Highlights in Clinical Science

The June issue of Transplantation showcases a selection of high-quality clinical research articles relating to key topics of interest to the journal's readership. These special articles are organized under 5 headings, namely, “donor and recipient factors,” “antibodies,” “outcomes,” “pathology,” and “infection.” Here, the editors précis each article and provide links to relevant online resources. Through this resynthesis, we aim to stimulate interdisciplinary exchange of concepts and research approaches. Donor and Recipient Factors Doshi and colleagues'1 article on, “utility of applying quality assessment tools for kidneys with KDPI ≥80” examines the fate of 80 or greater KDPI kidneys and the factors explaining the discard rate which is known to be the highest in this category of donors. They show that some of these kidneys are viable but that current factors (eg, biopsy, machine perfusion, urine biomarkers) used to choose to discard or not are not sufficiently discriminatory. Soares and colleagues report on the, “successful renal transplantation of deceased donor kidneys with 100% glomerular fibrin thrombi and acute renal failure due to disseminated intravascular coagulation.” Their article describes 2 renal transplant patients who received grafts from donors with known disseminated intravascular coagulopathy, and who are now longer than 14 months posttransplant with stable allograft function.2 Lim and colleagues'3 article entitled, “association between delayed graft function and graft loss in donation after cardiac death kidney transplants—a paired kidney registry analysis,’ uses data from the Australia and New Zealand Dialysis and Transplant Registry [A] together with paired donation-after-cardiac-death (DCD) kidney data to explore the impact of delayed graft function (DGF) on long-term graft survival. Overall graft loss and death-censored graft loss proved to be worse in case of DGF, suggesting potential for improvement in graft survival by decreasing DGF in this setting. Peters-Sengers and colleagues find, “similar 5-year estimated glomerular filtration rates in kidney transplants from uncontrolled and controlled donors after circulatory death,” based on a cohort study performed in The Netherlands.4 Specifically, although primary nonfunction and DGF were higher in uncontrolled DCD than in controlled DCD, after censoring of primary nonfunction, estimated glomerular filtration rates at 1 and 5 years were comparable in recipients of uncontrolled and controlled donors. Wong and colleagues5 examined, “the impact of total ischemic time, donor age and the pathway of donor death on graft outcomes after deceased donor kidney transplantation,” to discover that duration of ischemic time has the greatest impact on kidney graft survival and there is on average, a 9% increase in the overall risk of graft loss per hour increase in the total ischemic time in recipients with older DCD kidneys. Alhamad and colleagues6 investigated whether, “selected mildly obese donors can be used safely in simultaneous pancreas and kidney transplantation.” Mild obesity (D-BMI 30-35 kg/m2) did not impact pancreas or kidney allograft failure; moreover, pancreases from mildly obese donors could be safely used for transplantation, with comparable short and long-term outcomes as organs from lean donors. Gordon and colleagues7 assessed the, “effect of a mobile web app on kidney transplant candidates' knowledge about increased risk donor kidneys.” This randomized controlled trial, conducted at 2 transplant centers, demonstrated that InformMe increases knowledge acquisition and retention regarding increased-risk donors compared to routine transplant education alone, although its influence on acceptance remains to be determined [B]. Marlais and colleagues8 report on the 3-year results of kidney transplantation in children, according to the category of donor: DCD, donation-after-brain-death or living-donation. Outcomes were comparable in the 3 groups, which supports transplantation of DCD kidneys in children. Mucsi and colleagues9 address the important topic of mental health and behavioral barriers in access to kidney transplantation. This single-center, retrospective cohort analysis from Canada suggests that patients with a history of mental health disorders or nonadherence have lower chance of completing the workup and/or undergoing kidney transplantation, opening opportunities for investigations of targeted psychosocial support interventions. Freeman and colleagues10 ask, “has the Department of Veterans Affairs found a way to avoid racial disparities in the evaluation process for kidney transplantation?” This study from 4 transplant centers associated with the US Department of Veterans Affairs found there were no racial disparities in the time from first evaluation to listing for a kidney transplant. Caplan and colleagues'11 article on, “the ethics of penile transplantation,” tackles the challenging option of penile transplantation as a treatment for the increasingly severe injuries in the era of modern warfare. The authors rightly emphasize that great care must be taken to assess risks and benefits of highly experimental penile transplantation and conclude that patient-oriented medical and ethical guidelines are now mandatory. Antibodies Taylor and colleagues'12 article examines the “technical limitations of the C1q single antigen bead assay to detect complement-binding HLA-specific antibodies.” The authors show that C1q-binding to HLA-class I single-antigen-beads (SAB) is influenced by denatured HLA on SAB, antibody titer, and complement. These technical factors affect the clinical interpretation of the C1q-SAB assay and make C1q-binding assay difficult to apply in routine clinical practice. Reinsmoen and colleagues13 studied 162 lung transplant recipients from 3 centers to establish, firstly, that freedom from antibody-mediated rejection is decreased in recipients with intermediate to strong non-HLA antibodies, and secondly that occurrence of posttransplant de novo DSA is increased in patients with pretransplant HLA and non-HLA antibodies. Moreno Gonzales and colleagues14 report the important negative result that, “32 doses of bortezomib for desensitization is not well-tolerated and is associated with only modest reductions in anti-HLA antibody.” The authors show that extended bortezomib treatment for desensitization of highly sensitized patients is not well tolerated, does not result in a negative cross match, does not reduce calculated panel reactive antibody, and only modestly reduces antibody levels. Outcomes Butts and colleagues investigated the, “effect of induction therapy on graft survival in primary pediatric heart transplantation,” using a propensity score method to match children who received a heart transplant with induction therapy and those who do not.15 It appears that induction does not improve graft survival except in immunized recipients and those with congenital heart defect. Gharibi and colleagues16 examined the, “cost-effectiveness of antibody-based induction therapy in deceased donor kidney transplantation in the United States,” using outcome data from the United States Renal Data System [C] from 2000 to 2008. The authors' pharmacoeconomic analysis suggests that antibody-based induction is cost-effective compared to no-induction in high immunological risk categories over the first 3 years after kidney transplantation. Stojanovic and colleagues'17 work addresses the difficulty of blood group incompatible (ABOi) transplantation in children owing to the unique challenges of pretransplant conditioning in pediatric patients. Encouragingly, the authors report on 11 pediatric ABOi transplants after individually tailored desensitization therapies, which resulted in excellent outcomes comparable to blood group–compatible transplants. Kopp and colleagues'18 examined possible determinants of pancreas transplant outcome within the Eurotransplant zone [D] to discover that center volume was a key factor. Notably, patient and graft survival following pancreas transplantation were superior in higher volume centers, and high-volume centers achieved better results despite transplanting organs with higher pancreas donor-risk indexes. Shin and colleagues'19 article considers, “the long-term metabolic outcomes of functioning pancreas transplants in type 2 diabetic recipients.” Metabolic outcomes of pancreas transplants in patients with type 2 diabetes mellitus (T2DM) was compared with patients with type 1 diabetes mellitus (T1DM) revealing favorable endocrine function for more than 5 years in both T1DM and T2DM recipients. Lindahl and colleagues'20 article describes a small study assessing cardiac disease in patients with T1DM at a median of 10 years after successful simultaneous pancreas and kidney transplantation. Strikingly, the authors found that simultaneous kidney-pancreas transplant recipients had similar long-term progression of coronary artery disease compared with living donor kidney recipients. Based on a small, single-center study in selected patients with pronounced glycolic variability, Holmes-Walker and colleagues21 report that, “islet transplantation provides superior glycemic control with less hypoglycemia compared to continuous subcutaneous insulin infusion or multiple daily insulin injections.” Using integrated national registry data and prescriptions for diabetic medications, Lam and colleagues22 were able to identify that diabetes is more common after living donor pancreas transplantation than living donor kidney transplantation. Eide and colleagues23 performed a single-center retrospective cohort study of 2749 adult Norwegian renal transplant recipients to confirm an association between posttransplantation diabetes mellitus and the risk of overall, but not death-censored graft loss. This is an intriguing clinical association, although the underlying pathophysiological mechanisms remain elusive. Pérez-Sáez and colleagues24 studied “bone density, microarchitecture and tissue quality long-term after kidney transplant.” Bone health, judged by bone mineral density measured by dual-energy x-ray absorptiometry, was compromised in long-term kidney transplant patients compared to matched controls, but bone mineral strength index and trabecular bone score were not. Hellström and colleagues25 report on a retrospective case-control study suggesting that kidney transplant recipients with adequately treated pretransplant cancer carry a nearly fourfold higher risk of developing cancers of any type after kidney transplantation, which translates to a 1.6-fold higher mortality rate compared to control groups. Similarly, using OPTN/UNOS [E] data, Kang and colleagues26 observed an, “association of pretransplant skin cancer with posttransplant malignancy, graft failure and death in kidney transplant recipients.” Watanabe and colleagues'27 work concerns the impact of donor-transmitted atherosclerosis on clinical outcome in cardiac transplant recipients. Serial volumetric intravascular ultrasound analyses demonstrated that donor-transmitted atherosclerosis was associated with cardiac allograft vasculopathy at 3 years after transplantation. Hernandez and colleagues’ study showed that peripheral vascular disease in Southern European kidney transplant candidates was associated with a twofold increased risk of death on the waitlist with 61% of deaths occurring within 2 years of listing.28 Kaboré and colleagues'29 retrospective French national cohort study confirmed previous reports that risk of kidney allograft failure is higher in recipients aged 13 to 21 years compared with older or younger recipients. As yet, the reasons for this effect are sadly unknown. In a randomized controlled trial of 246 solid organ transplant recipients, Harrison and colleagues30 evaluated the benefit of a computer-based patient education system in terms of imparting knowledge about transplantation, satisfaction, and adherence. Trial participants received either standard teaching with or without postdischarge computer-based education at home. Disappointingly, no significant improvements were observed in the intervention group, suggesting other barriers to this general approach. Frank and colleagues31 compared the use of 3-dimensional ultrasound to 2-dimensional ultrasound in kidney transplant recipients as means of visualizing anastomoses and anatomic variants. Based on their findings, the authors suggest that 3-dimensional ultrasound could replace confirmatory testing with magnetic resonance angiography or computed tomographic angiography. Molnar and colleagues present a new, online tool [F] that uses patient-related variables to predict graft survival.32 David-Neto and colleagues’ pharmacokinetic study monitored 12-hour tacrolimus levels in 44 elderly (65 ± 3 year) renal transplant recipients and compared these results to 12-hour tacrolimus levels in 31 younger controls (35 ± 6 years) recipients.33 Elderly recipients exhibited a lower tacrolimus clearance rate, hence required lower tacrolimus doses than younger recipients. Schold and colleagues34 evaluated incidence, survival rates and volume of low performance centers with Bayesian, Old- and New-CMS criteria among US kidney transplant programs. The incidence of flagging and differences in observed and expected outcomes were significantly different by performance criteria. Aycart and colleagues'35 article entitled, “Outcomes of Solid Organ Transplants Following Simultaneous Solid Organ and Vascularized Composite Allograft Procurements: A Nationwide Analysis,” considers whether recovery of facial tissue for transplantation adversely affected the outcome of other transplanted organs from the same donor. The authors conclude that facial allograft procurement does not adversely affect outcomes of concomitantly recovered solid organ allografts. Matthaei and colleagues36 provide a systematic review of 34 years of global reporting about penetrating keratoplasty and its changing indications. Pathology Crespo and colleagues37 report on a single-center study that suggests combining the transcriptional kidney solid organ response test and the IFN-γ ELISPOT assay may help to identify high-risk patients for subclinical acute rejection from 6-month protocol biopsies. García-Carro and colleagues'38 article investigates, “inflammation in early kidney allograft surveillance biopsies with and without associated tubulointerstitial chronic damage as a predictor of fibrosis progression and development of de novo donor specific antibodies.” This retrospective sequential histological analysis suggests that subclinical inflammation in surveillance kidney biopsies with or without tubulointerstitial chronic lesions at 6 weeks is associated with an increased risk of de novo donor specific anti-HLA antibody development at 1 year. In a retrospective study involving 327 living donor-kidney transplant recipients, Masutani and colleagues39 convincingly demonstrate that screening biopsies performed at 3 months and 1 year posttransplantation give similar results between ABO-compatible or -incompatible patients, as well as revealing a similar incidence of rejection, infection and graft survival. Ishihara and colleagues’ study examined microvascular inflammation in ABO-incompatible kidney transplants within the first year of transplantation as a marker of later clinical outcome. A g + ptc score greater than 2 was associated with worse outcomes (graft survival and function) during the 5 years after biopsy, suggesting it is a good diagnostic marker of antibody-mediated rejection.40 Chow and colleagues'41 article claims that ABO-incompatible renal transplant recipients receiving conventional immunosuppression and antibody removal, but without rituximab treatment or splenectomy, can achieve 4-year outcomes comparable to ABO-compatible transplant recipients with low rates of progressive interstitial fibrosis and tubular atrophy and no indication of transplant glomerulopathy. Alves and colleagues42 describe the immunopathological characteristics of a newly identified inflammatory disorder of the oral cavity, named giant papillae tongue disorder which may develop after solid organ transplantation in children. Infection Natori and colleagues43 observe that CMV recurs in 30% of patients after treatment of the first episode of CMV viremia or disease. Donation by a CMV+ donor to a CMV− recipient, lung transplant, and slow resolution of viremia are predictive of recurrence; by contrast, prolonged secondary antiviral prophylaxis does not appear to reduce risk of recurrence. Based on a small cohort study, Bonani and colleagues44 report that secondary lactose maldigestion is associated with chronic symptomatic norovirus infection in kidney transplant recipients. Bialasiewicz and colleagues45 present a case report entitled, “A Difficult Decision: Atypical JC Polyomavirus Encephalopathy in a Kidney Transplant Recipient.” Although JC polyomavirus infection of a kidney transplant is extremely rare, this case documents JC transplant nephropathy progressing to atypical JC polyomavirus encephalopathy that was difficult to diagnose, followed by allograft nephrectomy and discontinuation leading to improvement in the patient. Simkins and colleagues46 discuss the treatment of latent tuberculosis in renal transplant candidates, who are at significant risk for tuberculosis reactivation after transplantation. Twelve-week rifapentine/isoniazid appears to be an excellent choice of therapy for these patients, owing to a higher treatment completion rate and fewer adverse effects. Bamoulid and colleagues47 present a prospective study of EBV monitoring demonstrating that transplantation from an EBV+ donor to a EBV− recipient, as well as treatment with antithymocyte globulin, increases the risk of persistent EBV viremia, which is associated with the occurrence of cancer. Schaenman and colleagues48 report that, “increased frequency of BK virus-specific polyfunctional CD8+ T cells predict successful control of BK viremia after kidney transplantation.” Alexiev and colleagues49 report a retrospective case-control study of 1866 mostly kidney-only transplant recipients, showing that polyomavirus replication (defined by polyomavirus nephropathy, urine cytology, and/or viremia) and smoking are independent risk factors associated with bladder carcinoma; this finding leads to a recommendation for long-term cancer surveillance in these patients. Abend and colleagues50 present a retrospective study showing that kidney transplant recipients from donors with significant serum neutralizing activity (donor-positive) for all 4 BK serotypes had an elevated risk of BK viraemia, regardless of recipient serostatus (donor positive or recipient positive). This study confirms and extends prior studies implicating donor origin of BK. Links [A] http://www.anzdata.org.au/v1/. [B]http://mohrlab.northwestern.edu/informme/app/build/. [C]https://www.usrds.org/. [D]https://www.eurotransplant.org/cms/. [E]https://optn.transplant.hrsa.gov/data/about-data/optn-database/. [F]http://www.transplantscore.com/.

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