Comprehensive review: Frailty in pancreas transplant candidates and recipients.

Well-selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney-pancreas transplantation often experience dramatic improvements in quality of life and long-term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well-validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

Daratumumab Interferes with Allogeneic Crossmatch Impacting Immunological Assessment in Solid Organ Transplantation.

We report the first case of Daratumumab interference of allogeneic crossmatch tests repeatedly causing aberrant false-positive results, which inadvertently delayed transplant for a waitlisted renal patient with multiple myeloma. Daratumumab is an IgG1κ human monoclonal antibody commonly used to treat multiple myeloma, characterized by cancerous plasma cells and often leads to renal failure requiring kidney transplant, by depleting CD38-expressing plasma cells. In this case study, the patient had end-stage renal disease secondary to multiple myeloma and was continuously receiving Daratumumab infusions. The patient did not have any detectable antibodies to human leukocyte antigens but repeatedly had unexpected positive crossmatch by the flow cytometry-based method with 26 of the 27 potential deceased organ donors, implying donor-recipient immunological incompatibility. However, further review and analysis suggested that the positive crossmatches were likely false-positive as a result of interference from Daratumumab binding to donor cell surface CD38 as opposed to the presence of donor-specific antibodies. The observed intensity of the false-positive crossmatches was also highly variable, potentially due to donor- and/or cell-dependent expression of CD38. The variability of CD38 expression was, therefore, for the first time, characterized on the T and B cells isolated from various tissues and peripheral blood of 78 individuals. Overall, T cells were found to have a lower CD38 expression profile than the B cells, and no significant difference was observed between deceased and living individuals. Finally, we show that a simple cell treatment by dithiothreitol can effectively mitigate Daratumumab interference thus preserving the utility of pre-transplant crossmatch in multiple myeloma patients awaiting kidney transplant.

Center variations in patient selection for simultaneous heart-kidney transplantation.

There are no established regulations governing patient selection for simultaneous heart-kidney (SHK) transplantation, creating the potential for significant center-level variations in clinical practice. METHODS: Using the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) file, we examined practice trends and variations in patient selection for SHK at the center level between January 1, 2004 and March 31, 2019. RESULTS: Overall, SHK is becoming more common with most centers performing heart transplants also performing SHK. Among patients who underwent heart transplant who were receiving dialysis, the rate of SHK varied from 22% to 86% at the center level. Among patients not on dialysis, the median estimated glomerular filtration rate (eGFR) of patients receiving SHK varied between 19 and 59 mL/min/1.73 m2 . When adjusting for other factors, the odds of SHK varied 57-fold between the highest and lowest SHK performing centers. CONCLUSION: Variation in SHK at the center level suggests the need for national guidelines around the selection of patients for SHK.

CT-measured Cortical Volume Ratio Is an Accurate Alternative to Nuclear Medicine Split Scan Ratio Among Living Kidney Donors.

BACKGROUND: The 125I-iothalamate clearance and 99mTc diethylenetriamine-pentaacetic acid (99mTc-DTPA) split scan nuclear medicine studies are used among living kidney donor candidates to determine measured glomerular filtration rate (mGFR) and split scan ratio (SSR). The computerized tomography-derived cortical volume ratio (CVR) is a novel measurement of split kidney function and can be combined with predonation estimated GFR (eGFR) or mGFR to predict postdonation kidney function. Whether predonation SSR predicts postdonation kidney function better than predonation CVR and whether predonation mGFR provides additional information beyond predonation eGFR are unknown. METHODS: We performed a single-center retrospective analysis of 204 patients who underwent kidney donation between June 2015 and March 2019. The primary outcome was 1-y postdonation eGFR. Model bases were created from a measure of predonation kidney function (mGFR or eGFR) multiplied by the proportion that each nondonated kidney contributed to predonation kidney function (SSR or CVR). Multivariable elastic net regression with 1000 repetitions was used to determine the mean and 95% confidence interval of R2, root mean square error (RMSE), and proportion overprediction ≥15 mL/min/1.73 m2 between models. RESULTS: In validation cohorts, eGFR-CVR models performed best (R2, 0.547; RMSE, 9.2 mL/min/1.73 m2, proportion overprediction 3.1%), whereas mGFR-SSR models performed worst (R2, 0.360; RMSE, 10.9 mL/min/1.73 m2, proportion overprediction 7.2%) (P < 0.001 for all comparisons). CONCLUSIONS: These findings suggest that predonation CVR may serve as an acceptable alternative to SSR during donor evaluation and furthermore, that a model based on CVR and predonation eGFR may be superior to other methods.

The temporal and long-term impact of donor body mass index on recipient outcomes after kidney transplantation - a retrospective study.

The impact of increasing body mass index (BMI) on development and progression of chronic kidney disease is established. Even implantation kidney biopsies from obese living donors demonstrate subtle histologic changes despite normal function. We hypothesized that kidneys from obese living (LD) and deceased donors (DD) would have inferior long-term allograft outcomes. In a study utilizing US transplant registry, we studied adult kidney transplant recipients from 2000 to 2014. Donors were categorized as BMI <20 (underweight), 20-25 (normal), 25-30 (overweight), 30-35 (mildly obese), and >35 kg/m2 (very obese). Our outcome of interest was death censored graft failure (DCGF). Cox proportional hazards model were fitted separately for recipients of DD and LD kidneys, and adjusted for donor, recipient, and transplant characteristics, including donor and recipient size mismatch ratio. Among 118 734 DD and 84 377 LD transplants recipients, we observed a significant and graded increase in DCGF risk among the overweight (LD:HR = 1.06, DD:HR = 1.04), mildly obese (LD:HR = 1.16, DD:HR = 1.10), and very obese (LD:HR = 1.22, DD:HR = 1.22) compared to normal BMI (P < 0.05). The graded effect of donor BMI on outcomes begins early and persists throughout the post-transplant period. Donor obesity status is an independent risk factor for inferior long-term renal allograft outcome despite adjusting for donor and recipient size mismatch and other donor, recipient, and transplant factors.

Risk of Cardiovascular Disease and Mortality in Young Adults With End-stage Renal Disease: An Analysis of the US Renal Data System.

Importance: Cardiovascular disease (CVD) is a leading cause of death among patients with end-stage renal disease (ESRD). Young adult (ages 22-29 years) have risks for ESRD-associated CVD that may vary from other ages. Objective: To test the hypothesis that young adult-onset ESRD is associated with higher cardiovascular (CV) hospitalizations and mortality with different characteristics than childhood-onset disease. Design, Setting, and Participants: This population-based cohort study used the US Renal Data System to categorize patients who initiated ESRD care between 2003 and 2013 by age at ESRD onset (1-11, 12-21, and 22-29 years). Cardiovascular hospitalizations were identified via International Classification of Diseases, Ninth Revision discharge codes and CV mortality from the Centers for Medicare & Medicaid ESRD Death Notification Form. Patients were censored at death from non-CVD events, loss to follow-up, recovery, or survival to December 31, 2014. Adjusted proportional hazard models (95% CI) were fit to determine risk of CV hospitalization and mortality by age group. Data analysis occurred from May 2016 and December 2017. Exposures: Onset of ESRD. Main Outcomes and Measures: Cardiovascular mortality and hospitalization. Results: A total of 33 156 patients aged 1 to 29 years were included in the study population. Young adults (aged 22-29 years) had a 1-year CV hospitalization rate of 138 (95% CI, 121-159) per 1000 patient-years. Young adults had a higher risk for CV hospitalization than children (aged 1-11 years; hazard ratio [HR], 0.41 [95% CI, 0.26-0.64]) and adolescents (aged 12-21 years; HR, 0.86 [95% CI, 0.77-0.97]). Of 4038 deaths in young adults, 1577 (39.1%) were owing to CVD. Five-year cumulative incidence of mortality in this group (7.3%) was higher than in younger patients (adolescents, 4.0%; children, 1.7%). Adjusted HRs for CV mortality were higher for young adults with all causes of ESRD than children (cystic, hereditary, and congenital conditions: HR, 0.22 [95% CI, 0.11-0.46]; P < .001; glomerulonephritis: HR, 0.21 [95% CI, 0.10-0.44]; P < .001; other conditions: HR, 0.33 [95% CI, 0.23-0.49]; P < .001). Adolescents had a lower risk for CV mortality than young adults for all causes of ESRD except glomerulonephritis (cystic, hereditary, and congenital conditions: HR, 0.45 [95% CI, 0.27-0.74]; glomerulonephritis: HR, 0.99 [95% CI, 0.76-1.11]; other: HR, 0.47 [95% CI, 0.40-0.57]). Higher risks for CV hospitalization and mortality were associated with lack of preemptive transplant compared with hemodialysis (hospital: HR, 14.24 [95% CI, 5.92-34.28]; mortality: HR, 13.64 [95% CI, 8.79-21.14]) and peritoneal dialysis [hospital: HR, 8.47 [95% CI, 3.50-20.53]; mortality: HR, 7.86 [95% CI, 4.96-12.45]). Nephrology care before ESRD was associated with lower risk for CV mortality (HR, 0.77 [95% CI, 0.70-0.85]). Conclusions and Relevance: Cardiovascular disease accounted for nearly 40% of deaths in young adults with incident ESRD in this cohort. Identified risk factors may inform development of age-appropriate ESRD strategies to improve the CV health of this population.

Risk of peritoneal dialysis catheter-associated peritonitis following kidney transplant.

OBJECTIVE: Peritoneal dialysis (PD) patients have equivalent or slightly better kidney transplant outcomes when compared to hemodialysis (HD) patients. However, given the risk for postoperative infection, we sought to determine the risk factors for PD catheter-associated infections for patients who do not have the PD catheter removed at the time of engraftment. METHODS: Demographic and outcomes data were collected from 313 sequential PD patients who underwent kidney transplant from 2000 to 2015. Risk factors for postoperative peritonitis were analyzed using logistical regression. RESULTS: Of 329 patients with PD catheters at transplant, 16 PD catheters were removed at engraftment. Of the remaining 313 patients, 8.9% suffered post-transplant peritonitis. On univariate analysis, patients with peritonitis were significantly more likely to have used the PD catheter or HD within 6 weeks after transplant. Multivariate analysis had similar findings, with increased risk for those using the PD catheter after transplant, with a trend for those who underwent HD only within 6 weeks of transplant. CONCLUSION: These results suggest that delayed graft function requiring any type of dialysis is associated with increased post-transplant peritonitis risk.

Temporal trends, center-level variation, and the impact of prevalent state obesity rates on acceptance of obese living kidney donors.

The impact of pre-donation obesity on long-term outcomes of living kidney donors remains controversial. Published guidelines offer varying recommendations regarding BMI (kg/m2 ) thresholds for donor acceptance. We examined temporal and center-level variation in BMI of accepted donors across US transplant centers. Using national transplant registry data, we performed multivariate hierarchical logistic regression modeling using pairwise comparisons (overweight, BMI: 25-29.9; mildly obese, BMI: 30-34.9; very obese, BMI: ≥35; versus normal BMI: 18.5-24.9). Metrics of heterogeneity, including median odds ratio (MOR), were calculated. Among 90 013 living kidney donors, 2001-2016, proportions who were very obese decreased and proportions who were mildly obese or overweight increased. Significant center-level heterogeneity was noted in BMI of accepted donors; the MOR varied from 1.10 for overweight to 1.93 for very obese donors. At centers located in the 10 states with the highest general population obesity rates, adjusted odds of very obese donor status were 185% higher (reference: normal BMI) than in states with the lowest obesity rates. Although there is a declining trend in acceptance of very obese living kidney donors, variation across centers is significant. Furthermore, local population obesity rates may affect the decision to accept obese individuals as donors.

Promising insights into the health related quality of life for children with severe obesity.

BACKGROUND: Childhood obesity is a growing health concern known to adversely affect quality of life in children and adolescents. The Patient Reported Outcomes Measurement Information System (PROMIS) pediatric measures were developed to capture child self-reports across a variety of health conditions experienced by children and adolescents. The purpose of this study is to begin the process of validation of the PROMIS pediatric measures in children and adolescents affected by obesity. METHODS: The pediatric PROMIS instruments were administered to 138 children and adolescents in a cross-sectional study of patient reported outcomes in children aged 8-17 years with age-adjusted body mass index (BMI) greater than the 85th percentile in a design to establish known-group validity. The children completed the depressive symptoms, anxiety, anger, peer relationships, pain interference, fatigue, upper extremity, and mobility PROMIS domains utilizing a computer interface. PROMIS domains and individual items were administered in random order and included a total of 95 items. Patient responses were compared between patients with BMI 85 to<99th percentile versus ≥99th percentile. RESULTS: 136 participants were recruited and had all necessary clinical data for analysis. Of the 136 participants, 5% ended the survey early resulting in missing domain scores at the end of survey administration. In multivariate analysis, patients with BMI ≥ 99th percentile had worse scores for depressive symptoms, anger, fatigue, and mobility (p<0.05). Parent-reported exercise was associated with better scores for depressive symptoms, anxiety, and fatigue (p<0.05). CONCLUSIONS: Children and adolescents ranging from overweight to severely obese can complete multiple PROMIS pediatric measures using a computer interface in the outpatient setting. In the 5% with missing domain scores, the missing scores were consistently found in the domains administered last, suggesting the length of the assessment is important. The differences in domain scores found in this study are consistent with previous reports investigating the quality of life in children and adolescents with obesity. We show that the PROMIS instrument represents a feasible and potentially valuable instrument for the future study of the effect of pediatric obesity on quality of life.

Aldosterone in the pathogenesis of chronic kidney disease and proteinuria.

There has been much recent interest in the role of aldosterone as an independent contributor to the progression of chronic kidney disease. Despite treatment with agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, many studies have shown that there is incomplete blockade of the renin-angiotensin cascade evidenced by persistent or rising plasma aldosterone levels despite therapeutic renin-angiotensin blockade. This phenomenon is commonly referred to as "aldosterone escape" and is thought to be one of the main contributors to chronic kidney disease progression despite conventional therapeutics. Animal models of the effects of exposure to exogenous aldosterone demonstrate the development of inflammation and fibrosis in both the myocardium and renal parenchyma. In limited human studies, aldosterone receptor antagonism is associated with decreased proteinuria and improved glomerular filtration rate. Although data support the addition of an aldosterone antagonist to conventional therapy when treating patients with chronic kidney disease, more studies are needed to determine the precise clinical indications and the appropriate safety monitoring.

Economics of central line--associated bloodstream infections.

Hospital-acquired infections add considerable morbidity and mortality to patient care. However, a detailed economic analysis of these infections on an individual case basis has been lacking. The authors examined both the hospital revenues and expenses in 54 cases of patients with central line-associated bloodstream infections (CLABs) over 3 years in 2 intensive care units and compared these financial data with patients who were matched for age, severity of illness on admission, and principal diagnosis. The average payment for a case complicated by CLAB was $64 894, and the average expense was $91733 with gross margin of -$26 839 per case and a total loss from operations of $1 449 306 in the 54 cases. The costs of CLABs and the associated complications averaged 43% of the total cost of care. The elimination of these preventable infections constitutes not only an opportunity to improve patient outcomes but also a significant financial opportunity.