Alfonso H. Santos

The Success of Continued Steroid Avoidance After Kidney Transplantation in the US

There has been a significant increase in the use of steroid avoidance regimens as initial treatment for kidney transplant recipients. Early results of the effectiveness of this strategy has been mixed with certain prospective trials indicating increased acute rejection but population‐based studies indicating similar or better graft survival as compared to steroid maintenance. We conducted a retrospective study of national registry data to evaluate risk factors for discontinuation of steroid avoidance protocols based on patient characteristics and concomitant immunosuppression. We evaluated 84 647 solitary kidney transplant recipients in the US with at least 6 months graft survival including 24 218 initially discharged without maintenance steroids. We utilized logistic models to assess risk factors for new initiation of steroids after initial steroid‐avoidance and survival models to describe graft survival for patients after return to steroids. The most prominent risk factors for new initiation of steroids after deceased donor kidney transplantation included African‐American race (AOR = 1.32, p < 0.01), retransplants (AOR = 1.81, p < 0.01), highly sensitized recipients (AOR = 1.29, p < 0.01), recipients with Medicaid (AOR = 1.85, p < 0.01), elevated HLA‐MM (AOR = 1.26, p < 0.01) and older donor age (AOR = 1.19, p < 0.01). Concomitant medications were also significantly associated with the propensity to newly initiate steroids. Cumulatively the study suggests that both patient characteristics and concomitant medications are strongly associated with the success of steroid avoidance immunosuppressive regimens.

Comparison of Utilization and Clinical Outcomes for Belatacept‐ and Tacrolimus‐ Based Immunosuppression in Renal Transplant Recipients

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1‐year clinical outcomes between belatacept‐ and tacrolimus‐treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1‐year acute rejection, with the highest rates associated with non–lymphocyte‐depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90–3.70, p < 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial–Extended Criteria Donors (BENEFIT‐EXT), 1‐year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m2, respectively; p < 0.001). The incidence of new‐onset diabetes after transplantation was significantly lower with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (1.7%, 2.2%, and 3.8%, respectively; p = 0.01). Despite improved graft function and metabolic complications with belatacept alone, it may be advisable to add short‐term tacrolimus in the first year after transplant and to consider lymphocyte‐depleting induction in patients with high rejection risk, as the risk–benefit ratio allows.

Effect of different tacrolimus levels on early outcomes after kidney transplantation

BACKGROUND There is a paucity of modern data on the impact of high tacrolimus levels early after kidney transplantation. MATERIAL/METHODS This study analyzed the impact of various trough levels of tacrolimus in the first 2 weeks post-transplant on rates of delayed graft function (DGF), length of stay (LoS), hyperkalemia, hyperglycemia, and biopsy-proven acute rejection (BPAR) rates in the first 3 months post-transplant in a retrospective single-center cohort of patients. Patients were divided into 4 groups based on the average of two highest 12-hour trough tacrolimus levels: <10 ng/mL, 10-12 ng/mL, 12-15 ng/mL, >15 ng/mL. RESULTS The incidence of DGF was noted to be significantly higher in the <10 ng/mL, >15 ng/mL and the 12-15 ng/mL tacrolimus groups as compared to the 10-12 ng/mL group (49%, 25% and 4%, respectively, p≤0.0001). Mean LoS was also noted to be significantly higher in the >15 ng/mL tacrolimus group as compared to the 10-12 ng/mL group (7.4 days and 6.1 days respectively, p=0.0007). There was no difference in the rates of hyperkalemia, hyperglycemia or BPAR. CONCLUSIONS This is a modern confirmation of the association between higher tacrolimus levels early after kidney transplantation and increased rate of DGF and increased LoS.

Association of Baseline Viral Serology and Sirolimus Regimens With Kidney Transplant Outcomes: A 14-Year Registry-Based Cohort Study in the United States.

BackgroundThe risks for transplant outcomes associated with baseline viral serostatus in kidney transplant recipients (KTR) on sirolimus have not been widely studied. MethodsWe performed a cohort-study of 61 590 adult KTR in 2000 to 2013. We used Cox regression models to determine the adjusted hazard ratio (aHR) of patient death, death-censored graft loss and posttransplant malignancy associated with the baseline serostatus (+ or −: hepatitis B core [HBc], hepatitis C virus [HCV], Epstein-Barr virus [EBV], or cytomegalovirus [CMV]) in KTR on sirolimus (SRL) + mycophenolate (MPA) or SRL + tacrolimus (Tac), relative to the control-regimen: Tac + MPA. ResultsCompared with Tac + MPA, SRL + MPA, and SRL + Tac were associated with higher risks of 5-year mortality (aHR, 1.41; 95% CI, 1.23-1.60 and aHR, 1.59; 95% CI, 1.38-1.83, respectively) and death-censored graft loss (aHR, 1.41; 95% CI, 1.24-1.60 and aHR, 1.38; 95% CI, 1.21-1.57, respectively). In KTR with negative pretransplant EBV, CMV, HBc, or HCV serostatus, SRL + MPA not SRL + Tac was associated with a lower risk of posttransplant malignancy compared with control (aHR, 0.27; 95% CI, 0.10-0.72; aHR, 0.61; 95% CI, 0.43-0.88; aHR, 0.79; 95% CI, 0.64-0.97; and aHR, 0.80; 95% CI, 0.65-0.98, respectively, for SRL + MPA and aHR, 0.98: 95% CI, 0.52-1.80; aHR, 0.69; 95% CI, 0.46-1.06; aHR, 0.83; 95% CI, 0.66-1.06 and aHR, 0.85; 95% CI, 0.67-1.07, respectively, for SRL + Tac). In KTR with positive serostatus to any of the above viruses, SRL + MPA or SRL + Tac was not associated with a different malignancy risk compared with control. ConclusionsCompared with Tac + MPA, SRL regimens were associated with higher risks for patient death and graft loss, although SRL + MPA was associated with a lower risk for posttransplant malignancy in kidney allograft recipients with negative pretransplant HBc, HCV, EBV, or CMV serology.

Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation

The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero‐HLA mismatches. However, in unrelated living donor kidney transplants (LDKT)—the same donor source in KPD—no study has shown whether zero‐HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero‐HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero‐HLA mismatches were compared to a 1:1–5 matched (by donor age ±1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death‐censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero‐HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan–Meier analyses for death‐censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero‐HLA mismatches saw no benefit with death‐censored graft survival (HR = 1.46, 95% CI 0.78–2.73) or patient survival (HR = 1.43, 95% CI 0.68–3.01). Our data suggest that in unrelated LDKT, zero‐HLA mismatches may not offer any survival advantage. Therefore, particular study of zero‐HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm.

Nebivolol Effects on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

In hypertensive kidney transplant recipients, the effects of nebivolol vs metoprolol on nitric oxide (NO) blood level, estimated glomerular filtration rate (eGFR), and blood pressure (BP) have not been previously reported. In a 12‐month prospective, randomized, open‐label, active‐comparator trial, hypertensive kidney transplant recipients were treated with nebivolol (n=15) or metoprolol (n=15). Twenty‐nine patients (nebivolol [n=14], metoprolol [n=15]) completed the trial. The primary endpoint was change in blood NO level after 12 months of treatment. Secondary endpoints were changes in eGFR, BP, and number of antihypertensive drug classes used. After 12 months of treatment, least squares mean change in plasma NO level in the nebivolol kidney transplant recipient group younger than 50 years was higher by 68.19% (99.17% confidence interval [CI], 13.02–123.36), 69.54% (99.17% CI, 12.71–126.37), and 66.80% (99.17% CI, 12.95–120.64) compared with the metoprolol group younger than 50 years, the metoprolol group 50 years and older, and the nebivolol group 50 years and older, respectively. The baseline to month 12 change in mean arterial BP, eGFR, and number of antihypertensive drug classes used was not significantly different between the treatment groups. In hypertensive kidney transplant recipients, nebivolol use in patients younger than 50 years increased blood NO.

Fever in a transplant recipient: think beyond infection

Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated inflammatory cascade initiated in response to immune recovery during the resolution of an infection. Reduction in calcineurin inhibitor levels in organ transplant recipients due to enhanced metabolism from interaction with rifampin can predispose these individuals to develop IRIS during the treatment of tuberculosis and mimic sepsis.

Not all inflammation in a renal allograft is rejection

High index of suspicion for adenovirus infection is required in renal graft dysfunction, especially in the setting of hematuria. Histology can mimic acute rejection, which creates a diagnostic dilemma. Tissue adenovirus immunostains, though usually reliable, may not be always positive like in our case.

The skin-kidney connection: bullous pemphigoid associated with acute allograft rejection and membranous nephropathy

Bullous pemphigoid has been linked to allograft rejection, as well as membranous nephropathy in renal transplant recipients. Although there is a possibility of multiple distinct autoimmune processes, immune stimulation induced by allograft rejection or antibasement zone antibody interactions are possible mechanisms for the simultaneous skin and renal involvement.

Analysis of Risk Factors for Kidney Retransplant Outcomes Associated with Common Induction Regimens: A Study of over Twelve-Thousand Cases in the United States

We studied registry data of 12,944 adult kidney retransplant recipients categorized by induction regimen received into antithymocyte globulin (ATG) (N = 9120), alemtuzumab (N = 1687), and basiliximab (N = 2137) cohorts. We analyzed risk factors for 1-year acute rejection (AR) and 5-year death-censored graft loss (DCGL) and patient death. Compared with the reference, basiliximab: (1) one-year AR risk was lower with ATG in retransplant recipients of expanded criteria deceased-donor kidneys (HR = 0.56, 95% CI = 0.35–0.91 and HR = 0.54, 95% CI = 0.27–1.08, resp.), while AR risk was lower with alemtuzumab in retransplant recipients with >3 HLA mismatches before transplant (HR = 0.63, 95% CI = 0.44–0.93 and HR = 0.81, 95% CI = 0.63–1.06, resp.); (2) five-year DCGL risk was lower with alemtuzumab, not ATG, in retransplant recipients of African American race (HR = 0.54, 95% CI = 0.34–0.86 and HR = 0.73, 95% CI = 0.51–1.04, resp.) or with pretransplant glomerulonephritis (HR = 0.65, 95% CI = 0.43–0.98 and HR = 0.82, 95% CI = 0.60–1.12, resp.). Therefore, specific risk factor-induction regimen combinations may predict outcomes and this information may help in individualizing induction in retransplant recipients.