Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection.

BACKGROUND: To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS: We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS: The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS: Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.

Implementing a regional standardized BK polyomavirus screening protocol across eleven transplant centres.

BK polyomavirus (BKPyV) reactivation is regularly monitored after kidney transplant to prevent progression to BK associated nephropathy (BKAN). The New England BK Consortium, made up of 12 transplant centres in the northeastern United States, conducted a quality improvement project to examine adherence to an agreed upon protocol for BKPyV screening for kidney transplants performed in calendar years 2016-2017. In a total of 1047 kidney transplant recipients (KTR) from 11 transplant centres, 204 (19%) had BKPyV infection, defined as detection of BKPyV in plasma, with 41 (4%) KTR progressing to BKAN, defined by either evidence on biopsy tissues or as determined by treating nephrologists. BKPyV infection was treated with reduction of immune suppressants (RIS) in >70% of the patients in all but two centres. There was no graft loss because of BKAN during the two-year follow-up. There were nine cases of post-RIS acute rejection detected during this same period. Adherence to the protocol was low with 54% at 12 months and 38% at 24 months, reflecting challenges of managing transplant patients at all centres. The adherence rate was positively correlated to increased detection of BKPyV infection and was unexpectedly positively correlated to an increase in diagnosis of BKAN.

Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: Implications for therapeutic planning.

The practice of transplanting hepatitis C (HCV)-infected livers into HCV-uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct-acting antivirals (DAAs) provide an opportunity to treat donor-derived HCV-infection and should be administered early in the posttransplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV-positive donor organs. We report the results of a trial in which 14 HCV-negative patients underwent successful liver transplantation from HCV-positive donors. Nine patients received viremic (nucleic acid testing [NAT]-positive) livers and started a 12-week course of oral glecaprevir-pibrentasvir within 5 days of transplant. Five patients received livers from HCV antibody-positive nonviremic donors and were followed using a reactive approach. Survival in NAT-positive recipients is 100% at a median follow-up of 46 weeks. An immediate treatment approach for HCV NAT-positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the posttransplant course could enable need-based allocation of HCV-positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

New England BK consortium: Regional survey of BK screening and management protocols in comparison to published consensus guidelines.

INTRODUCTION: BK polyomavirus (BKPyV) continues to impact renal transplant recipients (RTR). The New England BK Consortium aims to jointly optimize screening and management of BKPyV. METHODS: Our first project was to survey centers' BKPyV screening protocols and compare them to consensus guidelines. RESULTS: Thirteen of 15 centers (86.7%) returned the survey. Only two center reported using monitoring parameters that were in line with consensus guidelines for BKPyV screening, while the majority of centers reported less intensive methods and shorter duration. One center reported performing renal biopsies in all patients with plasma viral loads >10 000 copies/mL, while all other centers only perform for-cause biopsies. For presumptive nephropathy, 11 centers recommend a biopsy for confirmation. For management of documented BKPyV-associated nephropathy, 12 centers propose further immunosuppression reduction. Nine centers report CNI dose reduction as their primary treatment. More than half of centers surveyed reported use of leflunomide, cidofovir or intravenous immunoglobulin. CONCLUSIONS: There was a large variance in BKPyV screening and management strategies among centers. Due to these results, all participating centers agreed to implement uniform screening and aim to optimize management protocols.

Long-term Outcome Reporting in Older Kidney Transplant Recipients and the Limitations of Conventional Survival Metrics.

Introduction: The kidney transplant recipient population in the United States is aging rapidly, which may exacerbate some of the limitations of conventional outcome metrics. Methods: Using data from the Scientific Registry of Transplant Recipients (SRTR), age-stratified unadjusted Kaplan-Meier and competing risk survival analyses were performed on a cohort of 238,123 adult recipients of a first-time single kidney transplant between 2000 and 2017. These were compared with a multistate model incorporating 5 post-transplant states (alive with functioning graft, death with functioning graft, graft failed (alive), retransplanted, and death after graft failure). Results: Kaplan-Meier resulted in an age-dependent overestimation of the risks of graft failure and death with functioning graft, compared with competing risk or multistate models. In elderly (≥75 years old) recipients, the absolute overestimation of the risk of death with functioning graft was 4-fold higher than in those younger than 55 years. The multistate model demonstrated that for patients transplanted at age 55 years and older, the probability of being back on dialysis was never more than 4% at any point post-transplant. The underlying reasons were low graft failure rates and high mortality after resuming dialysis as follows: 2-year mortality after graft failure was 38%, 54%, and 67% in recipients aged from 55 to 64 years, from 65 to 74 years, and those aged 75 years and older, versus 20% in those younger than 55 years. Conclusion: Multistate models provide an accurate and comprehensive assessment of the life course of kidney transplant recipients. This may be particularly relevant in older recipients, who are more prone to event rate overestimation and for whom outcomes after graft failure are substantially worse than for younger recipients.

Short Bowel Syndrome and Kidney Transplantation: Challenges, Outcomes, and the Use of Teduglutide.

Among patients with short bowel syndrome who commonly have kidney disease, kidney transplantation remains challenging. We describe the clinicopathologic course of a 59-year old man with short bowel syndrome secondary to Crohn's disease who underwent a deceased donor kidney transplant that was complicated by recurrent acute kidney allograft injury due to volume depletion from diarrhea, ultimately requiring the placement of permanent intravenous access for daily volume expansion at home resulting in the recovery of allograft function. Teduglutide treatment at 1.8 years post-transplant led to a dramatic decrease in diarrhea. A literature review of similar cases yielded 18 patients who underwent 19 kidney transplants. Despite high rates of complications, at the time of last follow-up (median 2.1 years [0.04-7]), 94% of the patients were still alive and 89% had functioning allografts, with a median eGFR of 37.5 [14-122] ml/min/1.73m2. In conclusion, despite high rates of complications, kidney transplantation in patients with short bowel syndrome is associated with acceptable short- and midterm outcomes. Further, we report for the first time the effects of the glucagon-like peptide-2 analogue teduglutide for short bowel syndrome in a kidney transplant recipient.

Prognosis of Patients with Cirrhosis and AKI Who Initiate RRT.

BACKGROUND AND OBJECTIVES: Literature on the prognosis of patients with cirrhosis who require RRT for AKI is sparse and is confounded by liver transplant eligibility. An update on outcomes in the nonlisted subgroup is needed. Our objective was to compare outcomes in this group between those diagnosed with hepatorenal syndrome and acute tubular necrosis, stratifying by liver transplant listing status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective cohort study of patients with cirrhosis acutely initiated on hemodialysis or continuous RRT at five hospitals, including one liver transplant center. Multivariable regression and survival analysis were performed. RESULTS: Four hundred seventy-two subjects were analyzed (341 not listed and 131 listed for liver transplant). Among nonlisted subjects, 15% (51 of 341) were alive at 6 months after initiating RRT. Median survival was 21 (interquartile range [IQR], 8, 70) days for those diagnosed with hepatorenal syndrome and 12 (IQR, 3, 43) days for those diagnosed with acute tubular necrosis (P=0.25). Among listed subjects, 48% (63 of 131) received a liver transplant. Median transplant-free survival was 15 (IQR, 5, 37) days for those diagnosed with hepatorenal syndrome and 14 (IQR, 4, 31) days for those diagnosed with acute tubular necrosis (P=0.60). When stratified by transplant listing, with adjusted Cox models we did not detect a difference in the risk of death between hepatorenal syndrome and acute tubular necrosis (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.59 to 1.11, among those not listed; HR, 0.73; 95% CI, 0.44 to 1.19, among those listed). CONCLUSIONS: Cause of AKI was not significantly associated with mortality in patients with cirrhosis who required RRT. Among those not listed for liver transplant, mortality rates were extremely high in patients both with hepatorenal syndrome and acute tubular necrosis. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_11_09_CJASNPodcast_18_1_A.mp3.

Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports.

BACKGROUND: Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. AIM: Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. CASE PRESENTATION: Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. CONCLUSIONS: Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes.

Macrophages from lupus-prone MRL mice are characterized by abnormalities in Rho activity, cytoskeletal organization, and adhesiveness to extracellular matrix proteins.

Macrophages (mphi) from prediseased mice of the major murine models of lupus have an identical defect in cytokine expression that is triggered by serum and/or apoptotic cells. It is striking that cytokine expression in the absence of serum and apoptotic cells is equivalent to that of nonautoimmune mice. Here, we show that mphi from prediseased lupus-prone MRL/MpJ (MRL/+) or MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) mice also have reversible abnormalities in morphology, cytoskeletal organization, and adhesive properties. In the presence of serum, MRL mphi adhered in increased numbers to a variety of extracellular matrix proteins compared with mphi from two nonautoimmune strains. However, in the absence of serum, adhesion by MRL mphi was similar to that of nonautoimmune mphi. Increased adhesion by MRL mphi was also observed in the presence of apoptotic, but not necrotic, cells. The morphology and actin-staining pattern of adherent MRL mphi were consistent with reduced activity of Rho, a cytoskeletal regulator. Indeed, MRL mphi cultured in the presence of serum had markedly decreased levels of active Rho compared with nonautoimmune mphi. It is remarkable that when cultured in the absence of serum, MRL mphi displayed normal Rho activity and cytoskeletal morphology. Addition of a Rho inhibitor to normal mphi reproduced the morphologic and cytoskeletal abnormalities observed in MRL mphi. Taken together, our findings support the hypothesis that mphi from MRL and other systemic lupus erythematosus-prone mice have an apoptotic, cell-dependent, autoimmune phenotype that affects a broad range of mphi functions, including cytokine gene expression and Rho-dependent cytoskeletal regulation.

BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience.

BK virus (BKV) is a common infection encountered after kidney transplantation. BKV is associated with a spectrum of manifestations, starting with sub-clinical viruria, followed by viremia and BKV-associated nephropathy. Standard of care includes routine post-transplant screening for BK viruria and/or viremia. Both the Kidney Disease Improving Global Outcomes and the American Society of Transplantation Infectious Diseases Community of Practice have published screening recommendations. Although they vary slightly, they both highlight the importance of early detection with serial screening. Once BK viremia is detected, the standard management approach includes a reduction of immunosuppression. Guidelines differ slightly about the sequence of the immunosuppression reduction, but the end result is the same: lowering the overall immunosuppressive burden in the patient with BKV infection. At the Massachusetts General Hospital, from 2007 to 2009, there was no BKV screening protocol in place. The rate of screening during this time period increased from 62% to 81%. A total of 29 of the 243 patients were diagnosed with BK viremia (11.9%), with 23 identified as a result of screening and 6 as a result of testing for graft dysfunction. We developed a BKV screening protocol consisting of BKV polymerase chain reaction testing in blood starting 2 months after kidney transplantation and every 2 months thereafter, continuing through month 24 regardless of the allograft function. Additional screening for 6 more months is performed in patients who receive anti-lymphocyte globulin for the treatment of acute rejection. Finally, all patients with otherwise unexplained allograft dysfunction are screened. Currently, work is being done investigating the use of mammalian target of rapamycin inhibitors to treat BKV infection. Trials are also ongoing evaluating cell-based therapies for BKV. Research to develop a vaccine or a direct-acting antiviral agent is in critical need and an area of research that should be given high priority.

Immunophenotyping and efficacy of low dose ATG in non-sensitized kidney recipients undergoing early steroid withdrawal: a randomized pilot study.

UNLABELLED: Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00548405.