Mineral Disorders Research Articles

Analysis of mineral and bone disorder in patients treated at a specialized peritoneal dialysis service in the Federal District.

Introduction: the prevalence of mineral and bone disorders in patients undergoing peritoneal dialysis is essential to understand and address the metabolic imbalances associated with chronic kidney disease (CKD). Regular monitoring of parathyroid hormone, alkaline phosphatase, calcium, and phosphorus levels plays a crucial role in identifying and treating these alterations. Objective: To analyze the prevalence of mineral and bone disorders in patients with chronic kidney disease receiving treatment at a specialized peritoneal dialysis service in the Federal District. Method: Retrospective, quantitative analytical study. Data collection was performed from both physical and electronic medical records. The study included 44 male patients aged 60 years or older with hypertension. The Statistical Package for the Social Sciences version 23.0 software was used for statistical analysis. Conclusion: Maleindividuals over 60 years of age with comorbidities and low educational attainment represent a high-risk group with a greater likelihood of poor treatment adherence.

Supplements and Their Role in Reducing Chronic Kidney Disease Progression

Conservative treatment of chronic kidney disease, apart from simply treating symptoms and associated complications, consists in slowing chronic kidney disease progression, in order to improve patient and family quality of life, to postpone the need for renal replacement therapy and to reduce the treatment costs. Slowing chronic kidney disease progression involves therapeutic strategies, aiming to avoid/treat malnutrition and inflammation, correct anemia, treat mineral bone disorders of CKD and correct vitamin, mineral and microelement’s deficit. This review aims to shed light to the rationale behind these strategies through evidence from clinical studies and the recent guideline recommendations for use of ketoanalogues, essential aminoacids, calcium, Vit D3, iron, Vit B12, folates and unsaturated fatty acid supplements.

#3388 ASSOCIATIONS BETWEEN PHYSICAL ACTIVITY, PHYSICAL FUNCTION AND BONE METABOLISM MARKERS IN HAEMODIALYSIS PATIENTS: A PRELIMINARY CROSS-SECTIONAL STUDY

Abstract Background and Aims Chronic kidney disease (CKD) patients suffering from end-stage renal disease often undergo dialysis treatment. Haemodialysis (HD) patients spend most of their time in sedentary behaviour, having therefore poor physical function, as well as frequently develop mineral and bone disorders due to disease-induced systemic alterations such as abnormally high bone resorption rates exceeding bone formation. In healthy individuals, there is considerable evidence highlighting the associations between physical activity (PA), physical function (PF), and bone health. In HD patients, however, evidence on the association between these variables is still scarce. Therefore, the present preliminary study seeks to characterise HD patients in terms of their PA and PF, and to identify any associations between these and markers of bone metabolism. Method A cross-sectional design study recruited 88 adult HD patients (males: 68%, age: 66±14 years, dialysis vintage: 42±52 months) from three clinics in Portugal. Resting blood samples were collected from the patients’ fistula at the start of the second dialysis session of the week. Plasma levels of the bone markers tartrate-resistant acid phosphatase 5b (TRAP-5b) (IDS, Tyne and Wear, UK), and sclerostin (SOST) and receptor activator of nuclear factor kappa-Β ligand (RANKL) (Biomedica Immunoassays, Vienna, Austria) were measured by commercially-available enzyme-linked immunosorbent assays (ELISA), and osteocalcin (OCN) (Biogen, Madrid, Spain) and osteoprotegerin (OPG) (R&D Systems, Abingdon, UK) via DuoSet ELISA kits. PF was assessed by completing the Sit to Stand 60 (STS60), the STS5, the Incremental Shuttle Walk Test (ISWT), the Timed Up and Go (TUG), and handgrip strength (HGS). All participants worn tri-axial accelerometers continuously for a week to estimate PA levels. Results Accelerometers were worn for an average 13±2h/day and data showed that 81±11% of the time was spent in sedentary behaviour, and 18±10% in light PA. Associations between PA, PF and markers of bone metabolism are described in Table 1. Weekly sedentary time was associated with reduced agility (TUG), muscle endurance (STS60, ISWT), and muscle power and strength (STS5), whereas light PA levels were associated with an increment in overall PF. Also, light PA levels were associated with decreased TRAP-5b and OPG, but elevated circulating OCN, supporting a potential modulatory effect of PA on bone turnover. Decreased overall PF were associated with increased concentrations of OPG, with muscle endurance and strength associated with increased circulating TRAP-5b. Conclusion Our data suggests that sedentarism may be responsible for a reduced PF, which in turn was associated with increased inhibition of osteoclastogenesis via OPG activity. Yet, a rather small increase in PA levels may lead to PF gains and could be a trigger for OCN activity and TRAP-5b inhibition. Therefore, increasing PA levels may modulate bone metabolism through mechanisms that favor bone formation.

#3165 ASSOCIATION BETWEEN CKD-MBD AND MORTALITY IN OLDER PATIENTS WITH ADVANCED CKD – RESULTS FROM THE EQUAL STUDY

Abstract Background and Aims Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) is a common complication of CKD, associated with higher mortality in dialysis patients. Its impact in non-dialysis patients remains mostly unknown. We investigate the associations between parathyroid hormone (PTH), phosphate, and calcium (and their interactions) and all-cause, cardiovascular (CV), and non-CV mortality in older non-dialysis patients with advanced CKD. Method We used data from the EQUAL study, which included patients aged ≥65 with eGFR ≤20 ml/min/1.73m2 from six European countries. Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV, and non-CV mortality. Models were sequentially adjusted for other mineral biomarkers, age, sex, country, eGFR, albumin, BMI, comorbidities and medications. Effect modification between biomarkers was also assessed. Results In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH (aHR 1.12, 95%CI 1.03-1.23, p 0.01) and phosphate (aHR 1.35, 95%CI 1.00-1.84, p 0.05), but not calcium (aHR 1.11, 95%CI 0.57-2.17, p 0.76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality. Conclusion CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

#5454 DESIGN AND OPTIMIZATION OF DRUG COMBINATION THERAPIES FOR OSTEOPOROSIS VIA SIMULATIONS OF BONE TURNOVER

Abstract Background and Aims Many chronic kidney disease (CKD) patients suffer from mineral and bone disorders like osteoporosis, which also affects a huge part of the general population, predominantly postmenopausal women. For the treatment of osteoporosis, several drug types with different mechanisms of action are available, such as bisphosphonates, PTH analogs, RANKL inhibitors and sclerostin inhibitors (some of which are contraindicated for CKD patients beyond CKD stage 3). Different drugs can be given individually or combined in various ways, simultaneously or sequentially, resulting in a huge number of theoretically possible drug combinations that are practically impossible to study in clinical studies. We aimed to study using simulations whether there are combination therapies that would work considerably better than those tested and employed in clinical practice. If so, this could be beneficial for the treatment of a large number of osteoporosis patients by leading to a higher increase in bone strength and a higher reduction in bone fracture risk than standard therapies. Method We developed a physiology-based mathematical model that simulates the process of bone renewal in the human body and can predict how different osteoporosis drugs (including bisphosphonates, PTH analogs, RANKL inhibitors, and sclerostin inhibitors) affect this process, alone and in combination [1]. Results The model was validated on over 30 clinical osteoporosis studies with about 90 study arms. It predicted the time courses of bone mineral density and bone turnover markers with a high degree of accuracy based on the knowledge of the used drugs and dosing schemes alone. We used the model to study how treatment results changed when merely reshuffling the order in which different drugs were given. For example, for 3-year drug therapies involving alendronate, denosumab and romosozumab (1 year each), our simulations showed that the order in which these drugs were given can have a considerable effect on short- and long-term therapy success [1]. This is due to different drugs favorably interacting when applied in the right sequence. Conclusion Our findings indicate that some osteoporosis drug administration schemes are superior to others while relying on the exact same types and amounts of drugs. Therefore, there is a large potential to improve pharmacologic therapies of osteoporosis using physiological simulations. For renal patients beyond CKD stage 3, a restricted set of drug types may be considered to account for contraindications related to impaired renal clearance. If translated into clinical practice, findings obtained using our model could give rise to novel treatments using combinations of existing drugs for osteoporosis that lead to a lower bone fracture risk than standard treatments. Moreover, our model could serve as a basis for personalizing osteoporosis therapy to individual patients.

#3312 EFFICACY OF TRANSCATHETER AORTIC VALVE IMPLANTATION FOR SEVERE AORTIC VALVE STENOSIS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims In Japan, of the >340,000 chronic dialysis patients, approximately 60% have lifestyle-related diseases including diabetes and nephrosclerosis. Two-thirds of maintenance dialysis patients (age, ≥65 years) often develop aortic stenosis (AS) and other serious and complex systemic cardiovascular disease complications associated with chronic kidney disease mineral and bone disorder (CKD-MBD). Furthermore, renal function loss and a prolonged state of renal failure are observed requiring renal replacement therapy (RRT). AS in dialysis patients progresses quickly, and the frequency of hospitalized treatment for heart failure increases with the worsening condition, leading to ADL deterioration, which may subsequently cause dialysis hypotension/interruption. At our hospital, of the 420 maintenance dialysis patients who died during hospitalization in 5 years before 2020 (420/2,637 = 16%), 32 cases (8%) developed AS complications, which became their direct cause of death in 12 cases (3%), and aortic valve replacement (AVR) was performed in 5 cases (1%). Maintenance hemodialysis patients (HD) are at high risk group and have a poor prognosis for life. Previously, transcatheter aortic valve implantation (TAVI) was not indicated., but recently TAVI has been approved in Japan. Efficacy of TAVI for HD patients remains unclear, here we investigated several outcomes. Method A total of 123 maintenance dialysis patients with severe AS were included in 2019–2021. We examined TAVI group and AVR group for length of hospital stay, hospitalization costs, life expectancy, and rates of complications such as occurrence of arrhythmias. Results Over a 3-year period, we performed TAVI for 58 maintenance dialysis patients (mean age, 81 years); their median duration of hospitalization was 14 days for a median cost of 6,259,350 JPY. The mean age was older than that of 66 patients who underwent open-heart AVR during the same period (mean age, 73 years; 35 days for 7,192,570 JPY); therefore, the cost was less, and the rate of complications, including vital prognosis and arrhythmia, was not inferior in hospitalization period. Conclusion In conclusion, TAVI is effective for elderly maintenance dialysis patients with severe AS and has a positive health care economics, ADL maintenance.

Effects of food, fasting, and exercise on plasma pyrophosphate levels and ENPP1 activity in healthy adults.

Inorganic pyrophosphate (PPi) is highly regulated as it plays a critical role in the regulation of physiological mineralization. Dysregulation of plasma PPi is associated with skeletal hypomineralization and pathogenic mineralization in soft connective tissue, arteries, and heart valves. There is no standard approach to measuring PPi, making it difficult to establish PPi as a biomarker of mineralization disorders. This study aims to determine the impact of time of day, meals, or exercise on plasma PPi homeostasis using a highly sensitive PPi assay. In this single-center trial, a clinical laboratory improvement amendment (CLIA) validated modified sulfurylase-based adenosine 5-triphosphate (ATP) assay was used to measure PPi levels throughout the day in 10 healthy adults under 3 conditions; normal diet (non-fasting), fasting, and normal diet with exercise. Serum ectonucleotide pyrophosphatase/phosphodiesterase 1 activity (ENPP1; an enzyme that produces PPi) was also measured to determine whether these conditions influence PPi levels through ENPP1 activity. There is a circadian increase in mean PPi levels under fasting and non-fasting conditions between 8am and 6pm, followed by a rapid return to baseline overnight. A circadian increase in ENPP1 activity was also measured under fasting but was lost under non-fasting conditions. Meals increased the individual variability of PPi levels when compared to the same individual fasting. PPi levels and ENPP1 activity exhibited a short-term increase after intense exercise. We found PPi ranges from 1465nM to 2969nM (mean 2164nM) after fasting overnight. Within this range, there was lower intra-subject variability in PPi, suggesting that each individual has a uniquely regulated normal PPi range. Plasma levels of PPi can be reliably measured after an overnight fast and show promise as a biomarker of mineralization disorders.

Thyroid, Gonadal and Adrenal Dysfunction in Kidney Transplant Recipients: A Review for the Clinician

While chronic kidney disease-associated mineral and bone disorders (CKD-MBD) prevail in the endocrinological assessment of CKD patients, other endocrine abnormalities are usually overlooked. CKD is associated with significant thyroid, adrenal and gonadal dysfunction, while persistent and de novo endocrinological abnormalities are frequent among kidney transplant recipients (KTR). Low T3 levels prior to transplantation may help identify those at risk for delayed graft function and are often found in KTR. Thyroid surveillance after kidney transplantation should be considered due to structural anomalies that may occur. Despite the rapid recovery of gonadal hormonal secretion after renal transplantation, fertility is not completely restored. Testosterone may improve anemia and general symptoms in KTR with persistent hypogonadism. Female KTR may still experience abnormal uterine bleeding, for which estroprogestative administration may be beneficial. Glucocorticoid administration suppresses the hypothalamic-pituitary–adrenal axis in KTR, leading to metabolic syndrome. Patients should be informed about signs and symptoms of hypoadrenalism that may occur after glucocorticoid withdrawal, prompting adrenal function assessment. Clinicians should be more aware of the endocrine abnormalities experienced by their KTR patients, as these may significantly impact the quality of life. In clinical practice, awareness of the specific endocrine dysfunctions experienced by KTR patients ensures the correct management of these complications in a multidisciplinary team, while avoiding unnecessary treatment.

Dentoalveolar Alterations in an Adenine-Induced Chronic Kidney Disease Mouse Model.

Chronic kidney disease (CKD) is characterized by kidney damage and loss of renal function. CKD mineral and bone disorder (CKD-MBD) describes the dysregulation of mineral homeostasis, including hyperphosphatemia and elevated parathyroid hormone (PTH) secretion, skeletal abnormalities, and vascular calcification. CKD-MBD impacts the oral cavity, with effects including salivary gland dysfunction, enamel hypoplasia and damage, increased dentin formation, decreased pulp volume, pulp calcifications, and altered jaw bones, contributing to clinical manifestations of periodontal disease and tooth loss. Underlying mechanisms are not fully understood, and CKD mouse models commonly require invasive procedures with high rates of infection and mortality. We aimed to characterize the dentoalveolar effects of an adenine diet (AD)-induced CKD (AD-CKD) mouse model. Eight-week-old C57BL/6J mice were provided either a normal phosphorus diet control (CTR) or adenine and high-phosphorus diet CKD to induce kidney failure. Mice were euthanized at 15 weeks old, and mandibles were collected for micro-computed tomography and histology. CKD mice exhibited kidney failure, hyperphosphatemia, and hyperparathyroidism in association with porous cortical bone in femurs. CKD mice showed a 30% decrease in molar enamel volume compared to CTR mice. Enamel wear was associated with reduced ductal components, ectopic calcifications, and altered osteopontin (OPN) deposition in submandibular salivary glands of CKD mice. Molar cusps in CKD mice were flattened, exposing dentin. Molar dentin/cementum volume increased 7% in CKD mice and pulp volume decreased. Histology revealed excessive reactionary dentin and altered pulp-dentin extracellular matrix proteins, including increased OPN. Mandibular bone volume fraction decreased 12% and bone mineral density decreased 9% in CKD versus CTR mice. Alveolar bone in CKD mice exhibited increased tissue-nonspecific alkaline phosphatase localization, OPN deposition, and greater osteoclast numbers. AD-CKD recapitulated key aspects reported in CKD patients and revealed new insights into CKD-associated oral defects. This model has potential for studying mechanisms of dentoalveolar defects or therapeutic interventions. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

High-resolution peripheral quantitative computed tomography: research or clinical practice?

High-resolution peripheral quantitative CT (HR-pQCT) is a low-dose three-dimensional imaging technique, originally developed for in vivo assessment of bone microarchitecture at the distal radius and tibia in osteoporosis. HR-pQCT has the ability to discriminate trabecular and cortical bone compartments, providing densitometric and structural parameters. At present, HR-pQCT is mostly used in research settings, despite evidence showing that it may be a valuable tool in osteoporosis and other diseases. This review summarizes the main applications of HR-pQCT and addresses the limitations that currently prevent its integration into routine clinical practice. In particular, the focus is on the use of HR-pQCT in primary and secondary osteoporosis, chronic kidney disease (CKD), endocrine disorders affecting bone, and rare diseases. A section on novel potential applications of HR-pQCT is also present, including assessment of rheumatic diseases, knee osteoarthritis, distal radius/scaphoid fractures, vascular calcifications, effect of medications, and skeletal muscle. The reviewed literature seems to suggest that a more widespread implementation of HR-pQCT in clinical practice would offer notable opportunities. For instance, HR-pQCT can improve the prediction of incident fractures beyond areal bone mineral density provided by dual-energy X-ray absorptiometry. In addition, HR-pQCT may be used for the monitoring of anti-osteoporotic therapy or for the assessment of mineral and bone disorder associated with CKD. Nevertheless, several obstacles currently prevent a broader use of HR-pQCT and would need to be targeted, such as the small number of installed machines worldwide, the uncertain cost-effectiveness, the need for improved reproducibility, and the limited availability of reference normative data sets.

Prevalence and current approaches to the treatment of secondary hyperparathyroidism and its complications in chronic kidney disease: a literature review

There is a universal trend towards increase of patients with chronic kidney disease by 7% on average. In the Russian Federation, the annual increase is even higher, at about 10%. The average age of patients receiving renal replacement therapy is 60 years in the Tomsk region and 56 years in Russia, which is relatively lower than in European countries and the United States. With increasing age of patients receiving dialysis treatment, a progressive increase in the incidence of secondary hyperparathyroidism is recorded. Mineral and bone disorders, hyperphosphatemia, hypercalcemia all lead to premature vascular calcification, increase the risk of cardiovascular complications and death. At the same time, elderly patients are characterized by an increase in risks immediately after the start of dialysis therapy. There is a global tendency towards increase in the target level of parathyroid hormone. Parathyroidectomy is recognized as a gold standard for treatment of drug-resistant hyperparathyroidism across the world. As the development of hyperplasia in the parathyroid glands does not proceed synchronously, instead progressing at different rates and in the selective glands, methods of local influence on the altered glands have recently been developed in order to gradually control secondary hyperparathyroidism. Alternative to the total parathyroidectomy are minimally invasive non-surgical methods, attractive due to a smaller number of complications, such as bleeding and paresis of the recurrent laryngeal nerve. Examples of minimally invasive methods are local injections of preparations of the active form of vitamin D, which lead to apoptosis of parathyroid gland cells instead of their destruction, and are safer in relation to surrounding tissues. This article presents current data on the prevalence of secondary hyperparathyroidism in chronic kidney disease. An analysis of clinical trials was carried out based on articles indexed in the Scopus database, the Russian Science Citation Index, PubMed and Web of Science.

Serum Bicarbonate Deficiency in Dogs with Acute and Chronic Kidney Disease.

Serum bicarbonate deficiency is a disorder frequently found in human patients with acute (AKI) and chronic (CKD) kidney disease, due to abnormalities in kidney generation and reabsorption of bicarbonate. Although alkali supplementation is usually performed in both humans and veterinary CKD patients, data regarding the frequency of bicarbonate disorders in AKI and CKD dogs are scarce. The aim of the present study is to assess the frequency and the severity of bicarbonate deficiency of dogs affected by AKI, acute chronic kidney disease (ACKD), and CKD, and to investigate its possible association with the IRIS grade/stage as well as with disorders of calcium phosphate metabolism. A retrospective evaluation of the serum biochemical panels of all dogs with diagnoses of AKI, ACKD, and CKD referred to the nephrology and urology service of the Veterinary Teaching Hospital of the University of Pisa, between January 2014 and January 2022, was performed. Bicarbonate deficiency was defined as serum bicarbonate < 22 mmol/L and classified as moderate (between 18 and 22 mmol/L) or severe (<18 mmol/L). Serum bicarbonate deficiency was found in 397/521 dogs (76%), of which 142/397 (36%) showed moderate deficiency, and 255/397 (64%) severe deficiency. Dogs with AKI and ACKD showed a significantly higher frequency of bicarbonate deficiency (p = 0.004) and severe forms compared to CKD dogs (p = 0.02). In AKI and ACKD dogs, a negative linear correlation was found between serum bicarbonate and serum creatinine, urea, and phosphate. The frequency of bicarbonate deficiency was higher in the later stages of the disease in both AKI (p = 0.01), ACKD (p = 0.0003), and CKD dogs (p = 0.009). Dogs with serum CaxP ≥ 70 mg2/dL2 showed a higher frequency of bicarbonate deficiency (p = 0.01) and showed severe forms (p = 0.01) compared to dogs with CaxP < 70 mg2/dL2. Serum bicarbonate deficiency seems to be a very frequent disorder in both AKI, ACKD, and CKD dogs, with an increasing frequency and severity in more advanced stages of kidney disease. The higher frequency and severity of bicarbonate deficiency in AKI and ACKD may be caused by a more severe and sudden loss of kidney function, or extra-renal factors. Finally, the association between frequency and severity of bicarbonate deficiency and abnormal CaxP may suggest a potential connection between metabolic acidosis and bone mineral disorders.

The rationale for intermittent administration of PTH in the management of mineral and bone disorder of chronic kidney disease.

A major complication of chronic kidney disease is the derangement of mineral metabolism, leading to increased risk of fractures and cardiovascular mortality. Current therapeutic regimens are focused on reducing parathyroid hormone levels caused by secondary hyperparathyroidism, and the active vitamin D metabolite l,25(OH)2D, with limited success. It may be a more effective approach, however, if we could target the delayed response of parathyroid hormone in the early retention of phosphate following loss of renal function.We propose intermittent administration (even in stage 2 chronic kidney disease) of parathyroid hormone, known for its bone anabolic effects compared to the catabolic effects of the continuously elevated parathyroid hormone associated with the hyperparathyroid state, to mitigate the retention of phosphate. This approach may prevent the compensatory responses of the other two major calcium- and phosphate-regulating hormones (FGF-23 and l,25(OH)2D) that lead to further worsening of the derangement of mineral metabolism.In addition to its strong theoretical basis, there are data supporting the need for further research focused on the use of intermittent parathyroid hormone in the management of chronic kidney disease-mineral bone disorder.

Pattern of biochemical markers of mineral and bone disorders in kidney transplant recipients: real-world data

There is a lack of studies providing comprehensive data on the prevalence of mineral and bone disorders (MBD) laboratory abnormalities after kidney transplantation in Russia. to obtain real-world data on the prevalence of the main mineral abnormalities among kidney transplant recipients and to revise their concomitant MBD therapy. This cross-sectional study included 236 patients with successful kidney transplantation. Their serum intact parathyroid hormone (iPTH), total calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP) levels were measured. Only 6.2% of our cohort had all laboratory parameters within the target range, whereas persistent HPT along with hypercalcemia was noted in almost one third of the patients (31%). Normal iPTH levels were observed in 13% cases; 84% of the patients had hyperparathyroidism. The fraction of patients with target iPTH did not differ between the groups with normal and decreased estimated glomerular filtration rate (eGFR) (p=0.118). Hypercalcemia was observed in 29% cases. The serum P level varied significantly in groups with different eGFR (p&lt;0.0001), increasing with declining graft function. Furthermore, 40.7% of patients had ALP above the target range. While 123 patients received active vitamin D (alfacalcidol), 33 received monotherapy with inactive vitamin D (cholecalciferol). The control group consisted of 57 medication-naïve patients. The serum total Ca level varied significantly between the groups (p=0.0006), being higher in patients supplemented with cholecalciferol. The fraction of patients with normocalcemia was lowest in the cholecalciferol group (chi-square, р=0.0018). The prevalence of biochemical abnormalities after kidney transplantation is high. Alfacalcidol usage may be safer than using cholecalciferol to prevent hypercalcemia development.

Assessing the Risk of Postoperative Complications for Proximal Humeral Fractures Treated by Open Reduction and Internal Fixation in Patients With Diabetes and Chronic Kidney Disease

The prevalence of diabetes mellitus (DM) and chronic kidney disease (CKD) has markedly risen over the past three decades. Patients with DM and CKD are at increased risk of infection, immune dysfunction, as well as bone and mineral disorders. Although we know that patients with DM and CKD have these risks, we do not know how these translate to proximal humeral fracture (PHF) healing. We sought to analyze whether these established comorbidities had increased rates of complications after open reduction and internal fixation (ORIF) for PHF treatment. Using a national insurance database, 72,365 patients with PHF managed with ORIF were identified using records from 2010 to 2022. Patients were initially split into those with DM and those without and were further stratified by the presence or absence of CKD. For our comparison baseline cohort, patients were not diagnosed with either DM or CKD. Post-ORIF complication rates were assessed looking specifically at nonunion, postoperative infection, and all-cause revision surgery. A logistic regression statistical analysis was also conducted. Of the 72,365 patients with PHF treated by ORIF, 41,047 were non-DM without CKD (comparison); 17,025 had DM alone (no CKD); 11,729 had DM and CKD; and 2564 had CKD alone (non-DM). Multivariate analysis indicated that patients with DM and/or CKD were at increased risk of developing nonunion (odds ratio [OR] = 1.37, 1.48, 1.23) and all-cause revision surgery (OR = 1.21, 1.11, 1.18) after ORIF for PHF compared with our comparison cohort. In addition, all patients with DM alone (non-CKD) and DM with CKD had an increased risk of postoperative infection (OR = 1.39, 1.26). The management of PHF is a controversial topic, particularly regarding the degree of intervention and optimal treatment choice. Regardless, using a pragmatic design and reviewing a national insurance database, this study provides information for patients in high-risk populations, specifically patients with DM and CKD, and may prove beneficial when selecting a patient-specific treatment plan. Additional studies are needed to assess varying stages of both DM and CKD in patients who sustain PHF treated by ORIF along with postoperative strategies to minimize complications.

Progression of Vascular Calcification and Clinical Outcomes in Patients Receiving Maintenance Dialysis

Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. This cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. Patient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)-related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR], 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure]: HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use]: HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31]; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33]) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52]; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth factor 23 level and calcium-based phosphate binder use]: OR, 2.76 [95% CI, 1.48-5.16]), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88]; model 2: OR, 3.62 [95% CI, 2.26-5.78]; model 3: OR, 2.19 [95% CI, 1.33-3.61]), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26]; model 2: OR, 2.69 [95% CI, 1.71-4.25]; model 3: OR, 1.72 [95% CI, 1.06-2.79]) had higher odds of CAC progression compared with patients who achieved all 3 target levels. In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease-mineral and bone disorder among patients undergoing dialysis.

Clinical and Functional Assessment of Digenicity in Renal Phosphate Wasting

Apart from increased fluid intake, patients with kidney stone disease (KSD) due to renal phosphate wasting require specific metaphylaxis. NaPi2a, NaPi2c, and NHERF1 regulate plasma phosphate concentration by reabsorbing phosphate in proximal kidney tubules and have been found altered in monogenic hypophosphatemia with a risk of KSD. In this study, we aimed at assessing the combined genetic alterations impacting NaPi2a, NaPi2c, and NHERF1. Therefore, we screened our hereditary KSD registry for cases of oligo- and digenicity, conducted reverse phenotyping, and undertook functional studies. As a result, we identified three patients from two families with digenic alterations in NaPi2a, NaPi2c, and NHERF1. In family 1, the index patient, who presented with severe renal calcifications and a bone mineralization disorder, carried digenic alterations affecting both NaPi transporter 2a and 2c. Functional analysis confirmed an additive genetic effect. In family 2, the index patient presented with kidney function decline, distinct musculature-related symptoms, and intracellular ATP depletion. Genetically, this individual was found to harbor variants in both NaPi2c and NHERF1 pointing towards genetic interaction. In summary, digenicity and gene dosage are likely to impact the severity of renal phosphate wasting and should be taken into account in terms of metaphylaxis through phosphate substitution.

Endoplasmic reticulum chaperone GRP78 participates in fluoride-induced autophagy in LS8 cells by regulating the IRE1-TRAF2-JNK pathway.

Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride-induced cellular stress and autophagy remain unclear. This study investigated ER stress-induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride-induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride-induced ER stress and autophagy, we assessed changes in fluoride-induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride-induced autophagy was reduced in GRP78-silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride-treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride-induced damage by inducing ameloblast autophagy.

The effects and safety of high dose vitamin D3 in hemodialysis patients.

Different studies have shown that hemodialysis patients require higher doses of Vitamin D3 (VD3) than the general population to achieve satisfactory replenishment. This study aims to assess the safety of such practice and its benefits on some of the parameters of Chronic Kidney Disease- Mineral and Bone Disorder (CKD-MBD). A single-center clinical trial assessing the benefits of high dose VD3 in hemodialysis patients. The dose of VD3 (300,000 IU) was administered orally and monthly from April to December 2020 (9 months) at the dialysis unit. The data analyzed were blood levels of calcium, phosphorus, alkaline phosphatase, 25(OH)D, 1,25(OH)2D and intact parathyroid hormone (iPTH) done every three months. We could recruit a cohort of 23 patients. Blood levels of 25(OH)D increased significantly in 82.6% of the patients to above 30 ng/ml. A similar effect was observed with 1, 25(OH)2D levels. iPTH levels decreased significantly when levels of 25(OH)D exceeded 30ng/ml at the end of the nine months. Vitamin D serum levels were typically measured immediately before the next monthly dose was administered. Blood levels of calcium, phosphorus, and alkaline phosphatase were stable during the study period. No events of hypercalcemia were reported, and no patient discontinued the monthly VD3 supplementation. Monthly administration of a high dose of VD3 over a long period of nine months in hemodialysis patients was found to be safe and beneficial in VD3 replenishment. It also allowed a significant decrease in iPTH levels. Further studies are warranted to identify the therapeutic target level of 25(OH)D in hemodialysis patients, allowing beneficial effects on iPTH.

Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines.

Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.