Chakkera, Harini A.

AbstractThe OPTN/UNOS utilizes the calculated estimated posttransplant survival (EPTS) score as the measure of post‐kidney transplant survival to guide allocation of deceased donor kidney transplantation. This score does not include any metric of functional capacity. Peak oxygen uptake (VO2peak), is an established predictor of survival among both the general and diseased populations. We assessed the association and discriminative capacity of VO2peak and that of EPTS score and all‐cause mortality post‐kidney transplant. Additionally, we assessed the “mortality risk” lower VO2peak conferred on those patients with low EPTS score. Among a cohort of 293 transplant recipients with at least 3‐years post‐transplant follow‐up, the median VO2peak was 15.0 ml/Kg/min. Lower pre‐transplant VO2peak and higher EPTS score conferred higher risk of post‐transplant mortality. Among the cohort of “low‐risk” patients (patients with EPTS score < 50) those with lower VO2peak had significantly higher risk of mortality (log rank p = 0.045). In fact, the mortality risk among those with low‐EPTS (< 50) and low VO2peak < 12 ml/Kg/min was equivalent to those with high EPTS (> 80) score. We concluded functional capacity as defined by VO2peak is an important reflection of post‐transplant survival. VO2peak is able to identify those with low EPTS who have similar survival to that of high EPTS phenotype.

Background Data regarding changes in markers of cardiovascular and all‐cause mortality, namely, VO 2peak and minute ventilation/carbon dioxide production (V E /VCO 2 ) slope following renal transplantation past 1‐year post‐transplant are lacking. We examined changes in VO 2peak and V E /VCO 2 before and after ~3‐years after renal transplantation. Methods Eighteen patients (age 56.2 ± 2.5 years; 82.9 ± 4.9 kg; 9 male) completed an exercise test to exhaustion using a ramp treadmill protocol. Subjects underwent pre‐transplant exercise testing (PreTx) following which they were placed on the transplant wait‐list. Average time on the waitlist was 15.6 ± 2 months. Following transplant, subjects underwent follow‐up maximal exercise testing using the same protocol (PostTx). Mean duration to post‐transplant exercise testing was 35 ± 2 months. Gas exchange data, heart rate and respiratory exchange ratios were recorded throughout exercise testing. All variables are reported as mean ± standard error. α was set at 0.05 and a paired t‐test carried out to examine changes in VO 2peak and maximal V E /VCO 2 slope before and after transplant. Results Significant reductions in relative VO 2peak were observed from PreTx = 15.2 ± 0.8 mL/kg/min to PostTX = 12.2 ± 0.4 mL/kg/min (p = 0.002 ). Also, significant increases in V e /VCO 2 were observed from PreTx = 30 ± 1.4 to PostTx = 43 ± 1.6 (p < .001). Conclusions Long term follow‐up (~3‐years) in this small cohort of patients following renal transplantation demonstrated significant reductions in VO 2peak (20%) and worsening of the V E /VCO 2 slope (30%) which are modifiable markers of mortality risk. This underscores the need for larger cohort studies to be undertaken in this population given that these markers are independently linked to cardiovascular and all‐cause mortality risk. These data may have implications for cardiovascular stratification and cardiovascular risk reduction in this population. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background. The study aims is to use the fragility index (FI) to examine the strength of evidence of randomized controlled trials (RCTs) published in the last decade on kidney transplantation. Methods. We searched MEDLINE for studies on kidney transplantation. We included the RCTs that compared 2 groups with 1:1 randomization and reported significant P values (<0.05) for a dichotomous outcome and were published in the top 10 transplant journals. We calculated the FI; a calculation used to determine the minimum number of subjects needed to change from a nonevent to an event to make the study results nonsignificant (P ≥ 0.05). Results. Fifty-seven RCTs met our inclusion criteria. The median sample size was 100 participants in each arm, the median number of events was 16 (interquartile range, 8–30) in the intervention group. Among the included trials, 79% were industry-funded, 93% involved medications, and the majority were open label. The median FI was 3 (interquartile range, 1–11). In 43% of the trials, the number of patients reported lost to follow-up was higher than or equal to the FI. Only 4% of the RCTs imputed a value for the missing dichotomous outcome. Furthermore, the median number of subjects who discontinued the trial because of adverse effects was 21, which was greater than the FI in 60% of the RCTs. Conclusions. The arbitrary classification of results into “significant” and “nonsignificant” based on P value <0.05 should perhaps be interpreted with the help of other statistical parameters and FI is one of them.

Background. Participant withdrawal from clinical trials occurs for various reasons, predominantly adverse effects or intervention inefficacy. Because these missing participant data can have implications for the validity, reproducibility, and generalizability of study results, when conducting a systematic review, it is important to collect and appropriately analyze missing data information to assess its effects on the robustness of the study results. Methods. In this methodologic survey of missing participant data reporting and handling in systematic reviews, we included meta-analyses that provided pooled estimates of at least 1 dichotomous intervention outcome of a randomized controlled trial performed in adult kidney transplant subjects. Results. Eighty-three systematic reviews (17 Cochrane and 66 non-Cochrane reviews) met the inclusion criteria. The most common intervention was drugs (80%), with the majority involving immunosuppressant drugs 55% (n = 46), followed by surgery in 14% (n = 12). The median follow-up duration was 12 months (maximum, 240 mo). Intention-to-treat or modified intention-to-treat analysis was reported in 24% (n = 20) of the reviews (76% of Cochrane and 10% of non-Cochrane). Overall, the majority of systematic reviews did not quantify (90% [n = 60] non-Cochrane and 29% [n = 5] Cochrane) or include the reasons for missing participant data (88% [n = 58] non-Cochrane and 24% [n = 4] Cochrane). Eleven percent (n = 9) handled missing participant data, 5% (n = 4) justified the analytical method(s) used to handle it, and 2% (n = 2) performed a sensitivity analysis for it. Conclusions. Systematic reviews of kidney transplantation provide inadequate information on missing participant data and usually do not handle or discuss the associated risk of bias with it.

Problem definition: Organ-transplanted patients typically receive high amounts of immunosuppressive drugs (e.g., tacrolimus) as a mechanism to reduce their risk of organ rejection. However, because of the diabetogenic effect of these drugs, this practice exposes them to a greater risk of new-onset diabetes after transplantation (NODAT), and hence, becoming insulin dependent. We study and develop effective medication management strategies to address the common conundrum of balancing the risk of organ rejection versus that of NODAT. Academic/practical relevance: Our research contributes to the healthcare operations management literature by developing a robust stochastic decision-making framework that allows for incorporating (1) false-positive and false-negative errors of medical tests, (2) inevitable estimation errors when data sets are used, (3) variability among physician’ attitudes toward ambiguous outcomes, and (4) dynamic and patient risk-profile-dependent progression of health conditions. Methodology: We apply an ambiguous partially observable Markov decision process (APOMDP) approach where dynamic optimization with respect to a “cloud” of possible models allows us to make decisions that are robust to potential misspecifications of risks. Results: We first provide various structural results that facilitate characterizing the optimal medication policies. Utilizing a clinical data set, we then compare the performance of the optimal medication policies obtained from our APOMDP model with the policies currently used in the medical practice. We observe that, in one year after transplant, our proposed policies can improve the life expectancy of each patient up to 4.58%, while reducing the medical expenditures up to 11.57%. Managerial implications: Balancing the risks of organ rejection and diabetes complications and considering factors such as physicians’ attitudes toward ambiguous outcomes, partial observability of medical tests, and patient-specific risk factors are shown to result in more cost-effective strategies for management of post-transplant medications compared with the current medical practice. Finally, simultaneous management of medications can facilitate the care coordination process between transplantation/nephrology and endocrinology departments of a hospital that are typically in charge of administering such medications.

Significance Statement The quality of a kidney obtained from a living donor is often inferred from the donor’s age, risk factors, and kidney function. Little is known about the influence of a donated kidney’s structural features on the risk of death-censored graft failure in the recipient. In an analysis of 2293 kidney donor-recipient pairs, the authors identified subclinical nephrosclerosis, larger nephron size (but not nephron number), and smaller medullary volume as structural predictors of death-censored graft failure that were independent of both donor and recipient clinical characteristics. These findings provide important insights into the factors that define the “intrinsic quality” of the living kidney donor graft at the time of donation, and support use of intraoperative biopsies to identify donor kidneys that are at higher risk for failure. Background Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. Methods Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. Results The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. Conclusions Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft’s “intrinsic quality” at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Abstract Background High glomerular filtration rate (GFR) is often used as a surrogate for single-nephron hyperfiltration. Our objective was to determine the definition for high GFR that best reflects clinical and structural characteristics of hyperfiltration. Methods We studied living kidney donors at the Mayo Clinic and Cleveland Clinic. Potential donors underwent evaluations that included measured GFR (mGFR) by iothalamate clearance and estimated GFR (eGFR) by the serum creatinine–based Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI) equation. High GFR was defined by the 95th percentile for each method (mGFR or eGFR) using either overall or age-specific thresholds. High mGFR was defined as both corrected and uncorrected for body surface area. The association of high GFR by each definition with clinical characteristics and radiologic findings (kidney volume) was assessed. In the subset that donated, the association of high GFR with kidney biopsy findings (nephron number and glomerular volume) and single-nephron GFR was assessed. Results We studied 3317 potential donors, including 2125 actual donors. The overall 95th percentile for corrected mGFR was 134 mL/min/1.73 m2 and for eGFR was 118 mL/min/1.73 m2. The age-based threshold for uncorrected mGFR was 198 mL/min − 0.943×Age, for corrected mGFR it was 164 mL/min/1.73 m2 − 0.730×Age and for eGFR it was 146 mL/min/1.73 m2 − 0.813×Age. High age-based uncorrected mGFR had the strongest associations with higher single-nephron GFR, larger glomerular volume, larger kidney volume, male gender, higher body mass index and higher 24-h urine albumin, but also had the strongest association with high nephron number. A high age-height-gender–based uncorrected mGFR definition performed almost as well but had a weaker association with nephron number and did not associate with male gender. Conclusions High age-based uncorrected mGFR showed the most consistent associations reflective of hyperfiltration. However, high age-based uncorrected mGFR has limited clinical utility because it does not distinguish between hyperfiltration and high nephron number.

Background Significant heterogeneity exists in practice patterns and algorithms used for cardiac screening before kidney transplant. Cardiorespiratory fitness, as measured by peak oxygen uptake (VO 2peak ), is an established validated predictor of future cardiovascular morbidity and mortality in both healthy and diseased populations. The literature supports its use among asymptomatic patients in abrogating the need for further cardiac testing. Methods and Results We outlined a pre–renal transplant screening algorithm to incorporate VO 2peak testing among a population of asymptomatic high‐risk patients (with diabetes mellitus and/or >50 years of age). Only those with VO 2peak <17 mL/kg per minute (equivalent to <5 metabolic equivalents) underwent further noninvasive cardiac screening tests. We conducted a retrospective study of the a priori dichotomization of the VO 2peak <17 versus ≥17 mL/kg per minute to determine negative and positive predictive value of future cardiac events and all‐cause mortality. We report a high (>90%) negative predictive value, indicating that VO 2peak ≥17 mL/kg per minute is effective to rule out future cardiac events and all‐cause mortality. However, lower VO 2peak had low positive predictive value and should not be used as a reliable metric to predict future cardiac events and/or mortality. In addition, a simple mathematical calculation documented a cost savings of ≈$272 600 in the cardiac screening among our study cohort of 637 patients undergoing evaluation for kidney and/or pancreas transplant. Conclusions We conclude that incorporating an objective measure of cardiorespiratory fitness with VO 2peak is safe and allows for a cost savings in the cardiovascular screening protocol among higher‐risk phenotype (with diabetes mellitus and >50 years of age) being evaluated for kidney transplant.