Longitudinal analysis of living donor kidney transplant rates in pediatric candidates in the United States.

Among adults, living donor kidney transplant rates began declining in the United States after 2004 but whether a similar decline is occurring in the pediatric candidates has not been well studied. Share 35, a change in allocation rules implemented in October of 2005, may also have influenced rates of living donation. We sought to determine whether a decline in rates was occurring in pediatric candidates and whether the Share 35 program was the cause of the decline. All children listed for a kidney transplant or transplanted with a living donor without listing between 1996 and 2011 were identified in the United States (N=14 911) of which 6046 had received a living donor transplant during follow-up. Kaplan-Meier analysis showed a decline in living donor rates in candidates listed after 2001. Logistic regression analysis for living donor kidney transplantation confirmed the timing of the drop but also showed that changes in candidate demographics and center listing practices were impacting rates. A large drop in parental donation was the main cause for the drop. The rate of living donor transplant among pediatric candidates declined after 2001 predating by 4 years the implementation of Share 35, suggesting that factors other than changes in allocation rules are responsible for the decline.

Therapeutic apheresis in renal transplantation; current practices.

Apheresis is an important treatment modality for the removal of pathologic antibodies and circulating proteins in kidney transplantation. The use of apheresis has been shown to be a necessary preconditioning component in ABO incompatible kidney transplant. Removal of pathologic anti-A and anti-B antibodies has been accomplished with a variety of apheresis modalities including plasma exchange, fractional plasma exchange, and immunoabsorption techniques. Using these modalities in conjunction with potent modern immunosuppression, ABO incompatible kidney transplants have achieved graft and patient survivals similar to that seen in ABO compatible transplants. Apheresis has also been an important modality in the removal of anti-human leukocyte antigen (HLA) antibodies both for the purposes of desensitization and treatment of antibody mediated rejection of the kidney. Although good randomized controlled trials are lacking in the treatment of acute antibody mediated rejection, most treatment regimens include the use of apheresis as an essential component for reduction of anti-HLA antibody titers. Similarly, a variety of desensitization protocols have been developed to allow highly sensitized kidney transplant candidates to be successfully transplanted in the presence of donor-specific HLA antibodies. Most of these protocols involve apheresis to improve the removal of pathologic antibodies. Finally, aphereis has been used with mixed success for the treatment of recurrent focal segmental glomerulosclerosis. Evidence indicates that in some cases a circulating factor exists which apheresis can remove and ameliorate the nephrotic proteinuria.

Successful Development of a Natural Language Processing Algorithm for Pancreatic Neoplasms and Associated Histologic Features.

OBJECTIVES: Natural language processing (NLP) algorithms can interpret unstructured text for commonly used terms and phrases. Pancreatic pathologies are diverse and include benign and malignant entities with associated histologic features. Creating a pancreas NLP algorithm can aid in electronic health record coding as well as large database creation and curation. METHODS: Text-based pancreatic anatomic and cytopathologic reports for pancreatic cancer, pancreatic ductal adenocarcinoma, neuroendocrine tumor, intraductal papillary neoplasm, tumor dysplasia, and suspicious findings were collected. This dataset was split 80/20 for model training and development. A separate set was held out for testing purposes. We trained using convolutional neural network to predict each heading. RESULTS: Over 14,000 reports were obtained from the Mass General Brigham Healthcare System electronic record. Of these, 1252 reports were used for algorithm development. Final accuracy and F1 scores relative to the test set ranged from 95% and 98% for each queried pathology. To understand the dependence of our results to training set size, we also generated learning curves. Scoring metrics improved as more reports were submitted for training; however, some queries had high index performance. CONCLUSIONS: Natural language processing algorithms can be used for pancreatic pathologies. Increased training volume, nonoverlapping terminology, and conserved text structure improve NLP algorithm performance.

Preemptive deceased donor kidney transplant not associated with patient survival benefit in minority kidney transplant recipients.

Previous studies have shown an inverse association between pre-transplant dialysis exposure and post-kidney transplant outcomes. Socioeconomic and allocation factors, in contrast to medical factors, play a greater role in dialysis exposure among minorities, and medical causes for delay may impact post-transplant outcomes. This study sought to test whether minorities behaved similarly to Caucasians with regard to the effect of duration of dialysis on post-transplant outcomes. All primary deceased donor kidney transplants between 1997 and 2004 (n = 54,162) were analyzed from the Organ Procurement and Transplant Network database and were categorized as either Caucasian or minority. Adjusted patient and graft survivals were determined in each subgroup based on the duration of pre-transplant dialysis. Caucasians recipients show a clear stepwise increase in risk of graft failure and death with increasing duration of dialysis. The risk of graft failure among minorities increased less without a clear stepwise pattern. The risk of death, however, showed a U-shaped risk profile with the highest risk of death among preemptive transplants and recipients with more than five yr of dialysis. The disparate effect of dialysis on minorities suggests that a selection bias and not a biologic effect may explain the association between dialysis duration and outcomes after kidney transplantation previously reported.

Therapeutic apheresis rescue mission: recurrent focal segmental glomerulosclerosis in renal allografts.

Recurrent idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation can lead to a rapid failure of the allograft. A circulating, nonimmunoglobulin factor appears to be important in the pathogenesis of this complication in many cases. Between 30% and 50% of transplant recipients with FSGS develop recurrent disease. Three major risk factors for recurrence have been identified: short duration of native kidney disease, history of recurrence with previous kidney transplant, and pediatric aged recipients. Although no properly controlled trials have been conducted, plasmapheresis has emerged as one of the important treatment modalities for this entity. Retrospective studies prior to the routine use of plasmapheresis showed graft loss rates as high as 80%, a rate much higher than that seen in more recent series managed with plasmapheresis. Duration and intensity of treatment of plasmaphersis have not been studied rigorously, but in most case series, plasmapheresis was continued until a clear diminution of proteinuria was seen. The benefit of other adjuvant therapies for this condition remains unclear, but also may play a role in the treatment of this entity.

The effect of music-based listening interventions on the volume, fat content, and caloric content of breast milk-produced by mothers of premature and critically ill infants.

PURPOSE: Maternal breast milk is considered the nutritional "gold standard" for all infants, especially premature infants. However, preterm mothers are at risk of not producing adequate milk. Multiple factors affect the production of milk, including stress, fatigue, and the separation of the breastfeeding dyad-for example, when mother or infant is hospitalized. The purpose of this study was to examine the effects of listening and visual interventions on the quantity and quality of breast milk produced by mothers using a double electric breast pump. SUBJECTS: Mothers of 162 preterm infants were randomly assigned to 1 of 4 groups. METHODS: The control group received standard nursing care, whereas mothers in the 3 experimental groups additionally listened to a recording of 1 of 3 music-based listening interventions while using the pump. RESULTS: Mothers in the experimental groups produced significantly more milk (P < .0012). Mothers in these groups also produced milk with significantly higher fat content during the first 6 days of the study.

Short-term kidney transplant outcomes among African American recipients do not predict long-term outcomes: donor pair analysis.

African American (AA) renal transplant recipients have poorer graft survival compared to other racial and ethic groups. This study was undertaken to determine whether pre-transplant factors and events occurring in the first six months post-transplant were predictive of the poorer long-term outcomes in AA recipients. To control for kidney quality, a paired analysis of deceased donor kidneys in which one donor kidney was transplanted into an adult AA recipient and the other was transplanted into an adult Caucasian was undertaken. Cox proportional hazard modeling was used to determine the impact of outcome variables at six months. Outcomes at six months among the paired recipients were very similar for graft and patient survival, and estimated glomerular filtration rate (GFR). Less than 10% of difference in long-term outcomes was explained by differences in the pre-transplant covariates and events in the first six months. Causes of graft failure after six months revealed a two to three times higher rate of chronic allograft nephropathy (CAN) and late acute rejection among AA. In conclusion, early outcomes after kidney transplant did not predict the poor long-term graft survival among AA, and AA recipients appear to be more prone to graft loss because of CAN and late acute rejection.

Parsing the 100% calculated panel reactive antibody kidney transplant candidates: Who gets transplanted?

The new kidney allocation system in the United States has improved deceased donor transplant rates among candidates with high calculated panel reactive antibodies (CPRAs). Probability analysis predicts a very low transplant rate as the CPRA approaches 100%. This study sought to determine if the rate of deceased donor kidney transplant based on the actual CPRA in the cohort of 100% qualifying candidates behaved as predicted by probability analysis. Nine thousand two hundred and twenty eight patients were identified on the waiting list on or after December 2014 that had at least one CPRA greater than or equal to 99.5%. The distribution of the 100% CPRA group was highly skewed toward 100% (Median CPRA 99.98%). The decile group within the 100% CPRA qualifying population was by far the most important factor determining kidney transplantation. The highest two deciles of CPRA had a very low rate of transplantation. Options to improve the prospects of deceased donor transplant include intelligently lowering the CPRA by reducing unacceptable antigens, expanding the donor pool by listing candidates for higher risk donors, or through desensitization. The CPRA calculator should display the non-integer CPRA out to several decimal points so that informed decisions can be made for these candidates regarding their prospects of receiving a deceased donor offer.

Emerging therapies for PBC.

Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middle-aged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.

The effects of music listening on inconsolable crying in premature infants.

Over the decades, medical staff have developed strategies to manage crying episodes of the critically ill and convalescing premature infant. These episodes of crying occur frequently after infants are removed from ventilation, but before they are able to receive nutrition orally. Not only are these episodes stressful to infants and upsetting to parents, but they are also stressful and time consuming for the staff that take care of these patients. Although the literature supports the benefits of music therapy in regard to physiological and certain behavioral measures with premature infants, no research exists that explores the use of music therapy with inconsolability related to the "nothing by mouth" status. This study explored the effects of music therapy on the crying behaviors of critically ill infants classified as inconsolable. Twenty-four premature infants with gestational age 32-40 weeks received a developmentally appropriate music listening intervention, alternating with days on which no intervention was provided. The results revealed a significant reduction in the frequency and duration of episodes of inconsolable crying as a result of the music intervention, as well as improved physiological measures including heart rate, respiration rate, oxygen saturation, and mean arterial pressure. Findings suggest the viability of using recorded music in the absence of a music therapist or the maternal voice to console infants when standard nursing interventions are not effective.

Living Donor Nephrectomy: Is It as Safe as It Can Be? Analysis of Living Donor Deaths in the United States.

INTRODUCTION: The reported 90-day rate of death from living donor nephrectomy is 3 in 10,000 donations. Although this risk is low, the important question is how many deaths are preventable? METHODS: To study this question, all living donor nephrectomy cases, 139,186 procedures, recorded in the Scientific Registry of Transplant Recipients database since its inception in 1987 were analyzed to determine the death rate and the number of deaths that were potentially preventable. Preventable deaths were defined as any death in the first 7 days except due to clearly unrelated events or death from hemorrhage, pulmonary embolism, infection, cardiovascular cause, or suicide in the first 90 days. RESULTS: The numbers of deaths at 7, 30, 90, and 365 days after donation were 16, 26, 38, and 86, which translated into 1.15, 1.87, 2.73, and 6.18 deaths per 10,000 donations, respectively. From 2000 onward, when coding was available for cause of death, 19 of the 30 deaths were deemed potentially preventable. The nonrisk-adjusted rate of death with laparoscopic donation was higher than open nephrectomy, but this difference did not reach statistical significance. Conversion from laparoscopic to open nephrectomy occurs in approximately 1 in 100 surgeries, and this rate has remained fairly steady since 2005. CONCLUSIONS: This analysis suggests that up to two thirds of deaths are potentially preventable. The transplant community should consider additional safety strategies such as simulation training of rare complications to lower donor risk.

How Organisms Gained Causal Independence and How It Might Be Quantified.

Two broad features are jointly necessary for autonomous agency: organisational closure and the embodiment of an objective-function providing a ‘goal’: so far only organisms demonstrate both. Organisational closure has been studied (mostly in abstract), especially as cell autopoiesis and the cybernetic principles of autonomy, but the role of an internalised ‘goal’ and how it is instantiated by cell signalling and the functioning of nervous systems has received less attention. Here I add some biological ‘flesh’ to the cybernetic theory and trace the evolutionary development of step-changes in autonomy: (1) homeostasis of organisationally closed systems; (2) perception-action systems; (3) action selection systems; (4) cognitive systems; (5) memory supporting a self-model able to anticipate and evaluate actions and consequences. Each stage is characterised by the number of nested goal-directed control-loops embodied by the organism, summarised as will-nestedness N. Organism tegument, receptor/transducer system, mechanisms of cellular and whole-organism re-programming and organisational integration, all contribute to causal independence. CONCLUSION: organisms are cybernetic phenomena whose identity is created by the information structure of the highest level of causal closure (maximum N), which has increased through evolution, leading to increased causal independence, which might be quantifiable by ‘Integrated Information Theory’ measures.

Graft Function and Intermediate-Term Outcomes of Kidney Transplants Improved in the Last Decade: Analysis of the United States Kidney Transplant Database.

BACKGROUND: Previous analyses of the United States transplant database regarding long-term outcomes in kidney transplantation have shown minimal improvement in the rate of long-term graft loss. This study sought to analyze intermediate-term outcomes and graft function at 6 months in kidney transplantation in adult living and deceased donor recipients in the last decade. METHODS: Survival analysis was performed based on the year of transplant between 6 months and 3 years' posttransplant. The Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) was determined at 6 months. RESULTS: The unadjusted graft survival between 6 months and 3 years improved significantly in the latter half of the decade in both deceased and living donor kidney recipients. Cox analysis showed a 33% reduction in the rate of graft loss and that the improvement in graft survival was due to similar improvements in both death-censored graft and death with graft function survival. A 10% improvement in median eGFR occurred despite worsening donor demographics over time in both donor types. This improvement in eGFR and graft survival occurred in association with a consolidation of chronic discharge immunosuppression from a variety of combinations to over 85% of recipients receiving tacrolimus and mycophenolate derivative immunosuppression. CONCLUSIONS: In the latter half of last decade graft survival improved in adult kidney transplant recipients. The improvement in graft survival occurred in temporal association with an improvement in median eGFR at 6 months and consolidation of discharge immunosuppression in most patients to tacrolimus and mycophenolate derivatives.

Prediction of the glomerular filtration rate using equations in kidney-pancreas transplant patients receiving cimetidine.

BACKGROUND: Current estimates of renal function in kidney transplant patients are frequently inaccurate compared to radionuclide GFR (rGFR) measurement. Cimetidine inhibits tubular secretion of creatinine and improves the accuracy of formulas to estimate GFR. METHODS: We studied the effect of a cimetidine-aided (800 mg tid for 24 hr) serum creatinine on the correlation of creatinine clearance and three prediction formulas (Cockroft-Gault, Levey, and Nankivell) compared to rGFR in 15 kidney-pancreas transplant patients. Results were adjusted for body surface area. RESULTS: Correlations with rGFR using cimetidine-aided creatinine were: Cockroft-Gault, r=0.710; Levey, r=0.752; Nankivell, r=0.676; creatinine clearance, r=0.643. By Bland and Altman analysis, agreement with rGFR was best with the Nankivell and Cockroft-Gault equations and worst with creatinine clearance. Cimetidine ($0.48 Canadian) costs substantially less than the rGFR test ($66.00 Canadian). CONCLUSION: Using cimetidine, prediction equations give a stronger correlation with GFR than creatinine clearance.

Impact of comorbidities on mortality in managed care patients with CKD.

BACKGROUND: Our previous work showed that patients with chronic kidney disease (CKD) were 10 times more likely to die than progress to end-stage renal disease. This study examines the impact of comorbidities on mortality risk in a cohort with CKD at 3 levels of progression and a sex- and age-matched comparison group. METHODS: In a historical, prospective, cohort study, we selected electronic medical record data for health maintenance organization (HMO) members with an index and repeated glomerular filtration rate (GFR) in the range of 15 to 90 mL/min/1.73 m(2) (0.25 to 1.50 mL/s/1.73 m(2)) in 1996 who were followed up for at least 54 months or died during this period. These were matched for birth year and sex with HMO members not meeting GFR criteria, but with the same follow-up criteria. Major comorbid chronic conditions also were identified based on International Classification of Diseases, Ninth Revision, diagnostic codes in the electronic medical record. Conditional logistic regression was used to estimate the relative risk for mortality versus comparison subjects as a function of GFR, age, and other chronic conditions. RESULTS: In the final sample of 19,945 pairs, we found that risk for mortality increases as GFR decreases, but also that both age and other chronic conditions are significant risk factors for mortality. CONCLUSION: Baseline levels of estimated GFR and other major chronic disorders all contributed negatively to survival. The relative impact of these comorbidities was greatest among younger (<60 years) patients with CKD, and their relative effect diminished with age.

Approach to the Highly Sensitized Kidney Transplant Candidate.

For patients with ESRD, kidney transplant offers significant survival and quality-of-life advantages compared with dialysis. But for patients seeking transplant who are highly sensitized, wait times have traditionally been long and options limited. The approach to the highly sensitized candidate for kidney transplant has changed substantially over time owing to new advances in desensitization, options for paired donor exchange (PDE), and changes to the deceased-donor allocation system. Initial evaluation should focus on determining living-donor availability because a compatible living donor is always the best option. However, for most highly sensitized candidates this scenario is unlikely. For candidates with an incompatible donor, PDE can improve the prospects of finding a compatible living donor but for many highly sensitized patients the probability of finding a match in the relatively small pools of donors in PDE programs is limited. Desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of sensitization by calculated panel-reactive antibody (cPRA) is critical in counseling the highly sensitized patient on expected wait times to deceased-donor transplant. For candidates with a high likelihood of finding a compatible deceased donor in a reasonable time frame, waiting for a kidney is a good strategy. For the candidate without a living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can be considered. The approach to the highly sensitized kidney transplant candidate must be individualized and requires careful discussion among the transplant center, patient, and referring nephrologist.

Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.

BACKGROUND: Chronic kidney disease is the primary cause of end-stage renal disease in the United States. The purpose of this study was to understand the natural history of chronic kidney disease with regard to progression to renal replacement therapy (transplant or dialysis) and death in a representative patient population. METHODS: In 1996 we identified 27 998 patients in our health plan who had estimated glomerular filtration rates of less than 90 mL/min per 1.73 m(2) on 2 separate measurements at least 90 days apart. We followed up patients from the index date of the first glomerular filtration rates of less than 90 mL/min per 1.73 m(2) until renal replacement therapy, death, disenrollment from the health plan, or June 30, 2001. We extracted from the computerized medical records the prevalence of the following comorbidities at the index date and end point: hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, hyperlipidemia, and renal anemia. RESULTS: Our data showed that the rate of renal replacement therapy over the 5-year observation period was 1.1%, 1.3%, and 19.9%, respectively, for the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) stages 2, 3, and 4, but that the mortality rate was 19.5%, 24.3%, and 45.7%. Thus, death was far more common than dialysis at all stages. In addition, congestive heart failure, coronary artery disease, diabetes, and anemia were more prevalent in the patients who died but hypertension prevalence was similar across all stages. CONCLUSION: Our data suggest that efforts to reduce mortality in this population should be focused on treatment and prevention of coronary artery disease, congestive heart failure, diabetes mellitus, and anemia.

Infectious complications in living-donor kidney transplant recipients undergoing multi-modal desensitization.

BACKGROUND: Pre-existing humoral barriers challenge the transplantation of living donor kidneys (LDK) into highly sensitized ABO- and human leukocyte antigen (HLA)-incompatible recipients. Conditioning these LDK recipients' immune systems is required before they undergo transplantation. We hypothesized that medical desensitization would yield higher post-transplantation rates of infection. METHODS: We conducted a study in which matched controls consisting of non-desensitized (NDS) LDK recipients were compared with desensitized (DS) receipients. Pre-transplantation desensitization included treatment with rituximab and mycophenolate mofetil followed by intravenous immunoglobulin (IVIg) and plasmapheresis. All participants in the study underwent induction therapy and maintenance immunosuppression. Primary outcomes included infection (opportunistic, local, systemic) within 12 mo after transplantation. RESULTS: Twenty-five patients underwent desensitization and LDK transplantation. Graft survival in the DS and NDS groups of patients was 96% and 98%, respectively. The mean 3- and 12-mo serum creatinine concentrations in the DS and NDS groups were 1.1±0.2 mg/dL and 1.2±0.3 mg/dL and 0.95±0.4 mg/dL and 0.73±0.8 mg/dL (p=0.3 and p=0.01), respectively. Thirty-six percent of the patients in the DS group had one or more infections, vs. 28% of those in the NDS group (p=0.1). No difference was observed in the frequency of opportunistic or systemic infections in the two groups. Local infections were statistically significantly more frequent in the DS group (60% vs. 30%, respectively; p=0.02). CONCLUSION: Pre-operative desensitization in highly sensitized LDK recipients is followed by a similar incidence of opportunistic and systemic infections as in NDS patients. Local infections were significantly more frequent in the DS than in the NDS patients in the study. With careful monitoring of infectious complications, pre-transplant desensitization permits LDK transplantation into highly sensitized patients.

Transplantation in the elderly patient.

During the last 2 decades, the number of kidney transplants performed in the candidates older than 65 years has grown dramatically. For selected geriatric patients with end-stage kidney failure, kidney transplantation has emerged as a potential option for treatment of their end organ failure. Aging is associated with functional changes to the immune system known as immunosenescence, and this age-related decline in immune function has important implications for immunosuppression in this subgroup of kidney transplant recipients.

H-Y Antigen Incompatibility Not Associated with Adverse Immunologic Graft Outcomes: Deceased Donor Pair Analysis of the OPTN Database.

Background. H-Y antigen incompatibility adversely impacts bone marrow transplants however, the relevance of these antigens in kidney transplantation is uncertain. Three previous retrospective studies of kidney transplant databases have produced conflicting results. Methods. This study analyzed the Organ Procurement and Transplantation Network database between 1997 and 2009 using male deceased donor kidney transplant pairs in which the recipient genders were discordant. Death censored graft survival at six months, five, and ten years, treated acute rejection at six months and one year, and rates of graft failure by cause were the primary endpoints analyzed. Results. Death censored graft survival at six months was significantly worse for female recipients. Analysis of the causes of graft failure at six months revealed that the difference in death censored graft survival was due primarily to nonimmunologic graft failures. The adjusted and unadjusted death censored graft survivals at five and ten years were similar between the two genders as were the rates of immunologic graft failure. No difference in the rates of treated acute rejection at six months and one year was seen between the two genders. Conclusions. Male donor to female recipient discordance had no discernable effect on immunologically mediated kidney graft outcomes in the era of modern immunosuppression.