Elizabeth A. King

Frailty and Mortality in Kidney Transplant Recipients

We have previously described strong associations between frailty, a measure of physiologic reserve initially described and validated in geriatrics, and early hospital readmission as well as delayed graft function. The goal of this study was to estimate its association with postkidney transplantation (post‐KT) mortality. Frailty was prospectively measured in 537 KT recipients at the time of transplantation between November 2008 and August 2013. Cox proportional hazards models were adjusted for confounders using a novel approach to substantially improve model efficiency and generalizability in single‐center studies. We precisely estimated the confounder coefficients using the large sample size of the Scientific Registry of Transplantation Recipients (n = 37 858) and introduced these into the single‐center model, which then estimated the adjusted frailty coefficient. At 5 years, the survivals were 91.5%, 86.0% and 77.5% for nonfrail, intermediately frail and frail KT recipients, respectively. Frailty was independently associated with a 2.17‐fold (95% CI: 1.01–4.65, p = 0.047) higher risk of death. In conclusion, regardless of age, frailty is a strong, independent risk factor for post‐KT mortality, even after carefully adjusting for many confounders using a novel, efficient statistical approach.

Perioperative Complications after Living Kidney Donation: A National Study

We integrated the US transplant registry with administrative records from an academic hospital consortium (97 centers, 2008–2012) to identify predonation comorbidity and perioperative complications captured in diagnostic, procedure, and registry sources. Correlates (adjusted odds ratio, aOR) of perioperative complications were examined with multivariate logistic regression. Among 14 964 living kidney donors, 11.6% were African American. Nephrectomies were predominantly laparoscopic (93.8%); 2.4% were robotic and 3.7% were planned open procedures. Overall, 16.8% of donors experienced a perioperative complication, most commonly gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), surgical/anesthesia‐related injuries (2.4%), and “other” complications (6.6%). Major Clavien Classification of Surgical Complications grade IV or higher affected 2.5% of donors. After adjustment for demographic, clinical (including comorbidities), procedure, and center factors, African Americans had increased risk of any complication (aOR 1.26, p = 0.001) and of Clavien grade II or higher (aOR 1.39, p = 0.0002), grade III or higher (aOR 1.56, p < 0.0001), and grade IV or higher (aOR 1.56, p = 0.004) events. Other significant correlates of Clavien grade IV or higher events included obesity (aOR 1.55, p = 0.0005), predonation hematologic (aOR 2.78, p = 0.0002) and psychiatric (aOR 1.45, p = 0.04) conditions, and robotic nephrectomy (aOR 2.07, p = 0.002), while annual center volume >50 (aOR 0.55, p < 0.0001) was associated with lower risk. Complications after live donor nephrectomy vary with baseline demographic, clinical, procedure, and center factors, but the most serious complications are infrequent. Future work should examine underlying mechanisms and approaches to minimizing the risk of perioperative complications in all donors.

Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients.

Background Mycophenolate mofetil (MMF) side effects often prompt dose reduction or discontinuation, and this MMF dose reduction (MDR) can lead to rejection and possibly graft loss. Unfortunately, little is known about what factors might cause or contribute to MDR. Frailty, a measure of physiologic reserve, is emerging as an important, novel domain of risk in kidney transplantation recipients. We hypothesized that frailty, an inflammatory phenotype, might be associated with MDR. Methods We measured frailty (shrinking, weakness, exhaustion, low physical activity, and slowed walking speed), other patient and donor characteristics, longitudinal MMF doses, and graft loss in 525 kidney transplantation recipients. Time-to-MDR was quantified using an adjusted Cox proportional hazards model. Results By 2 years after transplantation, 54% of frail recipients and 45% of nonfrail recipients experienced MDR; by 4 years, incidence was 67% and 51%. Frail recipients were 1.29 times (95% confidence interval [95% CI], 1.01–1.66; P = 0.04) more likely to experience MDR, as were deceased donor recipients (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.44–2.54, P < 0.001) and older adults (age ≥ 65 vs <65; aHR, 1.47; 95% CI, 1.10–1.96, P = 0.01). Mycophenolate mofetil dose reduction was independently associated with a substantially increased risk of death-censored graft loss (aHR, 5.24; 95% CI, 1.97–13.98, P = 0.001). Conclusion A better understanding of risk factors for MMF intolerance might help in planning alternate strategies to maintain adequate immunosuppression and prolong allograft survival.

Changes in Frailty After Kidney Transplantation.

To understand the natural history of frailty after an aggressive surgical intervention, kidney transplantation (KT).

Loss of Pediatric Kidney Grafts during the "High-Risk Age Window": Insights from Pediatric Liver and Simultaneous Liver-Kidney Recipients

Pediatric kidney transplant recipients experience a high–risk age window of increased graft loss during late adolescence and early adulthood that has been attributed primarily to sociobehavioral mechanisms such as nonadherence. An examination of how this age window affects recipients of other organs may inform the extent to which sociobehavioral mechanisms are to blame or whether kidney‐specific biologic mechanisms may also exist. Graft loss risk across current recipient age was compared between pediatric kidney (n = 17,446), liver (n = 12,161) and simultaneous liver–kidney (n = 224) transplants using piecewise‐constant hazard rate models. Kidney graft loss during late adolescence and early adulthood (ages 17–24 years) was significantly greater than during ages <17 (aHR = 1.79, 95%CI = 1.69–1.90, p < 0.001) and ages >24 (aHR = 1.11, 95%CI = 1.03–1.20, p = 0.005). In contrast, liver graft loss during ages 17–24 was no different than during ages <17 (aHR = 1.03, 95%CI = 0.92–1.16, p = 0.6) or ages >24 (aHR = 1.18, 95%CI = 0.98–1.42, p = 0.1). In simultaneous liver–kidney recipients, a trend towards increased kidney compared to liver graft loss was observed during ages 17–24 years. Late adolescence and early adulthood are less detrimental to pediatric liver grafts compared to kidney grafts, suggesting that sociobehavioral mechanisms alone may be insufficient to create the high–risk age window and that additional biologic mechanisms may also be required.

Health-Related and Psychosocial Concerns about Transplantation among Patients Initiating Dialysis

BACKGROUND AND OBJECTIVES Disparities in kidney transplantation remain; one mechanism for disparities in access to transplantation (ATT) may be patient-perceived concerns about pursuing transplantation. This study sought to characterize prevalence of patient-perceived concerns, explore interrelationships between concerns, determine patient characteristics associated with concerns, and assess the effect of concerns on ATT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Prevalences of 12 patient-perceived concerns about pursuing transplantation were determined among 348 adults who recently initiated dialysis, recruited from 26 free-standing dialysis centers around Baltimore, Maryland (January 2009-March 2012). Using variable reduction techniques, concerns were clustered into two categories (health-related and psychosocial) and quantified with scale scores. Associations between patient characteristics and concerns were estimated using modified Poisson regression. Associations between concerns and ATT were estimated using Cox models. RESULTS The most frequently cited patient-perceived concerns were that participants felt they were doing fine on dialysis (68.4%) and felt uncomfortable asking someone to donate a kidney (29.9%). Older age was independently associated with having high health-related (adjusted relative risk, 1.35 [95% confidence interval, 1.20 to 1.51], for every 5 years older for those ≥ 60 years) or psychosocial (1.15 [1.00 to 1.31], for every 5 years older for those aged ≥ 60 years) concerns, as was being a woman (1.72 [1.21 to 2.43] and 1.55 [1.09 to 2.20]), having less education (1.59 [1.08 to 2.35] and 1.77 [1.17 to 2.68], comparing postsecondary education to grade school or less), and having more comorbidities (1.18 [1.08 to 1.30] and 1.18 [1.07 to 1.29], per one comorbidity increase). Having never seen a nephrologist before dialysis initiation was associated with high psychosocial concerns (1.48 [1.01 to 2.18]). Those with high health-related (0.37 [0.16 to 0.87]) or psychosocial (0.47 [0.23 to 0.95]) concerns were less likely to achieve ATT (median follow-up time 2.2 years; interquartile range, 1.6-3.2). CONCLUSIONS Patient-perceived concerns about pursuing kidney transplantation are highly prevalent, particularly among older adults and women. Reducing these concerns may help decrease disparities in ATT.

The role of fiber supplementation in the treatment of irritable bowel syndrome: a systematic review and meta-analysis

Irritable bowel syndrome (IBS) is a functional bowel disorder associated with a wide variety of clinical symptoms. The use of fiber in treatment of IBS is well established, but recent reviews have shown conflicting evidence. The aim of our review was to study the effects of fiber (soluble and insoluble) on the symptoms of IBS. Medline, EMBASE, Cochrane Central, CINAHL, LILACS, and ClinicalTrials.gov were searched for appropriate studies. Two reviewers screened the title/abstract and full text against the inclusion criterion – that is, randomized control trials/crossover studies that compare fiber with placebo for its effect on IBS in an outpatient setting. Independent double data extraction was performed across multiple fields. An assessment of the risk of bias and tests for heterogeneity were carried out, along with a meta-analysis of the outcomes of interest. The search yielded 4199 unique records: 121 were selected after title/abstract screening and 22 after full screening. There was moderate clinical, methodological, and statistical heterogeneity across studies, with a moderate risk of bias. Overall, there was a significant improvement in global assessment of symptoms among those randomized to fiber [risk ratio: 1.27; 95% confidence interval (CI): 1.05–1.54]. Soluble fiber improved assessment of symptoms (risk ratio 1.49; 95% CI: 1.09–2.03), as well as the abdominal pain score (mean difference: −1.84; 95% CI: −2.72 to −0.97), with insoluble fiber not showing improvement in any outcome. Soluble fiber appears to improve symptoms of IBS, whereas there is no evidence for recommending insoluble fiber for IBS.

Individual Frailty Components and Mortality in Kidney Transplant Recipients

Background Frailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear. Methods Six hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models. Results Frailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio [PR], 2.22; 95% confidence interval [CI], 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poor: PR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk. Conclusions Age was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.

Frailty, Length of Stay, and Mortality in Kidney Transplant Recipients: A National Registry and Prospective Cohort Study

Objective: To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. Background: Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality. Methods: We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOS: negative binomial regression; LOS ≥2 weeks: logistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis). Results: Frailty was independently associated with longer LOS [relative risk = 1.15, 95% confidence interval (CI): 1.03–1.29; P = 0.01] and LOS ≥2 weeks (odds ratio = 1.57, 95% CI: 1.06–2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI: 1.30–1.86; P < 0.001; frail hazard rate = 0.97, 95% CI: 0.79–1.19, P = 0.80; P for interaction = 0.001). Conclusions: Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.

Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor‐specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22‐center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant‐matched controls and to waitlist‐only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed‐effects Poisson regression. In the first month, ILDKTs had a 1.28‐fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13‐1.46; P < .001). Risk peaked at 6‐12 months (relative risk [RR] 1.67, 95% CI 1.49‐1.87; P < .001), attenuating by 24‐36 months (RR 1.24, 95% CI 1.10‐1.40; P < .001). ILDKTs had a 5.86‐fold higher readmission risk (95% CI 4.96‐6.92; P < .001) in the first month compared to waitlist‐only controls. At 12‐24 (RR 0.85, 95% CI 0.77‐0.95; P = .002) and 24‐36 months (RR 0.74, 95% CI 0.66‐0.84; P < .001), ILDKTs had a lower risk than waitlist‐only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist‐only controls should be considered in regulatory/payment schemas and planning clinical care.