Noninvasive biomarkers are needed to monitor stable patients after kidney transplant (KT), because subclinical acute rejection (subAR), currently detectable only with surveillance biopsies, can lead to chronic rejection and graft loss. We conducted a multicenter study to develop a blood-based molecular biomarker for subAR using peripheral blood paired with surveillance biopsies and strict clinical phenotyping algorithms for discovery and validation. At a predefined threshold, 72% to 75% of KT recipients achieved a negative biomarker test correlating with the absence of subAR (negative predictive value: 78%-88%), while a positive test was obtained in 25% to 28% correlating with the presence of subAR (positive predictive value: 47%-61%). The clinical phenotype and biomarker independently and statistically correlated with a composite clinical endpoint (renal function, biopsy-proved acute rejection, ≥grade 2 interstitial fibrosis, and tubular atrophy), as well as with de novo donor-specific antibodies. We also found that <50% showed histologic improvement of subAR on follow-up biopsies despite treatment and that the biomarker could predict this outcome. Our data suggest that a blood-based biomarker that reduces the need for the indiscriminate use of invasive surveillance biopsies and that correlates with transplant outcomes could be used to monitor KT recipients with stable renal function, including after treatment for subAR, potentially improving KT outcomes.

Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.

Background We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplant termed FCRx. Here we provide intermediate-term follow-up on this phase 2 trial. Methods Fifteen HLA mismatched living donor renal transplant recipients underwent low intensity conditioning (fludarabine, cyclophosphamide, 200cGyTBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression(IS),consisting of tacrolimus and mycophenolate, was weaned over one year. Results All but one patient demonstrated peripheral blood macrochimerism post-transplantation. Engraftment failure occurred in a highly sensitized (PRA of52%) recipient. Chimerism was lost in 3patients at 2, 3, and 6 months post transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other 2 had PRA >20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full dose immunosuppression. Complete immunosuppression withdrawal at one year post-transplant was successful in all patients with durable chimerism. There has been no GVHD or engraftment syndrome. Renal transplant loss occurred in 1 patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness. Conclusions Low intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.

No abstract

This paper reports a case of migrating intravascular bullet embolus that initially produced no symptoms but resulted in an above-knee amputation 14 months after its entry into a peripheral artery. The missile entered through a penetrating gunshot wound to the abdominal aorta and later became lodged in the left popliteal artery. However, the bullet fragment migrated further into the posterior tibial artery with consequent vascular insufficiency requiring a supracondylar amputation of the left lower extremity 14 months later. Emphasis is placed on the need for a high index of suspicion for bullet embolism, aggressive search for any bullets unaccounted for, and early surgical removal of all confirmed arterial emboli.

Generally chronic steroid therapy is standard care for African American (AA) kidney recipients because of their higher incidence of rejections and lower longterm graft survival. This prospective study evaluated the long-term safety and efficacy of early steroid withdrawal (ESW) in AA recipients. A total of 206 recipients were studied; 103 AA and 103 non-AA recipients monitored by serial surveillance biopsies from 1 to 60 months posttransplantation to evaluate subclinical acute rejections (SCAR) and chronic allograft injury (CAI). Biopsy-proven clinical acute rejections (BPAR) and SCAR were treated. Primary end point was BPAR and secondary end points were 5-year SCAR, CAI and survival. Incidences of BPAR was 16% versus 14% (p = 1.0), prevalence of CAI due to hypertension was 48% versus 30% (p = 0.05) and interstitial fibrosis/tubular atrophy was 47% versus 32% (p = 0.05) and the mean serum creatinine levels were 2.1 versus 1.8 mg/dL (p = 0.05) at 5-years in AA versus non-AA recipients. The incidence of SCAR was 23% versus 11% at 1 month (p = 0.04), 12% versus 3% at 3 years (p = 0.04) and 10% versus 1% at 5 years (p = 0.04) in AA and non-AA recipients, respectively. Five-year patient survivals were 81% and 88% (p = 0.09) and graft survivals were 71% and 73%(p = 0.19) in AA and non-AA groups, respectively. After early steroid withdrawal AA kidney recipients have significantly lower renal function and higher SCAR and CAI but 5-year graft survival are comparable to non-AA recipients.

Homozygosity for apolipoprotein-L1 (APOL1) risk variants has emerged as an important predictor of renal disease in individuals of African descent over the past several years. Additionally, these risk variants may be important predictors of renal allograft failure when present in a living or deceased donor. Currently, there is no universal recommendation for screening of potential donors. We present a case of end-stage renal disease with focal segmental glomerulosclerosis in a living donor 7 years following donor nephrectomy. Genetic assessment revealed homozygosity for the G1 high-risk APOL1 variant.

Tacrolimus and Sirolimus are commonly used maintenance immunesuppressants in kidney transplantation. Since their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of Tacrolimus to Sirolimus conversion on frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late Sirolimus conversion and 12 on Tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12 and 24-months post-randomization with T cell subpopulations analyzed by flow cytometry and T cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24-months post-randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4+25+++Foxp3+ regulatory T cells. While Tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post-transplant, Sirolimus conversion increased indirect alloreactive T cell frequencies compared to Tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in Sirolimus-converted patients. Thus, chronic immune alterations are induced after Sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.