Niraj M. Desai

Frailty and delayed graft function in kidney transplant recipients

The ability to predict outcomes following a kidney transplant is limited by the complex physiologic decline of kidney failure, a latent factor that is difficult to capture using conventional comorbidity assessment. The frailty phenotype is a recently described inflammatory state of increased vulnerability to stressors resulting from decreased physiologic reserve and dysregulation of multiple physiologic systems. We hypothesized that frailty would be associated with delayed graft function, based on putative associations between inflammatory cytokines and graft dysfunction. We prospectively measured frailty in 183 kidney transplant recipients between December 2008 and April 2010. Independent associations between frailty and delayed graft function were analyzed using modified Poisson regression. Preoperative frailty was independently associated with a 1.94-fold increased risk for delayed graft function (95% CI, 1.13-3.36; P = .02). The assessment of frailty may provide further insights into the pathophysiology of allograft dysfunction and may improve our ability to preoperatively risk-stratify kidney transplant recipients.

Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation

Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor‐specific antibodies. After follow‐up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation.

Frailty and Mortality in Kidney Transplant Recipients

We have previously described strong associations between frailty, a measure of physiologic reserve initially described and validated in geriatrics, and early hospital readmission as well as delayed graft function. The goal of this study was to estimate its association with postkidney transplantation (post‐KT) mortality. Frailty was prospectively measured in 537 KT recipients at the time of transplantation between November 2008 and August 2013. Cox proportional hazards models were adjusted for confounders using a novel approach to substantially improve model efficiency and generalizability in single‐center studies. We precisely estimated the confounder coefficients using the large sample size of the Scientific Registry of Transplantation Recipients (nu2009=u200937 858) and introduced these into the single‐center model, which then estimated the adjusted frailty coefficient. At 5 years, the survivals were 91.5%, 86.0% and 77.5% for nonfrail, intermediately frail and frail KT recipients, respectively. Frailty was independently associated with a 2.17‐fold (95% CI: 1.01–4.65, pu2009=u20090.047) higher risk of death. In conclusion, regardless of age, frailty is a strong, independent risk factor for post‐KT mortality, even after carefully adjusting for many confounders using a novel, efficient statistical approach.

Survival Benefit of Primary Deceased Donor Transplantation With High‐KDPI Kidneys

The Kidney Donor Profile Index (KDPI) has been introduced as an aid to evaluating deceased donor kidney offers, but the relative benefit of high‐KDPI kidney transplantation (KT) versus the clinical alternative (remaining on the waitlist until receipt of a lower KDPI kidney) remains unknown. Using time‐dependent Cox regression, we evaluated the mortality risk associated with high‐KDPI KT (KDPI 71–80, 81–90 or 91–100) versus a conservative, lower KDPI approach (remain on waitlist until receipt of KT with KDPI 0–70, 0–80 or 0–90) in first‐time adult registrants, adjusting for candidate characteristics. High‐KDPI KT was associated with increased short‐term but decreased long‐term mortality risk. Recipients of KDPI 71–80 KT, KDPI 81–90 KT and KDPI 91–100 KT reached a “break‐even point” of cumulative survival at 7.7, 18.0 and 19.8 months post‐KT, respectively, and had a survival benefit thereafter. Cumulative survival at 5 years was better in all three high‐KDPI groups than the conservative approach (pu2009<u20090.01 for each comparison). Benefit of high‐KDPI KT was greatest in patients age >50 years and patients at centers with median wait time ≥33 months. Recipients of high‐KDPI KT can enjoy better long‐term survival; a high‐KDPI score does not automatically constitute a reason to reject a deceased donor kidney.

Listing for expanded criteria donor kidneys in older adults and those with predicted benefit

Certain patient groups are predicted to derive significant survival benefit from transplantation with expanded criteria donor (ECD) kidneys. An algorithm published in 2005 by Merion and colleagues characterizes this group: older adults, diabetics and registrants at centers with long waiting times. Our goal was to evaluate ECD listing practice patterns in the United States in terms of these characteristics. We reviewed 142 907 first‐time deceased donor kidney registrants reported to United Network for Organ Sharing (UNOS) between 2003 and 2008. Of registrants predicted to benefit from ECD transplantation according to the Merion algorithm (ECD‐benefit), 49.8% were listed for ECD offers (ECD‐willing), with proportions ranging from 0% to 100% by transplant center. In contrast, 67.6% of adults over the age of 65 years were ECD‐willing, also ranging from 0% to 100% by center. In multivariate models, neither diabetes nor center waiting time was significantly associated with ECD‐willingness in any subgroup. From the time of initial registration, irrespective of eventual transplantation, ECD‐willingness was associated with a significant adjusted survival advantage in the ECD‐benefit group (HR for death 0.88, p < 0.001) and in older adults (HR 0.89, p < 0.001), but an increased mortality in non‐ECD‐benefit registrants (HR 1.11, p < 0.001). In conclusion, ECD listing practices are widely varied and not consistent with published recommendations, a pattern that may disenfranchise certain transplant registrants.

Center-Level Factors and Racial Disparities in Living Donor Kidney Transplantation

BACKGROUNDnOn average, African Americans attain living donor kidney transplantation (LDKT) at decreased rates compared with their non-African American counterparts. However, center-level variations in this disparity or the role of center-level factors is unknown.nnnSTUDY DESIGNnObservational cohort study.nnnSETTING & PARTICIPANTSn247,707 adults registered for first-time kidney transplants from 1995-2007 as reported by the Scientific Registry of Transplant Recipients.nnnPREDICTORSnPatient-level factors (age, sex, body mass index, insurance status, education, blood type, and panel-reactive antibody level) were adjusted for in all models. The association of center-level characteristics (number of candidates, transplant volume, LDKT volume, median time to transplant, percentage of African American candidates, percentage of prelisted candidates, and percentage of LDKT) and degree of racial disparity in LDKT was quantified.nnnOUTCOMESnHierarchical multivariate logistic regression models were used to derive center-specific estimates of LDKT attainment in African American versus non-African American candidates.nnnRESULTSnRacial parity was not seen at any of the 275 transplant centers in the United States. At centers with the least racial disparity, African Americans had 35% lower odds of receiving LDKT; at centers with the most disparity, African Americans had 76% lower odds. Higher percentages of African American candidates (interaction term, 0.86; P = 0.03) and prelisted candidates (interaction term, 0.80; P = 0.001) at a given center were associated with increased racial disparity at that center. Higher rates of LDKT (interaction term, 1.25; P < 0.001) were associated with less racial disparity.nnnLIMITATIONSnSome patient-level factors are not captured, including a given patients pool of potential donors. Geographic disparities in deceased donor availability might affect LDKT rates. Center-level policies and practices are not captured.nnnCONCLUSIONSnRacial disparity in attainment of LDKT exists at every transplant center in the country. Centers with higher rates of LDKT attainment for all races had less disparity; these high-performing centers might provide insights into policies that might help address this disparity.

Improving Distribution Efficiency of Hard-to-Place Deceased Donor Kidneys: Predicting Probability of Discard or Delay

We recently showed that DonorNet 2007 has reduced the efficiency of kidney distribution in the United States, particularly for those with prolonged cold ischemia time (CIT), by requiring systematic allocation of all kidneys regardless of quality. Reliable early identification of those most likely to be discarded or significantly delayed would enable assigning them to alternate, more efficient distribution strategies. Based on 39u2003035 adult kidneys recovered for possible transplantation between 2005 and 2008, we created a regression model that reliably (AUC 0.83) quantified the probability that a given kidney was either discarded or delayed beyond 36 h of CIT (Probability of Discard/Delay, PODD). We then analyzed two PODD cutoffs: a permissive cutoff that successfully flagged over half of those kidneys that were discarded/delayed, while only flagging 7% of kidneys that were not eventually discarded/delayed, and a more stringent cutoff that erroneously flagged only 3% but also correctly identified only 34%. Kidney transplants with high PODD were clustered in a minority of centers. Modifications of the kidney distribution system to more efficiently direct organs with high PODD to the centers that actually use them may result in reduced CIT and fewer discards.

Changes in Discard Rate After the Introduction of the Kidney Donor Profile Index (KDPI)

Since March 26, 2012, the Kidney Donor Profile Index (KDPI) has been provided with all deceased‐donor kidney offers, with the goal of improving the expanded criteria donor (ECD) indicator. Although an improved risk index may facilitate identification and transplantation of marginal yet viable kidneys, a granular percentile system may reduce provider–patient communication flexibility, paradoxically leading to more discards (“labeling effect”). We studied the discard rates of the kidneys recovered for transplantation between March 26, 2010 and March 25, 2012 (“ECD era,” N = 28 636) and March 26, 2012 and March 25, 2014 (“KDPI era,” N = 29 021) using Scientific Registry of Transplant Recipients (SRTR) data. There was no significant change in discard rate from ECD era (18.1%) to KDPI era (18.3%) among the entire population (adjusted odds ratio [aOR] = 0.971.041.10, p = 0.3), or in any KDPI stratum. However, among kidneys in which ECD and KDPI indicators were discordant, “high risk” standard criteria donor (SCD) kidneys (with KDPI > 85) were at increased risk of discard in the KDPI era (aOR = 1.071.421.89, p = 0.02). Yet, recipients of these kidneys were at much lower risk of death (adjusted Risk Ratio [aRR] = 0.560.770.94 at 2 years posttransplant) compared to those remaining on dialysis waiting for low‐KDPI kidneys. Our findings suggest that there might be an unexpected, harmful labeling effect of reporting a high KDPI for SCD kidneys, without the expected advantage of providing a more granular risk index.

Early Changes in Kidney Distribution under the New Allocation System

The Kidney Allocation System (KAS), a major change to deceased donor kidney allocation, was implemented in December 2014. Goals of KAS included directing the highest-quality organs to younger/healthier recipients and increasing access to deceased donor kidney transplantation (DDKT) for highly sensitized patients and racial/ethnic minorities. Using national registry data, we compared kidney distribution, DDKT rates for waitlist registrants, and recipient characteristics between January 1, 2013, and December 3, 2014 (pre-KAS) with those between December 4, 2014, and August 31, 2015 (post-KAS). Regional imports increased from 8.8% pre-KAS to 12.5% post-KAS; national imports increased from 12.7% pre-KAS to 19.1% post-KAS (P<0.001). The proportion of recipients >30 years older than their donor decreased from 19.4% to 15.0% (P<0.001). The proportion of recipients with calculated panel-reactive antibody =100 increased from 1.0% to 10.3% (P<0.001). Overall DDKT rate did not change as modeled using exponential regression adjusting for candidate characteristics (P=0.07). However, DDKT rate (incidence rate ratio, 95% confidence interval) increased for black (1.19; 1.13 to 1.25) and Hispanic (1.13; 1.05 to 1.20) candidates and for candidates aged 18-40 (1.47; 1.38 to 1.57), but declined for candidates aged >50 (0.93; 0.87 to 0.98 for aged 51-60 and 0.90; 0.85 to 0.96 for aged >70). Delayed graft function in transplant recipients increased from 24.8% pre-KAS to 29.9% post-KAS (P<0.001). Thus, in the first 9 months under KAS, access to DDKT improved for minorities, younger candidates, and highly sensitized patients, but declined for older candidates. Delayed graft function increased substantially, possibly suggesting poorer long-term outcomes.

A Risk Index for Living Donor Kidney Transplantation

Choosing between multiple living kidney donors, or evaluating offers in kidney paired donation, can be challenging because no metric currently exists for living donor quality. Furthermore, some deceased donor (DD) kidneys can result in better outcomes than some living donor kidneys, yet there is no way to compare them on the same scale. To better inform clinical decision‐making, we created a living kidney donor profile index (LKDPI) on the same scale as the DD KDPI, using Cox regression and adjusting for recipient characteristics. Donor age over 50 (hazard ratio [HR] per 10 years = 1.151.241.33), elevated BMI (HR per 10 units = 1.011.091.16), African‐American race (HR = 1.151.251.37), cigarette use (HR = 1.091.161.23), as well as ABO incompatibility (HR = 1.031.271.58), HLA B (HR = 1.031.081.14) mismatches, and DR (HR = 1.041.091.15) mismatches were associated with greater risk of graft loss after living donor transplantation (all p < 0.05). Median (interquartile range) LKDPI score was 13 (1–27); 24.2% of donors had LKDPI < 0 (less risk than any DD kidney), and 4.4% of donors had LKDPI > 50 (more risk than the median DD kidney). The LKDPI is a useful tool for comparing living donor kidneys to each other and to deceased donor kidneys.