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

Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision of denosumab in advanced CKD that reduced the risk of hypocalcemia by 37% at our hospital. Similar pathways could be adopted and tested in other centers. PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Bones of contention: Predicting and preventing fractures in patients receiving peritoneal dialysis.

Low bone density is common among those individuals receiving peritoneal dialysis. While cross-sectional studies support an association between low bone mineral density (BMD) and prevalent fracture, relying on bone density alone, particularly at the lumbar spine and in those with high degrees of hyperparathyroidism may underestimate fracture risk. Commonly used risk calculators in the general population have been shown to perform reasonably well in those receiving dialysis although they do not include any risk factors for high turnover bone disease that may play a role in increased fracture risk. The best options for decreasing fracture risk in patients receiving peritoneal dialysis are unclear. The evidence for bisphosphonates is limited to small studies of BMD, and concerns about drug accumulation have limited their use. Denosumab is more commonly used and has some evidence for improvement in BMD but carries with it a high risk of hypocalcaemia requiring rigorous prophylaxis. More research is needed to explore practical methods to identify those at risk of fracture and determine the efficacy of antiresorptive and anabolic therapies to decrease this risk.

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 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).

Magnesium and Fracture Risk in the General Population and Patients Receiving Dialysis: A Narrative Review.

Purpose of Review: Magnesium is an essential mineral for bone metabolism, but little is known about how magnesium intake alters fracture risk. We conducted a narrative review to better understand how magnesium intake, through supplementation, diet, or altering the concentration of dialysate magnesium, affects mineral bone disease and the risk of fracture in individuals across the spectrum of kidney disease. Sources of Information: Peer-reviewed clinical trials and observational studies. Methods: We searched for relevant articles in MEDLINE and EMBASE databases. The methodologic quality of clinical trials was assessed using a modified version of the Downs and Black criteria checklist. Key Findings: The role of magnesium intake in fracture prevention is unclear in both the general population and in patients receiving maintenance dialysis. In those with normal kidney function, 2 meta-analyses showed higher bone mineral density in those with higher dietary magnesium, whereas 1 systematic review showed no effect on fracture risk. In patients receiving maintenance hemodialysis or peritoneal dialysis, a higher concentration of dialysate magnesium is associated with a lower concentration of parathyroid hormone, but little is known about other bone-related outcomes. In 2 observational studies of patients receiving hemodialysis, a higher concentration of serum magnesium was associated with a lower risk of hip fracture. Limitations: This narrative review included only articles written in English. Observed effects of magnesium intake in the general population may not be applicable to those with chronic kidney disease particularly in those receiving dialysis.

Justification: Le magnésium est un minéral essentiel pour le métabolisme osseux, mais on en sait peu sur la façon dont un apport en magnésium modifie le risque de fracture. Nous avons procédé à un examen narratif afin de mieux comprendre comment les maladies liées à la densité minérale osseuse et le risque de fracture sont affectés par un apport en magnésium (supplémentation, régime alimentaire ou modification de la concentration de dialysat de magnésium) chez les personnes atteintes d'insuffisance rénale. Sources: Essais cliniques et études observationnelles examinés par des pairs. Méthodologie: Nous avons répertorié les articles pertinents dans les bases de données MEDLINE et EMBASE. Une version modifiée des critères de contrôle de la qualité des études de Downs et Black a servi à évaluer la qualité méthodologique des essais cliniques retenus. Principaux résultats: Le rôle d'un apport en magnésium dans la prévention des fractures n'est pas clair, tant dans la population générale que chez les patients sous dialyse d'entretien. Chez les personnes ayant une fonction rénale normale, deux méta-analyses ont montré que les personnes dont le régime alimentaire est riche en magnésium présentent une densité minérale osseuse plus élevée; alors qu'une revue systématique n'a montré aucun effet sur le risque de fracture. Chez les patients sous hémodialyse d'entretien ou dialyse péritonéale, une concentration plus élevée de dialysat de magnésium est associée à une plus faible concentration d'hormone parathyroïdienne, mais on en sait peu sur les autres effets liés aux os. Dans deux études observationnelles portant sur des patients sous hémodialyse, une concentration plus élevée de magnésium sérique a été associée à un risque plus faible de fracture de la hanche. Limites: Cet examen narratif ne comprend que des articles rédigés en anglais. Il est possible que les effets d'un apport en magnésium observés dans la population générale ne puissent s'appliquer aux personnes atteintes d'une néphropathie chronique, en particulier aux personnes sous dialyse.

Fracture Risk of Sodium-Glucose Cotransporter-2 Inhibitors in Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a higher risk of skeletal fractures in some randomized, placebo-controlled trials. Secondary hyperparathyroidism and increased bone turnover (also common in CKD) may contribute to the observed fracture risk. We aimed to determine if SGLT2 inhibitor use associates with a higher risk of fractures compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, which have no known association with fracture risk. We hypothesized that this risk, if present, would be greatest in patients with lower eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a population-based cohort study in Ontario, Canada between 2015 and 2019 using linked provincial administrative data to compare the incidence of fracture between new users of SGLT2 inhibitors and DPP-4 inhibitors. We used inverse probability of treatment weighting on the basis of propensity scores to balance the two groups of older adults (≥66 years of age) on indicators of baseline health. We compared the 180- and 365-day cumulative incidence rates of fracture between groups. Prespecified subgroup analyses were conducted by eGFR category (≥90, 60 to <90, 45 to <60, and 30 to <45 ml/min per 1.73 m2). Weighted hazard ratios were obtained using Cox proportional hazard regression. RESULTS: After weighting, we identified a total of 38,994 new users of a SGLT2 inhibitor and 37,449 new users of a DPP-4 inhibitor and observed a total of 342 fractures at 180 days and 689 fractures at 365 days. The weighted 180- and 365-day risks of a fragility fracture did not significantly differ between new users of a SGLT2 inhibitor versus a DPP-4 inhibitor: weighted hazard ratio, 0.95 (95% confidence interval, 0.79 to 1.13) and weighted hazard ratio, 0.88 (95% confidence interval, 0.88 to 1.00), respectively. There was no observed interaction between fracture risk and eGFR category (P=0.53). CONCLUSIONS: In this cohort study of older adults, starting a SGLT2 inhibitor versus DPP-4 inhibitor was not associated with a higher risk of skeletal fracture, regardless of eGFR.

Higher-Dose Gabapentinoids and the Risk of Adverse Events in Older Adults With CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Gabapentinoids are opioid substitutes whose elimination by the kidneys is reduced as kidney function declines. To inform their safe prescribing in older adults with chronic kidney disease (CKD), we examined the 30-day risk of serious adverse events according to the prescribed starting dose. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 74,084 older adults (64% women; median age, 79 [interquartile range, 73-85] years) with CKD (defined for this study as an estimated glomerular filtration rate <60 mL/min/1.73 m2 and excluding those receiving dialysis) and a newly prescribed gabapentinoid between 2008 and 2020 in Ontario, Canada. EXPOSURE: Higher-dose gabapentinoids (gabapentin >300 mg/d or pregabalin >75 mg/d) versus lower-dose gabapentinoids (gabapentin ≤300 mg/d or pregabalin ≤75 mg/d). OUTCOMES: The primary composite outcome was the 30-day risk of a hospital visit with encephalopathy, a fall, or a fracture or a hospitalization with respiratory depression. ANALYTICAL APPROACH: Comparison groups were balanced on indicators of baseline health using inverse probability of treatment weighting using propensity score analysis that generated a pseudosample for the reference group with a distribution of measured covariates similar to the exposed group. Weighted risk ratios were estimated using modified Poisson regression, and weighted risk differences were estimated using binomial regression. Prespecified subgroup analyses were conducted by estimated glomerular filtration rate category and type of gabapentinoid. RESULTS: Among 74,084 patients identified with CKD and a new prescription for gabapentin or pregabalin, 41% started at >300 or >75 mg/d, respectively. From this set of patients, a weighted study population with a size of 61,367 was generated. Patients who started at a higher dose had a higher 30-day risk of the primary outcome than patients who started at lower dose. Within the weighted population, the numbers of events for higher versus lower dose were 585 of 30,660 (1.9%) versus 462 of 30,707 (1.5%), respectively. The weighted risk ratio was 1.27 (95% CI, 1.13-1.42), and the weighted risk difference was 0.40% (95% CI, 0.21%-0.60%). In subgroup analyses, neither multiplicative nor additive interactions were statistically significant. LIMITATIONS: Residual confounding. CONCLUSIONS: In this population-based study, starting a gabapentinoid at a higher versus a lower dose was associated with a slightly higher risk of a hospital visit with encephalopathy, a fall, or a fracture or hospitalization with respiratory depression. If verified, these risks should be balanced against the benefits of using a higher-dose gabapentinoid.

Cardiovascular Safety of Metoclopramide Compared to Domperidone: A Population-Based Cohort Study.

BACKGROUND: Metoclopramide and domperidone are common prokinetics used to alleviate gastrointestinal symptoms. However, both drugs may trigger ventricular arrhythmias. AIM: We conducted this population-based study to compare the 30-day cardiovascular safety of metoclopramide versus domperidone in outpatient care. METHODS: We used health care databases to identify a cohort of patients in Ontario, Canada newly dispensed metoclopramide or domperidone. Inverse probability of treatment weighting based on propensity scores was used to balance the baseline characteristics of the two groups. All outcomes were assessed in the 30 days following drug dispensing. The primary outcome was hospital encounter with ventricular arrhythmia. The secondary outcomes were hospital encounter with cardiac arrest, all-cause mortality and cardiovascular mortality. RESULTS: We identified 196,544 patients, 19% of whom were prescribed metoclopramide. There was no difference in the risk of a hospital encounter with ventricular arrythmia (0.02% in both groups), or cardiac arrest (0.10% with metoclopramide and 0.08% with domperidone). However, 1.34% of patients died after starting metoclopramide compared to 0.52% of patients starting domperidone; weighted risk ratio 2.50 (95% confidence interval [CI] 2.13 to 3.03). Similarly, 0.42% of patients died of cardiovascular causes after starting metoclopramide compared to 0.19 % of patients starting domperidone; weighted risk ratio 2.00 (95% CI 1.44 to 2.77). CONCLUSION: The 30-day risk for a hospital encounter with ventricular arrhythmia was low for both metoclopramide and domperidone, with no significant difference in the rate between the two drugs. The higher 30-day risk of death observed with metoclopramide compared with domperidone in this study has also been observed in other studies and warrants further investigation.

Denosumab in chronic kidney disease: a narrative review of treatment efficacy and safety.

People with chronic kidney disease (CKD) are at high risk of bone fractures. In this review, we summarize the complexity of fracture prevention in CKD, describe the usefulness of a medication called denosumab, and review its safety in this population. Our article will help doctors manage brittle bones in CKD and encourage researchers to conduct more studies to improve bone health in CKD. PURPOSE: Patients with CKD are at increased risk of fragility fractures and associated consequences. We discuss the complexity of fracture prevention in CKD, summarize the efficacy and safety of denosumab, and provide an approach to denosumab-induced hypocalcemia. METHODS: Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for studies on fracture prevention in CKD and the efficacy and safety of denosumab. We included observational studies, randomized controlled trials (RCTs), meta-analyses, evidence-based reviews, and clinical practice guidelines. RESULTS: The diagnosis of osteoporosis and prevention of related fragility fractures is complex in CKD, particularly in those with advanced and end-staged kidney disease (ESKD). Prior to initiating denosumab, it is important to assess for and optimize CKD-mineral and bone disorders (CKD-MBD). In observational studies and small RCTs, denosumab has been shown to improve bone mineral density and reduce bone turnover in CKD, but there have been no studies focused upon its fracture efficacy. Denosumab-induced hypocalcemia has also been reported, which disproportionately impacts those with ESKD. Risk factors for hypocalcemia with denosumab use in CKD include lower baseline serum calcium and 25 hydroxyvitamin D and both low and high bone turnover. Choosing the "right patient" for denosumab, supplementing with calcium and vitamin D, adjusting calcium dialysate, and close clinical monitoring are essential if considering this drug. CONCLUSION: With optimization of CKD-MBD, calcium and vitamin D supplementation, and close monitoring, denosumab can be considered in CKD. There are however opportunities to better understand its fracture efficacy and safety in an RCT setting.

Starch or Saline After Cardiac Surgery: A Double-Blinded Randomized Controlled Trial.

BACKGROUND: Despite decades of investigation, the balance of clinical risks and benefits of fluid supplementation with starch remain unresolved. Patient-centered outcomes have not been well explored in a "real-world" trial in cardiac surgery. OBJECTIVE: We sought to compare a starch-based fluid strategy with a saline-based fluid strategy in the cardiac surgery patient. DESIGN: A pragmatic blinded randomized controlled trial comparing starch-based with saline-based fluid strategy. SETTING: A large tertiary academic center in London Ontario between September 2009 and February 2011. PARTICIPANTS: Patients undergoing planned, isolated coronary revascularization. MEASUREMENTS: Serum creatinine and patient weight were measured daily postoperatively. METHODS: Patients were randomized to receive 6% hydroxyethyl starch (Voluven) or saline for perioperative fluid requirements. Fluid administration was not protocolized. Co-primary outcomes were incidence of acute kidney injury (AKI) and maximum postoperative weight gain. Secondary outcomes included bleeding, transfusion, inotropic and ventilator support, and fluid utilization. RESULTS: The study was prematurely terminated due to resource limitations. A total of 69 patients (19% female, mean age = 65) were randomized. Using RIFLE criteria for AKI, "risk" occurred in 12 patients in each group (risk ratio [RR] = 1.0; 95% confidence interval [CI] = 0.5-1.9; P = 1.00), whereas "injury" occurred in 7 of 35 (20%) and 3 of 34 (9%) of patients in the starch and saline groups, respectively (RR = 2.3; 95% CI = 0.6-8.1; P = .31). Maximum weight gain, bleeding and blood product usage, and overall fluid requirement were similar between groups. LIMITATIONS: The study had to be prematurely terminated due to resource limitations which led to a small sample size which was not sufficiently powered to detect a difference in the primary outcomes. CONCLUSIONS: This pragmatic double-blinded randomized controlled trial revealed a number of interesting hypothesis-generating trends and confirmed the feasibility of undertaking a logistically complex trial in a pragmatic fashion.

CONTEXTE: L'équilibre entre les avantages et les risques cliniques d'une supplémentation en fluides à base d'amidon n'est toujours pas établi malgré des décennies d'études. Les résultats des patients subissant une chirurgie cardiaque n'ont pas été explorés suffisamment dans le cadre d'un essai concret. OBJECTIF: Comparer deux stratégies de supplémentation liquidienne, une solution à base d'amidon et une solution saline, chez des patients subissant une chirurgie cardiaque. TYPE D'ÉTUDE: Un essai pragmatique, contrôlé, à répartition aléatoire et mené en double insu comparant deux stratégies de supplémentation liquidienne une solution à base d'amidon et une solution saline. CADRE: Un grand centre universitaire de soins tertiaires de London (Ontario) entre septembre 2009 et février 2011. SUJETS: Des patients subissant une revascularisation coronarienne planifiée et isolée. MESURES: La créatinine sérique et le poids du patient ont été mesurés quotidiennement à la suite de l'intervention. MÉTHODOLOGIE: Les patients ont été répartis aléatoirement pour recevoir du Voluven (solution d'amidon hydroxyéthylé à 6 %) ou une solution saline pour les fluidiques périopératoires. L'administration ne s'est pas faite selon un protocole établi. L'incidence d'insuffisance rénale aiguë (IRA) et un gain pondéral maximal après l'intervention constituaient les deux principaux résultats mesurés. Les résultats secondaires incluaient une hémorragie, l'utilisation de transfusion sanguine, d'inotrope, d'assistance respiratoire et l'administration de fluides. RÉSULTATS: L'étude a été interrompue prématurément par manque de ressources. Les 69 patients (19 % de femmes) répartis aléatoirement avaient en moyenne 65 ans. La classification RIFLE avait permis de détecter un « risque ¼ d'IRA chez 12 patients dans chacun des groupes (RC: 1,0; IC 95 %: 0,5-1,9; p=1,00) et une « insuffisance ¼ chez 7 patients sur 35 (20 %) du groupe « amidon ¼ et 3 patients sur 34 (9 %) du groupe « saline ¼ (RC: 2,3; IC 95 %: 0,6-8,1; p=0,31). Le gain pondéral maximal, le nombre d'hémorragies, l'utilisation de produits sanguins et les besoins liquidiens étaient similaires dans les deux groupes. LIMITES: L'étude a été interrompue prématurément en raison d'un manque de ressources. Par conséquent, le faible échantillon de patients s'avère insuffisamment puissant pour détecter des différences significatives entre les deux groupes. CONCLUSIONS: Cette étude a mis en lumière quelques tendances permettant d'émettre des hypothèses intéressantes. L'étude a également confirmé la possibilité d'entreprendre un essai logistique complexe de manière pragmatique.

Advances in the management of hyperkalemia in chronic kidney disease.

PURPOSE OF REVIEW: Patients with chronic kidney disease (CKD) have an increased risk of hyperkalemia that increases both short-term and long-term mortality. Historically, managing hyperkalemia has relied upon dietary modifications, augmentation of urinary potassium excretion and enhanced enteral potassium elimination. This review discusses current treatments and their limitations and summarizes the evidence supporting novel agents for potassium lowering in patients with CKD. RECENT FINDINGS: The introduction of two novel ion exchange resins represents the first new pharmacologic therapies for hyperkalemia in the last 50 years. Patiromer, which was recently approved for use in the United States, has been shown to be well tolerated and effective for decreasing serum potassium in patients with CKD when taken for up to a year. Sodium zirconium cyclosilicate for which approval is pending has also shown promise in treating both acute and chronic hyperkalemia in patients with CKD. Both medications have been well tolerated with minimal adverse events in relatively short-term follow-up. SUMMARY: Novel ion exchange resins have the potential to provide new strategies for safely and effectively managing hyperkalemia in the CKD population. This may decrease morbidity and mortality associated with hyperkalemia and allow more broad use of medications whose use is otherwise limited by hyperkalemia.

Mortality and morbidity in African clawed frogs (Xenopus laevis) associated with construction noise and vibrations.

In Spring 2008, 175 adult female Xenopus laevis were exposed to construction-related vibrations that caused overt water rippling in the frog tanks. The 3 affected tanks were custom-built static, 300-gal 'pond-style' tanks that sat on the floor of the housing room. The water in the tank developed visible ripples as a result of the vibrations transmitted through the floor during jack-hammering in an adjacent room that was approximately 10 ftaway. All frogs in the tanks displayed buoyancy problems, excessive air gulping, and skin sloughing; ultimately 7 frogs died. In addition, these 7 animals were bloated, and 5 of these 7 had regurgitated and everted their stomach and distal esophagus into the oral cavity, resulting in airway obstruction and death. Gross pathologic findings included regurgitation and eversion of the stomach of the distal portion of the esophagus into the oral cavity, obstruction of the airway, and lung overinflation. No significant histologic lesions were observed. Construction vibrations transmitted through the water appeared to have disrupted the mechanoreceptive function of the lateral line system, resulting in overstimulation of the noxious feeding response, regurgitation, and eversion of the stomach and distal esophagus into the oral cavity and subsequent suffocation due to airway obstruction. After immediate cessation of the jack-hammering and relocation of the remaining frogs, no additional morbidities or mortalities occurred.