Chronic Kidney Disease Mineral Research Articles

Leveraging Quantitative Systems Pharmacology and Artificial Intelligence to advance treatment of Chronic Kidney Disease Mineral Bone Disorder.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a complex clinical syndrome responsible for the accelerated cardiovascular mortality seen in individuals afflicted with CKD. Current approaches to therapy have failed to improve clinical outcomes adequately, likely due to targeting surrogate biochemical parameters as articulated by the guideline developer, KDIGO (Kidney Disease: Improving Global Outcomes). We hypothesized that using a Systems Biology Approach combining machine learning with mathematical modeling, we could test a novel approach to therapy targeting the abnormal movement of mineral out of bone and into soft tissue that is characteristic of CKD-MBD. The mathematical model describes the movement of calcium and phosphate between body compartments in response to standard therapeutic agents. The machine learning technique we applied is Reinforcement Learning (RL). We compared calcium, phosphate, PTH, and mineral movement out of bone and into soft tissue under four scenarios: standard approach (KDIGO), achievement of KDIGO guidelines using RL (RLKDIGO), targeting abnormal mineral flux (RLFLUX), and combining achievement of KDIGO guidelines with minimization of abnormal mineral flux (RLKDIGOFLUX). We demonstrate through simulations that explicitly targeting abnormal mineral flux significantly decreases abnormal mineral movement compared to standard approach while achieving acceptable biochemical outcomes. These investigations highlight the limitations of current therapeutic targets, primarily secondary hyperparathyroidism, and emphasize the central role of deranged phosphate homeostasis in the genesis of the CKD-MBD syndrome.

#2823 High doses and levels of cholecalciferol for secondary hyperparathyroidism in hemodialysis patients

Abstract Background and Aims Vitamin D is crucial for musculoskeletal and general health. Low levels are associated with an increased risk of death and morbidity, including cancer, cardiovascular, autoimmune diseases and infections. In hemodialysis (HD) patients vitamin D deficiency plays additionally an important role in the pathogenesis of Chronic Kidney Disease–Mineral And Bone Disorder (CKD-MBD), including the development of secondary hyperparathyroidism (SHP). Determination of 25(OH)D levels in CKD patients and the administration of cholecalciferol according to the guidelines for the general population is recommended. The literature data show that therapy even with high doses of cholecalciferol appear to be safe and sufficient to increase 25(OH)D level > 30 ng/ml in HD patients. However, the prevailing opinion is that PTH lowering with cholecalciferol in CKD is unproven and clinically insignificant. The aim of the study was to evaluate the efficacy (including PTH concentration) and safety of increasing vitamin D levels from the recommended 30 ng/mL to >75 ng/mL in HD patients treated with high doses of cholecalciferol. Method 22 HD patients (16 M, 6 F)), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration 30–50 ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session) to reach the target serum 25(OH)D level > 75 ng/mL, but not longer than for 24 weeks. The baseline data on calcium, phosphate, 1,84 PTH, 25(OH)D and 1,25(OH)2D serum levels were compared with the data when 25(OH)D > 75 ng/mL was achieved or when the highest 25(OH)D levels were noted. Results A significant decrease in 1,84 PTH levels was observed during the study (542.36 ± 420.87 vs 230.99 ± 386.22 pg/mL; p < 0.005). No significant effect on calcium (8.91 ± 0.57 vs 9.03 ± 0.63 mg/dL; p = 0.23) and phosphate (4.6 ± 1.06 vs 4.81 ± 1.06 mg/dL; p = 0.93) concentrations was shown. There was also significant increase in 25(OH)D and 1,25(OH)2D levels (35.52 ± 8.26 vs 79.83 ± 21.38 ng/mL; p < 0.005, and 13.38 ± 7.26 vs 25.56 ± 12.80 pg/mL; p < 0.005, respectively). In the range of 25(OH)D levels 30-50 ng/mL 25(OH)D correlated positively with 1,25(OH)2D levels, r = 0.305. When 25(OH)D levels exceeded 50 ng/mL, there was negative correlation with 1,25(OH)2D levels (r = –0 .177 for 25(OH)D 50-75 ng/mL, and r = –0.262 for 25(OH)D >75 ng/mL). Conclusion Our study showed that the administration of high therapeutic doses of cholecalciferol to achieve 25(OH)D levels >75 ng/mL was safe, without the risk of hypercalcemia and hyperphosphatemia. Raising of 25(OH)D levels to the upper limit of the laboratory norm resulted in significant decrease in PTH levels. Cholecalciferol may be useful in the treatment of SHP in HD patients, but higher 25(OH)D levels seem to be crucial.

#3127 Bedside cycling modulated the bone-resorption markers in patients with end-stage renal disease

Abstract Background and Aims Exercise provided multifactorial benefits in improving the health of the CKD patients. The exercise itself improved the bone remodeling. For CKD patients, chronic kidney disease mineral bone disorder (CKD-MBD) is an important complication and the treatment for renal osteodystrophy is unsatisfactory. The aim of study is to validate the role of bedside cycling in bone remodeling markers for patients with end-stage renal disease (ESRD). Method Participants were grouped into 4 groups: health control, chronic kidney disease (GFR 15∼60 ml/min) and ESRD (GFR<15 ml/min with maintenance dialysis). For ESRD patients, 12-week bedside cycling ((30 minutes per session; 3 times per week) were given for subjects. The pre-and post-exercise bone remodeling markers and clinical outcome were compared in ESRD with and without exercise in ESRD subjects. Results Bone formation markers (Bone specific alkaline phosphatase (15.57 ± 1.59 pg/dL) and Procollagen type 1 amino-terminal propeptide (1269.12 ± 116.34 pg/dL) were higher in ESRD patients with correlation with indoxyl sulfate and intact parathyroid hormone concentration(p < 0.05) respectively. In ESRD patients, the post-exercise concentration of Tartrate-resistant acid phosphatase 5b (3.64 ± 0.25 pg/dL to 4.23 ± 0.31 pg/mL, p = 0.003) and N-terminal telopeptide-1 (113.67 ± 20.53 pg/mL to 260.61 ± 30.9 pg/mL, p = 0.001)increased after 12 weeks of bed-side cycling. The hospitalization and mortality were similar between ESRD with or without exercise. Conclusion The bone formation marker concentration increased along with the severity of CKD. Bedside cycling increased the concentration of the bone resorption markers in ESRD patients.

#2296 Time to get calciphylaxis on clinicians’ RaDaR?—a multicentre case series

Abstract Background and Aims Calciphylaxis is a rare, severe complication of chronic kidney disease mineral bone disorder. It is hosphorzed by arteriolar calcification of the subcutaneous fat and dermis, and associated with a mortality rate of approximately 50% within a year of diagnosis. The reported prevalence of calciphylaxis in dialysis patients ranges from 1–4%. Between March 2012 and March 2020 the UK calciphylaxis study (UKCS) recruited 139 patients from 36 enrolled renal centres; an average of 1 case every 2.6 years per centre. The multicentre case series presented here includes patients from two NHS Hospital Trusts in the UK. The aim is to raise awareness of i) calciphylaxis and possible risk factors and ii) the role of registry data in rare kidney diseases. Method Patients were included if they had a diagnosis of calciphylaxis between 01.02.2020 and 01.02.2022. Data regarding demographics, dialysis modality, BMI, medications, and mineral bone parameters were collected from clinical databases. A representative sample of results was recorded from initiation of renal replacement therapy through to diagnosis of calciphylaxis. Data regarding calciphylaxis lesions, treatments and current vital status are hosphorz. Results 17 patients with end stage kidney failure (ESKF) and clinical features of calciphylaxis were included; 8 of 17 (47%) had a skin biopsy of which 6 reported evidence of calcification. Median age was 57 years (IQR: 50-74), BMI 26.8 kg/m2 (IQR: 22.9-31.1), 100% were white, 53% female and 59% had diabetes. Median time from onset of ESKF to calciphylaxis diagnosis was 5.5 years (IQR: 1-16). 53% (9 of 17) had history of recurrent hypercalcaemia (corrected calcium >2.55 mmol/L) and 82% (14 of 17) recurrent hyperphosphatemia (phosphate >1.5 mmol/L). 41% (7 of 17) had refractory secondary hyperparathyroidism. Warfarin therapy exposure was recorded in 47% (8 of 17) patients; a finding consistent with the literature. 76% (13 of 17) had received active vitamin D and 76% (13 of 17) a calcium-based phosphate binder. 76% (13 of 17) had lower leg lesions; 2 of whom also had upper leg lesions. 1 patient had a thigh lesion and 2 patients had an abdominal wound. Median follow up time was 8.5 months (range 1-24). 9 of the 17 patients remain alive, of whom lesions have completely healed in 6 patients. All patients received sodium thiosulphate and 1 (transplant patient) received hyperbaric oxygen therapy and sodium thiosulphate. Only 1 patient has been enrolled into the UK registry of rare kidney diseases (RaDaR). Conclusion Calciphylaxis is a devastating condition for which there are no proven treatments. In this case series a history of hyperphosphataemia, calcium-based binder, alfacalcidol, and warfarin use were common. It remains unknown why some patients develop calciphylaxis and others do not. National registry data, such as RaDaR, plays a crucial role in furthering knowledge and understanding of rare diseases; it helps to determine calciphylaxis incidence, and inform possible prevention and treatment strategies. Yet, in reality, few patients maybe being recruited into RaDaR. The opportunity exists for an international calciphylaxis registry; for this to offer maximum impact individual countries need to explore, and where possible address, barriers to recruitment.

#2460 Haemodialysis-related periarticular calcifications as cause of recurrent severe inflammatory state

Abstract Background and Aims End stage chronic kidney disease (CKD) and haemodialysis (HD) are associated with disturbances in mineral and bone turnover ultimately leading to chronic kidney disease–mineral and bone disorder (CKD-MBD), which affects more than 90 % of patients with stage 5D CKD. The primary changes observed in CKD–MBD involve elevated phosphorus levels, decreased calcium levels, insufficient serum vitamin D, and heightened release of parathyroid hormone from the parathyroid glands, leading to secondary hyperparathyroidism. CKD-MBD leads to vascular calcification, increasing cardiovascular risk. There is also a correlation between abnormal bone remodeling activity in CKD-MBD and the likelihood of calcification in soft tissues. In rare instances, profound calcification occurs in periarticular tissues, resulting in severe inflammation and manifesting as systemic disease with articular involvement clinically. The objective of this case report is to demonstrate a recurrent inflammatory condition caused by severe periarticular calcification in a patient on HD. Case report We present a case of a middle-aged white male diagnosed with hypertension, hypercholesterolemia, chronic obstructive pulmonary disease, hepatitis C, and end-stage renal disease caused by hydronephrosis. He was undergoing HD since July 2020. From summer 2021 the patient experienced recurrent fever and arthralgias in the hips, elbows, and shoulders. Frequent acute hospitalizations were needed due to recurring fevers and severe inflammatory response with markedly elevated acute phase reactants (CRP was repeatedly >200 mg/l), raising suspicion of infection. Laboratory and imaging tests however showed no clear signs of infection, and antibiotic therapy was ineffective. An x-ray of the right AC-joint showed multiple periarticular calcifications dorsally from the AC-joint. Later, due to severe pain and swelling an MRI-scan of right elbow joint was conducted, revealing an osteomyelitis-suspect finding of the olecranon, and olecranon bursitis. No bacteria were detected in the punctate of olecranon bursa. X-ray scans of the elbows revealed bilateral soft tissue calcification dorsally from the proximal ulna. The x-ray scan of the right shoulder revealed calcific expansion in the AC-joint area, leading to total destruction of the lateral part of the clavicle. MRI and CT scans showed severe periarticular calcification around AC- and glenohumeral joints without inflammatory involvement of the synovium. Bony erosions were observed due to the pressure of calcified tissue on the bone. Whole-body CT-scan showed no sites of infection but there was a periarticular calcification observed around the hip joints. A PET-CT scan of the whole body, neck, and upper extremities revealed no signs of malignancy or infections, but there was an increased uptake of 18F-fluorodeoxyglucose detected in several periarticular sites, indicating a multi-site inflammatory process resulting from severe periarticular calcifications. A dual-energy CT-scan of upper extremities was performed, excluding the accumulation of monosodium urate crystals. The cycle of multiple hospitalizations and antibacterial therapies was broken with the diagnosis of CKD and HD-related inflammatory periarticular calcification. Initially, the inflammation was addressed with high-dose glucocorticoids. However, the dose was successfully tapered during the first month of treatment, and the patient continued to do well on a maintenance dose of 5 mg/day of prednisolone. Subsequently, hospitalizations, antibiotics, or surgical procedures were no longer required. Conclusion Severe CKD and HD cause disturbances in mineral and bone metabolism, that can lead to periarticular calcification. Like in our presented case, multi-site calcifications may mimic infection or autoimmune rheumatoid conditions making the way to correct diagnosis cumbersome and costly. Imaging techniques help us distinguish periarticular deposits from inflammatory and infectious arthritis. In our case low-dose prednisolone effectively reduced inflammation, obviating hospitalizations and minimizing healthcare burden.

Changes in Bone Mineral Density in Patients With Non-dialysis-Dependent Chronic Kidney Disease Are Associated With Body Composition

Chronic kidney disease (CKD) and low bone mineral density (BMD) are highly prevalent and can co-exist. Parameters of mineral metabolism are associated with BMD in CKD, but other contributing factors may contribute. The aim of this study was to assess changes in BMD and its determinants in patients with non-dialysis-dependent CKD (NDD-CKD). Body composition and biochemical profiles were assessed in a retrospective hospital-based cohort study of patients with NDD-CKD. BMD, lean soft tissue (LST), appendicular LST (ALST), and percentage fat mass were assessed by dual-energy X-ray absorptiometry (DXA). ALST index (ALSTI, ALST/height2) and load-capacity index (LCI, fat mass/LST) were calculated. Low BMD was defined as t-score ≤-1.0. Mean time between assessments was 2.8±1.3 years, 46 patients were included. A reduction in renal function was observed. Changes in body composition included reductions in ALST (p=0.031), ALSTI (p=0.021) and a trend for BMD (p=0.053); and an increase in percentage fat mass (p=0.044) and LCI (p=0.032). Females had a reduction in BMD (p=0.034), ALST (p=0.026), and ALSTI (p=0.037). Patients with low BMD at baseline had lower LST (p=0.013), ALST (p=0.023), and percentage fat mass (p=0.037) than those with normal BMD. Additionally, reductions in LST (p=0.041), ALST (p=0.006), and ALSTI (p=0.008) were observed in patients who had low BMD at baseline, while no significant changes in body composition were observed in those with normal BMD at baseline. The following body composition parameters at baseline were determinants of BMD status at follow-up: LST (OR:0.899, 95%CI:0.829-0.976, p=0.010), ALST (OR:0.825, 95%CI:0.704-0.967, p=0.017), and ALSTI (OR:0.586, 95%CI:0.354-0.968, p=0.037), independent of fat mass, and LCI. Detrimental body composition changes were observed without changes in body weight; these were more significant in females. Moreover, this is the first longitudinal study showing a protective effect of LST against BMD loss in patients with NDD-CKD.

WCN24-421 Mineral and bone disorders in chronic kidney disease

WCN24-421 Mineral and bone disorders in chronic kidney disease

Lanthanum Hydroxide and Chronic Kidney Disease Mineral and Bone Disorder: A Rat Model.

To investigate the pharmacological effects and molecular mechanisms of lanthanum hydroxide(LH) on ectopic mineralization of soft tissue and abnormal bone in rats with acute kidney injury(AKI). Wistar rats were modeled by 5/6 nephrectomy. After the operation, the rats were divided into different groups, the biochemical indexes of serum collected at different times. LH was administered by intragastric tube at doses of 0.4, 0.2, and 0.1g/kg, respectively. Rats were sacrificed in the 16th week after LH treatment. Observation of pathological changes in tissues were made by specific staining. Western Blot, Real-Time Quantitative PCR, and immunohistochemistry techniques were used to detect the impact on pathway-related proteins. Compared with the control group (no LH administered), the serum phosphate level of the LH group was significantly reduced (p<0.01), calcification of the thoracic aorta was reduced (p<0.05, p<0.01) (Serum biochemical tests before dosing and during drug treatment cycles), renal fibrosis was improved (p<0.01), nuclear entry of nuclear factor kappa-B (NF-κB) was reduced (p<0.01), and the expression of the smooth muscle protein 22α (SM22α) was significantly increased (p<0.01). The expression of osteogenic marker genes was decreased. In addition, compared with the controls, the receptor activator for nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio of the femur in the model group was increased (p<0.05). LH can inhibit the occurrence and development of vascular calcification and bone abnormalities in AKI rats by inhibiting the NF-κB and RANKL/OPG signaling pathways.

Correlation between soluble klotho and chronic kidney disease–mineral and bone disorder in chronic kidney disease: a meta-analysis

We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [− 0.21, (− 0.37, − 0.04)], with apparent heterogeneity (I2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [− 0.23,(− 0.29, − 0.17); − 0.15, (− 0.23, − 0.08)], with no significant heterogeneity among the studies. (I2 = 40%, P < 0.05; I2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD–MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD–MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification. As analysis showed that sKlotho has an important impact on the pathogenesis and progression of CKD–MBD in CKD patients. Nonetheless, further comprehensive and high-quality studies are needed to validate our conclusions.

Post-Transplant Bone Disease in Kidney Transplant Recipients: Diagnosis and Management.

Kidney transplantation is the preferred gold standard modality of treatment for kidney failure. Bone disease after kidney transplantation is highly prevalent in patients living with a kidney transplant and is associated with high rates of hip fractures. Fractures are associated with increased healthcare costs, morbidity and mortality. Post-transplant bone disease (PTBD) includes renal osteodystrophy, osteoporosis, osteonecrosis and bone fractures. PTBD is complex as it encompasses pre-existing chronic kidney disease-mineral bone disease and compounding factors after transplantation, including the use of immunosuppression and the development of de novo bone disease. After transplantation, the persistence of secondary and tertiary hyperparathyroidism, renal osteodystrophy, relative vitamin D deficiency and high levels of fibroblast growth factor-23 contribute to post-transplant bone disease. Risk assessment includes identifying both general risk factors and kidney-specific risk factors. Diagnosis is complex as the gold standard bone biopsy with double-tetracycline labelling to diagnose the PTBD subtype is not always readily available. Therefore, alternative diagnostic tools may be used to aid its diagnosis. Both non-pharmacological and pharmacological therapy can be employed to treat PTBD. In this review, we will discuss pathophysiology, risk assessment, diagnosis and management strategies to manage PTBD after kidney transplantation.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, βKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Biomechanical and histomorphological analysis of the mandible in rats with chronic kidney disease

The present study aimed to investigate the biomechanical and histomorphological features of mandibles in an adenine-induced chronic kidney disease–mineral and bone disorder (CKD-MBD) rat model of CKD. A total of 14 Sprague-Dawley rats were randomized into the following two groups: control group and CKD group. At the end of the sixth week, all rats were euthanized, and serum was collected for biochemical marker tests. Macroscopic bone growth and biomechanical parameters were measured in the right hemimandible, while the left hemimandible was used for bone histomorphometric analysis. Compared to the control group, the CKD group showed a significant increase in serum creatinine, blood urea nitrogen, and serum parathyroid hormone at the end of the sixth week. The biomechanical structural properties significantly decreased in the CKD group compared to the control group. Bone histomorphometric analysis indicated that the trabecular bone volume of rats in the CKD group was significantly lower than that of the control group. In the CKD groups, the bone formation parameters of the trabecular bone were significantly increased, while the bone mineralization apposition rates of both the trabecular bone and periosteal cortical bone were significantly increased. The rat CKD model showed deteriorated structural mechanics, low trabecular bone volume, high trabecular bone formation, increased trabecular bone mineralization apposition rate, and increased cortical bone mineralization apposition rate, which met the characteristics of osteitis fibrosa, indicating that this model is a useful tool for the study of mandible diseases in CKD patients.

Analysis of etiology and complications in children with stage 5 chronic kidney disease

Objective: To investigate the etiology, complications, and prognostic factors of stage 5 chronic kidney disease (CKD5) in children. Methods: A case series study was conducted to retrospectively analyze the general situation, clinical manifestations, laboratory tests, genetic testing, and follow-up data (until October 2022) of 174 children with CKD5 who were diagnosed and hospitalized at the Children's Hospital of Chongqing Medical University from April 2012 to April 2021. The characteristics of complications in the children were compared based on age, gender, and etiology. Based on the presence or absence of left ventricular hypertrophy (LVH), patients were divided into LVH group and non LVH group for analyzing the influencing factors of cardiovascular disease. Patients were also divided into death group and survival group, peritoneal dialysis group and hemodialysis group based on the follow-up data for analyzing the prognostic factors. The chi-square test, independent sample t-test, Fisher exact probability test, Mann-Whitney U test and Kruskal Wallis test were used to analyze data among different groups. Multivariate Logistic regression analysis was used to identify the prognostic factors. Results: A total of 174 children with CKD5 were enrolled in the study (96 boys and 78 girls), aged 11.2 (8.2, 13.0) years. Congenital kidney and urinary tract malformations (CAKUT) were the most common causes of the CKD5 (84 cases, 48.3%), followed by glomerular diseases (83 cases, 47.7%), and among which 28 cases (16.1%) were hereditary glomerular diseases. The common complications of CKD5 included anemia (98.2%, 165/168), mineral and bone disorder in chronic kidney disease (CKD-MBD) (97.7%, 170/174), lipid metabolism disorders (87.5%, 63/72), hypertension (81.4%, 127/156) and LVH (57.6%,57/99). The incidences of hypertension in primary glomerular disease were higher than that in CAKUT(93.8%(30/32) vs.73.7%(56/76),χ2=5.59,P<0.05). The incidences of hypertension in secondary glomerular disease were higher than that in CAKUT and that in hereditary kidney disease (100.0%(20/20) vs. 73.7%(56/76), 68.2%(15/22), both P<0.05). The incidence of hypocalcemia in CAKUT, primary glomerular disease, and hereditary kidney disease was higher than that in secondary glomerular disease (82.1%(69/84), 88.2%(30/34), 89.3%(25/28) vs. 47.6%(10/21), χ2=10.21, 10.75, 10.80, all P=0.001); the incidence of secondary hyperparathyroidism in women was higher than that in men (80.0%(64/80) vs. 95.0%(57/60), χ2=6.58, P=0.010). The incidence of LVH in children aged 6-<12 was higher than that in children aged 12-18 (73.5%(25/34) vs. 43.1%(22/51), χ2=7.62, P=0.006). Among 113 follow-up children, the mortality rate was 39.8% (45/113). Compared to the survival group, the children in the death group had lower hemoglobin, higher blood pressure, lower albumin, lower alkaline phosphatase and higher left ventricular mass index ((67±19) vs. (75±20) g/L, 142 (126, 154) vs. 128(113, 145) mmHg(1 mmHg=0.133 kPa), (91±21) vs. (82±22) mmHg, 32 (26, 41) vs. 40 (31, 43) g/L, 151 (82, 214) vs. 215 (129, 37) U/L, 48 (38, 66) vs. 38(32, 50) g/m2.7,t=2.03, Z=2.89, t=2.70, Z=2.49, 2.79, 2.29,all P<0.05), but no independent risk factors were identified (all P>0.05). The peritoneal dialysis group had better alleviation for anemia, low calcium, and high phosphorus than the hemodialysis group ((87±22) vs. (72±16) g/L, (1.9±0.5) vs. (1.7±0.4) mmol/L, (2.2±0.7) vs. (2.8±0.9) mmol/L, t=2.92, 2.29, 2.82, all P<0.05), and the survival rate of the peritoneal dialysis group was significantly higher than that of the hemodialysis group (77.8% (28/36) vs. 48.4% (30/62), χ2=8.14, P=0.004). Conclusions: CAKUT is the most common etiology in children with CKD 5, and anemia is the most common complication. The incidence of complications in children with CKD 5 varies with age, gender and etiology. Anemia, hypertension, hypoalbuminemia, reduced alkaline phosphatase and elevated LVMI may be the prognostic factors in children with CKD5. Peritoneal dialysis may be more beneficial for improving the long-term survival rate.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n=55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Reducing the risk of denosumab-induced hypocalcemia in patients with advanced chronic kidney disease: a quality improvement initiative.

There is an increased risk of hypocalcemia with denosumab in advanced chronic kidney disease (CKD). We aimed to reduce the proportion of patients with advanced CKD who experienced denosumab-induced hypocalcemia at our center. We conducted a quality improvement (QI) project of patients with CKD stage 3b or less (i.e., estimated glomerular filtration rate <45 mL/min/1.73m2 including dialysis) who were part of the Osteoporosis and Bone Disease Program at St. Joseph's Health Care London (Canada) between December 2020 and January 2023. Our intervention was a clinical care pathway which optimized CKD mineral and bone disorder (CKD-MBD) and 25-hydroxyvitamin levels; provided calcium and vitamin D prophylaxis; promoted multidisciplinary communication between bone and kidney specialists; and carefully monitored calcium post-denosumab injection. Our primary outcome measure was the proportion of patients with hypocalcemia (defined by albumin-corrected serum calcium <1.9mmol/L) at 60 days. Process measures included the appropriate provision of calcium and vitamin D prophylaxis. Balance measures included the development of hypercalcemia and hyperphosphatemia following prophylaxis. We used plan-do-see-act cycles to study four tests of change and presented results using descriptive statistics and run charts. There were 6 patients with advanced CKD treated with denosumab prior to the implementation of our care pathway (March 2015-October 2020; 83% receiving dialysis). At the time of their denosumab injection, 83% were using 500-1000 mg of calcium, and 83% used 1000-2000 IU of vitamin D3. Fifty percent developed denosumab-induced hypocalcemia. Following the implementation of our care pathway, 15 patients (40% receiving dialysis) were treated with denosumab. Ninety-three percent received calcium at a daily dose of 350 to 2250 mg and 87% received 1000-2000 IU of vitamin D3. Thirteen percent developed denosumab-induced hypocalcemia. There was no hypercalcemia or hyperphosphatemia. A clinical care pathway focused on the safe provision of denosumab in advanced CKD reduced the risk of hypocalcemia in patients treated in our hospital. Similar pathways could be adopted and tested in other centers.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Bone health in children undergoing solid organ transplantation.

Pediatric solid organ transplant recipients are a unique and growing patient population who are at risk for metabolic bone disease both before and after transplantation. The odds of sustaining a fracture in adulthood are significantly higher if an individual has sustained at least one childhood fracture, therefore, close monitoring before and after transplant is essential. Emerging data in patients with chronic kidney disease mineral and bone disorder (CKD-MBD) and hepatic osteodystrophy highlights the role of fibroblast growth factor 23 in the pathogenesis of metabolic bone disease in these conditions. While dual X-ray absorptiometry (DXA) is the most widely used imaging modality for assessment of bone mass in children, quantitative computer tomography (QCT) is an emerging modality, especially for patients with glucocorticoid-induced osteoporosis. Solid organ transplantation improves organ function and quality of life; however, bone mineral density can decline following transplantation, particularly during the first three to six months. Immunosuppressive medications, including glucocorticoids, are a major contributing factor. Following transplant, treatment should be tailored to achieve mineral homeostasis, correct nutritional deficiencies, and improve physical conditioning. In summary, early identification and treatment of metabolic bone disease can improve the bone health status of pediatric transplant recipients as they enter adulthood. http://links.lww.com/MOP/A71.

Myocardial Remodeling in Early Chronic Kidney Disease—Mineral and Bone Disorder Model with Low Bone Turnover

Chronic kidney disease—mineral and bone disorder (CKD-MBD) plays a significant role in causing cardiovascular morbidity and mortality related to CKD. CKD-MBD has been studied during advanced stages when changes in inorganic phosphate (Pi) and its hormonal regulation are obvious. The initial phases of myocardial remodeling (MR) in early CKD-MBD remain poorly understood. We induced mild CKD-MBD in spontaneously hypertensive rats using 3/4 nephrectomy. Animals were fed standard chow, containing 0.6% phosphate. In each animal, we analyzed indices of chronic kidney injury, bone turnover and Pi exchange, and assessed the myocardial histology and gene expression profile. Applied CKD-MBD models corresponded to human CKD S1-2 with low bone turnover and without an increase in systemic Pi-regulating factors (parathyroid hormone and fibroblast growth factor 23). In mild CKD-MBD models, we found MR features characterized by cardiomyocyte hypertrophy, interstitial and perivascular fibrosis, intramyocardial artery media thickening, along with alterations in Ppp3ca, Mapk1, Jag1, Hes1, Ptch1, Numb, Lgr4 and Bmp4 genes. Among other genes, the down-regulation of Jag1 was most tightly associated with either myocardial hypertrophy or fibrosis. Myocardial alterations concurrently occurred with mild CKD-MBD and comprised fibrosis preceding cardiomyocyte hypertrophy. The histological features of MR were associated with myocardial P accumulation in settings of low bone turnover, prior to a response of systemic Pi-regulating factors and with alterations in calcineurin, ERK1/2, Notch, BMP and Hedgehog genes.

Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study

(1) Background: Vitamin K deficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and an increased risk of vascular calcifications. A method to indirectly assess the vitamin K status is measuring the blood level of vitamin K-dependent proteins (VKDP): osteocalcin (OC) and matrix GLA protein (MGP). The aim of this study is to correlate the level of total OC and inactive MGP (dp-uc MGP) with markers of CKD mineral bone disorder (CKD-MBD). (2) Methods: We conducted a single-center cross-sectional study that included 45 CKD G5D patients and measured their blood biochemistry, complete blood count and total osteocalcin and dp-uc MGP contents. (3) Results: We found a strong, statistically significant correlation of the total OC with the markers of CKD-MBD, such as: iPTH, serum calcium and serum phosphorus, and a strong, indirect statistically significant correlation with abdominal circumference. There was also a statistically significant correlation of dp-uc MGP with the markers of inflammation (CRP). Higher levels of dp-uc MGP were found in the patients treated with vitamin K antagonists, non-calcium-based phosphate binders and the vitamin D receptor activator, paricalcitol. (4) Conclusions: In our study, we found that when it is measured indirectly using VKDP levels, vitamin K deficiency is associated with CKD-MBD. Certain widely used medications such as phosphate binders reduce vitamin K absorption, supplementary vitamin D increases vitamin K requirements, and also vitamin K antagonists influence the blood level of VKDPs.

B-171 Comparison of Intact PTH and PTH Assays using LC-MS/MS Among Non-Dialysis Dependent Chronic Kidney Disease Patients

Abstract Background Parathyroid hormone (PTH) is an important regulator of calcium and phosphate homeostasis and bone remodeling. It is metabolized into PTH fragments, which are measured to a different extent by PTH assays of different generations because of differences in fragments recognized and lack of assay standardization. Therefore, we developed an LC-MS/MS method for 1-84 PTH and aimed to compare with immunoassay among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. Methods Blood samples were collected from 252 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation—PTH intact and immunocapture in situ digestion LC-MS/MS spectrometry assays. The severity of the kidney disease was based on the eGFR calculated by using the Modification of Diet in Renal Disease (MDRD) formula. Results Serum 1-84 PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r = 0.956, P &amp;lt; 0.0001). This finding was consistent among CKD stages 3 to 5. PTH concentrations by both assays (intact and 1-84 PTH) positively correlated with BUN (r = 0.613, r = 0.61; P &amp;lt; 0.0001, respectively), phosphorus (r = 0.423, r = 0.427; P &amp;lt; 0.0001, respectively) and negatively correlated with blood calcium (r = −0.355, r = −0.421; P &amp;lt; 0.0001, respectively), protein (r = −0.289, r = −0.305; respectively, P &amp;lt; 0.0001) and the estimated glomerular filtration rate (r = −0.468, r = −0.485; P &amp;lt; 0.0001, respectively). Conclusion Among patients with CKD stages 3 to 5 not on dialysis, the 1-84 PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. This LC-MS/MS method can provide accurate and precise PTH results in patients with severe chronic renal failure. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders are needed to determine whether 1-84 PTH assay results are better surrogate markers in these early stages of CKD.