Consensus modeling: Safer transfer learning for small health systems.

Predictive modeling is becoming an essential tool for clinical decision support, but health systems with smaller sample sizes may construct suboptimal or overly specific models. Models become over-specific when beside true physiological effects, they also incorporate potentially volatile site-specific artifacts. These artifacts can change suddenly and can render the model unsafe. To obtain safer models, health systems with inadequate sample sizes may adopt one of the following options. First, they can use a generic model, such as one purchased from a vendor, but often such a model is not sufficiently specific to the patient population and is thus suboptimal. Second, they can participate in a research network. Paradoxically though, sites with smaller datasets contribute correspondingly less to the joint model, again rendering the final model suboptimal. Lastly, they can use transfer learning, starting from a model trained on a large data set and updating this model to the local population. This strategy can also result in a model that is over-specific. In this paper we present the consensus modeling paradigm, which uses the help of a large site (source) to reach a consensus model at the small site (target). We evaluate the approach on predicting postoperative complications at two health systems with 9,044 and 38,045 patients (rare outcomes at about 1% positive rate), and conduct a simulation study to understand the performance of consensus modeling relative to the other three approaches as a function of the available training sample size at the target site. We found that consensus modeling exhibited the least over-specificity at either the source or target site and achieved the highest combined predictive performance.

Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells.

Fatty acid binding protein 4 (FABP4) is a secreted adipokine linked to obesity and progression of a variety of cancers. Obesity increases extracellular FABP4 (eFABP4) levels in animal models and in obese breast cancer patients compared with lean healthy controls. Using MCF-7 and T47D breast cancer epithelial cells, we show herein that eFABP4 stimulates cellular proliferation in a time and concentration dependent manner while the non-fatty acid-binding mutant, R126Q, failed to potentiate growth. When E0771 murine breast cancer cells were injected into mice, FABP4 null animals exhibited delayed tumor growth and enhanced survival compared with injections into control C57Bl/6J animals. eFABP4 treatment of MCF-7 cells resulted in a significant increase in phosphorylation of extracellular signal-regulated kinase 1/2 (pERK), transcriptional activation of nuclear factor E2-related factor 2 (NRF2) and corresponding gene targets ALDH1A1, CYP1A1, HMOX1, SOD1 and decreased oxidative stress, while R126Q treatment did not show any effects. Proximity-labeling employing an APEX2-FABP4 fusion protein revealed several proteins functioning in desmosomes as eFABP4 receptor candidates including desmoglein (DSG), desmocollin, junction plankoglobin, desomoplankin, and cytokeratins. AlphaFold modeling predicted an interaction between eFABP4, and the extracellular cadherin repeats of DSG2 and pull-down and immunoprecipitation assays confirmed complex formation that was potentiated by oleic acid. Silencing of DSG2 in MCF-7 cells attenuated eFABP4 effects on cellular proliferation, pERK levels, and ALDH1A1 expression compared with controls. IMPLICATIONS: These results suggest desmosomal proteins, and in particular desmoglein 2, may function as receptors of eFABP4 and provide new insight into the development and progression of obesity-associated cancers.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity.

The obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

Gastroesophageal Reflux Disease Outcomes After Vertical Sleeve Gastrectomy and Gastric Bypass.

OBJECTIVE: The objective of this study is to assess whether vertical sleeve gastrectomy (VSG) increases the incidence of gastroesophageal reflux disease (GERD), esophagitis and Barrett esophagus (BE) relative to patients undergoing Roux-en-Y gastric bypass (RYGB) in patients with and without preoperative GERD. SUMMARY OF BACKGROUND DATA: Concerns for potentiation of GERD, supported by multiple high-quality retrospective studies, have hindered greater adoption of the VSG. METHODS: From the OptumLabs Data Warehouse, VSG and RYGB patients with ≥2 years enrollment were identified and matched by follow-up time. GERD [reflux esophagitis, prescription for acid reducing medication (Rx) and/or diagnosis of BE], upper endoscopy (UE), and re-admissions were evaluated beyond 90 days. RESULTS: A total of 8362 patients undergoing VSG were matched 1:1 to patients undergoing RYGB, on the basis of post-operative follow-up interval. Age, sex, and follow-up time were similar between the 2 groups (P > 0.05). Among all patients, postoperative GERD was more frequently observed in VSG patients relative to RYGB patients (60.2% vs 55.6%, respectively; P < 0.001), whereas BE was more prevalent in RYGB patients (0.7% vs 1.1%; P = 0.007). Postoperatively, de novo esophageal reflux symptomatology was more common in VSG patients (39.3% vs 35.3%; P < 0.001), although there was no difference in development of the histologic diagnoses reflux esophagitis and BE. Furthermore, postoperative re-admission was higher in the RYGB cohort (38.9% vs 28.9%; P < 0.001). CONCLUSIONS: Compared to RYGB, VSG may not have inferior long-term GERD outcomes, while also leading to fewer re-hospitalizations. These data challenge the prevailing opinion that patients with GERD should undergo RYGB instead of VSG.

Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

Background: Pancreatitis accounts for more than $2.5 billion of healthcare costs and remains the most common gastrointestinal (GI) admission. Few contemporary studies have assessed temporal trends of incidence, complications, management, and outcomes for acute pancreatitis in hospitalized patients at the national level. Methods: We used data from one of the largest hospital-based databases available in the United States, the Healthcare Cost and Utilization Project's (HCUP) State Inpatient Database, from 10 states between 2008 and 2015. We included patients with a diagnosis of acute pancreatitis (ICD-9 CM 577.0). Patient- and hospital-level data were used to estimate incidence and inpatient mortality rates. Results: From 80,736,256 hospitalizations, 929,914 (1.15%) cases of acute pancreatitis were identified, 186,226 (20.2%) of which were caused by gallbladder disease). The median age was 53 years (interquartile range [IQR], 41-67) and 50.8% were men. In-hospital mortality was 2.5% and crude mortality rates declined from 2.9% to 2.0% over the study period. Admission year remained significant after adjusting for patient demographics and comorbidities (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.89-0.90; p < 0.001). Gallbladder disease was associated with decreased odds of mortality (OR, 0.60; 95% CI, 0.57-0.62). Median length of stay was four days (IQR, 2-7) and decreased over time. The rates of surgical and endoscopic interventions were highest in 2011 (peak incidence of 16.1% and 9.5%, respectively) and have been decreasing since. Surgical providers were, on average, more likely than medical providers to perform surgery in both those with and without gallbladder disease etiology (gallbladder disease OR, 7.11; 95% CI, 5.46-9.25; non-gallbladder disease OR, 20.50; 95% CI, 16.81-25.01), endoscopy (gallbladder disease OR, 1.22; 95% CI, 0.87-1.72; non-gallbladder disease OR, 1.60; 95% CI, 1.18-2.16), or both (gallbladder disease OR, 7.00; 95% CI, 5.22-9.37; non-gallbladder disease OR, 8.85; 95% CI, 5.61-13.96). Conclusions: The incidence of pancreatitis, from 2008 to 2015, has increased whereas inpatient mortality (i.e., case fatality) has decreased. Understanding temporal trends in outcomes and management along with provider, hospital, and regional variation can better identify areas for future research and collaboration in managing these patients.

Applying Machine Learning Across Sites: External Validation of a Surgical Site Infection Detection Algorithm.

BACKGROUND: Surgical complications have tremendous consequences and costs. Complication detection is important for quality improvement, but traditional manual chart review is burdensome. Automated mechanisms are needed to make this more efficient. To understand the generalizability of a machine learning algorithm between sites, automated surgical site infection (SSI) detection algorithms developed at one center were tested at another distinct center. STUDY DESIGN: NSQIP patients had electronic health record (EHR) data extracted at one center (University of Minnesota Medical Center, Site A) over a 4-year period for model development and internal validation, and at a second center (University of California San Francisco, Site B) over a subsequent 2-year period for external validation. Models for automated NSQIP SSI detection of superficial, organ space, and total SSI within 30 days postoperatively were validated using area under the curve (AUC) scores and corresponding 95% confidence intervals. RESULTS: For the 8,883 patients (Site A) and 1,473 patients (Site B), AUC scores were not statistically different for any outcome including superficial (external 0.804, internal [0.784, 0.874] AUC); organ/space (external 0.905, internal [0.867, 0.941] AUC); and total (external 0.855, internal [0.854, 0.908] AUC) SSI. False negative rates decreased with increasing case review volume and would be amenable to a strategy in which cases with low predicted probabilities of SSI could be excluded from chart review. CONCLUSIONS: Our findings demonstrated that SSI detection machine learning algorithms developed at 1 site were generalizable to another institution. SSI detection models are practically applicable to accelerate and focus chart review.

Discordant Cardiopulmonary Resuscitation and Code Status at Death.

CONTEXT: One fundamental way to honor patient autonomy is to establish and enact their wishes for end-of-life care. Limited research exists regarding adherence with code status. OBJECTIVES: This study aimed to characterize cardiopulmonary resuscitation (CPR) attempts discordant with documented code status at the time of death in the U.S. and to elucidate potential contributing factors. METHODS: The Cerner Acute Physiology and Chronic Health Evaluation (APACHE) outcomes database, which includes 237 U.S. hospitals that collect manually abstracted data from all critical care patients, was queried for adults admitted to intensive care units with a documented code status at the time of death from January 2008 to December 2016. The primary outcome was discordant CPR at death. Multivariable logistic regression models were used to identify patient-level and hospital-level associated factors after adjustment for age, hospital, and illness severity (APACHE III score). RESULTS: A total of 21,537 patients from 56 hospitals were included. Of patients with a do-not-resuscitate code status, 149 (0.8%) received CPR at death, and associated factors included black race, higher APACHE III score, or treatment in small or nonteaching hospitals. Of patients with a full code status, 203 (9.0%) did not receive CPR at death, and associated factors included higher APACHE III score, primary neurologic or trauma diagnosis, or admission in a more recent year. CONCLUSION: At the time of death, 1.6% of patients received or did not undergo CPR in a manner discordant with their documented code statuses. Race and institutional factors were associated with discordant resuscitation, and addressing these disparities may promote concordant end-of-life care in all patients.

The addition of chemoradiation to adjuvant chemotherapy is associated with improved survival in lymph node-positive gastric cancer.

BACKGROUND: In the ARTIST trial, chemoradiation did not improve disease-free survival (DFS) in gastric cancer patients treated with curative-intent surgery and adjuvant chemotherapy. Subgroup analysis suggested chemoradiation improved DFS in patients with lymph node (LN) metastases, but the role of adjuvant chemoradiation remains uncertain. This study sought to determine the role of adjuvant chemoradiation using population-based methods. METHODS: Surveillance, Epidemiology and End Results-Medicare linked data from 2004 to 2013 was used to identify patients aged 66 and older with LN-positive gastric adenocarcinoma. Multivariable logistic regression evaluated factors associated with receipt of chemoradiation. The Kaplan-Meier method and Cox proportional hazards modeling were used to evaluate overall survival (OS). RESULTS: A total of 2409 patients with LN-positive gastric adenocarcinoma who underwent upfront surgical resection were identified; 309 (13%) received adjuvant chemotherapy and 407 (17%) received adjuvant chemotherapy and chemoradiation. Among all patients, median OS was 15 months. Median OS was 20 months for patients who received chemotherapy alone and 27 months for patients who received chemotherapy and chemoradiation (p < 0.05). Recent diagnosis, older age, tumor stage T3 or T4, and Charleston Comorbidity Index were associated with an increased hazard ratio for death (p < 0.05). Receipt of chemoradiation was associated with a decreased hazard ratio for death (p < 0.05). CONCLUSIONS: In patients with LN-positive gastric adenocarcinoma, the addition of chemoradiation to adjuvant chemotherapy after upfront surgical resection was associated with improved survival irrespective of the extent of lymphadenectomy. These data suggest chemoradiation should be considered in patients with LN-positive gastric adenocarcinoma.

Failure to administer multimodality therapy leads to sub-optimal outcomes for patients with node-positive biliary tract cancers in the United States.

BACKGROUND: Lymph node-positive biliary tract cancers have poor overall survival. Surgical resection followed by systemic chemotherapy is the mainstay of treatment. We sought to assess the delivery of multimodality therapy in the United States. METHODS: The Surveillance, Epidemiology, and End Results program database was used to identify patients with node-positive biliary tract cancers without distant metastases from 2000 to 2014. Patients were stratified by disease subtype (gallbladder cancer, intrahepatic, extrahepatic, or hilar cholangiocarcinoma) and treatment received (surgery alone, chemotherapy alone, or surgery + chemotherapy). Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard modeling. RESULTS: A total of 3226 patients with node-positive biliary tract cancers were identified. Of 2837 patients who underwent surgical resection, 1386 (49%) received no systemic chemotherapy following surgery, while 1451 (51%) received surgery + chemotherapy. A total of 389 patients (12%) received chemotherapy alone. Median overall survival was longer for patients who underwent surgery + chemotherapy (19 months, p < 0.0001). There was no difference in survival for those who received surgery alone versus chemotherapy alone (10 months for both, p = NS). Receipt of surgery + chemotherapy was independently associated with survival on Cox proportional hazard ratio modeling compared to surgery alone (HR for mortality 1.71, 95% CI 1.56-1.87, p < 0.0001) or chemotherapy alone (HR 1.68, 95% CI 1.46-1.92, p < 0.0001). These trends were consistent across all disease subtypes. DISCUSSION: Optimal survival for node-positive biliary tract cancers depends on multimodality therapy. Following surgery, a substantial proportion of patients do not receive guideline recommended adjuvant therapy.

Bariatric Surgery is Associated With Decreased Progression of Nonalcoholic Fatty Liver Disease to Cirrhosis: A Retrospective Cohort Analysis.

OBJECTIVE: This study sought to compare trends in the development of cirrhosis between patients with NAFLD who underwent bariatric surgery and a well-matched group of nonsurgical controls. SUMMARY OF BACKGROUND DATA: Patients with NAFLD who undergo bariatric surgery generally have improvements in liver histology. However, the long-term effect of bariatric surgery on clinically relevant liver outcomes has not been investigated. METHODS: From a large insurance database, patients with a new NAFLD diagnosis and at least 2 years of continuous enrollment before and after diagnosis were identified. Patients with traditional contraindications to bariatric surgery were excluded. Patients who underwent bariatric surgery were identified and matched 1:2 with patients who did not undergo bariatric surgery based on age, sex, and comorbid conditions. Kaplan-Meier analysis and Cox proportional hazards modeling were used to evaluate differences in progression from NAFLD to cirrhosis. RESULTS: A total of 2942 NAFLD patients who underwent bariatric surgery were identified and matched with 5884 NAFLD patients who did not undergo surgery. Cox proportional hazards modeling found that bariatric surgery was independently associated with a decreased risk of developing cirrhosis (hazard ratio 0.31, 95% confidence interval 0.19-0.52). Male gender was associated with an increased risk of cirrhosis (hazard ratio 2.07, 95% confidence interval 1.31-3.27). CONCLUSIONS: Patients with NAFLD who undergo bariatric surgery are at a decreased risk for progression to cirrhosis compared to well-matched controls. Bariatric surgery should be considered as a treatment strategy for otherwise eligible patients with NAFLD. Future bariatric surgery guidelines should include NAFLD as a comorbid indication when determining eligibility.

Nonalcoholic Steatohepatitis: A Review.

Importance: Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) and is associated with disease progression, development of cirrhosis, and need for liver transplant. Despite its importance, NASH is underrecognized in clinical practice. Observations: NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing. NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome. Although a number of noninvasive tests and scoring systems exist to characterize NAFLD and NASH, liver biopsy is the only accepted method for diagnosis of NASH. Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. Lifestyle modification is the mainstay of treatment, including dietary changes and exercise, with the primary goal being weight loss. Substantial improvement in histologic outcomes, including fibrosis, is directly correlated with increasing weight loss. In some cases, bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the US. The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years. Conclusions and Relevance: Nonalcoholic steatohepatitis affects 3% to 6% of the US population, is more prevalent in patients with metabolic disease and obesity, progresses to cirrhosis in approximately 20% of cases, and is associated with increased rates of liver-specific and overall mortality. Early identification and targeted treatment of patients with nonalcoholic steatohepatitis are needed to improve patient outcomes, including directing patients toward intensive lifestyle modification to promote weight loss and referral for bariatric surgery as indicated for management of obesity and metabolic disease.

The Impact of Bariatric Surgery on Breast Cancer Recurrence: Case Series and Review of Literature.

BACKGROUND: Excess body weight has been associated with worsening breast cancer survival. While bariatric surgery has been associated with less incident of breast cancer, the role that bariatric surgery plays after breast cancer diagnosis in terms of both feasibility and in preventing breast cancer recurrence is unclear. METHODS: We report the outcomes of 13 individuals who underwent bariatric surgery after definitive breast cancer treatment at a single institution. RESULTS: Thirteen females diagnosed with breast cancer (69.2% stage I, 23.1% stage II) at a median age of 42 years received bariatric surgery between 2001 and 2017. The median age of bariatric surgery was 52 years. Of the 13 patients, 46.2% underwent laparoscopic Roux-en-Y gastric bypass and 38.5% laparoscopic sleeve gastrectomy. The median time from breast cancer treatment to bariatric surgery was 3 years. The procedures were well tolerated. One female developed an abdominal wall hematoma. The average weight loss after 1 year and 2 years was 28.1% and 28.2%, respectively. There was a single breast cancer recurrence with a median follow-up of 11.7 years after breast cancer diagnosis and 5.3 years after bariatric surgery. CONCLUSIONS: Bariatric surgery after breast cancer treatment is feasible and well tolerated. Prospective trials evaluating bariatric surgery in obese breast cancer survivors should be considered.

Racial disparities in perioperative outcomes after bariatric surgery.

BACKGROUND: NonHispanic black patients bear a disproportionate burden of the obesity epidemic and its related medical co-morbidities. While bariatric surgery is the most effective treatment for morbid obesity, black patients access bariatric surgery at lower rates than nonHispanic white patients. OBJECTIVES: To examine racial differences before bariatric surgery and in short-term perioperative outcomes and complications, and the extent to which race is independently associated with perioperative morbidity and mortality. SETTING: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database. METHODS: Data were extracted from the 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program Participant Use File. Multivariate analysis was used to identify differences in mortality, length of stay, readmission, and reintervention by race in patients undergoing laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy (SG). RESULTS: A total of 108,198 patients were included in the analysis. There were significant differences in perioperative disease burden. Black patients had a higher body mass index at the time they underwent surgery (laparoscopic Roux-en-Y gastric bypass: 48.0 versus 45.7 kg/m2; SG: 46.8 versus 44.9 kg/m2; P < .001). Black patients had significantly longer length of stay and higher rates of readmission in both the laparoscopic Roux-en-Y gastric bypass and SG groups. In the SG group, black patients had significantly higher 30-day mortality (.2% versus .1%, odds ratio = 3.613, 95% confidence interval 1.990-6.558, P < .001) and higher rates of reoperation or reintervention. CONCLUSIONS: We found significant racial disparities in bariatric surgery outcomes, including higher mortality in black patients undergoing SG. The specific causes of these disparities remain unclear and must be the subject of future research.

The Log Odds of Positive Lymph Nodes Stratifies and Predicts Survival of High-Risk Individuals Among Stage III Rectal Cancer Patients.

INTRODUCTION: The log odds of positive lymph nodes (LODDS) is an empiric transform formula that incorporates positive and negative lymph node data into a single ratio for prognostic utility. We sought to determine the value of the log odds ratio as a prognostic indicator compared with established lymph node indices in advanced-stage rectal cancer patients who have undergone curative resection. METHODS: Retrospective analysis of rectal cancer operations from 1995 to 2013 identified all stage III cancer patients who underwent curative resection. Patients were stratified into three groups according to calculated lymph node ratios (LNRs) and log odds ratios (LODDS). The relationship between LNR, LODDS, and 5-year overall survival (OS) were assessed. RESULTS: OS for all patients was 81.4%. Both LNR and LODDS stratifications identified differences in 5-year OS. LODDS stratification was significantly associated with OS (p = .04). Additional significant clinicopathologic demographic variables included sex (p = .02), venous invasion (p = .02), tumor location (p < .001), and receipt of adjuvant chemotherapy (p = .047). LODDS separated survival among patients in the low LNR group (LNR1). CONCLUSION: This study confirms that the measure of lymph node involvement transformed by the log odds ratio is a suitable predictor of 5-year overall survival in stage III rectal cancer. LODDS may be applied to stratify high-risk patients in the management of adjuvant therapy. IMPLICATIONS FOR PRACTICE: Traditionally, clinicians have relied solely on the total number of positive lymph nodes affected when determining patient prognosis in rectal cancer. However, the current staging strategy does not account for "high-risk," biologically aggressive tumors that fall into the same risk categories as less clinically aggressive tumors. The log odds of positive lymph nodes is a logistic transform formula that uses pathologic lymph node data to stratify survival differences among patients within a single stage of disease. This formula allows clinicians to identify whether patients with clinically aggressive tumors fall into higher-risk groups, providing additional insight into how to better counsel patients and manage postoperative therapies.

Urinary tract infection after surgery for colorectal malignancy: risk factors and complications.

BACKGROUND: Over 4% of patients undergoing colorectal surgery develop postoperative urinary tract infection (UTI). METHODS: Using 2005 to 2012 American College of Surgeons National Surgical Quality Improvement Program data for 47,781 patients, we examined independent risk factors and complications associated with UTI using multivariate logistic regression. RESULTS: Independent predictors of UTI included female sex (odds ratio [OR] 1.705, 95% confidence interval [CI] 1.508 to 1.928), open procedure (OR 1.419, 95% CI 1.240 to 1.624), rectal procedure (OR 1.267, 95% CI 1.105 to 1.453), age greater than 65 years (OR 1.322, 95% CI 1.151 to 1.519), nonindependent functional status (OR 1.609, 95% CI 1.299 to 1.993), steroid use (OR 1.524, 95% CI 1.116 to 2.080), higher anesthesia class, and longer operative time. Patients with UTI had longer hospital stays (7 vs 12 days), higher reoperation rates (11.9% vs 5.1%), and higher 30-day mortality (3.3% vs 1.7%). Postoperative UTI correlated with other complications, including sepsis, surgical site infections, and pulmonary embolism (P < .001). CONCLUSIONS: Postoperative UTI in colorectal surgery patients correlates with increased morbidity and mortality. Patients who contract postoperative UTI may be more likely to develop multiple complications.

Pretransplant immune regulation predicts allograft outcome: bidirectional regulation correlates with excellent renal transplant function in living-related donor-recipient pairs.

BACKGROUND: Tolerance to noninherited maternal antigens has provided clinical advantage when kidney transplants are exchanged between siblings but not when mother herself is the donor. This paradox prompted us to revisit the "two-way" hypothesis of transplant tolerance--that the immune status of both the organ recipient and the organ donor critically influences allograft outcome. METHODS: We obtained peripheral blood monocyte cells from 29 living donor-recipient pairs before transplant and used the trans-vivo-delayed type hypersensitivity assay to measure immune regulation in both the recipient antidonor and donor antirecipient directions. RESULTS: We found preexisting bidirectional regulation in all human leukocyte antigen (HLA)-identical sibling pairs tested (7/7), and one half (9/18) of the HLA haploidentical pairs. No significant regulation was found in four control living unrelated and two HLA haploidentical living-related donor recipient pairs, whereas unidirectional regulation was found in the remaining seven haploidentical pairs. Of the nine HLA haploidentical transplants with unidirectional or no pretransplant regulation, seven had an acute rejection episode and four of these experienced graft loss. In contrast, of the nine HLA haploidentical transplants with bidirectional regulation, only one had rejection. Renal function for the latter group was similar to HLA-identical kidney recipients at 3 years posttransplant. Significantly (P<0.05) lower mean serum creatinine values in bidirectional regulators were noted as early as 4 months and this difference became more pronounced at 12 (P<0.005) and 36 months (P<0.0001). CONCLUSIONS: Contrary to the belief that only the recipient's immune status matters, the data indicate that pretransplant immune status of both donor and recipient influence posttransplant outcome.