Faculty Bibliography

A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = _0.09 0.13_0.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = _1.00 1.45_2.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = _0.47 0.73_1.12 ) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = _2.39 4.26_7.92 for mTORi+tacrolimus; _2.34 5.54_15.32 for mTORi-only; and _6.78 10.25_15.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = _0.81 1.54_2.98 for MMF + mTORi; and _0.81 1.51_2.87 for MMF-only). We repeated these analyses in an independent cohort (n = 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.

BACKGROUND:Cognitive impairment is common among persons with chronic kidney disease (CKD) due in part to reduced kidney function. Given that physical activity (PA) is known to mitigate cognitive decline, we examined whether associations between CKD stage and global/domain-specific cognitive function differs by PA. METHODS:We leveraged 3,223 participants (aged≥60years) enrolled in National Health and Nutrition Examination Survey (NHANES,2011-2014), with at least one measure of objective cognitive function (immediate recall [CERAD-WL], delayed recall [CERAD-DR], verbal fluency [AF], executive function/processing speed [DSST], global [average of 4 tests]) or self-perceived memory decline [SCD]. We quantified the association between CKD stage (no CKD: eGFR≥60 mL/min/1.73m2 and albuminuria(ACR)<30 mg/g; stage G1-G3: eGFR≥60mL/min/1.73m2 and ACR≥30mg/g or eGFR 30-59mL/min/1.73m2; stage G4-G5: eGFR<30mL/min/1.73m2) and cognitive function using linear regression (objective measures) and logistic regression (SCD), accounting for sampling weights for nationally-representative estimates. We tested whether associations differed by physical activity (Global Physical Activity Questionnaire, high PA≥600MET*min/week vs. low PA<600MET*min/week) using a Wald test. RESULTS:Among NHANES participants, 34.9% had CKD stageG1-G3, 2.6% had stageG4-G5, and 50.7% had low PA. CKD stageG4-G5 was associated with lower global cognitive function (difference = -0.38SD, 95%CI:-0.62,-0.15). This association differed by PA (pinteraction = 0.01). Specifically, among participants with low PA, those with CKD stageG4-G5 had lower global cognitive function (difference = -0.57SD, 95%CI: -0.82,-0.31) compared to those without CKD. Among those with high PA, no difference was found (difference = 0.10SD, 95%CI:-0.29,0.49). Similarly, CKD stage was only associated with immediate recall, verbal fluency, executive function, and processing speed among those with low PA; no associations were observed for delayed recall or self-perceived memory decline. CONCLUSIONS:CKD is associated with lower objective cognitive function among those with low, but not high PA. Clinicians should consider screening older patients with CKD who have low PA for cognitive impairment and encourage them to meet PA guidelines.

BACKGROUND:Elevated parathyroid hormone (PTH) levels have been reported as a potential risk factor for cognitive impairment. Compared to the general population, older adults with end-stage renal disease (ESRD) who are frequently affected by secondary hyperparathyroidism (SHPT) are at increased risk of developing dementia. The main objective of our study was to evaluate if the risk of dementia in older (age ≥ 65) ESRD patients differed if they were treated for SHPT. METHODS:Using the United States Renal Data System (USRDS) and Medicare claims, we identified 189 433 older adults without a diagnosis of dementia, who initiated dialysis between 2006-2016. SHPT treatment was defined as use of vitamin D analogs, phosphate binders, calcimimetics, or parathyroidectomy. We quantified the association between treated SHPT and incident dementia during dialysis using a multivariable Cox proportional hazards model with inverse probability weighting, considering SHPT treatment as a time varying exposure. RESULTS:Of 189 433 older ESRD adults, 92% had a claims diagnosis of SHPT, and 123 388 (65%) were treated for SHPT. The rate of incident dementia was 6 cases per 100 person-years among SHPT treated patients compared to 11 cases per 100 person-years among untreated patients. Compared to untreated SHPT patients, the risk of dementia was 42% lower (aHR = 0.58, 95% CI: 0.56-0.59) among SHPT treated patients. The magnitude of the beneficial effect of SHPT treatment differed by sex (pinteraction = 0.02) and race (pinteraction ≤ 0.01) with females (aHR = 0.56, 95% CI: 0.54-0.58) and those of Asian (aHR = 0.51, 95% CI: 0.46-0.57) or Black race (aHR = 0.51, 95% CI: 0.48-0.53) having greatest reduction in dementia risk. CONCLUSION/CONCLUSIONS:Receiving treatment for SHPT was associated with a lower risk of incident dementia among older patients with ESRD. This work provides additional support for treatment of SHPT in older ESRD patients.

Recently, the misuse of race as a biological variable, rather than a social construct, in biomedical research has received national attention for its contributions to medical bias. In national transplant registry data, bias may arise from measurement imprecision because of the collection of provider-perceived race rather than patients' own self-report.

Introduction/UNASSIGNED:Although life-saving, the physiologic stress of hemodialysis initiation contributes to physical impairment in some patients. Mortality risk assessment following hemodialysis initiation is underdeveloped and does not account for change over time. Measures of physical resilience, the ability of a physiologic state to overcome physiologic stressors, may help identify patients at higher mortality risk and inform clinical management. Methods/UNASSIGNED:over 4 years average follow-up. Results/UNASSIGNED: = 0.0004) resilience categories with mortality were found independent of covariates. Declining PF trajectory was associated with higher mortality risk (hazard ratio [HR] = 1.32; 95% confidence interval [CI], 1.05-1.66), whereas improving VT trajectory was associated with lower mortality risk (HR= 0.73; 95% CI, 0.53 to 1.00), each as compared to stable trajectory. Conclusion/UNASSIGNED:Decreased resilience in PF and VT was independently associated with mortality. Phenotypic trajectories provide added value to baseline markers and patient characteristics when evaluating mortality. Hence, resilience measures hold promise for targeting population health interventions to the highest risk patients.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m². At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m²) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

BACKGROUND:Hurricanes are severe weather events that can disrupt power, water, and transportation systems. These disruptions may be deadly for patients requiring maintenance dialysis. We hypothesized that the mortality risk among patients requiring maintenance dialysis would be increased in the 30 days after a hurricane. METHODS:Patients registered as requiring maintenance dialysis in the United States Renal Data System who initiated treatment between January 1, 1997 and December 31, 2017 in one of 108 hurricane-afflicted counties were followed from dialysis initiation until transplantation, dialysis discontinuation, a move to a nonafflicted county, or death. Hurricane exposure was determined as a tropical cyclone event with peak local wind speeds ≥64 knots in the county of a patient's residence. The risk of death after the hurricane was estimated using time-varying Cox proportional hazards models. RESULTS:The median age of the 187,388 patients was 65 years (IQR, 53-75) and 43.7% were female. There were 27 hurricanes and 105,398 deaths in 529,339 person-years of follow-up on dialysis. In total, 29,849 patients were exposed to at least one hurricane. Hurricane exposure was associated with a significantly higher mortality after adjusting for demographic and socioeconomic covariates (hazard ratio, 1.13; 95% confidence interval, 1.05-1.22). The association persisted when adjusting for seasonality. CONCLUSIONS:Patients requiring maintenance dialysis have a higher mortality risk in the 30 days after a hurricane.

BACKGROUND:Secondary hyperparathyroidism affects nearly all patients with renal failure on dialysis. Medical treatment of secondary hyperparathyroidism has considerably evolved over the past 2 decades, with parathyroidectomy reserved for severe cases. The primary objective of our study was to understand how trends in medical treatments affected parathyroidectomy rates in patients with secondary hyperparathyroidism on dialysis. METHODS:We used the United States Renal Data System to identify 379,835 adult patients (age ≥18) who were on maintenance dialysis in the United States between 2006 and 2016 with Medicare as the primary payor and ascertained treatment for secondary hyperparathyroidism. Adjusted rate ratios for rates of parathyroidectomy were calculated using multivariable-adjusted Poisson regression. RESULTS:Of 379,835 secondary hyperparathyroidism patients, 4,118 (1.1%) underwent parathyroidectomy, 39,835 (10.5%) received cinacalcet, 243,522 (64.1%) received phosphate binders, 17,571 (4.6%) received vitamin D analogs, and 86,899 (22.9%) received no treatment during the 10 years of follow-up. Over the entire study period, there was a 3.5-fold increase in the use of calcimimetics and a 3.4-fold increase in rates of parathyroidectomy. Compared to 2006 through 2009, utilization of parathyroidectomy increased 52% (adjusted rate ratio = 1.52, 95% confidence interval: 1.39-1.65) between 2010 and 2013 and by 106% (adjusted rate ratio = 2.06, 95% confidence interval: 1.90-2.24) between 2014 and 2016. The greatest increase in parathyroidectomy utilization occurred in younger patients (age 18-64 years), Black patients, female patients, those living in higher poverty neighborhoods, those listed for kidney transplant, and those who live in the Southern region of the United States. CONCLUSION:Despite the evolution of medical treatments and an increase in the use of calcimimetics to treat secondary hyperparathyroidism, parathyroidectomy rates have been steadily increasing among dialysis patients with Medicare coverage.

OBJECTIVE:Impairment in physical function and physical performance leads to decreased independence and health-related quality of life in people living with chronic kidney disease and end-stage kidney disease. Physical activity and exercise in kidney care are not priorities in policy development. We aimed to identify global policy-related enablers, barriers, and strategies to increase exercise participation and physical activity behavior for people living with kidney disease. DESIGN AND METHODS/METHODS:Guided by the Behavior Change Wheel theoretical framework, 50 global renal exercise experts developed policy barriers and enablers to exercise program implementation and physical activity promotion in kidney care. The consensus process consisted of developing themes from renal experts from North America, South America, Continental Europe, United Kingdom, Asia, and Oceania. Strategies to address enablers and barriers were identified by the group, and consensus was achieved. RESULTS:We found that policies addressing funding, service provision, legislation, regulations, guidelines, the environment, communication, and marketing are required to support people with kidney disease to be physically active, participate in exercise, and improve health-related quality of life. We provide a global perspective and highlight Japanese, Canadian, and other regional examples where policies have been developed to increase renal physical activity and rehabilitation. We present recommendations targeting multiple stakeholders including nephrologists, nurses, allied health clinicians, organizations providing renal care and education, and renal program funders. CONCLUSIONS:We strongly recommend the nephrology community and people living with kidney disease take action to change policy now, rather than idly waiting for indisputable clinical trial evidence that increasing physical activity, strength, fitness, and function improves the lives of people living with kidney disease.

RATIONALE & OBJECTIVE/UNASSIGNED:Disorders of bone and mineral metabolism frequently develop with advanced kidney disease, may be exacerbated by immunosuppression after kidney transplantation, and increase the risk of fractures. STUDY DESIGN/UNASSIGNED:Retrospective database study. SETTING & PARTICIPANTS/UNASSIGNED:Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States captured in US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. EXPOSURES/UNASSIGNED:Various immunosuppression regimens in the first 3 months after kidney transplantation. OUTCOMES/UNASSIGNED:The development of fractures, as ascertained using diagnostic codes on Medicare billing claims. ANALYTICAL APPROACH/UNASSIGNED:We used multivariable Cox regression with inverse propensity weighting to compare the incidence of fractures >3 months-to-3 years after kidney transplantation associated with various immunosuppression regimens compared to a reference regimen of antithymocyte globulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse probability treatment weighting. RESULTS/UNASSIGNED: < 0.001]). Induction with TMG or ALEM and the avoidance or early withdrawal of steroids significantly reduced the risk of fractures in younger (aHR, 0.63; 95% CI, 0.54-0.73) and older (aHR, 0.83; 95% CI, 0.74-0.94) patients. The avoidance or early withdrawal of steroids with any induction was associated with a reduced risk of fractures in women. LIMITATIONS/UNASSIGNED:This was a retrospective study which lacked data on immunosuppression levels. CONCLUSIONS/UNASSIGNED:Fractures after kidney transplantation are associated with significantly increased mortality risk and costs. The early avoidance or early withdrawal of steroids after induction with TMG or ALEM reduces the risk of fractures after kidney transplantation and should be considered for patients at high-risk of this complication, including older adults and women.