Faculty Bibliography

Transplantation is now lifesaving therapy for patients with end stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor-recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplant and pharmacological mobilization resulting in a chimeric, repopulated organ. We now confirm these findings in a well characterized large animal preclinical model. Here we show that AMD3100 (A) and FK506 (F) mobilization of endogenous stem cells immediately post kidney transplant combined with repeat therapy at 1, 2, and 3 months led to drug free long term survival in maximally immunologically mismatched swine. Three long term recipients have stable chimeric transplants, preserved anti-donor skin graft responses, and normal serum creatinine despite withdrawal of all medication for 3 years

Transplant tolerance allowing the elimination of life long immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been successfully extended to large animals and the clinic. However, it remains cumbersome and requires heavy early immunosuppression. Here, we report that 4 injections of AMD3100 (A), a CXCR-4 antagonist, plus 8 injections of low-dose FK506 (F, 0.05mg/kg/day) first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of A and F at 1, 2 and 3 months after transplant resulted in 92% allograft acceptance (n=12) at 7 months, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in post-transplant therapy

BACKGROUND: Recent evidence suggests that living kidney donors are at an increased risk of end-stage renal disease. However, predicting which donors will have renal dysfunction remains challenging, particularly among those with no clinical evidence of disease at the time of donation. Although renal biopsies are not routinely performed as part of the donor evaluation process, they may yield valuable information that improves the ability to predict renal function in donors. METHODS: We used implantation protocol biopsies to evaluate the association between histological abnormalities in the donated kidney and postdonation renal function (estimated glomerular filtration rate, eGFR) of the remaining kidney in living kidney donors. Longitudinal analysis using mixed-effects linear regression was used to account for multiple eGFR measures per donor. RESULTS: Among 310 donors between 1997 and 2012, median (IQR) follow-up was 6.2 (2.5-8.7; maximum 14.0) years. In this cohort, the overall prevalence of histological abnormalities was 65.8% (19.7% abnormal glomerulosclerosis, 23.9% abnormal interstitial fibrosis and tubular atrophy (IFTA), 4.8% abnormal mesangial matrix increase, 32.0% abnormal arteriolar hyalinosis, and 32.9% abnormal vascular intimal thickening). IFTA was associated with a 5-mL/min/1.73 m decrease of postdonation eGFR after adjusting for donor age at donation, sex, race, preoperative systolic blood pressure, preoperative eGFR, and time since donation (P < 0.01). CONCLUSIONS: In this single-center study, among healthy individuals cleared for living donation, IFTA was associated with decreased postdonation eGFR, whereas no other subclinical histological abnormalities provided additional information.

BACKGROUND: Kidney donors can develop end-stage renal disease (ESRD) after donation, but the outcomes of those who do remain poorly characterized. METHODS: Using United States Renal Data System and Scientific Registry for Transplant Research data, we compared access to kidney transplantation (KT), time from ESRD to listing, time from listing to KT, and post-KT graft failure and death between donors and matched nondonors with ESRD. RESULTS: Among 99 donors between April 1994 and November 2011 who developed ESRD, 78 initially received dialysis (of whom 37 listed for KT, 2 received live donor KT without listing, and 39 never listed for or received a KT), 20 listed preemptively (of whom 19 were subsequently transplanted), and 1 received a preemptive live donor KT without listing or ever receiving dialysis. Donors were listed earlier (median time to listing, 17 months vs 120 for nondonors; P < 0.001), received KT earlier (median waiting time, 2.8 months vs 21.5 for nondonors; P < 0.001), and received 13% live donor, 87% standard criteria, and 0% expanded criteria deceased donor KT (39%, 50%, and 11% in nondonors). Post-KT graft (adjusted hazard ratio, 1.9; 95% confidence interval, 0.9 to 4.1; P = 0.1) and patient (adjusted hazard ratio, 0.7; 95% confidence interval, 0.2 to 2.4; P = 0.5) survival were comparable in donors and nondonors. CONCLUSIONS: Our finding that 39 of 99 donors who developed ESRD never listed for a transplant warrants further study to ascertain why these donors with ESRD never gained access to the waiting list.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Antibody mediated injury to a renal allograft is biologically complex and is manifest by multiple phenotypes which appear to be defined by the extent and timing of the humoral response. Transplant glomerulopathy (tg) is the ultimate arbitrator of whether the injury becomes an enduring feature that limits the longevity of the allograft and it is the end stage lesion that unites the different phenotypes. For the last few decades the focus for treatment has been on removing or modulating donor specific antibody (DSA) with plasmapheresis and IVIg. This approach has been effective when the rejection is acute and the antibody production modest. Even under those circumstances tg will be present within a year of the antibody mediated rejection (ABMR) episode in nearly half of the allografts. Because IgG is distributed throughout the interstitium, the removal or inactivation of antibody is not immediate. While efforts are being made to manage DSA, the renal microcirculation remains vulnerable to the injurious effects of soluble DSA, especially antibodies that activate complement

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon glomerular disorder that may lead to end stage renal disease (ESRD). With new understanding of the disease pathogenesis, the classical classification as MPGN types I, II, III has changed. Data on post-transplant MPGN, in particular with the newly refined classification, is limited. We present our center's experience of MPGN after kidney transplantation using the new classification. METHODS: This is a retrospective study of 34 patients with ESRD due to MPGN who received 40 kidney transplants between 1994 and 2014. We reviewed the available biopsies' data using the new classification. We assessed post transplantation recurrence rate, risk factors of recurrence, the response to therapy and allografts' survival. RESULTS: Median time of follow up was 5.3 years (range 0.5-14 years). Using the new classification, we found that pre-transplant MPGN disease was due to immune complex-mediated glomerulonephritis (ICGN) in 89 % of cases and complement-mediated glomerulonephritis (CGN) in 11 %. Recurrence was detected in 18 transplants (45 %). Living related allografts (P = 0.045), preemptive transplantations (P = 0.018), low complement level (P = 0.006), and the presence of monoclonal gammopathy (P = 0.010) were associated with higher recurrence rate in ICGN cases. Half of the patients with recurrence lost their allografts. The use of ACEi/ARB was associated with a trend toward less allograft loss. CONCLUSIONS: MPGN recurs at a high rate after kidney transplantation. The risk of MPGN recurrence increases with preemptive transplantation, living related donation, low complement level, and the presence of monoclonal gammopathy. Recurrence of MPGN leads to allograft failure in half of the cases.