Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

Association between serum magnesium levels and cognitive function in patients undergoing hemodialysis.

BACKGROUND: The relationship between chronic kidney disease-mineral and bone disorder (CKD-MBD) and cognitive function remains largely unknown. This cross-sectional study aimed to explore the association between CKD-MBD and cognitive function in patients on hemodialysis. METHODS: Hemodialysis patients aged ≥ 65 years without diagnosed dementia were included. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). CKD-MBD markers, serum magnesium, intact parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OHD), fibroblast growth factor (FGF)-23, and soluble α-klotho were measured. RESULTS: Overall, 390 patients with a median age of 74 (interquartile range, 70-80) years, mean serum magnesium level of 2.4 ± 0.3 mg/dL, and median MoCA and MMSE scores of 25 (22-26) and 28 (26-29), respectively, were analyzed. MoCA and MMSE scores were significantly higher (preserved cognitive function) in the high-magnesium group than in the low-magnesium group according to the unadjusted linear regression analysis (ß coefficient [95% confidence interval (CI)] 1.05 [0.19, 1.92], P = 0.017 for MoCA; 1.2 [0.46, 1.94], P = 0.002 for MMSE) and adjusted multivariate analysis with risk factors for dementia (ß coefficient [95% CI] 1.12 [0.22, 2.02], P = 0.015 for MoCA; 0.92 [0.19, 1.65], P = 0.014 for MMSE). CONCLUSIONS: Higher serum magnesium levels might be associated with preserved cognitive function in hemodialysis patients. Conversely, significant associations were not observed between cognitive function and intact PTH, 25-OHD, FGF-23, or soluble α-klotho levels.

Estimating the prevalence of chronic kidney disease in the older population using health screening data in Japan.

BACKGROUND: In aging societies, the prevalence of chronic kidney disease (CKD) is expected to increase but may be underestimated because many asymptomatic patients remain undiagnosed. This study aimed to estimate the CKD prevalence among the general older population in Japan. METHODS: This cross-sectional study used health screening data from the Japan Health Insurance Association collected between April 2014 and March 2023. Data from older people aged 65-90 years who underwent renal function screening for estimated glomerular filtration rate (eGFR) and urine protein tests were analyzed. CKD was defined as eGFR < 60 mL/min/1.73 m2 or proteinuria ≥ 1 + . Inverse probability weighting was used to account for the selection bias. The variables used for weighting were age, sex, insurance status, and the number of previous screenings. RESULTS: Among 2.98 million older individuals, 588,809 (19.7%) had undergone screening (median [IQR] age, 69.9 [67.9-76.2] years, 337,862 women [57.4%]). Regarding the weighted CKD prevalence, 25.3% of the individuals aged 65-90 years had CKD; 11.8% of those aged 65-75 years and 34.6% of those aged 75 years and over showed an increase in prevalence with age. Among the patients with CKD, over half exhibited mild renal dysfunction without proteinuria. Hypertension and diabetes were common comorbidities in older patients with CKD. CONCLUSIONS: This cross-sectional study revealed that the weighted prevalence of CKD in the older population aged 65-90 years was high (one in four individuals), indicating that it increases with age. Further studies are required to examine the clinical significance of these findings.

The systemic immune response due to cholesterol crystal embolization syndrome: a case report.

BACKGROUND: Cholesterol crystal embolization syndrome (CES) occurs when an atherosclerotic plaque causes small-vessel embolization, resulting in multi-organ damage. Although CES is pathologically characterized by an infiltration of eosinophils, the implication of the systemic inflammatory response represented by hypereosinophilia is unclear in clinical practice. Herein we present the case of a patient diagnosed with CES who developed multiple allergic organ injuries, including daptomycin-related dermatitis and later vancomycin-induced acute tubulointerstitial nephritis, which was successfully treated by the withdrawal of each medicine with or without corticosteroid therapy, one by one. CASE PRESENTATION: A 76-year-old Japanese man diagnosed with thoracic aneurysm rupture underwent total arch replacement through the open stent graft technique. Postoperatively, he developed methicillin-resistant Staphylococcus epidermidis bacteremia, which was treated with daptomycin. Subsequently, he presented with palpable purpura on both dorsal feet, erythema around his body, and hypereosinophilia. Daptomycin was replaced with vancomycin due to suspicion of drug-induced erythema. The erythema gradually faded. On nine days after vancomycin therapy, the systemic erythema rapidly reappeared followed by acute renal failure. The renal function decline prompted hemodialysis. A skin biopsy revealed cholesterol embolization, whereas a kidney biopsy revealed acute tubulointerstitial nephritis. After vancomycin discontinuation and initiation of systemic corticosteroid treatment, his kidney function was restored to the baseline level. CONCLUSIONS: The present case highlights cholesterol embolization can cause allergic complications in addition to direct organ damage.

Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway.

The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.

Effect of denosumab on the incidence of fractures and mortality in patients undergoing hemodialysis: A retrospective cohort study.

BACKGROUND: Patients undergoing hemodialysis are at an elevated risk of fractures; however, substantial evidence for osteoporosis treatment in this population is lacking. We explored the efficacy of denosumab, an anti-IgG2 antibody that targets the receptor activator of nuclear factor-kappa B ligand, in reducing fracture incidence and all-cause mortality in patients undergoing hemodialysis. METHODS: This retrospective cohort study-conducted from December 2013 to December 2022-evaluated the effects of denosumab on fracture incidence and all-cause mortality. Patients who initiated denosumab treatment during the study period were defined as the denosumab group, while those without a history of denosumab administration were defined as the non-denosumab group. Kaplan-Meier curves and log-rank tests were used to assess survival and fracture/mortality risks, respectively. Cox proportional hazards models were used to analyze both fractures and all-cause mortality. RESULTS: Among 214 patients undergoing hemodialysis, 52 (24.3%) received denosumab. The median age was 73.0 ± 11.5 years, with 92 (43.0%) females, and the median dialysis duration was 59 months (interquartile range, 6-126). During the study, thirty-seven non-denosumab-treated patients had fractures compared to eight in the denosumab group. No significant differences were observed in the unadjusted model (HR, 0.53; 95% confidence interval (CI), 0.24-1.14). Adjusting for competing mortality and clinical factors, the HR remained at 0.64 (95% CI, 0.27-1.51). Regarding all-cause mortality, we found a statistically significant difference in the unadjusted model (HR, 0.61 [95% CI, 0.38-0.98]). A significant reduction in mortality was observed in the adjusted model (HR, 0.46 [95% CI, 0.26-0.80]). Notably, the denosumab group showed a significant decrease in mortality, particularly in cardiovascular disease-related cases (HR, 0.33 [95% CI, 0.14-0.78]). CONCLUSIONS: Denosumab may reduce all-cause mortality in patients undergoing hemodialysis, particularly in those with cardiovascular complications. This finding offers a promising direction for osteoporosis treatment in patients undergoing hemodialysis.

Active vitamin D analog and SARS-CoV-2 IgG after BNT162b2 vaccination in patients with hemodialysis.

INTRODUCTION: Vaccination is the effective strategy for coronavirus disease 2019 (COVID-19). However, few studies have investigated the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (Ig)G and vitamin D. METHODS: This study aimed to investigate the association between SARS-CoV-2 IgG and active vitamin D analogs in hemodialysis patients. Blood samples were collected four times: before vaccination and 30, 60, and 90 days after vaccination, BNT162b2 (Pfizer©). RESULTS: A total of 418 patients were enrolled. The mean age was 71.1 ± 12 years. Almost two thirds of the patients were prescribed active vitamin D analogs. The distribution of SARS-CoV-2 IgG before vaccination was 235 (93-454) AU/mL. After multiple regression analyses, active vitamin D analog use was found to be associated with higher SARS-CoV-2 IgG levels from prevaccination to 90 days postvaccination. CONCLUSION: This study demonstrated an association between higher SARS-CoV-2 IgG and active vitamin D analog use in hemodialysis patients. CLINICAL TRIAL REGISTRATION: The study information was registered in the UMIN-CTR (UMIN 000046906).

Hypercalcemia caused by comorbid parathyroid adenoma and pulmonary tuberculosis.

Hypercalcemia is usually secondary to one etiology, although two coexisting etiologies can rarely cause hypercalcemia. Here, we report a 47-year-old woman with hypercalcemia caused by comorbid parathyroid adenoma and pulmonary tuberculosis. Primary hyperparathyroidism is the most common cause of hypercalcemia. Tuberculosis is a rare cause of hypercalcemia, but Japan continues to have an intermediate tuberculosis burden. Therefore, tuberculosis should be considered as a cause of hypercalcemia in Japan. Patients with tuberculosis are often asymptomatic, making the diagnosis difficult. In the previous cases in which these diseases coexisted, one disease was diagnosed after treatment of the other. In our case, the very high 1,25-dihydroxyvitamin D level (162 pg/mL) helped us to diagnose asymptomatic tuberculosis and both diseases were diagnosed promptly. It is necessary to consider comorbidities, including tuberculosis in a case with a very high 1,25-dihydroxyvitamin D level. We report a valuable case in which the early diagnosis and treatment of tuberculosis and primary hyperparathyroidism prevented the spread of tuberculosis.

Renal Damage in Recurrent Atypical Hemolytic Uremic Syndrome Associated with C3 p.Ile1157Thr Gene Mutation.

Patients with atypical hemolytic uremic syndrome (aHUS) associated with a C3 p.Ile1157Thr mutation show a relatively high renal survival and low mortality rates, but renal histopathological findings after recurrence have been rarely reported. A 30-year-old man with a C3 p.Ile1157Thr mutation experienced a third recurrence of thrombotic microangiopathies with neurological and gastrointestinal disorders. A renal biopsy performed during the recovery phase of acute kidney injury revealed collapsed glomeruli and arteriolar vacuolization. Approximately 10% of glomeruli were globally sclerotic, despite the absence of arterio-/arteriolo-sclerosis. These findings suggest substantial progression of irreversible injuries in multiple organs, including kidneys, which occurs in aHUS patients with repeated thrombotic microangiopathies.

Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodelling after myocardial infarction.

AIMS: Accumulating evidence demonstrates that cardiomyocyte death contributes to the onset and progression of heart failure (HF) after myocardial injury. Recent studies revealed that immune/inflammatory reactions play important roles in cardiovascular diseases. However, it remains unclear whether immunosurveillance system, which eliminates cytopathic cells, including infected or malignant cancer cells, is involved in cardiomyocyte death, though cardiomyocytes are exposed to pathological stresses during post-infarct remodelling. The aim of this study is to clarify the pathophysiological significance of Natural Killer Group 2 member D (NKG2D)/NKG2D ligand (NKG2DL)-mediated cell death in HF after myocardial infarction (MI). METHODS AND RESULTS: MI was generated by ligating left anterior descending artery in mice. The expression of NKG2D, NKG2DLs, especially Retinoic acid early induced transcript-1ɛ (Rae-1ɛ), perforin and granzyme B was concomitantly up-regulated after MI. Immunohistological analysis revealed that Rae-1 was expressed on the membranes of injured cardiomyocytes in the infarct and border area. The MI-induced increase of Rae-1 expression was suppressed in p53-/- mice and Rae-1 was induced by the overexpression of p53. We identified p53-binding sites in Rae-1ɛ gene promoter, by chromatin immunoprecipitation assay, indicating that Rae-1 expression was mediated partially through p53. Flow cytometric analysis indicated that NKG2D-expressing immune cells in the post-infarct myocardium were mainly γδT cells. The co-culture with γδT cells increased the frequency of apoptotic cells in the cultured cardiomyocytes. The blockade of NKG2D/NKG2DL interaction by intraperitoneal injection of anti-Rae-1ɛ antibody after MI reduced the frequency of apoptotic cardiomyocytes, accompanied by suppression of cardiac fibrosis, attenuating cardiac dysfunction. Finally, tamoxifen-inducible cardiomyocyte-specific Rae-1ɛ overexpressing mice exhibited the susceptibility to post-infarct remodelling with increased cardiomyocyte apoptosis and severer cardiac dysfunction. CONCLUSION: The interaction between immune cells and cardiomyocytes via NKG2D/NKG2DL induces cardiomyocyte death, exacerbating cardiac remodelling after MI. The blockade of NKG2D/NKG2DL interaction could be a promising therapeutic strategy against HF.

RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction.

AIMS: Retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated. METHODS AND RESULTS: MI was generated by ligating coronary artery. The expression of RORγt and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that RORγt-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that RORγt-expressing cells were released from the spleen at day 1 after MI. Though RORγt-expressing cells in spleen expressed γδTCR or CD4, γδTCR+ cells were major population of RORγt-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of RORγt-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at RORγt locus (RORγt+/- mice), which physiologically showed reduced expression of RORγt mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in RORγt+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in RORγt+/- mice 7 days after MI (Injured area: RORγt+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: RORγt+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: RORγt+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in RORγt+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of RORγt, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in RORγt+/- hearts. CONCLUSIONS: Heterozygous deletion of RORγt gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that RORγt-expressing cells contribute to tissue repair in infarcted myocardium.

Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury.

AIM: To investigate the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, sitagliptin, for treating diabetes mellitus complicated by chronic liver injury. METHODS: Sitagliptin was administered for 13.7 ± 10.1 months to 122 patients with DM complicated by chronic liver injury (including 19 patients with liver cirrhosis), and changes in hemoglobin A1c (HbA1c) and liver enzymes (transaminases, etc.) were evaluated. RESULTS: HbA1c was reduced from 8.48 ± 1.43% to 7.87 ± 1.35% (P < 0.001). Among liver enzymes, alanine aminotransferase (ALT) levels improved from 75.1 ± 45.2 to 65.8 ± 35.8 IU/L (P = 0.012) and gamma-glut amyl-trans peptidase from 155.2 ± 161.1 to 133.2 ± 127.4 IU/L (P = 0.044). Among the causes of liver injury, non-alcoholic fatty liver disease and alcoholic liver disease both showed the reductions in HbA1c with no deterioration of liver enzymes. An analysis of 19 patients with liver cirrhosis also showed reductions in HbA1c with no deterioration of liver enzymes. CONCLUSION: It is suggested that sitagliptin can be administered effectively and safely to patients with diabetes mellitus complicated by chronic liver injury, including liver cirrhosis.