Shehzad Rehman

A lifetime versus a graft life approach redefines the importance of HLA matching in kidney transplant patients

Introduction. Human leukocyte antigen (HLA) matching has been de-emphasized in the allocation of renal allografts and further discounting is planned in the new United Network of Organ Sharing kidney allocation model. An unforeseen consequence of poorer matching could be increased sensitization for candidates pursuing retransplantation. Methods. We examined candidates listed in the United States from 1988 to 2007 from the Scientific Renal Transplant Registry (SRTR) database that were relisted after loss of a primary kidney transplant (n=15,980). The primary outcome was change in panel reactive antibody (PRA) from prior to recipients initial transplant to the subsequent listing. Absolute change in PRA levels were examined in general linear models and the likelihood of becoming newly sensitized in logistic models. Results. There was no appreciable change in PRA for patients receiving a first 0 HLA-A, -B, -DR, or 0 HLA-A, -B–mismatched kidney transplant; contrariwise, there was a significant increase in PRA by increasing HLA mismatch of the first transplant. Only 10% of patients became sensitized after a 0 HLA-A, -B–mismatched transplant, whereas the proportion rose up to 37% with increasing HLA mismatches. Other factors, notably younger age and African American race, also contributed to a higher PRA at relisting. Conclusions. Although there might be a limited impact of HLA matching on acute rejection and graft survival, many patients might be negatively impacted from poor HLA matching of their first kidney transplant when needing a second transplant. This might be particularly important in patients with a long life expectancy because of the high likelihood of needing a second transplant during their lifetime.

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.

Outcome of kidney transplants for adults with hemolytic uremic syndrome in the U.S.: a ten-year database analysis.

BACKGROUND There is currently no large study of the U.S. transplant registry comparing the outcome of kidney transplantation for adults with and without hemolytic uremic syndrome (HUS). To date, information on the outcome of transplants for HUS in the U.S. is derived from single or combined-centers studies, but none has been of a nationwide scope. MATERIAL AND METHODS We retrospectively studied a US registry for the outcome of 323 kidney transplants in adults with HUS and of 121,311 transplants in adults with other renal diseases during the period 1999-2009. We analyzed patient, over-all, and death-censored graft survival in the 5 years following transplantation using Kaplan-Meir curves and Cox hazard models. RESULTS In the 5 years following kidney transplantation, patient mortality was not significantly different [Hazard Ratio (HR) 1.27, 95% Confidence Interval (CI) 0.78-2.08], but death-censored graft loss was twice as common (HR 2.05, 95% CI 1.53-2.73) for allograft recipients whose native kidney disease was HUS compared to other transplant recipients. The subgroup (n=40 cases) with post-transplant HUS recurrence had a 5-year graft loss rate 5 times that of the subgroup (n=283 cases) without HUS-recurrence (graft survival 14.7% vs.77.4%, log rank 116.5; p<0.001). CONCLUSIONS In the largest US series to date of kidney transplants for adults with HUS, 5-year patient survival was not different, but graft outcome was inferior in recipients whose native renal disease were HUS compared to recipients with other kidney diseases. Native kidney HUS is associated with a 2-fold increased risk of death-censored graft loss after kidney transplantation.

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.

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.

Use of Intravenous Immune Globulin and Rituximab for Desensitization of Highly Human Leukocyte Antigen-sensitized Patients Awaiting Kidney Transplantation

The article by Vo et al. (1) about transplanting highly sensitized patients is one of their most recent contributions in trying to tackle this recalcitrant problem. The authors used a rituximab and intravenous immune globulin desensitization protocol, which is simple to administer. This, however, together with the fact that the Cedars-Sinai group is well respected and that the protocol is proposed for highly human leukocyte antigen-sensitized patients (as shown in the title) is promoting its use worldwide with no results to justify the expense. Their definition of “highly sensitized” patients by flow panel reactive antibody is questionable. This test is sensitive but can give high percentage values with low or no sensitization (in contrast to the traditional cytotoxicity panel reactive antibody where high values usually go together with high titers). In addition, they do acknowledge that a number of their transplanted patients had flow crossmatches of less than 250 mean channel shifts, which they defined as “acceptable positive.” Many centers transplant these patients with increased immunosuppression but no desensitization. The authors mention that in some cases, patients received the treatment but the donor-specific crossmatch with the pretransplant specimen turned out to be low by chance. True, but this is certainly not a case of success because of the protocol. The authors also state that they would not transplant such patients without using their protocol, but they have not shown that patients with a weakly positive flow crossmatch do better with the protocol than without. Thus, it is not clear from the data how many patients would have had acceptable positive crossmatches before desensitization, or how many patients were treated and not transplanted. In addition, the effect of rituximab itself on alloantibody, and its indications in transplant patients, has not been established, as one of the authors acknowledged recently (2). Although a strict quantitative evaluation on the effect of rituximab plus intravenous immune globulin on human leukocyte antigen antibody levels remains to be done, the patients transplanted were obviously not highly sensitized against their donors. Indeed, at the end of the discussion, the authors themselves state that patients with lower donorspecific antibody levels benefit more and that no protocol deals well with highly sensitized patients. Some readers may miss this statement, but no one will miss the title. In summary, it has to be made clear that this protocol does not represent a solution for highly sensitized patients.

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.

Survival with dialysis versus kidney transplantation in adult hemolytic uremic syndrome patients: A fifteen-year study of the waiting list

Background Survival data are lacking for kidney transplant recipients with rare native end-stage renal disease (ESRD) etiologies. There is currently no large registry study comparing dialysis versus kidney transplantation survival outcomes of waitlisted adults with hemolytic uremic syndrome (HUS). Materials and Methods We retrospectively studied adult-HUS end-stage renal disease patients (n = 559) placed on the US kidney transplant waitlist in 1996 to 2011. We analyzed 5-year transplantation and patient survival probabilities and risk factors using Kaplan-Meier and Cox hazards models, respectively. Using similar models, waitlist and transplantation outcomes of patients with diabetes mellitus (DM), hypertension (HTN), and glomerulonephritis (GN) were analyzed, and then compared with HUS patients. Results Compared with waitlisted adult HUS patients on dialysis, 5-year mortality risks were 73% and 48% lower in recipients of living (hazard ratio [HR], 0.27, 95% confidence interval [95% CI], 0.11-0.65) and standard deceased (HR, 0.52; 95% CI, 0.29-0.94) donor kidney transplants, respectively. Mortality risks over 5 years were 44%, 50%, 54%, and 55% lower in the overall transplant recipient cohorts than in the dialysis-maintained cohorts within the HUS (HR, 0.56; 95% CI, 0.35-0.91), HTN (HR, 0.50; 95% CI, 0.48-0.52), GN (HR, 0.46; 95% CI, 0.44-0.49), and DM (HR, 0.45; 95% CI, 0.44-0.47) groups, respectively. Five-year transplantation probability in the waitlisted HUS cohort was 60% versus 42% to 49% (P < 0.001) in the DM and HTN cohorts, and 62% (P = 0.93) in the GN cohort. Conclusions Living and standard criteria deceased donor kidney transplants provide significant survival benefit over dialysis in waitlisted adults with HUS. On the waitlist, the 5-year transplantation probability was higher in HUS than in DM and HTN patients.