Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study.

BACKGROUND: Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus and is often used for other inflammatory conditions, but a critical long-term adverse effect is vision-threatening retinopathy. OBJECTIVE: To characterize the long-term risk for incident hydroxychloroquine retinopathy and examine the degree to which average hydroxychloroquine dose within the first 5 years of treatment predicts this risk. DESIGN: Cohort study. SETTING: U.S. integrated health network. PARTICIPANTS: All patients aged 18 years or older who received hydroxychloroquine for 5 or more years between 2004 and 2020 and had guideline-recommended serial retinopathy screening. MEASUREMENTS: Hydroxychloroquine dose was assessed from pharmacy dispensing records. Incident hydroxychloroquine retinopathy was assessed by central adjudication of spectral domain optical coherence tomography with severity assessment (mild, moderate, or severe). Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to hydroxychloroquine weight-based dose (>6, 5 to 6, or ≤5 mg/kg per day) using the Kaplan-Meier estimator. RESULTS: Among 3325 patients in the primary study population, 81 developed hydroxychloroquine retinopathy (56 mild, 17 moderate, and 8 severe), with overall cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively. The cumulative incidences of retinopathy at 15 years were 21.6% for higher than 6 mg/kg per day, 11.4% for 5 to 6 mg/kg per day, and 2.7% for 5 mg/kg per day or lower. The corresponding risks for moderate to severe retinopathy at 15 years were 5.9%, 2.4%, and 1.1%, respectively. LIMITATION: Possible misclassifications of dose due to nonadherence to filled prescriptions. CONCLUSION: In this large, contemporary cohort with active surveillance retinopathy screening, the overall risk for hydroxychloroquine retinopathy was 8.6% after 15 years, and most cases were mild. Higher hydroxychloroquine dose was associated with progressively greater risk for incident retinopathy. PRIMARY FUNDING SOURCE: National Institutes of Health.

Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease : A Population-Based Cohort Study.

BACKGROUND: Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown. OBJECTIVE: To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD. DESIGN: Cohort study. SETTING: The Health Improvement Network U.K. primary care database (2000 to 2019). PARTICIPANTS: Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD. MEASUREMENTS: The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators. RESULTS: Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07). LIMITATION: Residual confounding cannot be ruled out. CONCLUSION: In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD. PRIMARY FUNDING SOURCE: Project Program of National Clinical Research Center for Geriatric Disorders.

A Comparison of US Medicare Expenditures for Hemodialysis and Peritoneal Dialysis.

BACKGROUND: Observations that peritoneal dialysis (PD) may be an effective, lower-cost alternative to hemodialysis for the treatment of ESKD have led to policies encouraging PD and subsequent increases in its use in the United States. METHODS: In a retrospective cohort analysis of Medicare beneficiaries who started dialysis between 2008 and 2015, we ascertained average annual expenditures (for up to 3 years after initiation of dialysis) for patients ≥67 years receiving in-center hemodialysis or PD. We also determined whether differences in Medicare expenditures across dialysis modalities persisted as more patients were placed on PD. We used propensity scores to match 8305 patients initiating PD with 8305 similar patients initiating hemodialysis. RESULTS: Overall average expenditures were US$108,656 (2017) for hemodialysis and US$91,716 for PD (proportionate difference, 1.11; 95% confidence interval [CI], 1.09 to 1.13). This difference did not change over time (P for time interaction term=0.14). Hemodialysis had higher estimated intravenous (iv) dialysis drug costs (1.69; 95% CI, 1.64 to 1.73), rehabilitation expenditures (1.35; 95% CI, 1.26 to 1.45), and other nondialysis expenditures (1.34; 95% CI, 1.30 to 1.37). Over time, initial differences in total dialysis expenditures disappeared and differences in iv dialysis drug utilization narrowed as nondialysis expenditures diverged. Estimated iv drug costs declined by US$2900 per patient-year in hemodialysis between 2008 and 2014 versus US$900 per patient-year in PD. CONCLUSIONS: From the perspective of the Medicare program, savings associated with PD in patients ≥67 years have remained unchanged, despite rapid growth in the use of this dialysis modality. Total dialysis expenditures for the two modalities converged over time, whereas nondialysis expenditures diverged.

Patient Health Outcomes following Dialysis Facility Closures in the United States.

BACKGROUND: Ongoing changes to reimbursement of United States dialysis care may increase the risk of dialysis facility closures. Closures may be particularly detrimental to the health of patients receiving dialysis, who are medically complex and clinically tenuous. METHODS: We used two separate analytic strategies-one using facility-based matching and the other using propensity score matching-to compare health outcomes of patients receiving in-center hemodialysis at United States facilities that closed with outcomes of similar patients who were unaffected. We used negative binomial and Cox regression models to estimate associations of facility closure with hospitalization and mortality in the subsequent 180 days. RESULTS: We identified 8386 patients affected by 521 facility closures from January 2001 through April 2014. In the facility-matched model, closures were associated with 9% higher rates of hospitalization (relative rate ratio [RR], 1.09; 95% confidence interval [95% CI], 1.03 to 1.16), yielding an absolute annual rate difference of 1.69 hospital days per patient-year (95% CI, 0.45 to 2.93). Similarly, in a propensity-matched model, closures were associated with 7% higher rates of hospitalization (RR, 1.07; 95% CI, 1.00 to 1.13; P=0.04), yielding an absolute rate difference of 1.08 hospital days per year (95% CI, 0.04 to 2.12). Closures were associated with nonsignificant increases in mortality (hazard ratio [HR], 1.08; 95% CI, 1.00 to 1.18; P=0.05 for the facility-matched comparison; HR, 1.08; 95% CI, 0.99 to 1.17; P=0.08 for the propensity-matched comparison). CONCLUSIONS: Patients affected by dialysis facility closures experienced increased rates of hospitalization in the subsequent 180 days and may be at increased risk of death. This highlights the need for effective policies that continue to mitigate risk of facility closures.

Estimation of total mediation effect for high-dimensional omics mediators.

BACKGROUND: Environmental exposures can regulate intermediate molecular phenotypes, such as gene expression, by different mechanisms and thereby lead to various health outcomes. It is of significant scientific interest to unravel the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposure and traits. Mediation analysis is an important tool for investigating such relationships. However, it has mainly focused on low-dimensional settings, and there is a lack of a good measure of the total mediation effect. Here, we extend an R-squared (R[Formula: see text]) effect size measure, originally proposed in the single-mediator setting, to the moderate- and high-dimensional mediator settings in the mixed model framework. RESULTS: Based on extensive simulations, we compare our measure and estimation procedure with several frequently used mediation measures, including product, proportion, and ratio measures. Our R[Formula: see text]-based second-moment measure has small bias and variance under the correctly specified model. To mitigate potential bias induced by non-mediators, we examine two variable selection procedures, i.e., iterative sure independence screening and false discovery rate control, to exclude the non-mediators. We establish the consistency of the proposed estimation procedures and introduce a resampling-based confidence interval. By applying the proposed estimation procedure, we found that 38% of the age-related variations in systolic blood pressure can be explained by gene expression profiles in the Framingham Heart Study of 1711 individuals. An R package "RsqMed" is available on CRAN. CONCLUSION: R-squared (R[Formula: see text]) is an effective and efficient measure for total mediation effect especially under high-dimensional setting.

Mortality, Kidney Failure, and Hospitalization Among Medicare Beneficiaries With CKD and Pulmonary Hypertension.

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) is highly prevalent among patients with chronic kidney disease (CKD) not requiring kidney replacement therapy. We studied the associations of PH with mortality, kidney failure, as well as cardiovascular (CV) and non-CV hospitalization among Medicare beneficiaries with a CKD diagnosis. STUDY DESIGN: Retrospective, observational study using a matched cohort design. SETTING & PARTICIPANTS: Patients with PH (based on 2 claims within 2 years) and patients without PH matched on CKD stage from the Medicare 5% CKD sample (1996-2016). PREDICTOR: Presence of pulmonary hypertension. OUTCOME: Mortality, kidney failure, and all-cause, CV, and non-CV hospitalization. ANALYTICAL APPROACH: Cox proportional hazards models to assess the association between PH and mortality, adjusting for age, sex, race, and comorbidities. Death was considered as a competing event in Fine-Gray models to assess the association between PH and kidney failure. Negative binomial model was used to evaluate the relationship between PH and all-cause, CV, and non-CV hospitalizations. RESULTS: 30,052 patients with PH and CKD and 150,260 CKD stage-matched patients without diagnosed PH were studied. The median age of the study population was 80.7 years, 57.8% were women, and 10.3% were African Americans. The presence of PH was associated with an increased risk of mortality after 1 (HR, 2.87 [95% CI, 2.79-2.95]), 2-3 (HR, 1.56 [95% CI, 1.51-1.61]), and 4-5 (HR, 1.47 [95% CI, 1.40-1.53]) years of follow-up, and a higher risk of all-cause, CV, and non-CV hospitalization during the same period. PH was also associated with kidney failure in after 1 and 2-3 years but not after 4-5 years of follow-up evaluation. Patients with PH also experienced higher rates of acute kidney injury (AKI), and AKI requiring dialysis support within 30 and 90 days of AKI. LIMITATIONS: Reliance on billing codes and lack of echocardiogram or right heart catheterization data CONCLUSIONS: Among older Medicare beneficiaries with a CKD diagnosis not requiring kidney replacement therapy, the presence of PH was associated with an increased risk of mortality, kidney failure, and hospitalization. Understanding of the mechanism of these associations, especially the increased risk of kidney failure, requires further study.

Hip Fracture Risk among Hemodialysis-Dependent Patients Prescribed Opioids and Gabapentinoids.

BACKGROUND: Despite opioids' known association with hip fracture risk in the general population, they are commonly prescribed to patients with ESKD. Whether use of opioids or gabapentinoids (also used to treat pain in patients with ESKD) contributes to hip fracture risk in patients with ESKD on hemodialysis remains unknown. METHODS: In a case-control study nested within the US Renal Data System, we identified all hip fracture events recorded among patients dependent on hemodialysis from January 2009 through September 2015. Eligible cases were risk-set matched on index date with ten eligible controls. We required >1 year of Medicare Parts A and B coverage and >3 years of part D coverage to study cumulative longer-term exposure. To examine new, short-term exposure, we selected individuals with >18 months of Part D coverage and no prior opioid or gabapentinoid use between 18 and 7 months before index. We used conditional logistic regression to estimate unadjusted and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (95% CI). RESULTS: For the longer-term analyses, we identified 4912 first-time hip fracture cases and 49,120 controls. Opioid use was associated with increased hip fracture risk (adjusted OR, 1.39; 95% CI, 1.26 to 1.53). Subgroups of low, moderate, and high use yielded adjusted ORs of 1.33 (95% CI, 1.20 to 1.47), 1.53 (95% CI, 1.36 to 1.72), and 1.66 (95% CI, 1.45 to 1.90), respectively. The association with hip fractures was also elevated with new, short-term use (adjusted OR, 1.38; 95% CI, 1.25 to 1.52). There were no associations between gabapentinoid use and hip fracture. CONCLUSIONS: Among patients dependent on hemodialysis in the United States, both short-term and longer-term use of opioid analgesics were associated with hip fracture events.

Selective Serotonin Reuptake Inhibitor Use and Hip Fracture Risk Among Patients on Hemodialysis.

RATIONALE & OBJECTIVE: Use of selective serotonin reuptake inhibitors (SSRIs) has been associated with hip fracture risk in the general population. This study examined this relationship among patients with kidney failure treated by hemodialysis, a unique high-risk subpopulation, within which the impact of SSRIs on hip fracture risk remains unexplored. STUDY DESIGN: Case-control study. SETTINGS & PARTICIPANTS: Eligible cases of hip fracture among maintenance hemodialysis patients between January 1, 2009, and September 30, 2015, were identified using the US Renal Data System. Each case was matched on index date with 10 eligible controls. To be eligible, study participants needed to have more than 1 year of Medicare Parts A and B coverage and more than 3 years of Part D coverage. For a separate examination of new short-term SSRI exposure, we selected cases and controls with more than 18 months of Part D coverage and no prior antidepressant use for 1 year. EXPOSURE: During the 3-year Part D coverage period, use of SSRIs characterized as any (≥1 prescription filled), low, moderate, and high use (<20%, 20%-<80%, and≥80% of days covered by filled prescriptions, respectively). OUTCOME: We selected cases using International Classification of Diseases, Ninth Revision codes 820.xx and 821.xx. In addition to 1 of these codes tied to a hospitalization, we required a corresponding surgical procedural code within 7 days of diagnosis. ANALYTIC APPROACH: Conditional logistic regression to estimate unadjusted and multivariable-adjusted ORs and 95% CIs. RESULTS: We identified 4,912 cases and 49,120 controls. SSRI use was associated with increased hip fracture risk (adjusted OR, 1.25; 95% CI, 1.17-1.35). Risk for fracture was estimated for any, low, moderate, and high SSRI use: adjusted conditional ORs were 1.25 (95% CI, 1.17-1.35), 1.20 (95% CI, 1.08-1.32), 1.31 (95% CI, 1.18-1.43), and 1.26 (95% CI, 1.12-1.41), respectively. The association between hip fracture events and SSRI use was also seen in the examination of new short-term use (adjusted OR, 1.43; 95% CI, 1.23-1.67). LIMITATIONS: Biomarkers of mineral bone disorder were not captured and accounted for in this analysis. CONCLUSIONS: We demonstrated an association between increased hip fracture risk and both long- and new short-term SSRI use. The stronger association with new short-term use may suggest an acute mechanism potentially related to falls.

Readmissions after Acute Kidney Injury during Left Ventricular Assist Device Implantation Hospitalization.

BACKGROUND: Acute kidney injury (AKI) frequently complicates hospitalizations for left ventricular assist device (LVAD) implantation. Little is known about the relationship of AKI with subsequent readmissions, and we investigated the relationship of AKI during LVAD implantation hospitalization with all-cause and cause-specific 30-day readmissions. METHODS: We used a United States (US) nationwide all-payer administrative database, identifying patients who underwent implantable LVAD placement 2010-2015. Patients were classified into 3 mutually exclusive groups based on presence and severity of AKI during the LVAD placement hospitalization: no AKI, AKI, and AKI requiring dialysis (AKI-D). Outcomes were all-cause and cause-specific 30-day readmissions. RESULTS: Within 30 days after discharge 25.4% of patients were readmitted. Of those without AKI, 23.9% were readmitted, compared to 25.5% of those with AKI and 42.2% of those with AKI-D. Compared to no AKI (adjusted for demographics, index hospitalization and chronic comorbidity factors, and year), odds of 30-day readmission were 2.18 (95% CI 1.37-3.49) times higher for those with AKI-D, whereas those with AKI not requiring dialysis had similar 30-day readmission risk (OR 1.03 [95% CI 0.89-1.20]). Those with AKI-D had higher risk of 30-day readmission for infection (OR 2.02 [95% CI 1.13-3.61]), gastrointestinal (GI) bleed (2.32 [95% CI 1.24-4.34]), and kidney disease (13.9 [95% CI 4.0-48]). There was no increased risk for stroke readmission with AKI or AKI-D. CONCLUSION: AKI-D was associated with highest -30-day readmission risk, possibly related to negatively synergistic effects of LVAD, kidney dysfunction, and dialysis related factors on infection and GI bleeding risks. AKI alone was not associated with increased readmission risk.

Patterns of Change Over Time in Knee Bone Shape Are Associated with Sex.

BACKGROUND: Knee osteoarthritis (OA) is more common in females than in males; however, the biological mechanisms for the difference in sex in patients with knee OA are not well understood. Knee shape is associated with OA and with sex, but the patterns of change in the bone's shape over time and their relation to sex and OA are unknown and may help inform how sex is associated with shape and OA and whether the effect is exerted early or later in life.Questions/purposes (1) Does knee shape segregate stably into different groups of trajectories of change (groups of knees that share similar patterns of changes in bone shape over time)? (2) Do females and males have different trajectories of bone shape changes? (3) Is radiographic OA at baseline associated with trajectories of bone shape changes? METHODS: We used data collected from the NIH-funded Osteoarthritis Initiative (OAI) to evaluate a cohort of people aged 45 to 79 years at baseline who had either symptomatic knee OA or were at high risk of having it. The OAI cohort included 4796 participants (58% females; n = 2804) at baseline who either had symptomatic knee OA (defined as having radiographic tibiofemoral knee OA and answering positively to the question "have you had pain, aching or stiffness around the knee on most days for at least one month during the past 12 months") or were at high risk of symptomatic knee OA (defined as having knee symptoms during the prior 12 months along with any of the following: overweight; knee injury; knee surgery other than replacement; family history of total knee replacement for OA; presence of Heberden's nodes; daily knee bending activity) or were part of a small nonexposed subcohort. From these participants, we limited the eligible group to those with radiographs available and read at baseline, 2 years, and 4 years, and randomly selected participants from each OAI subcohort in a manner to enrich representation in the study of the progression and nonexposed subcohorts, which were smaller in number than the OA incidence subcohort. From these patients, we randomly sampled 473 knees with radiographs available at baseline, 2 years, and 4 years. We outlined the shape of the distal femur and proximal tibia on radiographs at all three timepoints using statistical shape modelling. Five modes (each mode represents a particular type of knee bone shape variation) were derived for the proximal tibia and distal femur's shape, accounting for 78% of the total variance in shape. Group-based trajectory modelling (a statistical approach to identify the clusters of participants following a similar progression of change of bone shape over time, that is, trajectory group) was used to identify distinctive patterns of change in the bone shape for each mode. We examined the association of sex and radiographic OA at baseline with the trajectories of each bone shape mode using a multivariable polytomous regression model while adjusting for age, BMI, and race. RESULTS: Knee bone shape change trajectories segregated stably into different groups. In all modes, three distinct trajectory groups were derived, with the mean posterior probabilities (a measure of an individual's probability of being in a particular group and often used to characterize how well the trajectory model is working to describe the population) ranging from 84% to 99%, indicating excellent model fitting. For most of the modes of both the femur and tibia, the intercepts for the three trajectory groups were different; however, the rates of change were generally similar in each mode. Females and males had different trajectories of bone shape change. For Mode 1 in the femur, females were more likely to be in trajectory Groups 3 (odds ratio 30.2 [95% CI 12.2 to 75.0]; p < 0.001) and 2 than males (OR 4.1 [95% CI 2.3 to 7.1]; p < 0.001); thus, females had increased depth of the intercondylar fossa and broader shaft width relative to epicondylar width compared with males. For Mode 1 in the tibia, females were less likely to be in trajectory Group 2 (OR 0.5 [95% CI 0.3 to 0.9]; p = 0.01) than males (that is, knees of females were less likely to display superior elevation of tibial plateau or decreased shaft width relative to head width). Radiographic OA at baseline was associated with specific shape-change trajectory groups. For Mode 1 in the femur, knees with OA were less likely to be in trajectory Groups 3 (OR 0.4 [95% CI 0.2 to 0.8]; p = 0.008) and 2 (OR 0.6 [95% CI 0.3 to 1.0]; p = 0.03) than knees without OA; thus, knees with OA had decreased depth of the intercondylar fossa and narrower shaft width relative to epicondylar width compared with knees without OA. For Mode 1 in the tibia, knees with OA were not associated with trajectory. CONCLUSIONS: The shapes of the distal femur and proximal tibia did not change much over time. Sex and baseline knee radiographic OA status are associated with the trajectory of change in the bone's shape, suggesting that both may contribute earlier in life to the associations among trajectories observed in older individuals. Future studies might explore sex-related bone shape change earlier in life to help determine when the sex-specific shapes arise and also the degree to which these sex-related shapes are alterable by injury or other events. LEVEL OF EVIDENCE: Level III, prognostic study.

Dialysis Catheter-related Bloodstream Infections in Patients Receiving Hemodialysis on an Emergency-only Basis: A Retrospective Cohort Analysis.

BACKGROUND: An estimated 6500 undocumented immigrants with end-stage renal disease (ESRD) live in the United States. Those living in states that do not provide undocumented immigrants scheduled hemodialysis receive intermittent hemodialysis only when life-threatening conditions arise. Little is known about catheter-related bloodstream infections (CRBSIs) in this population. METHODS: We conducted a retrospective cohort study of emergency-only hemodialysis patients in the Harris Health System in Houston, Texas, between January 2012 and December 2015. We assessed CRBSI risk factors including demographics, comorbidities, and duration and frequency of hemodialysis. We investigated the microbiologic etiology of these infections, rates of recurrent CRBSI, and associated morbidity and mortality. RESULTS: The cohort included 329 patients; 90% were Hispanic, 60% had diabetes, and the average age was 51 years. A total of 101 CRBSIs occurred, with a rate of 0.84 infections per 1000 catheter-days. Cirrhosis and duration of hemodialysis during the study period were associated with increased risk of CRBSI. Seventeen CRBSIs were recurrent; infection with gram-positive bacteria predicted recurrence. Adherence to catheter-related infection guidelines was improved by infectious diseases consultation and associated with fewer recurrent infections. CRBSI was associated with prolonged hospitalization (mean, 15 days), composite complication rate of 8%, and a 4% mortality rate. CONCLUSIONS: Patients receiving emergency-only hemodialysis via tunneled catheters have a high CRBSI rate compared with infection rates previously reported in patients receiving scheduled maintenance hemodialysis. Increased CRSBI risk likely contributes to the increased morbidity and mortality seen in ESRD patients receiving emergency-only hemodialysis.

Dialysis Modality and Incident Atrial Fibrillation in Older Patients With ESRD.

RATIONALE & OBJECTIVE: Atrial fibrillation (AF) is common in patients with kidney failure treated by maintenance dialysis. Whether the incidence of AF differs between patients receiving hemodialysis and peritoneal dialysis is uncertain. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Using the US Renal Data System, we identified older patients (≥67 years) with Medicare Parts A and B who initiated dialysis therapy (1996-2011) without a diagnosis of AF during the prior 2 years. EXPOSURE: Dialysis modality at incident end-stage renal disease (ESRD) and maintained for at least 90 days. OUTCOME: Patients were followed up for 36 months or less for a new diagnosis of AF. ANALYTICAL APPROACH: Time-to-event analysis using multivariable Cox proportional hazards regression to estimate cause-specific HRs while censoring at modality switch, kidney transplantation, or death. RESULTS: Overall, 271,722 older patients were eligible; 17,487 (6.9%) were treated with peritoneal dialysis, and 254,235 (93.1%), with hemodialysis, at the onset of ESRD. During 406,225 person-years of follow-up, 69,705 patients had AF newly diagnosed. Because the proportionality assumption was violated, we introduced an interaction term between time (first 90 days vs thereafter) and modality. The AF incidence during the first 90 days was 187/1,000 person-years on peritoneal dialysis therapy and 372/1,000 person-years on hemodialysis therapy. Patients on peritoneal dialysis therapy had an adjusted 39% (95% CI, 34%-43%) lower incidence of AF than those on hemodialysis therapy. From day 91 onward, AF incidence was ∼140/1,000 person-years with no major difference between modalities. LIMITATIONS: Residual confounding from unobserved differences between exposure groups; ascertainment of AF from billing claims; study of first modality may not generalize to patients switching modalities; uncertain generalizability to younger patients. CONCLUSIONS: Although patients initiating dialysis therapy using peritoneal dialysis had a lower AF incidence during the first 90 days of ESRD, there was no major difference in AF incidence thereafter. The value of interventions to reduce the early excess AF risk in patients receiving hemodialysis may warrant further study.

Acute Kidney Injury With Ventricular Assist Device Placement: National Estimates of Trends and Outcomes.

RATIONALE & OBJECTIVE: Ventricular assist devices (VADs) are used for end-stage heart failure not amenable to medical therapy. Acute kidney injury (AKI) in this setting is common due to heart failure decompensation, surgical stress, and other factors. Little is known about national trends in AKI diagnosis and AKI requiring dialysis (AKI-D) and associated outcomes with VAD implantation. We investigated national estimates and trends for diagnosed AKI, AKI-D, and associated patient and resource utilization outcomes in hospitalizations in which implantable VADs were placed. STUDY DESIGN: Cohort study of 20% stratified sample of US hospitalizations. SETTING & PARTICIPANTS: Patients who underwent implantable VAD placement in 2006 to 2015. EXPOSURE: No AKI diagnosis, AKI without dialysis, AKI-D. OUTCOMES: In-hospital mortality, length of stay, estimated hospitalization costs. ANALYTICAL APPROACH: Multivariate logistic and linear regression using survey design methods to account for stratification, clustering, and weighting. RESULTS: An estimated 24,140 implantable VADs were placed, increasing from 853 in 2006 to 3,945 in 2015. AKI was diagnosed in 56.1% of hospitalizations and AKI-D occurred in 6.5%. AKI diagnosis increased from 44.0% in 2006 to 2007 to 61.7% in 2014 to 2015; AKI-D declined from 9.3% in 2006 to 2007 to 5.2% in 2014 to 2015. Mortality declined in all AKI categories but this varied by category: those with AKI-D had the smallest decline. Adjusted hospitalization costs were 19.1% higher in those with diagnosed AKI and 39.6% higher in those with AKI-D, compared to no AKI. LIMITATIONS: Administrative data; timing of AKI with respect to VAD implantation cannot be determined; limited pre-existing chronic kidney disease ascertainment; discharge weights not derived for subpopulation of interest. CONCLUSIONS: A decreasing proportion of patients undergoing VAD implantation experience AKI-D, but mortality among these patients remains high. AKI diagnosis with VAD implantation is increasing, possibly reflecting changes in AKI surveillance, awareness, and coding.

Meniscal body extrusion and cartilage coverage in middle-aged and elderly without radiographic knee osteoarthritis.

OBJECTIVES: To determine meniscal extrusion and cartilage coverage on magnetic resonance (MR) images and factors associated with these parameters in knees of middle-aged and elderly persons free from radiographic tibiofemoral osteoarthritis (OA). METHODS: Seven hundred eighteen persons, free of radiographic tibiofemoral OA, aged 50-90 years from Framingham, MA, USA, were included. We measured meniscal extrusion on 1.5 T MRI of both knees to evaluate both medial and lateral meniscal body extrusion and cartilage coverage. We also determined meniscal morphology and structural integrity. The multivariable association with age, body mass index (BMI), and ipsilateral meniscal damage was also evaluated. RESULTS: The mean meniscal body extrusion medially was 2.7 mm and laterally 1.8 mm. The tibial cartilage coverage was about 30% of ipsilateral cartilage surface (both compartments). The presence of ipsilateral meniscal damage was associated with more extrusion in only the medial compartment, 1.0 mm in men and 0.6 mm in women, and less cartilage coverage proportion, -5.5% in men and -4.6% in women. CONCLUSIONS: Mean medial meniscal body extrusion in middle-aged or older persons without radiographic tibiofemoral OA approximates the commonly used cutoff (3 mm) to denote pathological extrusion. Medial meniscal damage is a factor associated with medial meniscal body extrusion and less cartilage coverage. KEY POINTS: • Medial meniscal extrusion in middle-aged/older persons without OA is around 3 mm. • Lateral meniscal extrusion in middle-aged/older persons without OA is around 2 mm. • Meniscal damage is associated with medial meniscal extrusion and less cartilage coverage.

Smoking paradox in the development of psoriatic arthritis among patients with psoriasis: a population-based study.

OBJECTIVES: Smoking is associated with an increased risk of psoriatic arthritis (PsA) in the general population, but not among patients with psoriasis. We sought to clarify the possible methodological mechanisms behind this paradox. METHODS: Using 1995-2015 data from The Health Improvement Network, we performed survival analysis to examine the association between smoking and incident PsA in the general population and among patients with psoriasis. We clarified the paradox using mediation analysis and conducted bias sensitivity analyses to evaluate the potential impact of index event bias and quantify its magnitude from uncontrolled/unmeasured confounders. RESULTS: Of 6.65 million subjects without PsA at baseline, 225 213 participants had psoriasis and 7057 developed incident PsA. Smoking was associated with an increased risk of PsA in the general population (HR 1.27; 95% CI 1.19 to 1.36), but with a decreased risk among patients with psoriasis (HR 0.91; 95% CI 0.84 to 0.99). Mediation analysis showed that the effect of smoking on the risk of PsA was mediated almost entirely through its effect on psoriasis. Bias-sensitivity analyses indicated that even when the relation of uncontrolled confounders to either smoking or PsA was modest (both HRs=~1.5), it could reverse the biased effect of smoking among patients with psoriasis (HR=0.9). CONCLUSIONS: In this large cohort representative of the UK general population, smoking was positively associated with PsA risk in the general population, but negatively associated among patients with psoriasis. Conditioning on a causal intermediate variable (psoriasis) may even reverse the association between smoking and PsA, potentially explaining the smoking paradox for the risk of PsA among patients with psoriasis.

Body Mass Index Mediates the Association between Dietary Fiber and Symptomatic Knee Osteoarthritis in the Osteoarthritis Initiative and the Framingham Osteoarthritis Study.

Background: Dietary fiber reduces body weight and inflammation in clinical trials. It is unclear whether body mass index (BMI) and inflammation might explain the observed association between higher fiber intake and the lower risk of symptomatic knee osteoarthritis (SXKOA). Objectives: We quantified the extent to which BMI and inflammation influenced the relation between dietary fiber and SXKOA. Methods: We used longitudinal data from the Osteoarthritis Initiative (OAI) and the Framingham Offspring Osteoarthritis Study. At baseline of each study, men and women (mean age: 61 y) with or at risk of knee osteoarthritis were followed for 48 mo in the OAI. Adults (mean age: 53 y) were followed for 9.5 y in the Framingham study. Dietary fiber intake was estimated using a validated food-frequency questionnaire. Measured weight and height were used to calculate BMI. Serum high-sensitivity C-reactive protein (CRP) was measured in the Framingham study only. Incident SXKOA was defined as new onset of a combination of knee pain and radiographic osteoarthritis. We applied marginal structural models to quantify the mediation through BMI in the OAI and the sequential mediation through BMI and CRP in the Framingham study. Results: Incident SXKOA occurred in 861 knees among 2876 persons in the OAI and in 143 knees among 971 persons in the Framingham study. In persons whose fiber intake was ≥21 g/d compared with those with intakes <21 g/d, the OR (95% CI) was 0.70 (0.53, 0.91) for the overall association with SXKOA and was 0.93 (0.92, 0.95) for the mediation via BMI (per kg/m2) in the OAI. In the Framingham study, the overall association was 0.57 (0.30, 1.09), the mediation through BMI (via BMI and the influence of BMI on CRP) was 0.94 (0.85, 1.02), and the mediation through CRP (per milligram per liter) was 0.99 (0.84, 1.19). Conclusion: Our findings suggest that the inverse association of fiber intake and the risk of incident symptomatic knee osteoarthritis is partially mediated by BMI.

Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014).

BACKGROUND: Death with graft function remains an important cause of graft loss among kidney transplant recipients (KTRs). Little is known about the trend of specific causes of death in KTRs in recent years. METHODS: We analyzed United States Renal Data System data (1996-2014) to determine 1- and 10-year all-cause and cause-specific mortality in adult KTRs who died with a functioning allograft. We also studied 1- and 10-year trends in the various causes of mortality. RESULTS: Of 210,327 KTRs who received their first kidney transplant from 1996 to 2014, 3.2% died within 1 year after transplant. Cardiovascular deaths constituted the majority (24.7%), followed by infectious (15.2%) and malignant (2.9%) causes; 40.1% of deaths had no reported cause. Using 1996 as the referent year, all-cause as well as cardiovascular mortality declined, whereas mortality due to malignancy did not. For analyses of 10-year mortality, we studied 94,384 patients who received a first kidney transplant from 1996 to 2005. Of those, 22.1% died over 10 years and the causative patterns of their causes of death were similar to those associated with 1-year mortality. CONCLUSIONS: Despite the downtrend in mortality over the last 2 decades, a significant percentage of KTRs die in 10-years with a functioning graft, and cardiovascular mortality remains the leading cause of death. These data also highlight the need for diligent collection of mortality data in KTRs.

Risk profiles for acute health events after incident atrial fibrillation in patients with end-stage renal disease on hemodialysis.

Background: Little is known about the cardiovascular risks of incident atrial fibrillation/flutter (AF) in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Methods: We studied older US patients who newly initiated HD for ESRD (2006-11) and who had not previously been diagnosed with AF, stroke, myocardial infarction (MI) or hip fracture. We used Cox regression with AF as a time-varying covariate, adjusted for socio-demographic characteristics and comorbidities to estimate hazard ratios [HRs (95% confidence intervals)] for the events of ischemic stroke, MI and death. Hip fracture served as a negative control outcome. Results: We identified 85 377 older patients (mean age: 76.5 years) who initiated HD; of these, 14.3% were subsequently diagnosed with AF (14.9% thereof as primary diagnosis) and 49.8% died during follow-up. Incident AF was associated with nine times higher adjusted mortality during the first 30 days [9.2 (8.8-9.6)], 5-fold higher mortality between 31 and 90 days [4.6 (4.3-4.8)] and double the mortality beyond 90 days from first AF diagnosis [2.2 (2.1-2.3)]. Incident AF was similarly associated with higher adjusted risk of ischemic stroke: 2.1 (1.6-2.7) during the first 30 days, 2.5 (2.0-3.0) between 31 and 90 days and 1.5 (1.3-1.7) beyond 90 days. Similar findings were obtained for MI. However, the risk of hip fracture was only marginally increased following AF diagnosis [≤30 days: 1.1 (0.7-1.6); 31-90 days: 1.4 (1.0-1.8); >90 days: 1.2 (1.1-1.4)]. All associations were attenuated and the association with hip fracture was null when incident AF was defined by a primary diagnosis code. Conclusions: AF was strongly associated with increased risks of ischemic stroke, MI and death, with risks highest soon after AF diagnosis but extending beyond 90 days.

Physical Function After Total Knee Replacement: An Observational Study Describing Outcomes in a Small Group of Women From China and the United States.

OBJECTIVE: To describe physical function before and six months after Total Knee Replacement (TKR) in a small sample of women from China and the United States. DESIGN: Observational. SETTING: Community environment. OUTCOMES: Both groups adhered to the Osteoarthritis Research Society International (OARSI) protocols for the 6-minute walk and 30-second chair stand. We compared physical function prior to TKR and 6 months after using linear regression adjusted for covariates. PARTICIPANTS: Women (N=60) after TKR. INTERVENTIONS: Not applicable. RESULTS: Age and body mass index in the China group (n=30; 66y and 27.0kg/m2) were similar to those in the U.S. group (n=30; 65y and 29.6kg/m2). Before surgery, the China group walked 263 (95% confidence interval [CI], -309 to -219) less meters and had 10.2 (95% CI, -11.8 to -8.5) fewer chair stands than the U.S. group. At 6 months when compared with the U.S. group, the China group walked 38 more meters, but this difference did not reach statistical significance (95% CI, -1.6 to 77.4), and had 3.1 (95% CI, -4.4 to -1.7) fewer chair stands. The China group had greater improvement in the 6-minute walk test than did the U.S. group (P<.001). CONCLUSIONS: Despite having worse physical function before TKR, the China group had greater gains in walking endurance and similar gains in repeated chair stands than did the U.S. group after surgery.

Bone shape mediates the relationship between sex and incident knee osteoarthritis.

BACKGROUND: Knee bone shape differs between men and women and the incidence of knee osteoarthritis (OA) is higher in women than in men. Therefore, the purpose of the present study was to determine whether the observed difference in the incidence of knee radiographic OA (ROA) between men and women is mediated by bone shape. METHODS: We randomly sampled 304 knees from the OAI with incident ROA (i.e., development of Kellgren/Lawrence grade ≥ 2 by month 48) and 304 knees without incident ROA. We characterized distal femur and proximal tibia shape on baseline radiographs using Statistical Shape Modeling. If a specific bone shape was associated with the risk of incident ROA, marginal structural models were generated to assess the mediation effect of that bone shape on the relation of sex and risk of incident knee ROA adjusting for baseline covariates. RESULTS: Case and control participants were similar by age, sex and race, but case knees were from higher body mass index (BMI) participants (29.4 vs. 27.0; p < 0.001). Women had 49% increased odds of incident knee ROA compared with men (adjusted odds ratio (OR) = 1.49, 95% Confidence Interval (C.I.): 1.04, 2.12). There was an inconsistent mediation effect for tibial mode 2 between sex and incident knee ROA, with an indirect effect OR of 0.96 (95% C.I.: 0.91-1.00) and a direct effect OR of 1.56 (95% C.I.: 1.08-2.27), suggesting a protective effect for this mode. Similar findings were also observed for the mediation effect of tibia mode 10 and femur mode 4. These shape modes primarily involved differences in the angular relation of the heads to the shafts of the femur and tibia. CONCLUSIONS: Distal femur and proximal tibia bone shapes partially and inconsistently mediated the relationship between sex and incident knee OA. Women had a higher risk of incident ROA, and specific bone shapes modestly protected them from even higher risk of ROA. The clinical significance of these findings warrant further investigation.