Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

Association of Candidate Removals From the Kidney Transplant Waiting List and Center Performance Oversight.

Approximately 59 000 kidney transplant candidates have been removed from the waiting list since 2000 for reasons other than transplantation, death, or transfers. Prior studies indicate that low-performance (LP) center evaluations by the Scientific Registry of Transplant Recipients (SRTR) are associated with reductions in transplant volume. There is limited information to determine whether performance oversight impacts waitlist management. We used national SRTR data to evaluate outcomes of 315 796 candidates on the kidney transplant waiting list (2007-2014). Compared to centers without LP, rates of waitlist removal (WLR) were higher at centers with LP evaluations (44.6/1000 follow-up years, 95% confidence interval [CI] 44.0, 45.1 versus 68.0/1000 follow-up years, 95% CI 66.6, 69.4), respectively, which was consistent after risk adjustment (adjusted hazard ratio [AHR] = 1.59, 95% CI 1.55, 1.63). Candidate mortality following waitlist removal was lower at LP centers (AHR = 0.90, 95% CI 0.87, 0.94). Analyses limited to LP centers indicated a significant increase in WLR (+28.6 removals/1000 follow-up years, p < 0.001), a decrease in transplant rates (-11.9/1000 follow-up years, p < 0.001) and a decrease in mortality after removal (-67.5 deaths/1000 follow-up years, p < 0.001) following LP evaluation. There is a significant association between LP evaluations and transplant center processes of care for waitlisted candidates. Further understanding is needed to determine the impact of performance oversight on transplant center quality of care and patient outcomes.

Fibrin Glue Injections: A Minimally Invasive and Cost-Effective Treatment for Post-Renal Transplant Lymphoceles and Lymph Fistulas.

Pelvic lymphoceles/lymph fistulas are commonly observed after kidney allotransplantation, especially when the kidney is placed in a retroperitoneal position. While the majority are <5 cm in diameter and resolve without intervention, some may continue to enlarge, and cause local or systemic symptoms or graft dysfunction. Among 1662 recipients of both living and deceased donor kidney transplants between January 2003 and July 2014, we found 46 (2.7%) patients with symptomatic lymphoceles requiring intervention. We studied the clinical outcomes and charges for three treatment modalities including open surgical drainage (22), laparoscopic surgical drainage (11), and percutaneous fibrin glue injections into the drained lymphocele cavity (13). The patient demographics and clinical characteristics were comparable for each treatment group, although maintenance immunosuppressive drugs differed by era. We found fibrin glue injections resulted in significantly lower (p = 0.04) rates of recurrence (1; 7.7%) than either laparoscopic (6; 54%) or open surgical drainage (6; 27.3%). In addition, fibrin glue injections generated significantly (p < 0.001) lower median ($4559) charges compared to either laparoscopic ($26,330) or open surgical drainage ($23,758). Fibrin glue treatment has the advantage of being an outpatient procedure, performed with the patient under local anesthesia, and does not incur the expense of an operative procedure or hospital admission associated with laparoscopic or open surgery.

Primary Graft Dysfunction After Zero-Mismatch Kidney Transplantation Secondary to Early Biopsy-Proven Acute Cell-Mediated Rejection: Case Report.

We report a case of primary renal allograft dysfunction and early acute cell-mediated rejection after a 12/12 HLA antigen zero-mismatch (0MM) transplant. The recipient was a 40-year-old white man who was highly allosensitized, with a calculated panel reactive antibody score of 100%. In posteroperative day 1 the recipient remained anuric and underwent dialysis because of hyperkalemia. Graft biopsy showed early acute cellular rejection, Banff grade 2B. No evidence of antibody-mediated rejection was observed. To our knowledge, this case is the 1st to report early cell-mediated rejection after 12/12 HLA antigen 0MM kidney transplantation. This case suggests that highly sensitized candidates are at high immunologic risk even in the context of 0MM kidney transplantation.

Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

The Incorporation of an Advanced Donation Program Into Kidney Paired Exchange: Initial Experience of the National Kidney Registry.

The continued growth of kidney paired donation (KPD) to facilitate transplantation for otherwise incompatible or suboptimal living kidney donors and recipients has depended on a balance between the logistics required for patients and the collaborating transplant centers. The formation of chains for KPD and the shipping of kidneys have permitted networks such as the National Kidney Registry (NKR) to offer KPD to patients over a transcontinental area. However, over the last 3 years, we have encountered patient requests for a more flexible experience in KPD to meet their individual needs often due to rigid time constraints. To accommodate these requests, we have developed an Advanced Donation Program (ADP) in which the donor desires to donate by a specific date, but their paired recipient has not yet been matched to a specific donor or scheduled for surgery. After obtaining careful informed consent from both the donor and paired recipient, 10 KPD chains were constructed using an ADP donor. These 10 ADP donors have facilitated 47 transplants, and thus far eight of their paired recipients have received a kidney within a mean of 178 (range 10-562) days. The ADP is a viable method to support time limited donors in a KPD network.

Critical Factors Associated With Missing Follow-Up Data for Living Kidney Donors in the United States.

Follow-up care for living kidney donors is an important responsibility of the transplant community. Prior reports indicate incomplete donor follow-up information, which may reflect both donor and transplant center factors. New UNOS regulations require reporting of donor follow-up information by centers for 2 years. We utilized national SRTR data to evaluate donor and center-level factors associated with completed follow-up for donors 2008-2012 (n = 30 026) using multivariable hierarchical logistic models. We compared center follow-up compliance based on current UNOS standards using adjusted and unadjusted models. Complete follow-up at 6, 12, and 24 months was 67%, 60%, and 50% for clinical and 51%, 40%, and 30% for laboratory data, respectively, but have improved over time. Donor risk factors for missing laboratory data included younger age 18-34 (adjusted odds ratio [AOR] = 2.03, 1.58-2.60), black race (AOR = 1.17, 1.05-1.30), lack of insurance (AOR = 1.25, 1.15-1.36), lower educational attainment (AOR = 1.19, 1.06-1.34), >500 miles to center (AOR = 1.78, 1.60-1.98), and centers performing >40 living donor transplants/year (AOR = 2.20, 1.21-3.98). Risk-adjustment moderately shifted classification of center compliance with UNOS standards. There is substantial missing donor follow-up with marked variation by donor characteristics and centers. Although follow-up has improved over time, targeted efforts are needed for donors with selected characteristics and at centers with higher living donor volume. Adding adjustment for donor factors to policies regulating follow-up may function to provide more balanced evaluation of center efforts.

First-in-human study of the safety and efficacy of TOL101 induction to prevent kidney transplant rejection.

TOL101 is a murine IgM mAb targeting the αß TCR. Unlike other T cell targets, the αß TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm(3) ), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5-10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28 mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21-28-42-42-42 mg regimen.

Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling.

There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction.

Risk factors for retransplant kidney recipients: relisting and outcomes from patients' primary transplant.

As of November 2013, 14.5% of the waitlist for a donor kidney comprised patients awaiting a retransplant. We performed a retrospective cohort study of 11,698 adult solitary kidney recipients using national Scientific Registry of Transplant Recipients data transplanted between 2002 and 2011. The aim was to investigate whether outcomes from patients' initial transplants are significant risk factors for patients' repeat transplants or for likelihood of relisting after a failed primary transplant. Retransplant recipients were more likely to be treated for acute rejection [adjusted odds ratio (AOR), 95% confidence interval (CI) = 1.26 (1.07-1.48), p = 0.0053] or hospitalized (AOR = 1.19, 95% CI 1.08-1.31, p = 0.0005) within a year of retransplantation if these outcomes were experienced within a year of primary transplant. Delayed graft function following primary transplants was associated with 35% increased likelihood of recurrence (AOR = 1.35, 95% CI = 1.18-1.54, p < 0.0001). An increase in 1-year GFR after primary transplant was associated with GFR 1 year postretransplant (ß = 6.82, p < 0.0001), and retransplant graft failure was inversely associated with 1-year primary transplant GFR (adjusted hazard ratio = 0.74, 95% CI = 0.71-0.76 per 10 mL/min/1.73 m(2) ). A decreased likelihood for relisting was associated with hospitalization and higher GFR following primary transplantation. The increasing numbers of individuals requiring retransplants highlights the importance of incorporating prior transplant outcomes data to better inform relisting decisions and prognosticating retransplant outcomes.

Prominent impact of community risk factors on kidney transplant candidate processes and outcomes.

Numerous factors impact patients' health beyond traditional clinical characteristics. We evaluated the association of risk factors in kidney transplant patients' communities with outcomes prior to transplantation. The primary exposure variable was a community risk score (range 0-40) derived from multiple databases and defined by factors including prevalence of comorbidities, access and quality of healthcare, self-reported physical and mental health and socioeconomic status for each U.S. county. We merged data with the Scientific Registry of Transplant Recipients (SRTR) and utilized risk-adjusted models to evaluate effects of community risk for adult candidates listed 2004-2010 (n = 209 198). Patients in highest risk communities were associated with increased mortality (adjusted hazard ratio [AHR] = 1.22, 1.16-1.28), decreased likelihood of living donor transplantation (adjusted odds ratio [AOR] = 0.90, 0.85-0.94), increased waitlist removal for health deterioration (AHR = 1.36, 1.22-1.51), decreased likelihood of preemptive listing (AOR = 0.85, 0.81-0.88), increased likelihood of inactive listing (AOR = 1.49, 1.43-1.55) and increased likelihood of listing for expanded criteria donor kidneys (AHR = 1.19, 1.15-1.24). Associations persisted with adjustment for rural-urban location; furthermore the independent effects of rural-urban location were largely eliminated with adjustment for community risk. Average community risk varied widely by region and transplant center (median = 21, range 5-37). Community risks are powerful factors associated with processes of care and outcomes for transplant candidates and may be important considerations for developing effective interventions and measuring quality of care of transplant centers.

The impact of deceased donor kidney risk significantly varies by recipient characteristics.

As of May 2012, over 92 000 patients were awaiting a solitary kidney transplant in the United States and new waitlist registrations have been rising for over a decade. The decreasing availability of donor organs makes it imperative that organ allocation be as efficient and effective as possible. We performed a retrospective cohort study of adult recipients in the United States (n=109 392) using Scientific Registry of Transplant Recipients data. The primary aim was to evaluate the interaction of donor risk with recipient characteristics on posttransplant outcomes. Donor quality (based on kidney donor risk index [KDRI]) had significant interactions by race, primary diagnosis and age. The hazard of KDRI on overall graft loss in non-African Americans was 2.16 (95%CI 2.08-2.25) versus 1.85 (95%CI 1.75-1.95) in African Americans (p<0.0001), 2.16 (95%CI 2.08-2.24) in nondiabetics versus 1.84 (95%CI 1.74-1.94) in diabetics (p<0.0001), and 2.22 (95%CI 2.13-2.32) in recipients<60 years versus 1.83 (95%CI 1.74-1.92) in recipients≥60 (p<0.0001). The relative hazard for diabetics at KDRI=0.5 was 1.49 but at KDRI=2.0 the hazard was significantly attenuated to 1.17; among African Americans the respective risks were 1.50 and 1.17 and among recipients 60 and over, it was between 1.64 and 1.22. These findings are critical considerations for informed decision-making for transplant candidates.

The association of center performance evaluations and kidney transplant volume in the United States.

Report cards evaluating transplant center performance have received significant attention in recent years corresponding with the Centers for Medicare and Medicaid Services issue of the 2007 Conditions of Participation. Our primary aim was to evaluate the association of report card evaluations with transplant center volume. We utilized data from the Scientific Registry of Transplant Recipients (SRTR) along with six consecutive program-specific reports from January 2007 to July 2009 for adult kidney transplant centers. Among 203 centers, 46 (23%) were low performing (LP) with statistically significantly lower than expected 1-year graft or patient survival at least once during the study period. Among LP centers, there was a mean decline in transplant volume of 22.4 cases compared to a mean increase of 7.8 transplants among other centers (p = 0.001). Changes in volume between LP and other centers were significant for living, standard and expanded criteria deceased donor (ECD) transplants. LPs had a reduction in use of donors with extended cold ischemia time (p = 0.04) and private pay recipients (p = 0.03). Centers without low performance evaluations were more likely to increase the proportion of overall transplants that were ECDs relative to other centers (p = 0.04). Findings indicate a significant association between reduced kidney transplant volume and low performance report card evaluations.

Case-matched comparison of perioperative outcomes after surgical treatment of sigmoid diverticulitis in solid organ transplant recipients versus immunocompetent patients.

AIM: To compare the perioperative outcomes following surgery for sigmoid diverticulitis in transplant recipients and immunocompetent patients. METHOD: Solid organ transplant recipients operated on for sigmoid diverticulitis from 1995 to 2010 were case-matched to immunocompetent patients based on surgical procedure, American Society of Anesthesiologists classification, Hinchey score, elective vs urgent surgery, age ± 10 years and year of surgery ± 5 years. Demographics, clinical presentation and perioperative outcomes were assessed. RESULTS: Of 5329 consecutive patients undergoing heart, lung, kidney and liver transplantation since 1995, 51 (0.6%) underwent surgery for diverticulitis between 1995 and 2010 with 14% mortality and 45% morbidity. Urgent surgery in 37/51 patients [Hartmann's procedure 28, sigmoidectomy with diverting ileostomy 8, loop ileostomy 1 (9 cases within 2 months after transplantation)] was associated with significantly increased postoperative mortality (19%vs 0%, P = 0.01), increased morbidity (51%vs 24%, P = 0.03) and longer mean hospital stay (19 vs 13 days, P = 0.1) when compared with immunocompetent patients. Four patients undergoing urgent surgery had suffered previous episodes of diverticulitis treated nonoperatively. Elective surgery was associated with no mortality in 14 transplant recipients (nine sigmoidectomy with diverting ileostomy, five sigmoidectomy without diversion) or in immunocompetent controls. Following elective procedures, transplant recipients had similar morbidity and increased hospital stay (29% and 9.6 vs 6.5 days, P = 0.2, respectively). Permanent stoma rates and postoperative morbidity after stoma takedown were comparable in the two groups. All living patients except one (kidney) retained their graft function. CONCLUSIONS: Urgent surgery for sigmoid diverticulitis in transplant recipients is associated with worse postoperative outcomes when compared with immunocompetent patients, unlike elective surgery. Future studies will need to clarify the role of early surgery after the first diverticulitis episode.

The use of kidneys with small renal tumors for transplantation: who is taking the risk?

The ever-increasing disparity between the number of organs available for transplant and the need for organs drives further exploration into the use of compromised or marginal donors. There is now an emerging advocacy for the use of kidneys with existing tumors, which may be rendered tumor free after surgical excision and reconstruction. This practice is based on reliable data that renal cancers <3 cm in diameter behave with minimal malignant potential and likelihood of transmission to the immunosuppressed recipient. However, in the case of live donors this creates a potential ethical conflict between those treating patients with renal masses and those with an interest in renal donation. The best available treatment for patients with a small renal tumor is a form of nephron-sparing tumor excision or ablation, as this approach provides for the maximum amount of residual kidney function and enhances survival. Thus, patients newly diagnosed with small renal tumors should be referred to centers with expertise in nephron sparing techniques, not transplant centers. In the case of an individual undergoing a live donor evaluation in which a small renal tumor is detected, a careful analysis of risk and benefit for the potential donor and the recipient is indicated.

The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.

Allotransplantation of cryopreserved parathyroid tissue for severe hypocalcemia in a renal transplant recipient.

We report the successful allotransplantation of cryopreserved parathyroid tissue to reverse hypocalcemia in a kidney transplant recipient. A 36-year-old male received a second deceased donor kidney transplant, and 6 weeks later developed severe bilateral leg numbness and weakness, inability to walk, acute pain in the left knee and wrist tetany. His total calcium was 2.6 mg/dL and parathormone level 5 pg/mL (normal 10-60 pg/mL). He underwent allotransplantation of parathyroid tissue cryopreserved for 8 months into his left brachioradialis muscle. Immunosuppression included tacrolimus (target C(0) 10-12 ng/mL), mycophenolate mofetil and steroids. Within 2 weeks, the left knee pain, leg weakness and numbness resolved, and by 1 month he could walk normally. After a peak at month 2, his parathyroid hormone (PTH) level fell to <10 pg/mL; therefore at month 3 he received a second parathyroid transplant from the same donor. Eight months later (11 months after initial graft) he has a total calcium of 9.3 mg/dL, PTH level 15 pg/mL and is clinically asymptomatic. The amount of parathyroid tissue needed to render a patient normocalcemic is not known. In our case, the need for second transplant suggests that the amount of tissue transferred for an allograft may need to be substantially greater than for an autograft.

Reviewing the evidence for de novo immunosuppression with sirolimus.

Calcineurin inhibitors (CNIs), introduced in the 1980s, have been the foundation of maintenance immunosuppression in solid organ transplantation because they substantially reduce the risk of acute rejection and improve short-term outcomes. However, CNIs (both tacrolimus and cyclosporine) are implicated in direct and indirect nephrotoxicity, leading to tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Therefore, CNI reduction or minimization has been a longstanding goal, and reducing CNI drug doses at virtually any time posttransplantation will improve glomerular filtration rate (GFR) by 10%-20%. One approach to avoid these long-term changes is to use a CNI-free regimen for maintenance therapy based on sirolimus, which has a different mechanism of action. The use of a de novo regimen including an induction antibody followed by sirolimus, mycophenolate mofetil, and steroids has been used in several trials (>1000 patients), consistently demonstrating improved renal function at 1, 2, and now 5 years. Long-term analysis has confirmed significantly improved renal function (creatinine and estimated and measured GFR), preservation of kidney histology, and death censored graft survival compared with CNI-based regimens. This combination has a somewhat different side effect profile, and wider experience has revealed that the use of de novo sirolimus requires careful therapeutic drug level monitoring to optimize these results. In addition, the de novo introduction of sirolimus should be restricted in the obese, in the presence of dense oligoanuria, and among subjects at high immunologic risk for an acute rejection episode.