Efficacy of molnupiravir and sotrovimab in Japanese dialysis patients with COVID-19 in clinical practice during the Omicron (BA.1 and BA.2) pandemic.

INTRODUCTION: In the present study, the efficacy of sotrovimab and molnupiravir in dialysis patients with COVID-19 was investigated using a registry of COVID-19 in Japanese dialysis patients. METHODS: Dialysis patients with confirmed SARS-CoV-2 during the COVID-19 (Omicron BA.1 and BA.2) pandemic were analyzed. Patients were classified into four treatment groups: molnupiravir monotherapy (molnupiravir group), sotrovimab monotherapy (sotrovimab group), molnupiravir and sotrovimab combination therapy (combination group), and no antiviral therapy (control group). The mortality rates in the four groups were compared. RESULTS: A total of 1480 patients were included. The mortality of the molnupiravir, sotrovimab, and combination groups were significantly improved compared to the control group (p < 0.001). Multivariate analysis indicated that antiviral therapy improves the survival of dialysis patients with COVID-19 (hazard ratio was 0.184 for molnupiravir, 0.389 for sotrovimab, and 0.254 for combination groups, respectively). CONCLUSION: Sotrovimab showed efficacy in Omicron BA.1 but attenuated in BA.2. Molnupiravir also showed efficacy in BA.2, suggesting administration of molnupiravir would be important.

Delamination of Acuseal arteriovenous graft: Two case reports.

Acuseal arteriovenous graft is an early cannulation graft having a tri-layered structure with an elastomeric middle layer. However, delamination of Acuseal grafts has been reported recently. This article describes two cases with different characteristics of Acuseal delamination. In case 1, the delamination occurred 1 month after a percutaneous transluminal angioplasty (PTA); therefore, the PTA was suspected to be a trigger. The delamination was located between the outer expanded polytetrafluoroethylene (ePTFE) layer and the elastomeric middle layer. On the other hand, in case 2, the delamination was located between the luminal ePTFE layer and the elastomeric middle layer. A surveillance ultrasound examination detected the delamination unexpectedly in the uneventful course; however, the delaminating location corresponded to the cannulation puncture site and the intraoperative findings suggested the involvement of mis-needling as a possible cause. Interestingly, for the purpose of continued use on hemodialysis, specific treatments were required against the delamination itself in both cases. As we identified Acuseal delamination in 5.6% (2/36) of cases, concerns arise that numerous cases of Acuseal delamination may have been overlooked in general. Understanding and recognizing this phenomenon are important for adequate use of Acuseal graft.

Effectiveness of SARS-CoV-2 vaccines on hemodialysis patients in Japan: A nationwide cohort study.

INTRODUCTION: This study compared the outcomes of dialysis patients who received SARS-CoV-2 vaccine with those who did not use data from the Japanese COVID-19 registry. METHODS: A total of 1260 dialysis patients with confirmed positive SARS-CoV-2 infection was included in this study. Patients were divided into two groups: patients who experienced breakthrough infection and those who were unvaccinated. The need of oxygen supplementation and mortality risks were compared using multivariate logistic regression analysis. RESULTS: The mortality rate was 24.2% in unvaccinated patients and 8.6% in breakthrough patients. The odds ratio of need of oxygen supplementation in the breakthrough patients relative to unvaccinated patients was 0.197. The hazard ratio of mortality in the breakthrough patients relative to unvaccinated patients was 0.464. CONCLUSION: Our prospective observational study showed that SRAS-CoV-2 vaccination in hemodialysis patients is vital for reducing need of oxygen supplementation and mortality risk.

Significant Association of Diabetes With Mortality of Chronic Hemodialysis Patients, Independent of the Presence of Obesity, Sarcopenia, and Sarcopenic Obesity.

OBJECTIVES: This retrospective cohort study investigated the association of diabetes with mortality in hemodialysis patients with regard to obesity, sarcopenia, and sarcopenic obesity, along with examining the prevalence of each group and diabetes. METHODS: Muscle strength, muscle mass, and fat mass were evaluated using a hand dynamometer and dual-energy X-ray absorptiometry, respectively, in 308 chronic hemodialysis patients (age 58.0 ± 11.9 years, hemodialysis duration 6.5 ± 6.0 years, males 60.1%, diabetes 32.8%). Sarcopenia was defined according to the new criteria established by the Asian Working Group on Sarcopenia 2019. Obesity was defined by percent body fat mass (males ≥25%, females ≥35%). RESULTS: The enrolled patients were divided into the normal (38.7%), obesity (18.8%), sarcopenia (26.9%), and sarcopenic obesity (15.6%) groups. The prevalence of diabetes was significantly skewed among the 4 groups (χ2 test, P = .0057), being higher in the sarcopenic obesity group (54.2%) compared to the others (25.9-33.7%). Multivariate regression analysis revealed that diabetes was significantly and independently associated with sarcopenic obesity (odds ratio 3.495, 95% confidence interval 1.683-7.255, P = .0008) after adjustments for several cofounders, but not significantly associated with sarcopenia. During the follow-up period of 76 ± 35 months, 100 patients died. Those in the sarcopenia and sarcopenic obesity groups had significantly higher rates of all-cause mortality compared to patients in the normal and obesity groups (P = .0004, log-rank test). Furthermore, multivariate Cox proportional hazards analysis revealed that presence of diabetes was significantly associated with higher all-cause mortality in all 308 patients, after adjustments for several factors, including the presence of each group in 4 models. CONCLUSION: Sarcopenic obesity is highly prevalent in chronic hemodialysis patients. Diabetes was found to be a significant and independent contributor to the presence of sarcopenic obesity. Diabetes was shown to be a significant predictor of all-cause mortality, independent of the present normal, obesity, sarcopenia, and sarcopenic obesity groups.

Survival and predictive factors in dialysis patients with COVID-19 in Japan: a nationwide cohort study.

BACKGROUND: The Japanese Association of Dialysis Physicians, the Japanese Society for Dialysis Therapy, and the Japanese Society of Nephrology jointly established COVID-19 Task Force Committee and began surveying the number of newly infected patients. METHODS: This registry of the COVID-19 Task Force Committee was used to collect data of dialysis patients; a total of 1010 dialysis patients with COVID-19 were included in the analysis. Overall survival of patients was investigated with stratification by age group, complication status, and treatment. In addition, predictive factors for mortality were also investigated. The overall survival was estimated by Kaplan-Meier methods and compared by using log-rank test. Multivariate analysis was performed to identify the risk factor of mortality. For all statistical analyses, p < 0.05 was considered to be statistically significant. RESULTS: The mortality risk was increased with age (p < 0.001). The mortality risk was significantly higher in patients with peripheral arterial disease (HR: 1.49, 95% CI 1.05-2.10) and significantly lower in patients who were treated with remdesivir (HR: 0.60, 95% CI 0.37-0.98). Multivariate analysis showed increased risk of mortality with increment in BMI, and increment in CRP, and decreased risk with increment in albumin. CONCLUSION: Dialysis patients have a high severity of illness and a high risk of mortality in cases of COVID-19. Treatment with remdesivir might be effective in shortening the duration of hospitalization and reducing the risk of mortality.

REM sleep latency as an independent risk for cardiovascular events in hemodialysis patients.

BACKGROUND: Clinical significance of objectively measured poor sleep quality (SQ) as a risk for cardiovascular disease (CVD) events is not well known in hemodialysis (HD) patients, independently of sleep-related breathing disorders (SRBDs) and sleep-related metabolic abnormality. METHODS: The present study investigated baseline levels of objective sleep architecture together with obstructive sleep apnea (OSA) and central sleep apnea (CSA) using polysomnography in 88 HD study participants (M/F, 56/32; age 68.4 ± 9.3). Then, HD study participants were monitored for the occurrence of new-onset CVD events with a median (range) follow-up period of 33 (1-64) months. RESULTS: Among various measures of SQ, log (REM sleep latency [REM-SL]) (interval between sleep-onset and the first REM period) alone correlated in negative manners with triglycerides and non-HDL-C in all study participants and with fasting plasma glucose and HbA1c in study participants with type-2 diabetes mellitus. In the Kaplan-Meier analysis, HD study participants with shorter REM-SL had a significantly higher rate of new-onset CVD events than those with longer REM-SL. Stepwise logistic regression analysis and multivariate Cox proportional hazard regression analysis identified shorter REM-SL as an independent risk factor for the development of a new-onset CVD events, independent of mean oxygen saturation, log (AHI+1), log (central AHI+1), diabetes mellitus, CVD history, systolic blood pressure, statins use, and non-HDL-C. CONCLUSIONS: The present study demonstrated that reduction of REM-SL is independently associated with a higher rate of new-onset of CVD events, independent of SRBDs (OSA and CSA) and diabetes mellitus, non-HDL-C in HD study participants, suggesting impaired SQ as a potential CVD risk factor, and thus a definite treatment target to protect against CVD specifically in HD study participants. REM-SL might be a new risk factor of CVD events in HD patients with SRBDs.

Cinacalcet may suppress kidney enlargement in hemodialysis patients with autosomal dominant polycystic kidney disease.

A massively enlarged kidney can impact quality of life of autosomal dominant polycystic kidney disease (ADPKD) patients. A recent in vitro study demonstrated that an allosteric modulator of the calcium sensing receptor decreases adenosine-3',5'-cyclic monophosphate, an important factor for kidney enlargement in ADPKD. Therefore, the present study was performed to determine whether cinacalcet, a calcium sensing receptor agonist, suppresses kidney enlargement in hemodialysis patients with ADPKD. Alteration of total kidney volume together with clinical parameters was retrospectively examined in 12 hemodialysis patients with ADPKD treated at a single institution in Japan. In the non-cinacalcet group with longer hemodialysis duration (n = 5), total kidney volume had an annual increase of 4.19 ± 1.71% during an overall period of 877 ± 494 days. In contrast, the annual rate of increase in total kidney volume in the cinacalcet group (n = 7) was significantly suppressed after cinacalcet treatment, from 3.26 ± 2.87% during a period of 734 ± 352 days before the start of cinacalcet to - 4.71 ± 6.42% during 918 ± 524 days after initiation of treatment (p = 0.047). The present findings showed that cinacalcet could be a novel therapeutic tool for suppression of kidney enlargement in hemodialysis patients with ADPKD.

Hemodialysis using a low bicarbonate dialysis bath: Implications for acid-base homeostasis.

The low bath bicarbonate concentration ([ HCO3- ]) used by a nephrology group in Japan (25.5 mEq/L), coupled with a bath [acetate] of 8 mEq/L, provided an opportunity to study the acid-base events occurring during hemodialysis when HCO3- flux is from the patient to the bath. We used an analytic tool that allows calculation of HCO3- delivery during hemodialysis and the physiological response to it in 17 Japanese outpatients with an average pre-dialysis blood [ HCO3- ] of 25 mEq/L. Our analysis demonstrates that HCO3- addition is markedly reduced and that all of it comes from acetate metabolism. The HCO3- added to the extracellular fluid during treatment (19.5 mEq) was completely consumed by H+ mobilization from body buffers. In contrast to patients dialyzing with higher bath [ HCO3- ] values in the US and Europe, organic acid production was suppressed rather than stimulated. Dietary analysis indicates that these patients are in acid balance due to the alkaline nature of their diet. In a larger group of patients using the same bath solution, pre-dialysis blood [ HCO3- ] was lower, 22.2 mEq/L, but still in an acceptable range. Our studies indicate that a low bath [ HCO3- ] is well tolerated and can prevent stimulation of organic acid production.

Novel gene Merlot inhibits differentiation and promotes apoptosis of osteoclasts.

Extended osteoclast longevity is deeply involved in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis, though the mechanisms that determine osteoclast lifespan are not fully understood. Here we present findings indicating that the newly characterized gene Merlot, which encodes a highly conserved yet uncharacterized protein in vertebrates, is an important regulator for termination of osteoclastogenesis via induction of apoptosis. Mice lacking Merlot exhibited low bone mass due to increased osteoclast and bone resorption. Furthermore, osteoclast precursors overexpressing Merlot failed to differentiate into mature osteoclasts, while Merlot deficiency led to hyper-nucleation and prolonged survival of osteoclasts, accompanied by sustained nuclear localization of nuclear factor of activated T cell c1 (NFATc1) and derepression of glycogen synthase kinase-3ß (GSK3ß) activity, known to regulate NFATc1 activity and induce apoptosis. Merlot-deficient osteoclasts were found to represent suppression of caspase-3-mediated apoptosis and Merlot deficiency caused transcriptional downregulation of a proapoptotic cascade, including Bax, Bak, Noxa, and Bim, as well as the executor caspase members Casp-3, -6, and -7, and upregulation of anti-apoptotic Bcl2, resulting in a low apoptotic threshold. Thus, Merlot regulates osteoclast lifespan by inhibition of differentiation and simultaneous induction of apoptosis via regulation of the NFATc1-GSK3ß axis.

COVID-19 of dialysis patients in Japan: Current status and guidance on preventive measures.

In Japan, the first case of COVID-19 in dialysis patients was reported on March 1, 2020. A total of 31 cases were reported by April 10, and it increased to 95 by May 15. Thereafter, with the rapid increase in the number of COVID-19 cases in the general population since late March, there was a not surprising increase in the number of COVID-19 cases in dialysis patients. The mortality rate is 16.2% (16/99 cases) in dialysis patients, which is higher than 5.3% (874/16 532 cases) in the general population. This higher mortality rate in dialysis patients with COVID-19 might be related to their age; the majority of COVID-19 cases are aged between 70 and 90 years old in dialysis patients, compared with between 20 and 60 years old in the general population. As COVID-19 presents with severe symptoms and is associated with a high mortality rate in dialysis patients, dialysis patients who have contracted severe acute respiratory syndrome coronavirus 2 infection confirmed by polymerase chain reaction testing are required to be hospitalized under Japanese government policy. In cases of COVID-19 hospitalizations, it is essential to prevent nosocomial infection. Therefore, patients must be sufficiently instructed in infection prevention and robust measures to prevent contraction and spread of the infection must be taken at dialysis facilities.

Effects of N-methyl-d-aspartate receptor antagonist MK-801 (dizocilpine) on bone homeostasis in mice.

OBJECTIVES: To gain insight into the role of the N-methyl-d-aspartate (NMDA) receptor in bone metabolism by examining the effects of its noncompetitive antagonist, MK-801 (dizocilpine), on bone homeostasis and bone healing in mice. METHODS: MK-801 (2.5 mg/kg) or saline (in control groups) was intravenously administered to healthy mice and mice with bone-defects daily for seven to 14 days. Bone defects were artificially created in femurs using a drill and reamer. Following euthanasia, bones were extracted and processed for microcomputed tomography (µCT) and histological analyses. The effects of MK-801 on osteoclast differentiation by bone marrow macrophages (BMMs) were examined in vitro. mRNA expressionlevels of Grin3b levels were also examined using reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: Bone volume was significantly decreased in mice administered MK-801 for 14 days. Additionally, the number of osteoclasts was reduced, while number of osteoblasts and rate of bone formation were increased in these mice. MK-801 inhibited osteoclast differentiation dose-dependently in vitro. RT-PCR findings suggested expression of Grin3b, a subunit of the NMDA receptor, in BMMs. During the healing process of artificially created defects in femurs, no significant differences were found between the control and MK-801-treated groups, indicating no stimulatory or inhibitory effects by MK-801 administration. CONCLUSIONS: These results indicate that blockade of the NMDA receptor by MK-801 administration affects bone metabolism but not the healing process of artificial bone defects.

Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells.

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.

Inverse association of fat mass, but not lean mass, with glycated albumin in hemodialysis patients with or without diabetes mellitus.

Background: Glycated albumin (GA), which is independent of anemia and/or use of erythropoiesis-stimulating agents, might provide a more precise measure than glycated hemoglobin (HbA1c) in hemodialysis patients. The present study examines whether body composition is associated with GA besides glycemic control in hemodialysis patients. Methods: This study included 90 hemodialysis patients with diabetes mellitus (DM) and 86 hemodialysis patients without DM. We examined blood parameters after an overnight fast and body fat and lean mass using dual X-ray absorptiometry 21-24 h after completing the dialysis session. Results: The mean body mass index (BMI) was 22.0 kg/m2. BMI and truncal fat mass were significantly higher, and total fat mass tended to be higher in hemodialysis patients with DM than in those without DM. GA exhibited inverse correlations with BMI, total lean mass, total fat mass, and truncal fat mass in hemodialysis patients with and without DM; however, there was a lack of correlation with total lean mass in patients without DM. In multiple regression analysis including total fat mass and total lean mass simultaneously as independent variables, total fat mass (with DM: ß = -0.322, p = .006) (without DM: ß = -0.391, p < .001), but not total lean mass, in addition to log fasting plasma glucose, emerged as an independent factor associated with GA in hemodialysis patients with and without DM. When total fat mass was replaced with truncal fat mass (with DM: ß = -0.311, p = .007) (without DM: ß = -0.396, p < .001), the association remained significant and independent with GA in both patient groups. Conclusions: Higher total fat mass, particularly truncal fat mass, might be associated with lower GA levels, beside glycemic control, in hemodialysis patients with or without DM.

Bone loss caused by dopaminergic degeneration and levodopa treatment in Parkinson's disease model mice.

Accumulating evidence have shown the association of Parkinson's disease (PD) with osteoporosis. Bone loss in PD patients, considered to be multifactorial and a result of motor disfunction, is a hallmark symptom that causes immobility and decreased muscle strength, as well as malnutrition and medication. However, no known experimental evidence has been presented showing deleterious effects of anti-PD drugs on bone or involvement of dopaminergic degeneration in bone metabolism. Here, we show that osteoporosis associated with PD is caused by dopaminergic degeneration itself, with no deficit of motor activity, as well as treatment with levodopa, the current gold-standard medication for affected patients. Our findings show that neurotoxin-induced dopaminergic degeneration resulted in bone loss due to accelerated osteoclastogenesis and suppressed bone formation, which was associated with elevated prolactin. On the other hand, using an experimental model of postmenopausal osteoporosis, dopaminergic degeneration did not result in exacerbation of bone loss due to estrogen deficiency, but rather reduction of bone loss. Thus, this study provides evidence for the regulation of bone metabolism by the dopaminergic system through both gonadal steroid hormone-dependent and -independent functions, leading to possible early detection of osteoporosis development in individuals with PD.

A Delphinidin-Enriched Maqui Berry Extract Improves Bone Metabolism and Protects against Bone Loss in Osteopenic Mouse Models.

In our previous investigation, delphinidin, one of the most abundant anthocyanins found in vegetables and berry fruits, had been shown to inhibit osteoclasts and prevent bone loss in mouse models of osteoporosis. In the present study, we investigated whether a delphinidin glycoside-enriched maqui berry extract (MBE, Delphinol®) exhibits beneficial effects on bone metabolism both in vitro and in vivo. MBE stimulated the osteoblastic differentiation of MC3T3-E1 cells, as indicated by enhanced mineralized nodule formation, and increased alkaline phosphatase activity, through the upregulation of bone morphogenetic protein 2 (Bmp2), runt-related transcription factor 2 (Runx2), Osterix (Osx), osteocalcin (Ocn), and matrix extracellular phosphoglycoprotein (Mepe) mRNA expression. Immunostaining and immunoprecipitation assays demonstrated that MBE suppressed NF-κB transnucleation through acting as a superoxide anion/peroxynitrite scavenger in MC3T3-E1 cells. Simultaneously, MBE inhibited both osteoclastogenesis in primary bone marrow macrophages and pit formation by maturated osteoclasts on dentine slices. Microcomputed tomography (micro-CT) and bone histomorphometry analyses of femurs demonstrated that the daily ingestion of MBE significantly increased BV/TV (ratio of bone volume to tissue volume), Tb.Th (trabecular thickness), Tb.N (trabecular number), N.Nd/N.Tm (node to terminus ratio), OV/TV (ratio of osteoid volume to tissue volume), BFR/TV (bone formation rate per tissue volume), and significantly decreased Tb.Sp (trabecular separation), ES/BS (ratio of eroded surface to bone surface) and N.Oc/BS (number of osteoclast per unit of bone surface, compared to vehicle controls in osteopenic mouse models. These findings suggest that MBE can be a promising natural agent for the prevention of bone loss in osteopenic conditions by not only inhibiting bone resorption, but also stimulating bone formation.

Impact of diabetes on sarcopenia and mortality in patients undergoing hemodialysis.

BACKGROUND: Sarcopenia has become a serious disorder in modern society. Chronic kidney disease requiring dialysis and diabetes are some of the disorders that accelerate the onset and progression of sarcopenia. We, therefore, investigated the prevalence of sarcopenia in patients undergoing hemodialysis (HD) and confirmed the impact of diabetes mellitus (DM) on this population. METHODS: This study included 308 patients whose muscle strength and mass had been evaluated using handgrip strength and dual-energy X-ray absorptiometry, respectively. Sarcopenia was defined according to the criteria established by the Asian Working Group on Sarcopenia. In addition, this cohort had been followed up for 9 years. RESULTS: The prevalence of sarcopenia was 40% (37% in males and 45% in females) with gender differences being insignificant (p = 0.237). The DM morbidity rate was significantly higher in those with sarcopenia than in those without sarcopenia (41% vs. 27%, p = 0.015). Multivariate regression analyses showed that the presence of DM was an independent contributor to sarcopenia in patients undergoing HD (odds ratio 3.11; 95% confidence interval 1.63-5.93; p <  0.001). During the follow-up of 76 ± 35 months, 100 patients died. Patients with sarcopenia demonstrated significantly higher rates of all-cause mortality than those without sarcopenia (p <  0.001 using the log-rank test). Multivariate Cox proportional hazards analyses revealed that the presence of DM was significantly associated with higher all-cause mortality (adjusted hazard ratio: 2.39; 95% confidence interval 1.51-3.81; p <  0.001). CONCLUSIONS: The prevalence of sarcopenia among this cohort of patients undergoing HD was determined to be 40%. Moreover, the presence of DM was an independent contributor to sarcopenia and an independent predictor of all-cause mortality in this population.

Effects of Long-Term Cinacalcet Administration on Parathyroid Gland in Hemodialysis Patients with Secondary Hyperparathyroidism.

BACKGROUND/AIM: Cinacalcet, an allosteric modulator of the calcium (Ca) sensing receptor, reduces the level of parathyroid hormone (PTH) in serum as well as parathyroid gland volume following administration in hemodialysis patients with secondary hyperparathyroidism, though long-term results are yet to be reported. METHODS: Serum parameters (n = 23), together with total parathyroid gland volume (n = 18), were determined in Japanese hemodialysis patients given cinacalcet treatment for 8 years. RESULTS: Following initiation of cinacalcet therapy, levels of serum Ca, phosphate, and intact PTH were significantly decreased. Furthermore, the baseline total volume of the parathyroid gland was 1,272 mm3 (496-2,836 mm3), which was then decreased after 6 months to 796 mm3 (377-1,146 mm3) and then to 332 mm3 (175-570 mm3) after 8 years. There was significant positive correlation between parathyroid gland volume at the start of cinacalcet treatment and reduction in volume during the 8 years cinacalcet treatment. The dose of phosphate binder was significantly decreased in a time-dependent manner after 8 years of cinacalcet treatment, likely because serum phosphate showed a progressive decrease with the treatment. CONCLUSION: In the present patients, long-term treatment with cinacalcet progressively decreased the total volume of parathyroid glands, as well as levels of intact PTH and phosphate in serum in a time-dependent manner. On the contrary, cinacalcet administration did not cause secondary failure or over-suppress the transition of parathyroid gland activity to hypoparathyroid status. These results suggest that cinacalcet treatment may postpone the need for parathyroidectomy and/or reduce its use even after long-term administration for up to 8 years.

Effects of Uremic Serum Residue on OATP1B1- and OATP1B3-Mediated Pravastatin Uptake in OATP-Expressing HEK293 Cells and Human Hepatocytes.

Patients with end-stage renal disease have increased plasma concentrations of statins, which is a risk factor for rhabdomyolysis, as well as elevated levels of uremic toxins (UTs). We investigated the effects of uremic serum residue and UTs on organic anion-transporting peptide (OATP1B1)- and OATP1B3-mediated pravastatin uptake. We evaluated the effects of normal serum residue with four UTs (hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furan propionate, indole-3-acetic acid, and 3-indoxyl sulfate) and uremic serum residue on pravastatin uptake by OATP1B1- or OATP1B3-expressing HEK293 cells. Furthermore, we assessed the contribution of each transporter using cryopreserved human hepatocytes. Uremic serum residue and UTs significantly inhibited OATP1B1-mediated pravastatin uptake. Uremic serum residue accelerated OATP1B3-mediated pravastatin uptake, while UTs had no effect. There was no difference in pravastatin uptake between uremic- and normal serum residue-treated hepatocytes. The results suggest that the effects of uremic serum on pravastatin hepatic uptake may be considered negligible in end-stage renal disease patients.

Paradoxical positive association of serum adiponectin with all-cause mortality based on body composition in Japanese haemodialysis patients.

We have previously reported a paradoxical association of serum adiponectin with aortic calcification in haemodialysis patients. Because serum adiponectin is a nutritional marker, we examined the association between serum adiponectin and all-cause mortality based on body composition in haemodialysis patients. The trunk and total body fat were determined. The patients were divided into two groups based on serum adiponectin levels. In Kaplan-Meier analysis, the higher adiponectin group showed higher mortality than the lower adiponectin group. Serum adiponectin showed an inverse correlation with the percentage of truncal fat, suggesting serum adiponectin as an inverse marker for adiposity in haemodialysis patients. However, even after adjustment for other factors, multivariate Cox proportional hazards analysis identified higher serum adiponectin as an independent factor positively associated with higher mortality in haemodialysis patients. This association held true even when the total fat mass was replaced with the percentage of truncal fat, and when total fat mass and percentage of truncal fat were simultaneously included. Thus, we found a paradoxical association of higher serum adiponectin with higher all-cause mortality in Japanese haemodialysis patients, independent of adiposity.

Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease.

PURPOSE: Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients. METHODS: The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study. RESULTS: The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum. CONCLUSIONS: The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.