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BACKGROUND: Active antibody-mediated rejection (AMR) that occurs during the amnestic response within the first month post-transplant is a rare but devastating cause of early allograft loss after kidney transplant. Prior reports of eculizumab treatment for AMR have been in heterogeneous patient groups needing salvage therapy or presenting at varied time points. We investigated the role of Eculizumab as primary therapy for active AMR early post-transplant. METHODS: We performed a retrospective observational study of a consecutive cohort of solitary kidney transplant recipients who were transplanted between January 1, 2014 and January 31, 2018 and had AMR within the first 30 days post-transplant and treated with eculizumab ± plasmapheresis. RESULTS: Fifteen patients had early active AMR at a median [IQR] of 10 [7-11] days post-transplant and were treated with eculizumab ± plasmapheresis. Thirteen cases were biopsy proven and 2 cases were presumed based on donor specific antibody trends and allograft function. Within 1 week of treatment the median estimated glomerular filtration rate (eGFR) increased from 21 mL/min to 34 mL/min (P = .001); and persistent active AMR was only found in 16.7% (2/12) of biopsied patients within 4-6 months. No graft losses occurred and at last follow-up (median [IQR] of 13 [12-19] months) the median IQR eGFR increased to 52 (46-60) mL/min. CONCLUSIONS: Prompt eculizumab treatment as primary therapy is safe and effective for early active AMR after kidney transplant or abrupt increases in donor-specific antibodies when biopsy cannot be performed for diagnosis confirmation.

Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA- at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA- patients.From January 2013 to October 2016, 90 HS patients (PRA80%, DSA+ = 50 versus DSA- = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant.Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/- (n=19), DSA-/+ (n=10), and DSA-/- (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/- (11%), and DSA-/- (10%) patients (P0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar.Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.

BACKGROUND De novo donor HLA-specific (dnDSA) and non-HLA antibodies including antiangiotensin type 1 receptor antibodies (AT1R-abs) have been associated with antibody-mediated rejection (AMR) and decreased graft survival as well as cellular-mediated rejection (CMR) and early onset of microvasculopathy in heart transplantation. The aim of our study was to determine the impact of anti-AT1R-ab and anti-donor HLA-specific antibody (DSA) on clinical outcomes. METHODS Pretransplant and posttransplant sera from 200 recipients transplanted between May 2007 and August 2011 were tested for DSA (Luminex-based single antigen bead assay) and AT1R-ab (enzyme-linked immunosorbent assay). Two cutoff levels (≥ 17 and ≥ 12 units) were used to define high and intermediate binding of AT1R-ab. Clinical parameters examined were 5-year AMR/CMR (≥ grade 2), coronary artery vasculopathy, and survival. RESULTS At 2 years after transplant, freedom from AMR and/or CMR was 95.4% for those with no DSA (n=175), 66.9% for those with dnDSA (n=19), and 25% for those with DSA at transplant (n=6) (P

The requirements for potent immunosuppression coupled with the formidable risk of irreversible antibody-mediated rejection (AMR) have thus far limited the expansion of ABO incompatible (ABOi) kidney transplantation. We present a retrospective review of our single-center experience with 60 consecutive ABOi kidney transplants and describe the evolution of our treatment protocol to one that consists only of a brief escalation in immunosuppression without long-term B-cell suppression from splenectomy or anti-CD20. The 1-, 3-, and 5-year graft survival rates for the cohort were 98.3%, 92.9%, and 88.7%, respectively, which is comparable with United Network for Organ Sharing data for compatible live donor transplants. No instances of hyperacute rejection were observed, and no grafts were lost secondary to AMR. In fact, fewer than 15% of the patients experienced a clinical episode of AMR, and rejections were mild. Elimination of B-cell ablative therapies did not result in an increased incidence of AMR. Excellent graft function persists with a current median creatinine clearance of 60 mL/min. The findings of this study and the relatively simple therapeutic regimen used should facilitate widespread application of ABOi kidney transplantation resulting in one of the most rapid escalations in access to organs in the modern era of kidney transplantation.

Current desensitization (DES) methods are not always effective. Thus, novel, more effective approaches are desirable. Interleukin (IL)-6 is an attractive target as it promotes B-cell differentiation to plasma cells, is important for immunoglobulin production, and induces Th17 cells. Here, we undertook a phase I/II pilot study of DES using a novel drug (anti-IL-6 receptor (IL-6R),Tocilizumab [TCZ]) + intravenous Ig (IVIg) to assess safety and limited efficacy.From July 2012 to November 2013, 10 patients unresponsive to DES with IVIg + Rituximab were treated with IVIg + TCZ. Patients received IVIg on days 0 and 30 at 2 g/kg and TCZ 8 mg/kg on day 15 then monthly for 6 months. If transplanted, patients received IVIg once and TCZ monthly for 6 months.No differences in baseline characteristics were seen in patients not transplanted versus transplanted. Two patients in each group developed serious adverse events: not transplanted- pulmonary congestion with epilepticus (likely not related) versus transplanted infective colitis with colonic perforation and Bell Palsy (both possibly related). Five of 10 patients were transplanted. Mean time to transplant from first DES was 25 +/- 10.5 months but after TCZ was 8.1 +/- 5.4 months. Six-month protocol biopsies showed no antibody-mediated rejection. Donor-specific antibody strength and number were reduced by TCZ treatment. Renal function at 12 months was 60 +/- 25 mL/min.Tocilizumab and IVIg appear to be safe. From this pilot trial, we are cautiously optimistic that targeting the IL-6/IL-6R pathway could offer a novel alternative for difficult to desensitize patients. Larger controlled studies are essential to prove efficacy

Antibody-mediated rejection (AMR) is a severe form of rejection, mediated primarily by antibody-dependent complement (C) activation. C1 inhibitor (C1-INH, Berinert) inhibits the classical and lectin pathways of C activation. We performed a randomized, placebo-controlled study using C1-INH in highly sensitized renal transplant recipients for prevention of AMR.Twenty highly sensitized patients desensitized with IVIG+rituximab±plasma exchange were enrolled and randomized 1:1 to receive plasma-derived human C1-INH (20 IU/kg/dose) versus placebo intraoperatively, then twice weekly for 7 doses. Renal function, adverse events (AEs)/serious AEs, C3, C4, and C1-INH levels were monitored and C1q+ HLA antibodies were also blindly assessed.One patient in the C1-INH group versus 2 patients in the placebo group developed serious AEs, but none were related to study drug. Delayed graft function developed in 1 C1-INH subject and 4 in the placebo. The C1-INH trough levels increased with C1-INH treatment. C3 and C4 levels also increased significantly in the C1-INH group compared to placebo. No C1-INH patient developed AMR during the study. Two patients developed AMR after the study. Three placebo patients developed AMR, one during the study. C1q+ donor specific antibodies were reduced in 2 C1-INH treated patients tested, while immunoglobulin G DSA levels showed decreased binding for both groups.The C1-INH appears safe in the posttransplant period. The C1-INH treatment may reduce ischemia-reperfusion injury. The C1-INH also resulted in significant elevations of C1-INH levels, C3, C4, and reduced C1q+ HLA antibodies. Taken together, the combination of antibody reduction and C1-INH may prove useful in prevention of AMR. Further controlled studies are warranted.

Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern.Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed.Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036).Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.

BACKGROUND Outcomes after kidney transplantation using deceased donors with high terminal creatinine are not well described but potentially represent an underutilized source of renal allografts. Utility of renal biopsy of these kidneys is similarly not well established. METHODS To better understand the posttransplant function of kidneys from donors with high terminal creatinine, we reviewed our database of almost 500 cadaveric kidney transplants. We compared the 65 nonexpanded criteria donors with a final donor creatinine > or = 2.0 mg/dl (range 2.0-4.9 mg/dl) with kidneys procured from donors with terminal creatinine of

Background Perioperative treatment with plasmapheresis and intravenous immunoglobulin (IVIG), combined with a tacrolimus-based immunosuppressive regimen, has been used successfully to allow renal transplantations in cross-match-positive recipients. A common finding in biopsy specimens of these allografts is isometric vacuolization of proximal tubular epithelium. This finding presents a diagnostic dilemma because it may occur secondary to IVIG treatment or tacrolimus nephrotoxicity. Methods We compared the frequency and severity of isometric tubular vacuolization in renal allograft biopsy specimens obtained during the first 10 days after transplantation in 24 patients who received one or more postoperative treatments with IVIG (100 mg/kg; as part of a desensitization protocol also involving plasmapheresis) with specimens obtained in 91 patients who did not receive IVIG. All patients received tacrolimus. Isometric vacuolization was graded on a 0 to 4 scale based on the fraction of proximal tubules involved: 0, none; 1, less than 10%; 2, 10% to 25%; 3, 26% to 50%; 4, more than 50%. Results There was a higher frequency of isometric tubular vacuolization (71 % vs. 31%) and more widespread involvement in patients who received IVIG and tacrolimus versus tacrolimus alone, although mean tacrolimus levels were not significantly different between these groups. In control, but not IVIG, biopsy specimens, there was a significant association between vacuolization score and blood tacrolimus level on the day of biopsy. Conclusions Isometric tubular vacuolization is a common finding in renal transplant biopsy specimens of patients who receive low-dose IVIG and in many cases is likely to be related, at least in part, to IVIG. In these patients, this finding should not necessarily be interpreted as indicative of tacrolimus (or cyclosporine) nephrotoxicity.

Background. Deposition of C4d in peritubular capillaries (PTCs) has been shown to be a sensitive marker for antibody-mediated (humoral) rejection in renal transplant biopsies. Some studies also suggest that C4d in PTCs is specific for humoral rejection or, at least, for the presence of donor-specific antibodies. However, in other studies, PTC C4d deposits were noted in more than 40% of renal transplant biopsies performed for graft dysfunction and capillary C4d deposition in heart transplants may result from ischemic injury. Methods. To test the specificity of C4d staining as a marker for acute humoral rejection ACR in renal allografts, indirect immunofluorescence using a monoclonal anti-C4d antibody and a fluorescein-isothiocyanate-conjugated secondary antibody was performed on cryostat sections of 90 renal transplant biopsies, including 35 pairs of preimplantation and 1-hr postreperfusion biopsies of the same graft, postreperfusion biopsies of 12 additional grafts, and 8 positive controls (biopsies with known C4d-positive AHR). Eighteen grafts were cadaveric, 17 grafts were liviing-related, and 12 grafts were living-unrelated (excluding controls). Included in these grafts were 13 grafts that developed AHR 3 to 34 days posttransplantation. Results. Only 2 of 82 perioperative biopsies showed C4d staining in PTCs. Both perioperative biopsies were postreperfusion biopsies of grafts diagnosed with AHR 5 and 34 days posttransplantation, respectively, and, in each case, the recipient had been treated with plasmapheresis before transplantation because of a positive crossmatch (cytotoxic and flow cytometric) and continued to have a weakly positive flow crossmatch at the time of transplantation. In one biopsy, C4d staining was focal, and in the other biopsy, it was diffuse; in both biopsies, C4d staining was relatively mild (1+ on a 0-4+ scale). No C4d staining was noted on preimplantation biopsies of each graft. All biopsies that contained glomeruli showed linear capillary loop or blotchy mesangial staining, or both, which was similar in prereperfusion and postreperfusion biopsies. All positive controls showed diffuse C4d staining in PTCs. Conclusions. C4d staining in PTCs may be seen as early as 1 hr posttransplantation in some recipients with low levels of antidonor antibodies. However, this was not observed as a feature of ischemic or ischemia-reperfusion injury in perioperative renal transplant biopsies, including those of cadaveric grafts with cold ischemia times of as long as 41 hr.

Although polyoma virus infection is being increasingly recognized as a cause of renal allograft dysfunction and failure, the risk of polyoma recurrence in a subsequent transplant is unknown. We present the first reported case of successful retransplantation after polyoma virus-induced renal allograft loss.A 40-year-old Caucasian woman received a cadaveric kidney transplant. Baseline immunosuppression included corticosteroids, mycophenolate mofetil, and tacrolimus. Her post-transplant clinical course was complicated by an early acute rejection episode on posttransplant day (PTD) 6, that warranted treatment with OKT3. A biopsy performed on PTD 154 to evaluate a rise in creatinine revealed polyoma virus interstitial nephritis. Despite reduction in immunosuppression, the renal function progressively worsened and dialysis was initiated by PTD 160, followed by transplant nephrectomy on PTD 184. Four months later, she received a living related kidney from her sister. Immunosuppression was initiated with prednisone, azathioprine, and tacrolimus. She had immediate graft function with a decrease in serum creatinine from 12.8 to 1.1 mg/dl. Three and one-half years after her second renal transplant, her allograft functions well, with a serum creatinine of 1 mg/dl. Both quantitative and qualitative assays of blood and urine (by PCR) remain negative for BK virus, indicating the absence of virus reactivation.Judicious retransplantation should be considered as a therapeutic option in the management of polyoma virus induced graft failure. Previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation.

Background Highly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial. Methods Candidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed. Results Initially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04). Conclusions Based on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy.

Background. Angiotensin type 1 receptor (AT1R) mediates most physiologic and pathophysiologic actions of its endogenous ligand, angiotensin II, with overactivity leading to vascular remodeling and hypertension. Antibodies to AT1R are implicated in several vascular pathologies. The aim of our study was to determine the impact of antibody to AT1R on clinical outcomes including antibody mediated rejection (AMR), with or without C4d deposition, in patients whose sera contained no donor human leukocyte antigen (HLA)-specific antibody (HLA-DSA). Methods. Pretransplant sera from 97 recipients and sera obtained at the time of acute rejection (AR) were tested by Luminex-based single-antigen bead assays to determine HLA-DSA and antibodies to major histocompatibility class I chain-related gene A (MICA). The presence of antibody to AT1R was determined by a cell-based ELISA method using a cutoff of 17 units to distinguish high from low binding. Results. Sera from 63 recipients were determined to have no HLA-DSA and no donor-specific MICA antibodies pretransplantandatthetimeofAR,and16oftheserecipientswerediagnosedwithARincluding7withAMRand9with cellular AR (cell-mediated rejection). High-binding AT1R antibodies were identified for six of seven in the AMR group and zero of nine in the cell-mediated rejection group (P0.0009). Conclusions.A strong association was observed between the presence of high binding to AT1R and AMR in recipients whose sera contained no antibody to donor HLA or MICA. Assessing the AT1R antibody status along with the HLADSA provides additional information to determine the immunologic risk for recipients.

Background. Donor-specific antibody (DSA) is the major barrier to success of kidney transplants. Attempts to deal with this problem have used plasmapheresis to remove antibodies or high-dose pooled immunoglobulin (IVIg) to down-regulate DSA. However, elimination of antibodies by these methods has been limited in duration or scope. Methods. We have confirmed the presence of immunoglobulin (Ig)G antibody to one or more donor HLA antigens in 49 patients treated with alternate-day, single-volume plasmapheresis followed by low-dose cytomegalovirus (CMV) hyperimmune globulin (CMV-Ig) combined with quadruple immunosuppression. We examined the effect of the treatment protocol on antibodies to donor HLA, third-party HLA, and nominal antigens. Results. At the end of treatment, 63% of patients had lost antibody to donor HLA, whereas only 27% had lost antibody to third-party HLA (P

Deposition of C4d in peritubular capillaries (PTCs) has been shown to be a sensitive marker for antibody-mediated (humoral) rejection in renal transplant biopsies. Some studies also suggest that C4d in PTCs is specific for humoral rejection or, at least, for the presence of donor-specific antibodies. However, in other studies, PTC C4d deposits were noted in more than 40% of renal transplant biopsies performed for graft dysfunction and capillary C4d deposition in heart transplants may result from ischemic injury.To test the specificity of C4d staining as a marker for acute humoral rejection ACR in renal allografts, indirect immunofluorescence using a monoclonal anti-C4d antibody and a fluorescein-isothiocyanate-conjugated secondary antibody was performed on cryostat sections of 90 renal transplant biopsies, including 35 pairs of preimplantation and 1-hr postreperfusion biopsies of the same graft, postreperfusion biopsies of 12 additional grafts, and 8 positive controls (biopsies with known C4d-positive AHR). Eighteen grafts were cadaveric, 17 grafts were liviing-related, and 12 grafts were living-unrelated (excluding controls). Included in these grafts were 13 grafts that developed AHR 3 to 34 days posttransplantation.Only 2 of 82 perioperative biopsies showed C4d staining in PTCs. Both perioperative biopsies were postreperfusion biopsies of grafts diagnosed with AHR 5 and 34 days posttransplantation, respectively, and, in each case, the recipient had been treated with plasmapheresis before transplantation because of a positive crossmatch (cytotoxic and flow cytometric) and continued to have a weakly positive flow crossmatch at the time of transplantation. In one biopsy, C4d staining was focal, and in the other biopsy, it was diffuse; in both biopsies, C4d staining was relatively mild (1+ on a 0-4+ scale). No C4d staining was noted on preimplantation biopsies of each graft. All biopsies that contained glomeruli showed linear capillary loop or blotchy mesangial staining, or both, which was similar in prereperfusion and postreperfusion biopsies. All positive controls showed diffuse C4d staining in PTCs.C4d staining in PTCs may be seen as early as 1 hr posttransplantation in some recipients with low levels of antidonor antibodies. However, this was not observed as a feature of ischemic or ischemia-reperfusion injury in perioperative renal transplant biopsies, including those of cadaveric grafts with cold ischemia times of as long as 41 hr.

UNLABELLED Protocol biopsies were performed to define the histologic response to tacrolimus therapy in patients with refractory acute renal allograft rejection. Renal allograft biopsies were performed at defined intervals after initiation of tacrolimus therapy. Protocol biopsies were performed before tacrolimus therapy (within 48 hr of initiation of therapy) and after 1 week of therapy. If the 1-week biopsy did not show rejection reversal, repeat protocol biopsies were obtained at 1- to 2-week intervals, until histologic reversal was observed. Additional biopsies were obtained at 4 weeks and at 8-12 weeks after initiation of tacrolimus therapy. Indicated biopsies were also performed to evaluate increases in serum creatinine. A total of 92 biopsies were performed in 23 patients (average 4.0 biopsies/ patient). Biopsies were performed in each patient immediately before starting tacrolimus therapy (23 biopsies), and 69 biopsies (3.0 biopsies/patient) were performed during tacrolimus therapy. Rejection diagnosis was based on strict Banff criteria. Pretacrolimus biopsies demonstrated mild acute rejection in 64% of patients and moderate acute rejection in 36%. One week after initiation of tacrolimus therapy, protocol biopsies revealed the following: no rejection (60%), improvement (13%), no change (20%), and worsening rejection (7%). Histologic changes at 1 week did not correlate with changes in renal function, as 63% of patients that showed histologic improvement or reversal during the first 2 weeks of therapy did not show improvement in serum creatinine. A lack of histologic improvement (or worsening) at 1 week was demonstrated in a significant proportion of patients (27%); increased tacrolimus dosing provided rejection reversal or improvement in 1-2 weeks in each of these patients. Recurrent rejection was diagnosed on eight biopsies in seven patients, however six episodes were diagnosed by protocol biopsies alone (i.e., in the absence of an elevation in serum creatinine). Delayed improvement in renal function, despite histologic reversal, was likely due to physiologic effects of tacrolimus (i.e., afferent arteriolar vasoconstriction), as histologic evidence of tacrolimus toxicity was not observed during the first 2 weeks of therapy. Histologic evidence of tacrolimus nephrotoxicity (nodular arteriolar hyalinosis) was found in 21% (15 of 69) of biopsies in 39% of patients (9 of 23) at a median time of 60 days (range 12-150 days). Tacrolimus dose and blood levels (by IMx assay) did not correlate with development of clinically silent or clinically evident nephrotoxicity. IN CONCLUSION 1) protocol biopsies provide information that allows individualization of tacrolimus rejection therapy, 2) histologic resolution of rejection often precedes biochemical improvement, 3) histologic evidence of tacrolimus nephrotoxicity is seldom observed in the first 2 weeks of therapy, and 4) clinically silent recurrent rejection and clinically silent tacrolimus nephrotoxicity are observed with significant frequency during tacrolimus therapy for refractory renal allograft rejection.