Big Data, Predictive Analytics, and Quality Improvement in Kidney Transplantation: A Proof of Concept.

We sought proof of concept of a Big Data Solution incorporating longitudinal structured and unstructured patient-level data from electronic health records (EHR) to predict graft loss (GL) and mortality. For a quality improvement initiative, GL and mortality prediction models were constructed using baseline and follow-up data (0-90 days posttransplant; structured and unstructured for 1-year models; data up to 1 year for 3-year models) on adult solitary kidney transplant recipients transplanted during 2007-2015 as follows: Model 1: United Network for Organ Sharing (UNOS) data; Model 2: UNOS & Transplant Database (Tx Database) data; Model 3: UNOS, Tx Database & EHR comorbidity data; and Model 4: UNOS, Tx Database, EHR data, Posttransplant trajectory data, and unstructured data. A 10% 3-year GL rate was observed among 891 patients (2007-2015). Layering of data sources improved model performance; Model 1: area under the curve (AUC), 0.66; (95% confidence interval [CI]: 0.60, 0.72); Model 2: AUC, 0.68; (95% CI: 0.61-0.74); Model 3: AUC, 0.72; (95% CI: 0.66-077); Model 4: AUC, 0.84, (95 % CI: 0.79-0.89). One-year GL (AUC, 0.87; Model 4) and 3-year mortality (AUC, 0.84; Model 4) models performed similarly. A Big Data approach significantly adds efficacy to GL and mortality prediction models and is EHR deployable to optimize outcomes.

Kidney transplant access in the Southeastern United States: the need for a top-down transformation.

End-stage renal disease (ESRD) and poverty are highly prevalent conditions in the Southeastern United States. The American Southeast also has some of the lowest attainments of health status among its constituents. Transplantation rates are particularly low in the Southeast compared with other regions of the United States. These low kidney transplantation rates in the Southeast likely reflect poor access to medical care. This disproportionate lack of access to medical care among ESRD patients in the Southeast reflects the convergence and interaction of socioeconomic and biologic forces at the patient level interacting with the financial and organizational structure of the health-care system. Improving kidney transplant access in the Southeast will take disruptive political, financial and health system changes whose scope transcends transplant centers and dialysis units.

Risk factors for retransplant kidney recipients: relisting and outcomes from patients' primary transplant.

As of November 2013, 14.5% of the waitlist for a donor kidney comprised patients awaiting a retransplant. We performed a retrospective cohort study of 11,698 adult solitary kidney recipients using national Scientific Registry of Transplant Recipients data transplanted between 2002 and 2011. The aim was to investigate whether outcomes from patients' initial transplants are significant risk factors for patients' repeat transplants or for likelihood of relisting after a failed primary transplant. Retransplant recipients were more likely to be treated for acute rejection [adjusted odds ratio (AOR), 95% confidence interval (CI) = 1.26 (1.07-1.48), p = 0.0053] or hospitalized (AOR = 1.19, 95% CI 1.08-1.31, p = 0.0005) within a year of retransplantation if these outcomes were experienced within a year of primary transplant. Delayed graft function following primary transplants was associated with 35% increased likelihood of recurrence (AOR = 1.35, 95% CI = 1.18-1.54, p < 0.0001). An increase in 1-year GFR after primary transplant was associated with GFR 1 year postretransplant (ß = 6.82, p < 0.0001), and retransplant graft failure was inversely associated with 1-year primary transplant GFR (adjusted hazard ratio = 0.74, 95% CI = 0.71-0.76 per 10 mL/min/1.73 m(2) ). A decreased likelihood for relisting was associated with hospitalization and higher GFR following primary transplantation. The increasing numbers of individuals requiring retransplants highlights the importance of incorporating prior transplant outcomes data to better inform relisting decisions and prognosticating retransplant outcomes.

Prominent impact of community risk factors on kidney transplant candidate processes and outcomes.

Numerous factors impact patients' health beyond traditional clinical characteristics. We evaluated the association of risk factors in kidney transplant patients' communities with outcomes prior to transplantation. The primary exposure variable was a community risk score (range 0-40) derived from multiple databases and defined by factors including prevalence of comorbidities, access and quality of healthcare, self-reported physical and mental health and socioeconomic status for each U.S. county. We merged data with the Scientific Registry of Transplant Recipients (SRTR) and utilized risk-adjusted models to evaluate effects of community risk for adult candidates listed 2004-2010 (n = 209 198). Patients in highest risk communities were associated with increased mortality (adjusted hazard ratio [AHR] = 1.22, 1.16-1.28), decreased likelihood of living donor transplantation (adjusted odds ratio [AOR] = 0.90, 0.85-0.94), increased waitlist removal for health deterioration (AHR = 1.36, 1.22-1.51), decreased likelihood of preemptive listing (AOR = 0.85, 0.81-0.88), increased likelihood of inactive listing (AOR = 1.49, 1.43-1.55) and increased likelihood of listing for expanded criteria donor kidneys (AHR = 1.19, 1.15-1.24). Associations persisted with adjustment for rural-urban location; furthermore the independent effects of rural-urban location were largely eliminated with adjustment for community risk. Average community risk varied widely by region and transplant center (median = 21, range 5-37). Community risks are powerful factors associated with processes of care and outcomes for transplant candidates and may be important considerations for developing effective interventions and measuring quality of care of transplant centers.

The association of center performance evaluations and kidney transplant volume in the United States.

Report cards evaluating transplant center performance have received significant attention in recent years corresponding with the Centers for Medicare and Medicaid Services issue of the 2007 Conditions of Participation. Our primary aim was to evaluate the association of report card evaluations with transplant center volume. We utilized data from the Scientific Registry of Transplant Recipients (SRTR) along with six consecutive program-specific reports from January 2007 to July 2009 for adult kidney transplant centers. Among 203 centers, 46 (23%) were low performing (LP) with statistically significantly lower than expected 1-year graft or patient survival at least once during the study period. Among LP centers, there was a mean decline in transplant volume of 22.4 cases compared to a mean increase of 7.8 transplants among other centers (p = 0.001). Changes in volume between LP and other centers were significant for living, standard and expanded criteria deceased donor (ECD) transplants. LPs had a reduction in use of donors with extended cold ischemia time (p = 0.04) and private pay recipients (p = 0.03). Centers without low performance evaluations were more likely to increase the proportion of overall transplants that were ECDs relative to other centers (p = 0.04). Findings indicate a significant association between reduced kidney transplant volume and low performance report card evaluations.

Influence of CIT-induced DGF on kidney transplant outcomes.

Increased cold ischemia time (CIT) predisposes to delayed graft function (DGF). DGF is considered a risk factor for graft failure after kidney transplantation, but DGF has multiple etiologies. To analyze the risk of CIT-induced DGF on graft survival, we evaluated paired deceased-donor kidneys (derived from the same donor transplanted to different recipients) in which one donor resulted in DGF and the other did not, using national Scientific Registry of Transplant Recipients data between 2000 and 2009. Of 54 565 kidney donors, 15 833 were excluded for mate kidney non-transplantation, 27 340 because both or neither kidney developed DGF and 2310 for same/unknown CIT. The remaining 9082 donors (18 164 recipients) were analyzed. The adjusted odds (aOR) of DGF were significantly higher when CIT was longer by ≥ 1 h (aOR 1.81, 95% CI 1.7-2.0), ≥ 5 h (aOR 2.5, 95% CI 2.3-2.9), ≥ 10 h (aOR 3.3, 95% CI 2.7-2.9) and ≥ 15 h (aOR 4.4, 95% CI 3.4-5.8) compared to shorter CIT transplants. In the multivariable models adjusted for recipient characteristics, graft survival between paired donor transplants, with and without DGF, were similar. These results suggest that DGF, specifically induced by prolonged CIT, has limited bearing on long-term outcomes, which may have important implications for kidney utilization.

Impact of cold ischemia time on graft survival among ECD transplant recipients: a paired kidney analysis.

Delays in expanded criteria donor (ECD) kidney placement increases cold ischemia times (CIT) potentially leading to discard. The effect of increased CIT on ECD kidney transplant outcomes is unknown. We evaluated paired ECD kidneys (derived from the same donor transplanted to different recipients) from the SRTR registry transplanted between 1995 and 2009 (n = 17,514). To test the effect of CIT, we excluded paired transplants with the same CIT (n = 3286). Of 14,230 recipients (7115 donors) the median difference in CIT was 5 h (Q1 = 3 h, Q3 = 9 h). Delayed graft function (DGF) was significantly more likely between pairs with greater CIT (35% vs. 31%, p < 0.001) including substantially higher rates for CIT differences ≥ 15 h (42%). Overall graft loss was not significantly different between recipients with higher CIT relative to paired donor recipients with lower CIT (p = 0.47) or for pairs with differences of 1-3 h (p = 0.90), 4-9 h (p = 0.41), 10-14 h (p = 0.36) or ≥ 15 h (p = 0.10). Results were consistent in multivariable models adjusted for recipient factors. Although increasing cold ischemia time is a risk factor for DGF among ECD kidney transplants, there is no effect on graft survival which may suggest an important utility for donor kidneys that may not currently be considered viable.

Marked variation of the association of ESRD duration before and after wait listing on kidney transplant outcomes.

Numerous studies report a strong association between pretransplant end-stage renal disease (ESRD) duration and diminished transplant outcomes. However, cumulative waiting time may reflect distinct phases and processes related to patients' physiological condition as well as pre-existing morbidity and access to care. The relative impact of pre- and postlisting ESRD durations on transplant outcomes is unknown. We examined the impact of these intervals from a national cohort of kidney transplant recipients from 1999 to 2008 (n = 112,249). Primary factors explaining prelisting ESRD duration were insurance and race, while primary factors explaining postlisting ESRD duration were blood type, PRA% and variation between centers. Extended time from ESRD to waitlisting had significant dose-response association with overall graft loss (AHR = 1.26 for deceased donors [DD], AHR = 1.32 for living donors [LD], p values < 0.001). Contrarily, time from waitlisting (after ESRD) to transplantation had negligible effects (p = 0.10[DD], p = 0.57[LD]). There were significant associations between pre- and postlisting ESRD time with posttransplant patient survival, however prelisting time had over sixfold greater effect. Prelisting ESRD time predominately explains the association of waiting time with transplant outcomes suggesting that factors associated with this interval should be prioritized for interventions and allocation policy. The degree to which the effect of prelisting ESRD time is a proxy for comorbid conditions, socioeconomic status or access to care requires further study.

The overlapping risk profile between dialysis patients listed and not listed for renal transplantation.

The survival advantage of kidney transplantation extends to many high-risk ESRD patients; however, numerous factors ultimately determine which patients are evaluated and listed for the procedure. Broad goals of patient evaluation comprise identifying patients who will benefit from transplantation and excluding patients who might be placed at risk. There is limited data detailing whether current access limitations and screening strategies have achieved the goal of listing the most appropriate patients. The study estimated the life expectancy of adult patients in the United States prior to transplantation with ESRD onset from 1995 to 2003. Factors associated with transplant listing were examined based on patient prognosis after ESRD. Approximately one-third of patients listed for transplantation within 1 year of ESRD had 5-year life expectancy. The number of patients not listed with 'good' prognosis was significantly higher than those listed with 'poor' prognosis (134 382 vs. 16 807, respectively). Age, race, gender, insurance coverage and body mass index (BMI) were associated with likelihood for listing with 'poor' prognosis and not listing with 'good' prognosis. Over the past decade, many ESRD patients viable for transplantation have not listed for transplantation while higher-risk patients have listed rapidly.

Immunosuppression reduction for BK virus nephropathy: a case for caution.

BK virus nephropathy (BKVN) is increasingly recognized as a major cause of renal allograft failure. Recent reports demonstrate that prompt reduction of immunosuppression upon detection of persistent viremia can be associated with resolution of viremia, with minimal risk of acute rejection (AR). However, these experiences in general have occurred in centers with low baseline risks of AR. It is possible that a finer balance between overimmunosuppression and the risk of AR may exist in centers that routinely transplant patients with higher risk of AR. Thus the risk/benefit of this strategy may be altered in these centers. We report a case of antibody-mediated rejection that followed reduction of immunosuppression for BKVN diagnosed more than 3 months after the onset of viremia. This rejection episode resulted in a greater decrease in graft function than the initial BKVN episode. Issues relevant to the management of these patients are discussed, including the need for improved immune monitoring assays to determine more accurately the balance between infection and rejection.

Value of posttransplant antibody tests in the evaluation of patients with renal graft dysfunction.

Posttransplant HLA antibodies correlate with C4d positive rejection and decreased graft survival. However, the diagnostic value of various antibody tests in the management of patients presenting with graft dysfunction is uncertain. Whether all or some patients should be tested, how often, what antibodies to test for and how to interpret results in presensitized or transfused patients, are issues still unresolved. We tested for HLA and non-HLA antibodies by flow cytometry assays in 103 consecutive patients with graft dysfunction. The results show that: (1) C4d positive rejection was diagnosed in 75% of patients who developed posttransplant HLA antibodies, but only in 2% in antibody negative patients. (2) The correlation existed for donor specific IgG antibodies but not for IgM or nondonor specific IgG antibodies. (3) Weak antibody reactivity required confirmation by alternative testing as there were false positive results. (4) Posttransplant transfusions did not induce de novo HLA antibodies. (5) Negative antibody results were unlikely to turn positive after several months of follow-up. (6) Antibodies to the angiotensin II type 1 receptor, HLA-DP and MICA did not correlate with C4d+ rejection. We conclude that testing for posttransplant HLA antibodies is critical in narrowing the diagnostic alternatives in patients with graft dysfunction.

Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation.

We evaluated outcomes with the sirolimus (SRL) and mycophenolate mofetil (MMF) combination regimen (SRL/MMF) in solitary kidney transplant recipients transplanted between 2000 and 2005 reported to the Scientific Registry of Renal Transplant Recipients. Three-and-a-half percent received SRL/MMF (n = 2040). Six-month acute rejection rates were higher with SRL/MMF (SRL/MMF: 16.0% vs. other regimens: 11.2%, p < 0.001). Overall graft survival was significantly lower on SRL/MMF. SRL/MMF was associated with twice the hazard for graft loss (AHR = 2.0, 95% C.I., 1.8, 2.2) relative to TAC/MMF, also consistent in both living donor transplants (AHR = 2.4, 95% C.I., 1.9, 2.9) and expanded criteria donor transplants (AHR = 2.1, 95% C.I., 1.7-2.5). Among deceased donor transplants, DGF rates were higher in the SRL/MMF cohort (47% vs. 27%, p < 0.001). However, adjusted graft survival was also significantly inferior with SRL/MMF in DGF-free patients (AHR = 1.9, 95% C.I., 1.6-2.3). In analyses restricted to patients who remained on the discharge regimen at 6 months posttransplant, conditional graft survival in deceased donor transplants was significantly lower with SRL/MMF compared to patients on TAC/MMF or CsA/MMF regimens at 5 years posttransplant (64%, 78%, 78%, respectively, p = 0.001) and across all patient subgroups. In conclusion, SRL/MMF is associated with inferior renal transplant outcomes compared with other commonly used regimens.

A "weight-listing" paradox for candidates of renal transplantation?

Research suggests that end-stage renal disease patients with elevated body mass index (BMI) have superior outcomes on dialysis. In contrast, low and high BMI patients represent the highest risk cohorts for kidney transplant recipients. The important question remains concerning how to manage transplant candidates given the potentially incommensurate impact of BMI by treatment modality. We conducted a retrospective analysis of waitlisted and transplanted patients in the United States from 1990 to 2003. We constructed Cox models to evaluate the effect of BMI on mortality of waitlisted candidates and identified risk factors for rapid weight change. We then assessed the impact of weight change during waitlisting on transplant outcomes. Decline in BMI on the waiting list was not protective for posttransplant mortality or graft loss across BMI strata. Substantial weight loss pretransplantation was associated with rapid gain posttransplantation. The highest risk for death was among listed patients with low BMI (13-20 kg/m(2), adjusted hazard ratio = 1.47, p < 0.01). Approximately one-third of candidates had a change in BMI category prior to transplantation. While observed declines in BMI may be volitional or markers of disease processes, there is no evidence that candidates have improved transplant outcomes attributable to weight loss. Prospective trials are needed to evaluate the efficacy of weight loss protocols for candidates of kidney transplantation.

Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease.

Uric acid is strongly associated with cardiovascular and renal disease, but is usually not considered to have a causal role. However, recent experimental, epidemiological, and clinical studies provocatively suggest that uric acid may contribute to the development of hypertension, metabolic syndrome, and kidney disease in some patients. Clinical studies are urgently needed to examine this important possibility.

Preemptive retransplantation for BK virus nephropathy: successful outcome despite active viremia.

BK virus nephropathy (BKVN) is now recognized as a major cause of renal allograft loss. Recent reports suggest that retransplantation in patients with graft loss due to BKVN is safe after return to dialysis. Since early transplantation is associated with improved outcomes, it would be advantageous if this procedure could be performed prior to ultimate graft loss. However, little data are available regarding the safety of this approach during active viremia. In this report, we describe successful preemptive retransplantation with simultaneous allograft nephrectomy in two patients with active BKVN and viremia at the time of surgery. With 21- and 12-month follow-up, respectively, both patients have stable allograft function and no evidence for active viral replication. We conclude that preemptive retransplantation can be considered in patients with failing allografts due to BKVN.

The effects of renal transplantation on peripheral blood dendritic cells.

Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid dendritic cell (DC) populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. Using flow cytometry, PBDC levels were quantified in patients with end stage renal disease (ESRD) undergoing RT. PBDC levels were significantly reduced in ESRD patients pre-RT compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving anti-lymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pre-transplant values concurrent with overall reduction of immunosuppression (IS). Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall IS. Our findings suggest that PBDC levels reflect the degree of IS in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss and infectious complications.