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Chronic kidney disease-mineral and bone disorder (CKD-MBD) are recognized as a systemic disease affecting the prognosis of patients with CKD. Proper management of CKD-MBD is important to improve the prognosis of patients with CKD. Although proteinuria is recognized as a poor prognostic factor in these patients, few reports have examined its association with CKD-MBD. We examined the association between proteinuria and CKD-MBD using data from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex). Among the patients registered in the J-CKD-DB-Ex, 30,977 with CKD stages G2-G5 who had serum creatinine, albumin, calcium, and phosphate concentrations measured at least once and urinalysis performed were included. The patients were divided into four groups (negative, 1+, 2+, and 3+) according to the degree of proteinuria. The association between proteinuria and CKD-MBD was examined by a logistic regression analysis. In a model adjusted for age, sex, diabetes, and the estimated glomerular filtration rate (eGFR), the odds ratio of the 3 + group compared with the negative group significantly increased to 2.67 (95% confidence interval, 2.29-3.13) for hyperphosphatemia, 2.68 (1.94-3.71) for hypocalcemia, and 1.56 (1.24-1.98) for hypomagnesemia. Proteinuria is associated with hyperphosphatemia, hypocalcemia, and hypomagnesemia in patients with CKD independently of eGFR., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD., (© 2024. The Author(s).)

In dairy farming, the uncertainty of cow calving date often imposes waiting costs for days on farmers. Improving the accuracy of calving date prediction would mitigate these costs, specifically before a few days of the event. We monitored and analyzed the heart rate patterns of eight pregnant cows in the days leading up to calving using a dedicated monitoring device. We decomposed the heart rate data into three distinct components: trend, daily cycle, and the remainder, and discovered that the heart rate trend exhibited a sharp decline more than 40 h before the calving event via the trend turning point. To detect the turning point, we applied common financial technical indicators traditionally used to identify turning points of asset prices in trading markets for the extracted heart rate trend. This study remains a feasibility study because of the limited observations, but it indicates that these indicators can effectively capture the trend's turning point in real time, offering a promising approach for enhanced calving prediction. In addition to discussing the practical implications for cow management, we also contemplate the broader utility of these technical indicators in the context of various dynamic scientific data analyses., (© 2024. The Author(s).)

Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m 2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD., (© 2024. The Author(s).)

We retrospectively studied 12 eyes of 12 patients with central serous chorioretinopathy (CSC) to investigate choroidal thickness changes following half-fluence photodynamic therapy (PDT) using widefield choroidal thickness maps obtained by optical coherence tomography (OCT). Additionally, we assessed the relationship between choroidal thickness changes and the regional vortex veins as visualized on widefield en face OCT of the choroid. Pre-treatment en face images of the choroidal vasculature were superimposed on subtracted choroidal thickness maps before and 3 months after half-fluence PDT. The choroidal thickness decreased mainly in the irradiated macular area and in the region of vortex veins which function as drainage for the macula in all eyes. Eleven eyes (91.7%) showed choroidal thinning in the nasal area which overlapped with the nasal vortex vein distribution. Moreover, in 10 (90.9%) of those eyes, we observed intervortex venous anastomosis across the vertical watershed zone. Quantitative analysis revealed that the reduction in choroidal thickness was most pronounced in the macular area. Furthermore, the choroidal thickness reduction in the area with macular drainage vortex veins was significantly greater than that in the area without such vortex veins. These results suggest that half-fluence PDT might decrease choroidal thickness due to choriocapillaris occlusion in the irradiated macula, possibly leading to diminished venous drainage from the macula to regional vortex veins. Moreover, venous blood flow through the anastomotic vessels from the macular drainage vortex veins into the nasal vortex veins might be reduced post-treatment., (© 2023. The Author(s).)

Male and female pollinators often exhibit sex-specific preferences for visiting different flowers. Recent studies have shown that these preferences play an important role in shaping the network structure of pollination mutualism, but little is known about how they can mediate plant-plant interactions and coexistence of competing plants. The ecological consequences of sex-specific pollination can be complex. Suppose that a plant is favoured by female pollinators. They produce male pollinators, who may prefer visiting other competing plants and intensify the negative effects of inter-plant competition. Here, we analysed a simple two plant-one pollinator model with the sex structure of the pollinator. We observed that (i) sex-specific pollination can have complex consequences for inter-plant competition and coexistence (e.g. the occurrence of non-trivial alternative stable states in which one plant excludes or coexists with the other depending on the initial conditions), (ii) male and female pollinators have distinct ecological consequences because female pollinators have a demographic impact owing to reproduction, and (iii) plants are likely to coexist when male and female pollinators prefer different plants. These results suggest that sex-specific pollination is crucial for competition and coexistence of co-flowering plants. Future, pollination research should more explicitly consider the sex-specific behaviour of pollinating animals., (© 2023. The Author(s).)

The phenotypes of neovascular age-related macular degeneration (nAMD) are recognized as differing between Caucasian and Asian patients. Pachychoroid is thought to be more prevalent in Asians than in Caucasians, and may be involved in the development of nAMD in Asian patients. Therefore, we investigated the clinical characteristics and pachychoroid incidence in Japanese patients with nAMD. We retrospectively analyzed 385 eyes of 370 consecutive Japanese patients with treatment naïve nAMD. According to the nAMD nomenclature, type 1 macular neovascularization (MNV) was observed in 132 eyes (34.3%), polypoidal choroidal vasculopathy (PCV) in 137 (35.6%), mixed type 1 and type 2 MNV in 32 (8.3%), type 2 MNV in 43 (11.2%), and type 3 MNV in 41 (10.6%). Pachychoroid was seen in 58.3% of type 1 MNV, 75.2% of PCV, 34.4% of mixed type 1 and type 2 MNV, 14.0% of type 2 MNV, and 0% of type 3 MNV. Compared to nAMD patients without pachychoroid (188 eyes), those who had nAMD with pachychoroid (197 eyes) were significantly younger, had a higher proportion of males, greater central choroidal thickness, and a higher frequency of macular vortex vein anastomoses (all P < 0.001). Furthermore, drusen subtypes differed significantly between the two groups (P < 0.001). These results suggest that most Japanese nAMD patients might have type 1 MNV or PCV. Moreover, in approximately half of patients, nAMD might be associated with pachychoroid, and choroidal congestion may be involved in the development of MNV in these cases., (© 2022. The Author(s).)

We evaluated choroidal congestion using multimodal imaging in pachychoroid neovasculopathy (PNV). In a retrospective case series of 100 eyes of 99 treatment-naïve PNV patients, their clinical records were reviewed and the corresponding multimodal imaging studies were analyzed. We assessed areas of choriocapillaris filling delay which overlapped with dilated outer choroidal vessels, choroidal neovascularization (CNV), and retinal pigment epithelium (RPE) atrophy. The study subjects were 78 men (78.8%) and 21 women (21.2%). The mean patient age was 67.5 ± 10.5 years. On indocyanine green angiography, all eyes showed choriocapillaris filling delay in the early phase. Dilated outer choroidal vessels were demonstrated in all eyes by en face optical coherence tomography. The areas of choriocapillaris filling delay overlapped extensively with that of dilated outer choroidal vessels. All eyes showed CNV localized within the sites of choriocapillaris filling delay. RPE atrophy was noted in 71 eyes (71.0%), and 68 of these (95.8%) had RPE atrophy within the areas showing choriocapillaris filling delay. These findings indicate that chronic choriocapillaris ischemia secondary to vortex vein congestion may lead to CNV development as well as RPE atrophy in eyes with PNV., (© 2021. The Author(s).)

Accumulating evidence points to pachychoroid possibly being caused by vortex vein congestion which results in remodeling of choroidal drainage routes via intervortex vein anastomosis. This hypothesis prompted us to investigate vortex vein hemodynamics by studying videos of indocyanine green angiography (ICGA) in a retrospective case series of 295 eyes with pachychoroid spectrum diseases. In the early phase of the video-ICGA, pulsatile vortex venous flow was observed in 76 eyes (25.8%) at the vortex veins connected with anastomosis between superior and inferior vortex veins. The patients with pulsatile vortex venous flow were significantly older than those without pulsatile vortex venous flow (67.8 ± 13.2 vs. 63.9 ± 14.5 years, P < 0.05). Pulsatile vortex venous flow was 1.84 times more common in the inferior quadrants than in the superior quadrants. Interestingly, 14 of 76 eyes (18.4%) with pulsatile vortex venous flow showed retrograde pulsatile blood flow in the vortex veins. This retrograde pulsatile blood flow was 2.50 times more common in the inferior than in the superior quadrants. These findings indicate altered vortex vein hemodynamics due to vortex vein congestion in pachychoroid spectrum diseases., (© 2021. The Author(s).)

Pachychoroid spectrum diseases have attracted increasing attention, though their pathophysiology has yet to be fully elucidated. In this study, we assessed the vascular diameters of vortex veins in pachychoroid spectrum diseases such as central serous chorioretinopathy (CSC), pachychoroid neovasculopathy without polypoidal lesions (PNV), and pachychoroid neovasculopathy with polypoidal lesions (polypoidal choroidal vasculopathy: PCV). In a retrospective case series of 94 eyes with CSC, 60 eyes with PNV and 57 with PCV, we binarized en face optical coherence tomography (OCT) images of choroidal vortex veins and analyzed the mean diameter of vortex veins. The presence of anastomosis between the superior and inferior vortex veins and central choroidal thickness (CCT) were also evaluated using OCT images. CSC showed significantly larger mean diameter of vortex veins than PCV (P < 0.05). Anastomosis between superior and inferior vortex veins was observed in over 90% of eyes with each pachychoroid spectrum disease. The patients with CSC were the youngest, followed by PNV patients, and then patients with PCV. The largest CCT values were observed in CSC eyes, followed by PNV eyes, and then PCV eyes. CCT correlated with the mean diameter of vortex veins (rs = 0.51, P < 0.01). These findings suggest that congestion of vortex veins might show gradual amelioration corresponding to the development of anastomosis between the superior and inferior vortex veins during the course of progression of pachychoroid spectrum diseases. Moreover, the mean diameter of vortex veins can be used as a parameter indicating choroidal congestion.

Circulating ApolipoproteinL1 (ApoL1) is a component of pre-β-high-density lipoprotein (HDL), however little is known about the relationship of ApoL1 with cardiometabolic factors. Considering previous studies reporting the correlation of ApoL1 to triglyceride, we have hypothesized that ApoL1 associates with insulin-related metabolism. The current study examined their associations in 126 non-diabetic subjects and 36 patients with type 2 diabetes (T2DM). Non-diabetic subjects demonstrated triglyceride (standardized coefficients [s.c.] = 0.204, p < 0.05), body mass index (s.c. =0.232, p < 0.05) and HDL cholesterol (s.c. = -0.203, p < 0.05) as independent determinant of ApoL1 levels, and the significant elevation of ApoL1 in metabolic syndrome. Lipoprotein fractionation analysis revealed the predominant distribution of ApoL1 in large HDL fraction, and the significant increase of ApoL1 in large LDL fraction in high ApoL1 samples with insulin resistance. In T2DM, ApoL1 was higher in T2DM with metabolic syndrome, however ApoL1 was lower with β cell dysfunction. Insulin significantly promotes ApoL1 synthesis and secretion in HepG2 cells. In conclusion, circulating ApoL1 may be associated with abnormal HDL metabolism in insulin resistant status. This may suggest a regulation of insulin signal on the ApoL1 level, leading to offer a novel insight to the ApoL1 biology.

Superior and inferior macular vortex veins are divided by a horizontal watershed passing through the macula. We evaluated macular vortex vein remodeling in eyes with pachychoroid neovasculopathy (PNV). Thirty eyes of 30 patients with treatment-naïve PNV and 30 normal eyes of 30 age-, gender-, and refraction-matched subjects were studied. We assessed the features of macular vortex veins employing en face optical coherence tomography (OCT) and determined central choroidal thickness (CCT) using B-mode OCT. Of the 30 normal eyes, a horizontal watershed was identified in 24 eyes (80%), while venous anastomosis between the superior and inferior vortex veins was observed in 6 eyes (20%). Mean CCT was 233 μm. Of the 30 eyes with PNV, vortex veins were dilated in all 30 eyes with PNV. In 27 of the 30 PNV eyes (90%), the horizontal watershed had disappeared, and collateral veins had instead developed via anastomosis between the superior and inferior vortex veins, making this finding significantly more frequent than in normal eyes (P < 0.001). Mean CCT was 357 μm, significantly thicker than that of normal eyes (P < 0.001). Remodeling of choroidal drainage routes by venous anastomosis between superior and inferior vortex veins was common in eyes with PNV. This observation suggests longstanding congestion of the choroidal veins.

Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechanism of podocyte injury, the effect of BMP4 was investigated using streptozotocin (STZ)-induced, Bmp4 heterozygous knockout (Bmp4+/-) and podocyte-specific Bmp4 knockout mice. Mice with STZ-induced diabetes exhibited glomerular matrix hyperplasia and decreased numbers of podocyte nucleus-specific WT1-positive cells. The number of podocytes and proteinuria were improved in both diabetic Bmp4 knockout mouse models compared to the effects observed in the control mice. The effect of BMP4 overexpression on Bmp4-induced or podocyte-specific transgenic mice was examined. Tamoxifen-induced Bmp4-overexpressing mice exhibited mesangial matrix expansion and decreased numbers of WT1-positive cells. Podocyte-specific Bmp4-overexpressing mice displayed increased kidney BMP4 expression and mesangial matrix expansion but decreased nephrin expression and numbers of WT1-positive cells. Both lines of Bmp4-overexpressing mice exhibited increased albuminuria. In cultured podocytes, BMP4 increased phospho-p38 levels. BMP4 decreased nephrin expression but increased cleaved caspase-3 levels. p38 suppression inhibited caspase-3 activation. Apoptosis was confirmed in STZ-diabetic glomeruli and Bmp4-overexpressing mice. Bmp4 +/- mice with diabetes displayed reduced apoptosis. Based on these data, the BMP4 signaling pathway plays important roles in the development of both podocyte injury and mesangial matrix expansion in diabetic nephropathy.

Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality compared with other causes of renal diseases. We previously found that Smad1 plays a critical role in the development of DN both in vitro and in vivo. However, functional interaction between Smad1 and Smad3 signaling in DN is unclear. Here, we addressed the molecular interplay between Smad1 and Smad3 signaling under a diabetic condition by using Smad3-knockout diabetic mice. Extracellular matrix (ECM) protein overexpression and Smad1 activation were observed in the glomeruli of db/db mice but were suppressed in the glomeruli of Smad3 +/- ; db/db mice. Smad3 activation enhanced the phosphorylation of Smad1 C-terminal domain but decreased the phosphorylation of linker domain, thus regulating Smad1 activation in advanced glycation end product-treated mesangial cells (MCs). However, forced phosphorylation of the Smad1 linker domain did not affect Smad3 activation in MCs. Phosphorylation of the Smad1 linker domain increased in Smad3 +/- ; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression.

Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22 phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10 -6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.