Health Economics of Renal Replacement Therapy

The medical treatment of renal failure is increasingly being discussed in terms of medical economics against the background of disease mechanisms, treatment techniques, and related systems. Particularly, renal replacement therapy requires considerable medical resources and results in high medical costs; therefore, the interest in medical economics is increasing worldwide. This article discusses the cost-effectiveness of renal replacement therapy using macro- and micro-analyses. Based on the macroscopic analysis of international comparisons of renal replacement therapy systems based on medical expenses per patient with end-stage renal disease and a one-year mortality rate, Japan performed better than other developed countries. A clinical economic study of renal replacement therapy is significant because it quantitatively demonstrates the socioeconomic value of life-saving and health benefits (Hemodialysis: approximately 6.5 million JPY/Qaly). In other words, even with high annual medical expenses and a heavy financial burden, the level of medical fees is appropriate from the perspective of the public’s value judgment. A micro-analysis comparing the cost-effectiveness of marginal and standard donors revealed no statistically significant difference in their cumulative medical costs per long-term life expectancy. Thus, evidence and decision-making related to medical economics are required for the sustainable development of the medical system for end-stage renal disease

New mechanism leading to alleviation of salt-sensitive hypertension by a powerful angiotensin receptor blocker, azilsartan

Hypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which azilsartan brought about this reaction. We speculated that azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by azilsartan treatment may lead to totally new drug discoveries

Serum phosphate levels modify the impact of parathyroid hormone levels on renal outcomes in kidney transplant recipients

Separate assessment of mineral bone disorder (MBD) parameters including calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25D) predict renal outcomes in kidney transplant recipients (KTRs), with conflicting results. To date, data simultaneously evaluating these parameters and interwoven relations on renal outcomes are scarce. We conducted a prospective long-term follow-up cohort study included 263 KTRs with grafts functioning at least 1 year after transplantation. The outcome was a composite of estimated GFR halving and graft loss. Cox regression analyses were employed to evaluate associations between a panel of six MBD parameters and renal outcomes. The outcome occurred in 98 KTRs during a median follow-up of 10.7 years. In a multivariate Cox analysis, intact PTH (iPTH), phosphate, and 1,25D levels were associated with the outcome (hazard ratio, 1.60 per log scale; 95% confidence interval, 1.19–2.14, 1.60 per mg/dL; 1.14–2.23 and 0.82 per 10 pg/mL; 0.68–0.99, respectively). Competing risk analysis with death as a competing event yielded a similar result. After stratification into four groups by iPTH and phosphate medians, high risks associated with high iPTH was not observed in KTRs with low phosphate levels (P-interaction < 0.1). Only KTRs not receiving active vitamin D, poor 1,25D status predicted the worse outcome (P-interaction < 0.1). High iPTH, phosphate, and low 1,25D, but not FGF23, levels predicted poor renal outcomes. Simultaneous evaluation of PTH and phosphate levels may provide additional information regarding renal allograft prognosis.Doi Y., Hamano T., Ichimaru N., et al. Serum phosphate levels modify the impact of parathyroid hormone levels on renal outcomes in kidney transplant recipients. Scientific Reports 10, 13766 (2020); https://doi.org/10.1038/s41598-020-70709-4

New mechanism leading to alleviation of salt-sensitive hypertension by a powerful angiotensin receptor blocker, azilsartan

Hypertension is one of the most life-threatening health problems in the modern world. Particularly, salt-sensitive hypertension is often associated with cardiovascular disease and defects in the circadian rhythm of the blood pressure. To date, the effects of angiotensin receptor blocker (ARB) against salt sensitivity and the blood pressure’s circadian rhythm have been obscure. A strong ARB, azilsartan, was previously reported to improve the circadian rhythm of blood pressure in hypertensive patients. In a recently published study, we investigated the mechanism by which azilsartan brought about this reaction. We speculated that azilsartan modulated sodium transporters located in the renal tubules because the circadian rhythm of blood pressure is linked to salt handling in the kidney. We discovered that one sodium transporter, NHE3 protein, in the proximal tubules was greatly attenuated in the kidneys of 5/6 nephrectomized mice that had been treated with azilsartan, although the expression of other sodium transporter proteins remained unchanged. The genetic expression of NHE3, however, was not changed by azilsartan. In a subsequent in vitro study using OKP cells, we found that NHE3 protein reduction was induced by enhanced protein degradation by proteasomes, not lysosomes, leading to enhanced sodium excretion. It is suggested that diminished salt sensitivity in the 5/6 nephrectomized mice treated with azilsartan was due to a change in sodium handling induced by the reduction of NHE3 protein in the proximal tubules. These mechanisms underlying the decreased salt sensitivity by azilsartan treatment may lead to totally new drug discoveries

Oral active vitamin d therapy as a potential chemoprevention against post-transplant malignancy

Post-transplant malignancy (PTM) is a limiting factor for both patient and allograft survival in kidney transplant recipients (KTRs). We hypothesized that active vitamin D compounds (AVDs) could reduce the development of PTM in KTRs and evaluated the effects of AVD therapy in a prospective cohort of ambulatory KTRs in a Japanese single center. We used a propensity score (PS) of having received AVDs estimated by 25 clinically relevant factors to adjust for these confounders. Among 218 participants, the mean age was 49.4 (SD, 12.1) years, 63.3% were male, the median time since transplantation was 11.2 (interquartile range [IQR], 5.2–17.1) years, and 42.2% had been treated with AVDs at baseline. The AVDs consisted of calcitriol (58.7%) and alfacalcidol (41.3%), and their median doses were 0.5 (IQR, 0.5–0.5) μg and 0.5 (IQR, 0.25–1.0) μg, respectively. During a median follow-up of 2.9 (IQR, 2.1–3.0) years, PTM was observed to have developed in 5 (5.4%) of 92 AVD users and in 11 (8.7%) of 126 non-users. Cox regression analysis with stratification by the PS tertiles showed that AVDs were significantly associated with a lower risk of PTM (hazard ratio, 0.25 [95% confidence interval, 0.07–0.82], P=0.022). The level of serum 25-hydroxyvitamin D was generally low (median, 16.6 ng/ml), and not significantly associated with PTM. Sensitivity analyses with stratification by PS quartiles, PS matching, or inverse probability weighting yielded similar results. Our results suggest a novel potential strategy to prevent PTM by using a normal dose of AVDs with a well-known safety profile. A randomized controlled trial should be performed to confirm our findings

Trends of kidney transplantation in Japan in 2018: data from the kidney transplant registry

Abstract The number of kidney transplants has gradually increased in the last decade; it was 1742 in Japan in 2017. The outcomes have improved year by year, with the indications for transplantation expanding accordingly. In this paper, we will report the unique trends and outcomes of kidney transplantation in Japan. The detailed transplant characteristics and outcomes are also shown as an updated version of the previous report in the Renal Replacement Therapy. Transplantations in elderly, diabetic, and ABO-incompatible living donors have been more widely performed recently, with the outcomes of these transplants having improved remarkably. However, the number of deceased donor transplants is still quite small, and further efforts to increase deceased organ donation continue to be of utmost necessity in Japan

Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression

Abstract Fatty liver has lower tolerance against ischemia-reperfusion (I/R) injury in liver operations, including liver transplantation. Seeking to ameliorate liver injury following I/R in fatty liver, we examined the protective effect of hydrogen (H2) saline on I/R liver injury in a methionine and choline-deficient plus high fat (MCDHF) diet-induced fatty liver mouse model. Saline containing 7 ppm H2 was administrated during the process of I/R. Livers were obtained and analyzed. Primary hepatocytes and Kupffer cells (KCs) were obtained from fatty liver and subjected to hypoxia/reoxygenation. Apoptosis-related proteins and components of the signaling pathway were analyzed after treatment with hydrogen gas. The MCDHF I/R group showed higher levels of AST and ALT in serum, TUNEL-positive apoptotic cells, F4/80 immunopositive cells, mRNA levels of inflammatory cytokines, constituents of the signaling pathway, pro-apoptotic molecules in liver, and KCs and/or primary hepatocytes, compared to the control group. In contrast, H2 treatment significantly suppressed the signs of I/R injury in fatty liver. Moreover, the expression of Bcl-2, HO-1, and Sirt1 in liver, KCs, and hepatocytes by hydrogen gas were increased, whereas caspase activation, Bax, and acetylation of p53 were suppressed by hydrogen gas. These results demonstrated that H2 treatment ameliorated I/R liver injury in a fatty liver model by reducing hepatocyte apoptosis, inhibiting macrophage activation and inflammatory cytokines, and inducing HO-1 and Sirt1 expression. Taken togather, treatment with H2 saline may have a protective effect and safe therapeutic activity during I/R events, such as in liver transplantation with fatty liver

[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model

Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[11C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([11C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [11C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [11C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [11C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE