Kyla L. Naylor

The three-year incidence of fracture in chronic kidney disease

Knowing a persons fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2)), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials.

Fracture risk in kidney transplant recipients: a systematic review.

Background Fractures in men and women after kidney transplantation are associated with morbidity (including acute and chronic pain), mortality, and high economic costs. Methods We systematically reviewed cohort studies that provided estimates on incidence and risk factors for fracture in kidney transplant recipients. We abstracted data in duplicate and assessed the methodological quality of each study on a 17-point scale (17 representing the highest quality). Results We screened 2715 articles, reviewed 81, and included 10 studies totaling 262,678 recipients (study mean, 26,268 recipients; range, 61–77,430). The average follow-up ranged from 1.7 to 5.3 years. The study quality scores ranged from 8 to 13. Fracture sites varied by study resulting in a highly variable incidence rate ranging from 3.3 to 99.6 fractures per 1000 person-years. Similarly, the 5-year cumulative incidence for fracture varied ranging from 0.85% to 27%. Common factors associated with an increased fracture risk were older age, female sex, the presence of diabetes, and receipt of dialysis before transplantation. Other less common but statistically significant risk factors were a previous history of fracture and receipt of a kidney from a deceased (vs. living) donor. Conclusions There is poor consensus on the incidence and risk factors for fractures in kidney transplant recipients. Previous studies vary substantially in quality, fracture definitions, and the characteristics of recipients studied. Future research should clarify fracture incidence and risk, which will inform the design of future prevention trials and guide prognostication.

Fracture Risk in Living Kidney Donors: A Matched Cohort Study

BACKGROUND Chronic kidney disease increases the risk of bone fragility fractures (osteoporotic fractures). Living kidney donors lose 50% of their renal mass and show changes in calcium homeostasis. We studied whether living kidney donation increases the risk of fragility fracture. DESIGN Retrospective matched-cohort study. SETTING & PARTICIPANTS We reviewed the medical charts of all 2,015 adults in Ontario, Canada, who donated a kidney between 1992 and 2009 (surgeries performed across 5 transplant programs). We linked this information to health care databases and randomly selected 20,150 matched nondonors from the healthiest portion of the general population. Median age was 43 (95% CI, 24-50) years at study enrollment. Donors and nondonors were then followed up for a median of 6.6 years and a maximum of 17.7 years. PREDICTOR Living donor nephrectomy. OUTCOMES The primary outcome was lower- and upper-extremity fragility fractures. Individuals who reached 66 years or older in follow-up had bisphosphonate prescriptions recorded. RESULTS The rate of fragility fracture was no higher in donors compared with nondonors (16.4 vs 18.7 events/10,000 person-years; rate ratio, 0.88; 95% CI, 0.58-1.32). Results were similar in multiple additional analyses. There was little difference in the proportion of older adults in follow-up who received a bisphosphonate prescription (17.1% vs 15.2%; P = 0.4). LIMITATIONS These are interim results. Ongoing surveillance of this and other donor cohorts is warranted to be sure an association does not manifest with longer follow-up. CONCLUSIONS To date, there is no evidence of increased fragility fracture risk in living kidney donors. Our results meet an information need and are reassuring for the safety of the practice.

Comparison of Fracture Risk Prediction among Individuals with Reduced and Normal Kidney Function

BACKGROUND AND OBJECTIVES The Fracture Risk Assessment Tool (FRAX) is widely used to predict the 10-year probability of fracture; however, the clinical utility of FRAX in CKD is unknown. This study assessed the predictive ability of FRAX in individuals with reduced kidney function compared with individuals with normal kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The discrimination and calibration (defined as the agreement between observed and predicted values) of FRAX were examined using data from the Canadian Multicentre Osteoporosis Study (CaMos). This study included individuals aged ≥40 years with an eGFR value at year 10 of CaMos (defined as baseline). The cohort was stratified by kidney function at baseline (eGFR<60 ml/min per 1.73 m(2) [72.2% stage 3a, 23.8% stage 3b, and 4.0% stage 4/5] versus ≥60 ml/min per 1.73 m(2)) and followed individuals for a mean of 4.8 years for an incident major osteoporotic fracture (clinical spine, hip, forearm/wrist, or humerus). RESULTS There were 320 individuals with an eGFR<60 ml/min per 1.73 m(2) and 1787 with an eGFR≥60 ml/min per 1.73 m(2). The mean age was 67±10 years and 71% were women. The 5-year observed major osteoporotic fracture risk was 5.3% (95% confidence interval [95% CI], 3.3% to 8.6%) in individuals with an eGFR<60 ml/min per 1.73 m(2), which was comparable to the FRAX-predicted fracture risk (6.4% with bone mineral density; 8.2% without bone mineral density). A statistically significant difference was not observed in the area under the curve values for FRAX in individuals with an eGFR<60 ml/min per 1.73 m(2) versus ≥60 ml/min per 1.73 m(2) (0.69 [95% CI, 0.54 to 0.83] versus 0.76 [95% CI, 0.70 to 0.82]; P=0.38). CONCLUSIONS This study showed that FRAX was able to predict major osteoporotic fractures in individuals with reduced kidney function; further study is needed before FRAX should be routinely used in individuals with reduced kidney function.

FRAX predicts fracture risk in kidney transplant recipients.

Background The World Health Organization Fracture Risk Assessment Tool (FRAX) estimates the 10-year fracture probability. We assessed the prognostic value of FRAX in kidney transplant recipients, as its utility in recipients is unknown. Methods We considered 458 individuals (mean age 45 years, 64% men) who received a kidney transplant in the province of Manitoba, Canada at the time of their first bone mineral density (BMD) test posttransplant (mean 1.1 years posttransplant; transplant years 1996–2011). FRAX probabilities were calculated from baseline information (age, sex, clinical risk factors, with or without BMD). Recipients were followed a mean of 6.4 years (interquartile range 3.0–10.0 years) after cohort entry for an incident major osteoporotic fracture. Results In follow-up, 21 (4.6%) recipients experienced a major osteoporotic fracture. The observed 10-year major osteoporotic fracture risk of 6.3% (95% CI, 3.4–9.2%) was concordant with FRAX predictions (5.0% with BMD, 5.6% without BMD). Major osteoporotic fracture scores showed significant fracture prediction (hazard ratio per standard deviation, FRAX without BMD 1.66, 95% CI, 1.10–2.50; FRAX with BMD 1.64, 95% CI, 1.07–2.51). Area under the curve (AUC) for incident major osteoporotic fracture discrimination (AUC: FRAX with BMD 0.62, 95% CI, 0.50–0.74) was similar to the general population. Conclusions FRAX scores categorized most kidney transplant recipients as a low-risk fracture group, and the low observed fracture rates were consistent with the 10-year fracture predictions. FRAX showed modest fracture prediction and discrimination similar to the general population. Independent validation is needed before clinicians can routinely use FRAX in kidney transplant recipients.

Falls and Fractures With Atypical Antipsychotic Medication Use: A Population-Based Cohort Study

Discussion | In this study of health care utilization data, use of amiodarone but not of other antiarrhythmic drugs was associated with a 50% increased odds of acute pancreatitis among patients with NVAF. The odds were almost doubled in the 12 months after amiodarone therapy initiation and did not depend on cumulative use of amiodarone. Considering an incidence of acute pancreatitis of 3 to 4 cases per 10 000 adults per year,4 the observed association would result in approximately 1 to 2 additional cases of acute pancreatitis per 10 000 amiodarone users per year. A few isolated case reports of acute pancreatitis possibly linked to amiodarone use have been described in the literature.1-3 The mechanisms responsible for this association are unknown, although direct cytotoxicity or immune-mediated pathways, as described for amiodarone-related pulmonary toxic effects, could be potential explanations.5 Strengths of our study include the prospective assessment of medication use, the large sample size, and the availability of information on comorbidities and use of other medications potentially associated with increased risk of acute pancreatitis. Limitations are related to the use of health care utilization data: limited information on the validity of claims for acute pancreatitis, absence of clinical variables that characterize severity of the episode (eg, blood markers of acute pancreatitis), and the select group of patients included in this database. Our results indicate that acute pancreatitis could be an adverse effect of amiodarone use, an effect that may not be shared by other antiarrhythmic drugs. Even though the absolute risk of acute pancreatitis in the general population is low, health care professionals should be aware of this potential association in the treatment of patients with NVAF or acute pancreatitis. Further research should replicate our findings and determine potential mechanisms.

Trabecular Bone Score and Incident Fragility Fracture Risk in Adults with Reduced Kidney Function

BACKGROUND AND OBJECTIVES Trabecular bone score is a gray-level textural measure obtained from dual energy x-ray absorptiometry lumbar spine images that provides information independent of areal bone mineral density. The association between trabecular bone score and incident fractures in adults with reduced kidney function and whether this association differs from that of adults with normal kidney function are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We included 1426 participants ages ≥40 years old (mean age of 67 years) in the community-based Canadian Multicentre Osteoporosis Study. We stratified participants at cohort entry (2005-2008) by eGFR (eGFR<60 ml/min per 1.73 m2 [n=199; 72.4% stage 3a, 25.1% stage 3b, and 2.5% stage 4] versus ≥60 ml/min per 1.73 m2 [n=1227]). Trabecular bone score was obtained from lumbar spine (L1-L4) dual energy x-ray absorptiometry images, with a lower trabecular bone score representing worse bone structure. Over an average of 4.7 years follow-up (maximum follow-up of 5 years), we documented incident fragility (low-trauma) fracture events (excluding craniofacial, foot, and hand sites). We used a modified Kaplan-Meier estimator to determine the 5-year probability of fracture. Cox proportional hazard regression per SD lower trabecular bone score expressed the gradient of fracture risk. RESULTS Individuals with an eGFR<60 ml/min per 1.73 m2 who had a trabecular bone score value below the median (<1.277) had a significantly higher 5-year fracture probability than those above the median (18.1% versus 6.2%; P=0.01). The association between trabecular bone score and fracture was independent of bone mineral density and other clinical risk factors in adults with reduced and normal kidney function (adjusted hazard ratio per SD lower trabecular bone score: eGFR<60 ml/min per 1.73 m2: adjusted hazard ratio, 1.62; 95% confidence interval, 1.04 to 2.51; eGFR≥60 ml/min per 1.73 m2: adjusted hazard ratio, 1.44; 95% confidence interval, 1.13 to 1.83). CONCLUSIONS Lower lumbar spine trabecular bone score is independently associated with a higher fracture risk in adults with reduced kidney function. Additional study is needed to examine the association between trabecular bone score and fractures in individuals with diagnosed CKD-mineral and bone disorder.

The Risk of Cardiovascular Disease Is Not Increasing Over Time Despite Aging and Higher Comorbidity Burden of Kidney Transplant Recipients

Background Cardiovascular death remains the leading cause of mortality in kidney transplant recipients. Cardiovascular events are associated with significant morbidity. However, current trends in cardiovascular events after kidney transplantation are poorly understood. Methods We conducted a retrospective study using healthcare databases in Ontario, Canada, to determine whether the incidence of cardiovascular events after kidney transplantation has changed from 1994 to 2009. Our primary endpoint was a 3-year composite outcome of posttransplant death or major cardiovascular event (myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, stroke). Results Recipients (n = 4954) were older and had more baseline comorbidity in recent years. A total of 445 recipients (9.0%) died or experienced a major cardiovascular event within 3 years of transplantation. There was no significant change in the incidence of the composite outcome or death-censored cardiovascular events over time (P = 0.41 and 0.92, respectively). After adjusting for age, sex, and comorbidities, the risk of death or major cardiovascular event steadily declined across the years of transplant (2006-2009 adjusted hazard ratio, 0.70; P = 0.009; referent 1994-1997). When recipients were matched on age, sex, and date of cohort entry to members of the general population and to the chronic kidney disease population, the risk was lowest in the general population and highest in the chronic kidney disease population. Conclusion Despite transplant centers accepting recipients who are older with more comorbidities in recent years, the 3-year cumulative incidence of death or major cardiovascular event has remained stable over time.

Fracture incidence in adult kidney transplant recipients

Background It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. Methods We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). Results Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). Conclusions Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.

Long-term changes in bone mineral density in kidney transplant recipients.

Background Alterations in bone mineral metabolism occur when kidney function declines and often continue after transplantation. We investigated long-term changes in bone mineral density (BMD) among kidney transplant recipients undergoing routine clinical BMD monitoring and management. Methods We identified adults receiving a kidney transplant in the province of Manitoba, Canada (1996–2011) who had greater than or equal to 2 posttransplant dual energy X-ray absorptiometry examinations. Bone mineral density was expressed as Z scores (standard deviation above/below sex-matched and age-matched reference data). The main outcome was the change in BMD. Results A total of 326 kidney transplant recipients were included (mean age, 45 years; 61% men). Recipients were followed up for an average of 8.2 years (766 follow-up dual energy X-ray absorptiometry measurements). At baseline (first scan; median, 0.5 years after transplantation), bone density was slightly below average for age and sex (mean Z scores: lumbar spine, −0.4±1.6; femoral neck, −0.7±1.1; total hip, −0.7±1.1). At the second scan (mean, 2.7 years after first scan), mean bone density Z scores have increased (lumbar spine, −0.2±1.6; femoral neck, −0.6±1; total hip, −0.6±1.1; matched, P<0.01 at all sites). The only factor associated with a significant BMD change at all sites was osteoporosis treatment (BMD increase). Even after restricting the analysis to recipients who had not received osteoporosis treatment, final mean bone density (mean, 8.2 years after first scan) was average for age and sex (lumbar spine, +0.7±1.6; femoral neck, −0.1±1.1; total hip, 0.0±1.1). Conclusion With routine BMD monitoring and management, posttransplant bone density typically remains stable or improves with mean values that are average for age and sex.