphate after administration and satisfactorily maintained serum phosphate concentrations throughout the entire duration of the 52-week trial. Mean serum phosphate concentrations were kept lower than 5.5 mg/dL from weeks 5 to 52. The most common adverse events were gastrointestinal disorders, which were mild to moderate in intensity. Serum ferritin concentrations rose to a peak around week 28 and stabilized thereafter. The mean intravenous iron dose decreased from 57.3 mg/4 weeks (weeks 0-12) to 3.6 mg/4 weeks (weeks 28-52); weekly ESA dose declined by 25% over the same time frame, while mean hemoglobin concentrations remained stable. CONCLUSION: JTT-751 1.5-6.0 g/day controls serum phosphorus concentrations and reduces the need for ESAs and intravenous iron in patients receiving hemodialysis.

Methylglyoxal augments intracellular oxidative stress in human aortic endothelial cells.

Methylglyoxal (MGO) is a non-enzymatic metabolite in the glycolytic pathway and its concentration in blood and tissues is elevated in diabetes and renal failure. MGO induces tissue injuries via ROS; however, the mechanism remains to be clarified. The present study examined the harmful actions of MGO. Human aortic endothelial cells were assessed under real-time fluorescent microscopy with continuous superfusion. Increases in intracellular ROS were measured with fluorescent indicator, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester (DCFH-DA). The addition of MGO rapidly increased the ROS in a dose-dependent manner. The increment of DCF was entirely abolished by pre-treatment with superoxide anion scavenger and membrane-permeable catalase, indicating that MGO induces superoxide production. The increment was completely inhibited by 2-thenoyltrifluoroacetone or carbonyl cyanide 3-chlorophenylhydrazone and partially inhibited by N-methyl-L-arginine. These data suggest that MGO stimulates superoxide production from mitochondria and partially stimulates nitric oxide synthase in human endothelial cells.

Effect of repeated intravenous iron administration in haemodialysis patients on serum 8-hydroxy-2'-deoxyguanosine levels.

BACKGROUND: Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients. METHODS: Twenty-seven patients (62+/-14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht<30% and FTN<100 ng/ml; n=7); High FTN group (Ht>or=30% and FTN>or=100 ng/ml; n=11); and low FTN group (Ht>or=30% and FTN<100 ng/ml; n=9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks. RESULTS: At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2=0.47, P<0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22+/-0.07-0.50+/-0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52+/-0.20-0.58+/-0.28 ng/ml) and the low FTN group (0.39+/-0.11-0.36+/-0.11 ng/ml) (ANOVA for repeated measures P<0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner. CONCLUSIONS: Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.

Fluid status and its management in Japanese peritoneal dialysis patients.

This article reviews published studies related to fluid status of Japanese peritoneal dialysis (PD) patients and its impact on technique and patient survival. In addition, some specifics related to clinical background that potentially influence fluid status are described. According to a multicenter survey conducted in Japan, nearly 25% of Japanese PD patients are overhydrated. Available data indicate that a high salt diet may conceivably play an important role in the pathogenesis of fluid overload in Japanese PD patients, and it in turn negatively impacts patient prognosis. Because of the generally adopted policy among Japanese PD experts to avoid regular use of 3.86% glucose solution, icodextrin solution is now used in more than one third of all patients. Other means of managing fluid overload, such as drug therapy, combination (complementary) therapy with hemodialysis, and low sodium PD solution, are also explored and summarized in this article.

High iron storage levels are associated with increased DNA oxidative injury in patients on regular hemodialysis.

BACKGROUND: Accumulating evidence suggests that oxidative stress is enhanced in patients on regular hemodialysis (HD). Iron supplementation is essential for the treatment of renal anemia, but there is a possibility that it could enhance oxidative stress by inducing the Fenton reaction. Here, we report our investigation of the relation between iron storage and DNA oxidative injury in HD patients. METHODS: The study subjects were 48 patients on regular HD (age, 62.7 +/- 12.1 years; HD duration, 67.2 +/- 62.5 months; non-diabetic/diabetic; 22:26). Patients who were positive for hepatitis C virus antibody (HCV Ab), or hepatitis B surface antigen (HBsAg), and those with inflammatory or malignant diseases were excluded. The serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) level, a marker of DNA oxidative injury, was measured before the first HD session of the week in all patients, and factors associated with high serum 8-OHdG were investigated. In 9 patients with a serum ferritin level of more than 1000 ng/ml at study entry, serum 8-OHdG levels were followed up for 6 months in the absence of iron supplementation. RESULTS: Multivariate analysis showed that the serum ferritin level was a significant and independent determinant of serum 8-OHdG, and serum ferritin correlated significantly with the total dose of iron supplementation during the 6-month period of the study. In the nine patients, without iron supplementation, serum 8-OHdG levels, as well as serum ferritin, decreased significantly during follow-up. CONCLUSIONS: Our results suggest that increased iron storage may induce DNA oxidative injury in patients on regular HD, and that the serum ferritin level is a surrogate marker for this pathological condition.

Essential domain of receptor tyrosine phosphatase beta (RPTPbeta) for interaction with Helicobacter pylori vacuolating cytotoxin.

Helicobacter pylori produces a potent exotoxin, VacA, which causes progressive vacuolation as well as gastric injury. Although VacA was able to interact with two receptor-like protein tyrosine phosphatases, RPTPbeta and RPTPalpha, RPTPbeta was found to be responsible for gastric damage caused by VacA. To define the region of RPTPbeta involved in VacA binding, we made mutants of human cDNA RPTPbeta-B, a short receptor form of RPTPbeta. Immunoprecipitation experiments to assess VacA binding to RPTPbeta-B mutants indicated that five residues (QTTQP) at positions 747-751 of the extracellular domain of RPTPbeta-B (which is commonly retained in RPTPbeta-A, a long form of RPTPbeta) play a crucial role in its interaction with VacA, resulting in vacuolation as well as Git-1 phosphorylation. Transfected cells expressing deletion mutant Delta752, which lacks QTTQP, or the double point mutant Delta747 (T748A,T749A) had diminished vacuolation in response to VacA. Treatment of RPTPbeta-B and Delta747 (which have QTTQP at 747-751) with neuraminidase and O-glycosidase diminished their VacA binding, whereas chondroitinase ABC did not have an effect. No inhibitory effect of pleiotrophin, a natural RPTPbeta ligand, on VacA binding to RPTPbeta-B or Delta747 was observed, supporting the conclusion that the extracellular region of RPTPbeta-B responsible for VacA binding is different from that involved in binding pleiotrophin. These data define the region in the RPTPbeta extracellular domain critical for VacA binding, in particular the sequence QTTQP at positions 747-751 with crucial threonines at positions 748 and 749 and are consistent with a role for terminal sialic acids possibly because of threonine glycosylation.

The negative Ca(2+) balance is involved in the stimulation of PTH secretion.

The low calcium (Ca(2+)) dialysate have been developed to diminish the risk of hypercalcemia with the administration of active vitamin D and Ca(2+) carbonate as phosphate binder. Today, increasing numbers of hemodialysis (HD) patients have been on the low Ca(2+) dialysate (Ca(2+) = 2.5 mEq/l). However, the clinical consequences of a negative calcium net-balance which may be induced by the use of low Ca dialysate are not well evaluated. In the present study, we explored the effects of low Ca(2+) dialysate on the calcium balance and the PTH secretion. Eighty one chronic HD patients (male/female: 47/34; mean age: 60.2 +/- 1.5 years; mean HD periods: 11.1 +/- 0.8 years) who had been dialyzed with 3.0 mEq/l Ca(2+) dialysate were studied. All patients were transferred to the low Ca dialysate, which actually brought about a negative net-balance in Ca (mean: -94.5 mg) and an increase in serum intact PTH levels (mean: +23.7%: p = 0.03) during a single HD session. However, no changes in serum ionized Ca(2+) were found in spite of negative Ca(2+) balance. One month after change to the low Ca(2+) dialysate (total 12 sessions in each case), serum intact PTH levels increased significantly (186.7 +/- 19.5 vs. 216.2 +/- 21.9 pg/ml: p = 0.01) in spite of the fact that no changes were found in serum ionized Ca(2+), Pi and Mg. This result indicates that the negative Ca(2+) balance during low-Ca(2+) hemodialysis-stimulated PTH secretion, which offset the decrease of serum Ca(2+); a trade-off phenomenon between negative Ca balance and PTH. This suggests that low Ca(2+) dialysate may exaggerate the progression of secondary hyperparathyroidism.