Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex.

BACKGROUND AND PURPOSE: Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. METHODS: Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses of EGR2 were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. RESULTS: A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of the EGR2 gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. CONCLUSION: Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

Perinatal outcomes following bariatric surgery between a first and second pregnancy: a population data linkage study.

OBJECTIVES: To describe the population of women having bariatric surgery and compare the pregnancy outcomes for women having bariatric surgery with a non-bariatric surgery population having a first and second pregnancy. DESIGN: Population-based record linkage study. SETTING: New South Wales (NSW), Australia. POPULATION: All women aged 15-45 years with a hospital record in NSW (2002-2014) and all women giving birth in NSW (1994-2015; n = 1 606 737 women). METHODS: Pregnancy and birth outcomes were compared between first and second pregnancies using repeated-measures logistic regression and paired Student's t-tests. Bariatric and non-bariatric groups were also compared. MAIN OUTCOME MEASURES: Maternal diabetes, preterm birth (<37 weeks of gestation) and large for gestational age. RESULTS: There was a 13-fold increase in hospitalisations for primary bariatric surgery during 2002-2014. Compared with the general birthing population, women who had bariatric surgery experienced higher rates of hypertension, diabetes, and preterm birth. Among women who had bariatric surgery between a first and second pregnancy, there were reduced rates of hypertension (OR 0.39, 95% CI 0.29-0.53), spontaneous preterm birth (OR 0.37, 95% CI 0.16-0.86), infants that were large for gestational age (OR 0.63, 95% CI 0.44-0.88), and the admission of infants to a special care nursery or neonatal intensive care (OR 0.64, 95% CI 0.46-0.90) in the second pregnancy. Rates for small-for-gestational age and gestational diabetes following surgery were 8.3 and 11.4%, respectively CONCLUSIONS: Bariatric surgery between a first and second pregnancy was associated with reductions in obesity-related adverse pregnancy outcomes. Bariatric surgery performed for the management of obesity in accordance with current clinical criteria is associated with improved pregnancy outcomes in a subsequent pregnancy. TWEETABLE ABSTRACT: Bariatric surgery for obesity may improve pregnancy and birth outcomes in a subsequent pregnancy.

OPTN/SRTR 2016 Annual Data Report: Economics.

Medicare costs vary for solid organ transplant recipients by outcome: survival with graft function, survival with graft failure, and death. Average per-person per-year reimbursement was $75 thousand for kidney recipients who survived the first year posttransplant with a functioning graft, $171 thousand for those who required a return to dialysis or retransplant, and $350 thousand for those who died with function. For pancreas recipients: $105 thousand for those who survived the first year with a functioning graft, $120 thousand for those who survived pancreas failure, and $443 thousand for those who died with function. For liver recipients: $154 thousand for those who survived with a functioning graft, $388 thousand for those who required retransplant, and $740 thousand who died with function. For intestine recipients: $301 thousand for those who survived with a functioning graft and $1 million for those who died with function. For heart recipients: $272 thousand for those who survived with a functioning graft and $1.2 million for those who died with function. For lung recipients: $196 thousand for those who survived with a functioning graft, $642 thousand for those who required retransplant, and $761 thousand for those who died with function.

The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes.

Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post-DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.

Prescription opioid use before and after kidney transplant: Implications for posttransplant outcomes.

Evolving literature suggests that the epidemic of prescription opioid use affects the transplant population. We examined a novel database wherein national U.S. transplant registry records were linked to a large pharmaceutical claims warehouse (2007-2015) to characterize prescription opioid use before and after kidney transplant, and associations (adjusted hazard ratio, 95%LCL aHR95%UCL ) with death and graft loss. Among 75 430 eligible patients, 43.1% filled opioids in the year before transplant. Use was more common among recipients who were women, white, unemployed, publicly insured, and with longer pretransplant dialysis. Of those with the highest level of pretransplant opioid use, 60% continued high-level use posttransplant. Pretransplant opioid use had graded associations with one-year posttransplant outcomes; the highest-level use predicted 46% increased risk of death (aHR 1.28 1.461.66 ) and 28% increased risk of all-cause graft failure (aHR 1.17 1.281.41 ). Effects of high-level opioid use in the first year after transplant were stronger, predicting twice the risk of death (aHR 1.93 2.242.60 ) and 68% higher all-cause graft failure risk (aHR 1.50 1.681.89 ) over the subsequent year; increased risk persisted over five years. While associations may, in part, reflect underlying conditions or behaviors, opioid use history is relevant in assessing and providing care to transplant candidates and recipients.

Metformin use in the first year after kidney transplant, correlates, and associated outcomes in diabetic transplant recipients: A retrospective analysis of integrated registry and pharmacy claims data.

While guidelines support metformin as a therapeutic option for diabetic patients with mild-to-moderate renal insufficiency, the frequency and outcomes of metformin use in kidney transplant recipients are not well described. We integrated national U.S. transplant registry data with records from a large pharmaceutical claims clearinghouse (2008-2015). Associations (adjusted hazard ratio, 95% LCL aHR95% UCL ) of diabetes regimens (with and excluding metformin) in the first year post-transplant with patient and graft survival over the subsequent year were quantified by multivariate Cox regression, adjusted for recipient, donor, and transplant factors and propensity for metformin use. Among 14 144 recipients with pretransplant type 2 diabetes mellitus, 4.7% filled metformin in the first year post-transplant; most also received diabetes comedications. Compared to those who received insulin-based regimens without metformin, patients who received metformin were more likely to be female, have higher estimated glomerular filtration rates, and have undergone transplant more recently. Metformin-based regimens were associated with significantly lower adjusted all-cause (aHR 0.18 0.410.91 ), malignancy-related (aHR 0.45 0.450.99 ), and infection-related (aHR 0.12 0.320.85 ) mortality, and nonsignificant trends toward lower cardiovascular mortality, graft failure, and acute rejection. No evidence of increased adverse graft or patient outcomes was noted. Use of metformin-based diabetes treatment regimens may be safe in carefully selected kidney transplant recipients.

OPTN/SRTR 2015 Annual Data Report: Economics.

While the costs to Medicare of solid organ transplants are varied and considerable, the total Medicare expenditure of $4.4 billion for solid organ transplant recipients in 2014 remained less than 1% of all Medicare expenditures. For patients covered by Medicare, the ratio of pre- to posttransplant cost of care varied widely by organ and within some organ categories by patient characteristics. This chapter reports pretransplant costs for all solid organ candidates covered by Medicare to allow investigators to further explore the relative cost of transplant compared with alternative management.

The Changing Financial Landscape of Renal Transplant Practice: A National Cohort Analysis.

Kidney transplantation has become more resource intensive as recipient complexity has increased and average donor quality has diminished over time. A national retrospective cohort study was performed to assess the impact of kidney donor and recipient characteristics on transplant center cost (exclusive of organ acquisition) and Medicare reimbursement. Data from the national transplant registry, University HealthSystem Consortium hospital costs, and Medicare payments for deceased donor (N = 53 862) and living donor (N = 36 715) transplants from 2002 to 2013 were linked and analyzed using multivariate linear regression modeling. Deceased donor kidney transplant costs were correlated with recipient (Expected Post Transplant Survival Score, degree of allosensitization, obesity, cause of renal failure), donor (age, cause of death, donation after cardiac death, terminal creatinine), and transplant (histocompatibility matching) characteristics. Living donor costs rose sharply with higher degrees of allosensitization, and were also associated with obesity, cause of renal failure, recipient work status, and 0-ABDR mismatching. Analysis of Medicare payments for a subsample of 24 809 transplants demonstrated minimal correlation with patient and donor characteristics. In conclusion, the complexity in the landscape of kidney transplantation increases center costs, posing financial disincentives that may reduce organ utilization and limit access for higher-risk populations.

Predonation Prescription Opioid Use: A Novel Risk Factor for Readmission After Living Kidney Donation.

Implications of opioid use in living kidney donors for key outcomes, including readmission rates after nephrectomy, are unknown. We integrated Scientific Registry of Transplant Recipients data with records from a nationwide pharmacy claims warehouse and administrative records from an academic hospital consortium to quantify predonation prescription opioid use and postdonation readmission events. Associations of predonation opioid use (adjusted odds ratio [aOR]) in the year before donation and other baseline clinical, procedural, and center factors with readmission within 90 days postdonation were examined by using multivariate logistic regression. Among 14 959 living donors, 11.3% filled one or more opioid prescriptions in the year before donation. Donors with the highest level of predonation opioid use (>305 mg/year) were more than twice as likely as nonusers to be readmitted (6.8% vs. 2.6%; aOR 2.49, 95% confidence interval 1.74-3.58). Adjusted readmission risk was also significantly (p < 0.05) higher for women (aOR = 1.25), African Americans (aOR = 1.45), spouses (aOR = 1.42), exchange participants (aOR = 1.46), uninsured donors (aOR = 1.40), donors with predonation estimated glomerular filtration rate <60 mL/min/1.73 m2 (aOR = 2.68), donors with predonation pulmonary conditions (aOR = 1.54), and after robotic nephrectomy (aOR = 1.68). Predonation opioid use is independently associated with readmission after donor nephrectomy. Future research should examine underlying mechanisms and approaches to reducing risks of postdonation complications.

The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

National Variation in Use of Immunosuppression for Kidney Transplantation: A Call for Evidence-Based Regimen Selection.

Immunosuppression management in kidney transplantation has evolved to include an increasingly diverse choice of medications. Although informed by patient and donor characteristics, choice of immunosuppression regimen varies widely across transplant programs. Using a novel database integrating national transplant registry and pharmacy fill records, immunosuppression use at 6-12 and 12-24 mo after transplant was evaluated for 22 453 patients transplanted in 249 U.S. programs in 2005-2010. Use of triple immunosuppression comprising tacrolimus, mycophenolic acid or azathioprine, and steroids varied widely (0-100% of patients per program), as did use of steroid-sparing regimens (0-77%), sirolimus-based regimens (0-100%) and cyclosporine-based regimens (0-78%). Use of triple therapy was more common in highly sensitized patients, women and recipients with dialysis duration >5 years. Sirolimus use appeared to diminish over the study period. Patient and donor characteristics explained only a limited amount of the observed variation in regimen use, whereas center choice explained 30-46% of the use of non-triple-therapy immunosuppression. The majority of patients who received triple-therapy (79%), cyclosporine-based (87.6%) and sirolimus-based (84.3%) regimens continued them in the second year after transplant. This population-based study of immunosuppression practice demonstrates substantial variation in center practice beyond that explained by differences in patient and donor characteristics.

Economics.

While the costs to Medicare of solid organ transplants are varied and considerable, the total Medicare expenditure of $4.2 billion for solid organ transplant recipients in 2013 remains less than 1% of all Medicare expenditures. Kidney transplant remains one of the most cost-effective surgical interventions in medicine and exhibits a rare feature in that it is generally known to be cost-saving in the long term. For patients covered by Medicare, lung transplant is one of the more costly solid organ transplants performed. This chapter reports pretransplant costs for lung candidates to allow investigators to further explore the relative cost of lung transplant compared with alternative management.

Economic Impacts of ABO-Incompatible Live Donor Kidney Transplantation: A National Study of Medicare-Insured Recipients.

The infrequent use of ABO-incompatible (ABOi) kidney transplantation in the United States may reflect concern about the costs of necessary preconditioning and posttransplant care. Medicare data for 26 500 live donor kidney transplant recipients (2000 to March 2011), including 271 ABOi and 62 A2-incompatible (A2i) recipients, were analyzed to assess the impact of pretransplant, transplant episode and 3-year posttransplant costs. The marginal costs of ABOi and A2i versus ABO-compatible (ABOc) transplants were quantified by multivariate linear regression including adjustment for recipient, donor and transplant factors. Compared with ABOc transplantation, patient survival (93.2% vs. 88.15%, p = 0.0009) and death-censored graft survival (85.4% vs. 76.1%, p < 0.05) at 3 years were lower after ABOi transplant. The average overall cost of the transplant episode was significantly higher for ABOi ($65 080) compared with A2i ($36 752) and ABOc ($32 039) transplantation (p < 0.001), excluding organ acquisition. ABOi transplant was associated with high adjusted posttransplant spending (marginal costs compared to ABOc - year 1: $25 044; year 2: $10 496; year 3: $7307; p < 0.01). ABOi transplantation provides a clinically effective method to expand access to transplantation. Although more expensive, the modest increases in total spending are easily justified by avoiding long-term dialysis and its associated morbidity and cost.

The Impact of Redistricting Proposals on Health Care Expenditures for Liver Transplant Candidates and Recipients.

Redistricting, which means sharing organs in novel districts developed through mathematical optimization, has been proposed to reduce pervasive geographic disparities in access to liver transplantation. The economic impact of redistricting was evaluated with two distinct data sources, Medicare claims and the University HealthSystem Consortium (UHC). We estimated total Medicare payments under (i) the current allocation system (Share 35), (ii) full regional sharing, (iii) an eight-district plan, and (iv) a four-district plan for a simulated population of patients listed for liver transplant over 5 years, using the liver simulated allocation model. The model predicted 5-year transplant volumes (Share 35, 29,267; regional sharing, 29,005; eight districts, 29,034; four districts, 28,265) and a reduction in overall mortality, including listed and posttransplant patients, of up to 676 lives. Compared with current allocation, the eight-district plan was estimated to reduce payments for pretransplant care ($1638 million to $1506 million, p < 0.001), transplant episode ($5607 million to $5569 million, p < 0.03) and posttransplant care ($479 million to $488 million, p < 0.001). The eight-district plan was estimated to increase per-patient transportation costs for organs ($8988 to $11,874 per patient, p < 0.001) and UHC estimated hospital costs ($4699 per case). In summary, redistricting appears to be potentially cost saving for the health care system but will increase the cost of performing liver transplants for some transplant centers.

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.

Variation in biliary complication rates following liver transplantation: implications for cost and outcome.

Although biliary complications (BCs) have a significant impact on the outcome of liver transplantation (LT), variation in BC rates among transplant centers has not been previously analyzed. BC rate, LT outcome and spending were assessed using linked Scientific Registry of Transplant Recipients and Medicare claims (n = 16,286 LTs). Transplant centers were assigned to BC quartiles based upon risk-adjusted observed to expected (O:E) ratio of BC separately for donation after brain death (DBD) and donation after cardiac death (DCD) donors. The median incidence of BC was 300% greater in the highest versus lowest DBD quartiles (19.0% vs. 5.9%) and varied 250% between DCD quartiles (20.3%-8.4%). Donor and recipient characteristics suggest that high BC centers actually used lower donor risk index organs, fewer split livers and fewer imports (p < 0.001 for all). Transplant at a center in the highest O:E quartile was associated with increased posttransplant mortality (adjusted hazard ratio [aHR] 2.53, p = 0.007) in DCD transplant and increased graft loss (aHR 1.21, p = 0.02) in DBD transplant. Medicare spending was $22,895 (p < 0.0001) higher at centers in highest versus lowest BC quartile. In summary, BC rates vary widely among transplant centers and higher rates are a marker for an increased risk of death, graft failure and health-care spending.

OPTN/SRTR 2013 Annual Data Report: economics.

While the costs to Medicare of solid organ transplant are varied and considerable, the total Medicare expenditure of $4.4 billion for solid organ transplant recipients was less than 1 remains one of the most cost-effective surgical interventions in medicine. Heart transplant, the most expensive of the major transplants, is likely cost-effective; SRTR has released an Excel-based tool for investigators to use in exploring this question further. It is likely that most solid organ transplants are cost-effective, given the results presented here and the relatively high cost of heart transplant. However, this must be verified with further study.

Assessing variation in the costs of care among patients awaiting liver transplantation.

Previous economic analyses of liver transplantation have focused on the cost of the transplant and subsequent care. Accurate characterization of the pretransplant costs, indexed to severity of illness, is needed to assess the economic burden of liver disease. A novel data set linking Medicare claims with transplant registry data for 15,710 liver transplant recipients was used to determine average monthly waitlist spending (N = 249,434 waitlist months) using multivariable linear regression models to adjust for recipient characteristics including Model for End-Stage Liver Disease (MELD) score. Characteristics associated with higher spending included older age, female gender, hepatocellular carcinoma, diabetes, hypertension and increasing MELD score (p < 0.05 for all). Spending increased exponentially with severity of illness: expected monthly spending at a MELD score of 30 was 10 times higher than at MELD of 20 ($22,685 vs. $2030). Monthly spending within MELD strata also varied geographically. For candidates with a MELD score of 35, spending varied from $19,548 (region 10) to $36,099 (region 7). Regional variation in waitlist costs may reflect the impact of longer waiting times on greater pretransplant hospitalization rates among high MELD score patients. Reducing the number of high MELD waitlist patients through improved medical management and novel organ allocation systems could decrease total spending for end-stage liver care.

OPTN/SRTR 2012 Annual Data Report: kidney.

For most end-stage renal disease patients, successful kidney transplant provides substantially longer survival and better quality of life than dialysis, and preemptive transplant is associated with better outcomes than transplants occurring after dialysis initiation. However, kidney transplant numbers in the us have not changed for a decade. Since 2004, the total number of candidates on the waiting list has increased annually. Median time to transplant for wait-listed adult patients increased from 2.7 years in 1998 to 4.2 years in 2008. The discard rate of deceased donor kidneys has also increased, and the annual number of living donor transplants has decreased. The number of pediatric transplants peaked at 899 in 2005, and has remained steady at approximately 750 over the past 3 years; 40.9% of pediatric candidates undergo transplant within 1 year of wait-listing. Graft survival continues to improve for both adult and pediatric recipients. Kidney transplant is one of the most cost-effective surgical interventions; however, average reimbursement for recipients with primary Medicare coverage from transplant through 1 year posttransplant was comparable to the 1-year cost of care for a dialysis patient. Rates of rehospitalization are high in the first year posttransplant; annual costs after the first year are lower.

OPTN/SRTR 2012 Annual Data Report: liver.

Liver transplant in the us remains a successful life-saving procedure for patients with irreversible liver disease. In 2012, 6256 adult liver transplants were performed, and more than 65,000 people were living with a transplanted liver. The number of adults who registered on the liver transplant waiting list decreased for the first time since 2002; 10,143 candidates were added, compared with 10,359 in 2011. However, the median waiting time for active wait-listed adult candidates increased, as did the number of candidates removed from the list because they were too sick to undergo transplant. The overall deceased donor transplant rate decreased to 42.3 per 100 patient-years, and varied geographically from 18.9 to 228.0 per 100 patient-years. Graft survival continues to improve, especially for donation after circulatory death livers. The number of new active pediatric candidates added to the waiting list also decreased. Almost 75% of pediatric candidates listed in 2009 underwent transplant within 3 years; the 2012 rate of deceased donor transplants among active pediatric wait-listed candidates was 136 per 100 patient-years. Graft survival for deceased donor pediatric transplants was 92.8% at 30 days. Medicare paid for some or all of the care for more than 30% of liver transplants in 2010.