Doctor of Philosophy

dissertationAlthough renal transplant is the preferred modality for end-stage renal disease, it brings with it a number of challenges primarily associated with lack of individualized approach. The goals of the present project were: (1) to determine the most significant and clinically practical predictors of kidney transplant outcomes (patient survival, allograft survival, posttransplant complications) using United States Renal Data System (USRDS) data; (2) based on the selected predictors, to generate prediction models of renal transplant outcomes. Our initial study developed prediction models using logistic regression and treebased algorithms derived from data provided by the United Network of Organ Sharing (UNOS). A series of follow-up projects, using data supplied by the United States Renal Data System (USRDS), was performed. We were able to capture significant associations between donor, recipient, and transplant procedure variables (that could not be derived from UNOS data) and the allograph and recipient survival. Among our important findings, compared to peritoneal dialysis (PD), hemodialysis is associated with increased risk of graft failure and recipient death; preemptive retransplantation is associated with an increased risk of graft failure; increased time on dialysis between transplants is associated with a negative effect upon graft and recipient survival in most patient subgroups; short-term (6 months or less) dialysis had no negative effect on graft survival compared to preemptive transplants; certain socioeconomic factors, such as higher education level, citizenship, and type of insurance coverage, influenced graft and recipient outcomes, independent of racial differences; and that one particular iv immunosuppressive medication regimen was superior to others in prolonging graft and recipient survival. Based on these results, we developed a more comprehensive prediction model of the graft outcome using URSDS data using logistic regression and tree-based models. The new models included both deceased and living donor graft recipients, was based on the longer list of pertinent predictors while still being practical in the clinical setting, and addressed the probability of graft failure at five different time points (1, 3, 5, 7, and 10- year allograft survival). The models have been validated on the independent dataset and demonstrated performance suggesting implementation in the clinical decision support system

Single and multiple time-point prediction models in kidney transplant outcomes

abstractThis study predicted graft and recipient survival in kidney transplantation based on the USRDS dataset by regression models and artificial neural networks (ANNs). We examined single time-point models (logistic regression and single-output ANNs) versus multiple time-point models (Cox models and multiple-output ANNs). These models in general achieved good prediction discrimination (AUC up to 0.82) and model calibration. This study found that: (1) Single time-point and multiple time-point models can achieve comparable AUC, except for multiple-output ANNs, which may perform poorly when a large proportion of observations are censored, (2) Logistic regression is able to achieve comparable performance as ANNs if there are no strong interactions or non-linear relationships among the predictors and the outcomes, (3) Time-varying effects must be modeled explicitly in Cox models when predictors have significantly different effects on short-term versus long-term survival, and (4) Appropriate baseline survivor function should be specified for Cox models to achieve good model calibration, especially when clinical decision support is designed to provide exact predicted survival rates

New social adaptability index predicts overall mortality

Introduction: Definitions of underprivileged status based on race, gender and geographic location are neither sensitive nor specific; instead we proposed and validated a composite index of social adaptability (SAI). Material and methods: Index of social adaptability was calculated based on employment, education, income, marital status, and substance abuse, each factor contributing from 0 to 3 points. Index of social adaptability was validated in NHANES-3 by association with all-cause and cause-specific mortality. Results: Weighted analysis of 19,593 subjects demonstrated mean SAI of 8.29 (95% CI 8.17-8.40). Index of social adaptability was higher in Whites, followed by Mexican-Americans and then the African-American population (ANOVA, p < 0.001). The SAI was higher in subjects living in metropolitan compared to rural areas (T-test, p < 0.001), and was greater in men than in women (T-test, p < 0.001). In Cox models adjusted for age, comorbidity index, BMI, race, sex, geographic location, hemoglobin, serum creatinine, albumin, cholesterol, and glycated hemoglobin levels, SAI was inversely associated with mortality (HR 0.87 per point, 95% CI 0.84-0.90, p < 0.001). This association was confirmed in subgroups. Conclusions: We proposed and validated an indicator of social adaptability with a strong association with mortality, which can be used to identify underprivileged populations at risk of death

The best dialysis therapy? Results from an international survey among nephrology professionals

Background. There is little evidence for superior outcome of one dialysis therapy versus another. Still, nephrologists have to prescribe dialysis every day. It is therefore of interest to ascertain the opinion among nephrology professionals regarding which therapy they consider to be the best and to compare this to reality

Prediction Model and Risk Stratification Tool for Survival in Patients With CKD

Introduction: Because chronic kidney disease (CKD) adversely affects survival, prediction of mortality risk should help to identify individuals requiring therapeutic intervention. The goal of this project was to construct and to validate a risk scoring system and prediction model of the probability of 2-year mortality in a CKD population. Methods: We applied the Woodpecker approach to develop prediction equations using linear, exponential, and combined models. A risk indicator R on a scale of 0 to 10 was calculated as follows: starting with 0, add 0.048 for each year of age above 20, 0.45 for male sex, 0.49 for each stage of CKD over stage 2, 1.04 for proteinuria, 0.72 for smoking history, and 0.49 for each significant comorbidity up to 5. Results: Using R to predict 2-year mortality, the model yielded an area under the receiver operating characterisic curve of 0.83 (95% confidence interval = 0.81−0.86) with 5062 subjects with CKD ≥stage 2 from a National Health and Nutrition Examination Survey cohort (1999−2004) having a 3.2% 2-year mortality. The combined expression offered results closest to most actual outcomes for the entire population and for each CKD stage. For those patients with higher risk (R ≥ 4−5, >5−6, and >6), the predicted 2-year mortality rates were 3.8%, 6.4%, and 13.0%, respectively, compared to observed mortality rates of 2.7%, 4.5%, and 13.3%. Conclusion: The risk stratification tool and prediction model of 2-year mortality demonstrated good performance and may be used in clinical practice to quantify the risk of death for individual patients with CKD

Randomized Phase 2b Trial of Tofacitinib (CP‐690,550) in De Novo Kidney Transplant Patients: Efficacy, Renal Function and Safety at 1 Year

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93568/1/j.1600-6143.2012.04127.x.pd

Genetic variation in Caveolin-1 correlates with long-term pancreas transplant outcome

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long-term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin-1 gene (Cav1), previously shown to correlate with long-term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death-censored cumulative events were analyzed using Kaplan-Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long-term graft function (p = 0.331-0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long-term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16-2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03-2.73]) with long-term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long-term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results

Transplantation in Diabetic Kidney Failure Patients: Modalities, Outcomes, and Clinical Management

Diabetes mellitus (DM) is a common and devastating disease, affecting up to 19.3 million Americans. It is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. Diabetic patients with ESRD have a high incidence of cardiovascular disease and death. For those kidney transplant patients with no history of DM prior to transplantation, the development of new onset diabetes after transplantation (NODAT) also poses a serious threat to both graft and patient survival. Kidney transplantation is the best renal replacement option for diabetic ESRD and has the potential to halt the progression of cardiovascular diseases. Early referral for transplant evaluation is essential for pre-emptive or early kidney transplantation in this cohort of patients. In type 1 DM patients with ESRD, simultaneous pancreas and kidney transplantation (SPK) should be encouraged; and in patients facing prolonged waiting time for SPK transplantation but with an available living donor, living donor kidney transplantation followed by pancreas after kidney transplantation (PAK) is a suitable alternative. Islet transplantation in type 1 diabetics is deemed experimental by Medicare, and easy access to this modality remains restricted to qualified patients enrolled in clinical trials or with private insurance. The optimal management of kidney transplant patients with pre-existent DM or NODAT involves a multi-pronged approach consisting of pharmacological and nonpharmacological intervention to address all potential cardiovascular risk factors such as glycemic and lipid control, blood pressure control, weight loss, and smoking cessation. Finally, re-transplantation should be recommended in suitable kidney transplant patients when the kidney allograft demonstrates continuous and progressive decline in function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79210/1/j.1525-139X.2010.00708.x.pd

Family history of chronic renal failure is associated with malnutrition in Korean hemodialysis patients

The present study was to investigate the nutritional status and factors related to malnutrition in end-stage renal disease (ESRD) patients requiring hemodialysis (HD) in South Korea. Subjects were ESRD outpatients from general hospitals or HD centers in Seoul referred to the dialysis clinic for maintenance HD care. A total of 110 patients (46 men and 64 women; mean ages 58.6 ± 1.0 y) were eligible for this study. The family history of chronic renal failure (CRF) was considered positive if a patient reported having either a first-degree or second-degree relative with CRF. Malnutrition was defined as a triceps skinfold thickness or mid-arm muscle circumference below the fifth percentile for age and sex and forty-seven of the 110 patients were malnourished. Almost all (94%) patients had anemia (hemoglobin: <13 g/dL for men and <12 g/dL for women). Energy intake was below the recommended intake levels of energy [30-35 kcal/kg ideal body weight (IBW)] and protein (1.2 g/kg IBW) in 60% of patients. The duration of HD was longer in malnourished HD patients (P=0.0095). Malnutrition was more prevalent in women (P=0.0014), those who never smoked (P=0.0007), nondiabetic patients (P=0.0113), and patients with bone diseases (P=0.0427), adequate HD (spKt/V≥1.2) (P=0.0178), and those with a family history of CRF (P=0.0255). Multiple logistic regression was used to examine the relationship between malnutrition and potential risk factors. After adjusting for age, sex, and other putative risk factors for malnutrition, the OR for malnutrition was greater in HD patients with a family history of CRF (OR, 3.290; 95% CI, 1.003-10.793). Active nutrition monitoring is needed to improve the nutritional status of HD patients. A family history of CRF may be an independent risk factor for malnutrition in Korean HD patients. A follow-up study is needed to investigate whether there is a causal relationship between a family history of CRF and malnutrition in Korean ESRD patients

Kidney organ donation: developing family practice initiatives to reverse inertia

<p>Abstract</p> <p>Background</p> <p>Kidney transplantation is associated with greater long term survival rates and improved quality of life compared with dialysis. Continuous growth in the number of patients with kidney failure has not been matched by an increase in the availability of kidneys for transplantation. This leads to long waiting lists, higher treatment costs and negative health outcomes.</p> <p>Discussion</p> <p>Misunderstandings, public uncertainty and issues of trust in the medical system, that limit willingness to be registered as a potential donor, could be addressed by community dissemination of information and new family practice initiatives that respond to individuals' personal beliefs and concerns regarding organ donation and transplantation.</p> <p>Summary</p> <p>Tackling both personal and public inertia on organ donation is important for any community oriented kidney donation campaign.</p