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Background and Objective: In acute kidney injury (AKI), a strong inflammatory component is activated in response to the renal damage, and one of the main mediators behind this process is the pro-inflammatory interleukin 6 or IL-6. Beside to this phenomenon, there are also alterations in different components of mineral metabolism, such as those dependent on fibroblast growth factor (FGF)23 and the anti-ageing cofactor klotho. The aim of this work was to explore the association between renal function and systemic levels of IL-6, as well as FGF23 and klotho in the early stages of AKI, analysing the predictive capacity of IL-6 in early mortality associated with AKI., Material and Methods: Plasma levels of IL-6, klotho and FGF23 were analysed in samples from 28 patients with AKI and related to renal function on hospital admission, and after 24 and 72 h. In addition, the predictive capacity of IL-6 on AKI-associated mortality was analysed at the three study time points. In an experimental nephrotoxic -AKI mouse model, systemic IL-6 and FGF23 values were also analysed 24 and 72 h after induction of kidney damage, as well as in mice overexpressing the anti-ageing protein, klotho., Results: Systemic IL-6 levels increased in AKI patients, especially in hospital admission time, and decreased in parallel with improving renal function. At the same time as IL-6 values increased, there was an increase in FGF23 and a decrease in klotho levels, with a significant and positive correlation between IL-6 and FGF23 levels. In addition, we obtained that systemic IL-6 levels were a good predictor of mortality in these patients, with an area under the curve equal to one at 72 h after AKI. In the experimental mouse AKI model, we also observed an increase in plasma levels in both IL-6 and FGF23 after 24 h of kidney damage. Nevertheless, in transgenic mice overexpressing klotho, there was no such increase in any of them., Conclusions: There is an association between renal damage and increased levels of IL-6 and FGF23 in patients with AKI, especially on hospital admission time. Moreover, IL-6 levels are able to predict mortality in these patients, being a promising prognostic biomarker at any study time with a strong prediction at 72 h after patient admission. Maintaining adequate klotho levels could prevent the IL-6 mediated inflammatory response and therefore also reduce the degree and severity of renal damage after AKI., Competing Interests: Declaration of competing interest The authors of this paper have no conflicts of interest to declare., (Copyright © 2024 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Hemodialysis patients exhibit a reduced response to vaccination and have different vaccine dose regimens. Vaccines induce antibodies and affect the inflammatory balance through antibody glycosylation and effector functions. Therefore, we aimed to analyze the antibody glycosylation profiles in hemodialysis patients who were vaccinated against severe acute respiratory syndrome coronavirus 2, infected with the virus, or both, and compare them with those of dialysis patients in a control group., Methods: Plasma samples from 112 hemodialysis patients were assigned to four groups: control, infected, vaccinated, and post-vaccine-infected. Paired plasma samples from 47 people with vaccination (vaccinees) were analyzed before and after the booster dose. The same analytical approach was applied to the four groups for a cross-sectional comparison., Results: Our study found that both vaccination and infection groups showed decreased fucosylation of IgG1, which is associated with a proinflammatory biosignature. However, vaccination also leads to increased galactosylation and bisection of IgG antibodies, which are associated with anti-inflammatory effects and the additional regulation of immune responses. In contrast, infection led to an additional decrease in the fucosylation of IgG2 and IgA, demonstrating a more intense proinflammatory biosignature than vaccination., Conclusions: Our findings emphasize the proinflammatory biosignature of afucosylation in both vaccination and infection groups. Additionally, we uncovered further regulated profiles related to galactosylation in vaccinees. These findings suggest that antibody investigation for vaccination or infection should not solely focus on neutralization but should also consider effector function-related glycosylation profiling. This comprehensive information can be valuable for fine-tuning vaccine development in the future., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Recent studies have identified increased blood calciprotein particle (CPP) levels as risk factors for vascular calcification and cardiovascular events in patients undergoing maintenance hemodialysis. Although positively correlated with serum phosphate levels, serum CPP levels vary considerably among patients with similar serum phosphate levels. We investigated the capacity of the ratio of serum CPP levels to serum phosphate levels (CPP/Pi ratio) to predict cardiovascular events in incident hemodialysis patients compared to the serum calcification propensity test (T 50 )., Methods and Results: The association between the CPP/Pi ratio and major adverse cardiac and cerebrovascular events (MACCE) was investigated in 174 incident hemodialysis patients. Multivariate analysis revealed that the CPP/Pi ratio was independently associated with MACCE [hazard ratio 1.60, 95% confidence interval (1.15-2.23), p = 0.006] but serum T 50 levels were not., Conclusions: The CPP/Pi ratio is a useful, novel biomarker for predicting the risk of cardiovascular events in patients undergoing incident hemodialysis., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Introduction: Klotho, a key aging regulator, is predominantly expressed in the kidney. Various methods now enable the measurement of soluble αKlotho blood levels in humans. Limited studies have explored the renal origin of circulating αKlotho in humans., Methods: Soluble αKlotho in the inferior vena cava blood was measured using an enzyme-linked immunosorbent assay kit using blood samples from patients undergoing adrenal venous catheterization for close examination of primary aldosteronism., Results: The concentration at the suprarenal inferior vena cava (476±68.2) was significantly higher than that at the infrarenal inferior vena cava (434±74.8) (p=0.018), with a rate of change of 8.12 (2.3)%., Conclusions: We demonstrate a step-up in αKlotho concentration from the infrarenal to suprarenal vena cava in humans, supporting the kidney's origin of soluble αKlotho in the bloodstream., (Copyright © 2024 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: An increase in proximal tubule fluid phosphate concentration is caused by increased serum fibroblast growth factor-23 (FGF23) levels, which resulted in renal tubular damage in a mouse model of chronic kidney disease (CKD). However, few human studies have supported this concept. This study aimed to explore the association among estimated proximal tubule fluid phosphate concentration (ePTFp), serum FGF23 levels, and renal tubular damage biomarkers in middle-aged and older populations with mild decline in renal function., Methods: This cross-sectional study included 218 participants aged ≥45 with CKD stages G2-G4. Anthropometric measurements, blood tests, spot urine biomarkers, renal ultrasonography, cardiovascular assessment, smoking status, and medication usage were obtained in the morning in fasted states. The ePTFp was calculated using serum creatinine, urine phosphate, and creatinine concentrations. Urinary β2-microglobulin (β2-MG) and liver-type fatty acid-binding protein (L-FABP) levels were evaluated to assess renal tubular damage., Results: PTFp, serum FGF23, urinary β2-MG, and urinary L-FABP levels increased with CKD stage progression (stages G2, G3, and G4). However, serum and urine phosphate concentrations were comparable across the CKD stages. Univariate analysis revealed a stronger correlation of ePTFp with serum FGF23, urinary β2-MG, and urinary L-FABP levels than with the corresponding serum and urine phosphate concentrations. Multivariate analyses demonstrated that increased ePTFp was independently associated with elevated serum FGF23 and urinary β2-MG levels, even after adjusting for potential covariates, including the estimated glomerular filtration rate and urinary albumin-to-creatinine ratio., Conclusions: Our results are consistent with the concept in mouse model and suggest that increased ePTFp are associated with increased serum FGF23 levels and renal tubular damage during the early stages of CKD., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background/Objectives: Levels of circulating soluble thrombomodulin (sTM), an anticoagulant factor, are associated with the severity and progression of arteriosclerotic diseases. However, the role of elevated sTM levels remains to be clarified in patients on dialysis. As the calcification propensity time T50 is a novel marker of arterial calcification, we aimed to determine the association between sTM and T50 in patients on hemodialysis (HD). Methods: This cross-sectional study included 49 adult patients on maintenance HD. Correlation analysis was performed to test the association between T50 and patient characteristics. Linear regression was used to evaluate the association between T50 and sTM. Results: Partial correlation analysis showed a strong association between T50 and glycated albumin, phosphorous, and sTM levels (partial correlation coefficient: r [partial] = -0.359, p = 0.023; r [partial] = -0.579, p < 0.001; and r [partial] = 0.346, p = 0.029, respectively). Multivariate linear regression analysis revealed that only sTM level was significantly and positively associated with T50 (β = 0.288; t = 2.27; p = 0.029; 95% confidence interval, 0.082-1.403). Conclusions: sTM is independently and positively associated with the propensity time for calcification, suggesting that sTM could be a good marker of arterial calcification progression in patients on HD.

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related., (© 2024. The Author(s).)

Background and Hypothesis: Extended-hours haemodialysis (HD) is associated with better clinical outcomes than conventional HD. We investigated whether extended-hours HD and conventional HD have varying effects on blood levels of calciprotein particles (CPPs) and phosphorus, which have been identified as major pathogenic molecules for vascular calcification., Methods: Patients who underwent conventional or extended in-centre daytime HD between January and March 2020 were included. Plasma CPP levels, representing only secondary CPPs (CPP-II), were measured in pre-dialysis samples. Linear and non-linear associations between CPPs and serum phosphorus levels were examined across dialysis modalities., Results: A total of 382 participants (185 undergoing extended-hours HD and 197 undergoing conventional HD) were included in the analysis. The median age of participants was 71 years, 65% of the patients were men and the mean phosphorus level was 5.4 mg/dl. Plasma CPP (CPP-II) levels were lower in the extended-hours HD group than in the conventional HD group [40 018 (arbitrary units) AU versus 75 728 AU; P  < .01]. Multivariable linear regression analysis showed that extended-hours HD was associated with lower natural logarithmic plasma CPP (CPP-II) levels: -0.64 (95% confidence interval -0.74 to -0.55). A restricted cubic spline function indicated that extended-hours HD was associated with lower plasma CPP (CPP-II) levels across levels of serum phosphorus, with significant differences observed between groups, especially in hyperphosphataemic conditions ( P for interaction <.01)., Conclusions: The extended-hours HD group had lower CPP levels than the conventional HD group despite no significant differences in serum phosphorus levels, which may contribute to better clinical outcomes in patients on extended-hours HD., Competing Interests: T.I. received a research grant from Kyowa Kirin and consulting fees from GlaxoSmithKline. No conflicts of interest (financial or otherwise) are declared by the other authors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Paraneoplastic IgA nephropathy (IgAN) is an underrecognized condition in which malignancy manifests as symptoms of IgAN, and it remains controversial regarding their mechanistic relation between IgAN and malignancy. Herein, we report a case of a 68-year-old Japanese man with glottic cancer who developed nephrotic syndrome as a clinical manifestation of IgAN. Renal biopsy revealed diffuse proliferative glomerulonephritis with glomerular capillary IgA deposition that is a rare subtype of IgAN. After complete remission of the glottic cancer by irradiation, proteinuria and hematuria disappeared. Based on his clinical course, we diagnosed paraneoplastic IgAN. Therefore, we should consider the possibility that IgAN with glomerular capillary IgA deposition might be paraneoplastic glomerulopathy especially before initiating immunosuppressive therapy. The patient thereafter developed prostate cancer and hepatocellular cancer, but IgAN did not recur. The association of IgAN specifically with the glottic cancer in this triple-cancer patient may suggest a potential link between IgAN and mucosal cancer. Because galactose-deficient IgA1 (Gd-IgA1) was observed in the similar pattern as IgA, Gd-IgA1 also may play an important role in the pathogenesis of paraneoplastic IgAN., (© 2023. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need., Competing Interests: Disclosures S.M. Moe is a scientific advisor for Ardelyx, the maker of tenapenor. The other authors report no conflicts.

Background: Fetuin-A inhibits precipitation of calcium-phosphate crystals by forming calciprotein particles (CPP). A novel T50 test, which measures transformation time from primary to secondary CPP, is an index for calcification propensity. Both lower fetuin-A and shorter T50 levels were associated with cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). Extremely high risk for CVD death in advanced CKD patients consists of high-incidental CVD event and high mortality after CVD event. To date, it is unclear whether fetuin-A and/or T50 can equally predict each CVD outcome., Methods: This prospective cohort study examined patients undergoing maintenance hemodialysis. The exposures were fetuin-A and T50. The outcomes of interests were new CVD events and subsequent deaths. The patients were categorized into tertiles of fetuin-A or T50 (T1 to T3)., Results: We identified 190 new CVD events during the 5-year follow-up of the 513 patients and 59 deaths subsequent to the CVD events during 2.5-year follow-up. A lower fetuin-A but not T50 was significantly associated with new CVD events [subdistribution hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.15-2.61, P  = .009 for T1 vs T3]. In contrast, a shorter T50 but not fetuin-A was a significant predictor of deaths after CVD events (HR 3.31, 95% CI 1.42-7.74, P  = .006 for T1 + T2 vs T3). A lower fetuin-A was predictive of new CVD events, whereas a shorter T50 was more preferentially associated with subsequent death., Conclusion: These results indicate that fetuin-A and T50 are involved in cardiovascular risk in different manners., Competing Interests: MK received research funds from JSPS KAKENHI (Grant Number 22H00473), AMED-CREST (Grant Number JP23gm1510012h0002), and Cabinet Office, Government of Japan, Moonshot R&D Program for Agriculture, Forestry and Fisheries. The other authors declared no competing interest relevant to this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by osteocytes in response to dietary phosphate intake. An increase in FGF23 level is an indicator of excess phosphate intake relative to the residual nephron number. Therefore, avoiding excessive phosphate intake and inhibiting the elevation of serum FGF23 levels are important to preserve the number of functional nephrons. This randomized crossover trial aimed to determine the potential differences in the impacts on serum FGF23 levels between plant protein and animal protein-based meals in individuals with normal renal function. Nine young men were administered plant (no animal protein) or animal protein-based meals (70% of their protein was from animal sources) with the same phosphate content. The test meals consisted of breakfast, lunch, and dinner. Blood samples were collected in the morning, after overnight fasting, and before and after eating the test meals (for two consecutive days at the same hour each day). Furthermore, a 24-h urine sample was obtained on the day the test meal was consumed. No significant interactions were found among serum phosphate, calcium, and 1,25-dihydroxyvitamin D levels. However, after eating plant protein-based meals, serum FGF23 levels decreased and serum intact parathyroid hormone levels increased (interaction, p<0.05). Additionally, urine 24-h phosphate excretion tended to be lower in individuals consuming plant protein-based meals than in those consuming animal protein-based meals (p=0.06). In individuals with normal renal function, plant protein-based meals may prevent an increase in serum FGF23 levels and kidney damage caused by phosphate loading.