Yuichi Takashi

Introduction: Hyperphosphatemia is associated with increased mortality in chronic kidney disease (CKD), but the clinical relevance of variation within the normal serum phosphate range remains unclear. This study evaluated the association between higher-normal serum phosphate levels within the normal range and all-cause mortality among US adults. Methods: We conducted a cohort study using data from 15 848 individuals aged ≥20 years with serum phosphate levels between 2.5 and 4.5 mg/dL from the Third National Health and Nutrition Examination Survey (1988-1994) linked to mortality data ascertained by the National Center for Health Statistics with the National Death Index through December 2019. Baseline serum phosphate was the exposure. Participants were categorized into lower-normal (2.5 mg/dL to <3.5 mg/dL; n = 7691) and higher-normal (3.5 mg/dL to ≤4.5 mg/dL; n = 8157) serum phosphate groups. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) for all-cause mortality. A subgroup analysis was conducted by CKD status (estimated glomerular filtration rate ≥60 and <60 mL/min/1.73 m2). Results: Over a median follow-up of 26.3 years, 6660 (42%) participants died. Compared to the lower-normal group, the higher-normal group showed no significant increase in all-cause mortality risk in the overall population (aHR 1.06 [95% CI, 0.98-1.13]). However, among individual with CKD, higher-normal serum phosphate was significantly associated with increased all-cause mortality (aHR 1.13 [95% CI, 1.02-1.25]), wheres no association was observed in those with estimated glomerular filtration rate ≥60 mL/min/1.73 m2 (aHR 1.01 [95% CI, 0.92-1.12]; P for interaction, .14). Conclusion: Higher-normal phosphate levels were associated with an increased risk of all-cause mortality among people with CKD.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results from tumors that secrete fibroblast growth factor 23 (FGF23). This leads to chronic hypophosphatemia. Burosumab, an anti-FGF23 antibody, is an effective treatment when surgery is not possible; however, it complicates FGF23 measurements and postoperative monitoring. We describe the first case report of TIO in which the responsible tumors were discovered during burosumab therapy and successfully resected. Despite tumor removal, the serum FGF23 levels remained elevated. In the postoperative monitoring of patients treated with burosumab, physicians should focus on the serum and urine levels of phosphate rather than FGF23.

Objectives: To investigate the association between self-stigma evaluated using the Japanese version of the Self-Stigma Scale (SSS-J) and diabetic complications, such as diabetic retinopathy (DR) and diabetic kidney disease (DKD). Design: Cross-sectional study. Setting: One university hospital and one clinic in Fukuoka, Japan. Participants: People (age ≥20 years) with type 2 diabetes receiving outpatient care, who were treated by diabetologists, and completed the SSS-J questionnaire (n=259). Primary and secondary outcome measures: The primary outcome was the level of self-stigma assessed using the SSS-J. The presence of DR and DKD was evaluated as secondary outcomes. Results: A positive correlation was found between self-stigma and glycated haemoglobin (HbA1c) levels ( r =0.132, p=0.034). The mean SSS-J score was significantly higher in people with type 2 diabetes who had DR than in those without DR (p=0.006). There was no significant difference in the mean SSS-J scores of the patients with albuminuria (p=0.318) or a decreased kidney function (p=0.887). Additionally, the relative risk for the presence of DR, as assessed by quartiles of SSS-J scores and a logistic regression analysis, was significantly increased in the Q4 group with the highest SSS-J score after adjustment for sex, age and HbA1c (OR=3.91, 95% CI 1.49 to 10.3, p=0.006). The relative risk for the presence of albuminuria as a DKD significantly increased in the Q4 group immediately after adjustment for sex and age (OR=2.45, 95% CI 1.04 to 5.81, p=0.042). However, this association was attenuated and became non-significant after additional adjustment for HbA1c levels. In contrast, no significant association was observed between the SSS-J score quartiles and decreased kidney function. Conclusions: The presence of DR was more strongly associated with self-stigma than DKD. Although the causality between self-stigma and the presence of DR could not be elucidated due to the cross-sectional nature of the study, the present study suggests that addressing self-stigma may aid in glycaemic management and the prevention of DR, emphasising the need for healthcare providers to recognise self-stigma as a barrier to optimal diabetes care.

Aim: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitor and glucagon‐like peptide 1 receptor agonist (GLP‐1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP‐1RA first. Methods: We included 438 patients with CKD (GLP‐1RA‐first group, n = 223; SGLT2 inhibitor‐first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)‐matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. Results: Using the PS‐matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP‐1RA‐first group, 10%; SGLT2 inhibitor‐first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). Conclusion: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was significant. These results suggest that, in GLP‐1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP‐1RA treatment may lead to more favourable renal outcomes.

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: −3.5 ± 9.4 mL/min/1.73 m²/year, post: −0.4 ± 6.3 mL/min/1.73 m²/year, p < 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: −2.0 ± 10.9 mL/min/1.73 m²/year, post: −1.8 ± 5.4 mL/min/1.73 m²/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits—especially annual eGFR decline—of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.

Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human body, and around 85% of phosphate is present in bone as a constituent of hydroxyapatite, Ca10(PO4)6(OH)2. Because hypophosphatemia induces rickets/osteomalacia, and hyperphosphatemia results in ectopic calcification, blood phosphate (inorganic form) level must be regulated in a narrow range (2.5 mg/dL to 4.5 me/dL in adults). However, as yet it is unknown how bone senses changes in blood phosphate level, and how bone regulates the production of FGF23. Our previous data indicated that high extracellular phosphate phosphorylates FGF receptor 1 (FGFR1) in an unliganded manner, and its downstream intracellular signaling pathway regulates the expression of GALNT3. Furthermore, the post-translational modification of FGF23 protein via a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production due to high dietary phosphate. Therefore, our research group proposes that FGFR1 works as a phosphate-sensing receptor at least in the regulation of FGF23 production and blood phosphate level, and phosphate behaves as a first messenger. Phosphate is involved in various effects, such as stimulation of parathyroid hormone (PTH) synthesis, vascular calcification, and renal dysfunction. Several of these responses to phosphate are considered as phosphate toxicity. However, it is not clear whether FGFR1 is involved in these responses to phosphate. The elucidation of phosphate-sensing mechanisms may lead to the identification of treatment strategies for patients with abnormal phosphate metabolism.

Introduction: X-linked hypophosphatemia (XLH) is the most prevalent type of heritable fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets. Recently, anti-FGF23 antibody, burosumab, has become clinically available. We herein report a patient with adult XLH and tertiary hyperparathyroidism.Case presentation: The serum phosphate level and tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR) remained low, despite burosumab treatment. While the influence of the relationship between FGF23 and parathyroid hormone (PTH) on the phosphaturic effect is unclear, it was considered that a high level of PTH due to tertiary hyperparathyroidism remains to suppress renal phosphate reabsorption. A calcimimetic, evocalcet, increased the serum phosphate level and TmP/GFR.Discussion and conclusion: Therefore, it is important to evaluate the presence of secondary-tertiary hyperparathyroidism in patients whose serum phosphate level does not increase with burosumab treatment.

Context Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to ¹⁸F-fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography (FDG-PET) and ¹¹¹In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective This study aimed to evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Methods In an observational retrospective study of patients with adult-onset FGF23-related osteomalacia who underwent all 3 imaging studies (FDG-PET, SRS, and FGF23VS), the rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be due to other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of 2 or 3 tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.

Exercise results in mechanical loading of the bone and stimulates energy expenditure in the adipose tissue. It is therefore likely that the bone secretes factors to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)−11 is known to be expressed in the bone, it is upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Here, we show that systemic IL-11 deletion (IL-11^−/−) results in reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. At the same time, the enhancement of bone resorption by mechanical unloading was unaffected. Unexpectedly, IL-11^−/− mice have increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11^fl/fl mice have reduced serum IL-11 levels, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11^−/− mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre;IL-11^fl/fl did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.

Diabetic kidney disease (DKD) is a key determinant of morbidity and mortality in patients with type 1 diabetes (T1D). Identifying factors associated with early glomerular filtration rate (GFR) decline in T1D is important in prevention or early intervention for DKD. This study investigated whether phosphate metabolism, including fibroblast growth factor 23 (FGF23) is associated with the kidney function of patients with T1D. We randomly recruited 118 patients with T1D with a normal or mildly impaired kidney function [chronic kidney disease (CKD) stages of G1/G2, A1/A2], and measured their serum FGF23 levels. Serum FGF23 was significantly negatively associated with the estimated GFR (eGFR) (r = -0.292, P = 0.0016), but not urinary albumin creatinine ratio (UACR), and positively associated with serum phosphate (Pi; r = 0.273, P = 0.0027). Serum FGF23 increased with decreasing eGFR quartiles (P for linear trend = 0.0371), while FGF23 was modestly higher in the higher quartiles of UACR (not statistically significant). The multiple linear regression analysis also showed a significant inverse association between FGF23 and eGFR (Model 1: β = -0.149, P = 0.0429; Model 2: β = -0.141, P = 0.0370). The association remained significant after adjustment for Pi. We identified that FGF23 was inversely associated with the eGFR in T1D patients with a normal or mildly impaired kidney function.