Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation

Molecular mismatch analysis for assessment of histocompatibility in transplantation requires high-resolution HLA typing. Algorithms to “guesstimate” high-resolution from low-resolution typing exist, but their accuracy remains unknown. We converted high-resolution, sequence-based, HLA typing of 310 subjects from an ethnically heterogeneous population to low-resolution equivalents and tested the ability of the NMDP HaploStats and HLA Matchmaker programs to impute/reproduce the measured high-resolution HLA type, using the more common “winner-takes-all” approach. Only 35.6% of the HaploStats imputed HLA-A, -B, -C, -DRB1, and -DQB1 haplotypes had no mistakes, and the accuracy was significantly lower for non-Caucasians (29.1%) compared to Caucasians (45.2%) (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.8; P = .004). HLA Matchmaker was not able to provide high-resolution haplotypes for 45.2% of Caucasian subjects and 63.5% of non-Caucasian subjects (P = .002). Of those with an imputed result, only 10.3% of Caucasians and 4.8% of non-Caucasians had accurate 10-allele high-resolution output. Eplet analysis revealed additional, inaccurate eplets in 37% of individuals, with 22.5% showing at least 2 additional, inaccurate eplets; incorrect eplets were more common among non-Caucasians (OR, 1.8; 95% CI, 1.1-2.9; P = .018). Given this high error rate, caution should be taken before using imputation tools for clinical or research purposes, especially for non-Caucasian individuals.     

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

Increased risk of neonatal complications and infections in children of kidney-transplanted women: A nationwide controlled cohort study

Information related to short- and long-term risks of children born to kidney-transplanted women remains limited. With the aim of investigating the risk of neonatal complications, and the short- and long-term risk of infections in offspring of kidney-transplanted women, all children born to kidney-transplanted women in Denmark from 1964 to 2016 were identified in a nationwide retrospective matched cohort study. A total of 124 children of kidney-transplanted women were identified and matched on gender, birth year, and number of siblings at birth 1:10 with children born to nontransplanted women identified in the Danish general population. Prevalence of low birth weight (37.9%, risk ratio [RR] = 12.61; 95% confidence interval [CI], 8.5-18.5), premature birth (46.0%, RR = 11.32; 95% CI, 8.1-15.7) and malformations (11.3%, RR = 1.98; 95% CI, 1.2-3.4) was increased in children of kidney-transplanted women compared with controls. Similarly, prevalence of hospitalization due to infection was increased during the first year of life (21.0%, RR = 1.94; 95% CI, 1.3-2.8), from age 1 to 5 (34.2%, RR = 1.89; 95% CI, 1.4-2.5), and overall (41.9%, RR = 1.67; 95% CI, 1.3-2.1). The risk of infection was also higher in children of kidney-transplanted mothers born preterm or with low birth weight compared with similar controls. In conclusion, risk of neonatal complications, malformations, and both early and late infection were increased in children born to kidney-transplanted women.     

Cost-effectiveness of using hepatitis C viremic hearts for transplantation into HCV-negative recipients

Outcomes following hepatitis C virus (HCV)-viremic heart transplantation into HCV-negative recipients with HCV treatment are good. We assessed cost-effectiveness between cohorts of transplant recipients willing and unwilling to receive HCV-viremic hearts. Markov model simulated long-term outcomes among HCV-negative patients on the transplant waitlist. We compared costs (2018 USD) and health outcomes (quality-adjusted life-years, QALYs) between cohorts willing to accept any heart and those willing to accept only HCV-negative hearts. We assumed 4.9% HCV-viremic donor prevalence. Patients receiving HCV-viremic hearts were treated, assuming $39 600/treatment with 95% cure. Incremental cost-effectiveness ratios (ICERs) were compared to a $100 000/QALY gained willingness-to-pay threshold. Sensitivity analyses included stratification by blood type or region and potential negative consequences of receipt of HCV-viremic hearts. Compared to accepting only HCV-negative hearts, accepting any heart gained 0.14 life-years and 0.11 QALYs, while increasing costs by $9418/patient. Accepting any heart was cost effective (ICER $85 602/QALY gained). Results were robust to all transplant regions and blood types, except type AB. Accepting any heart remained cost effective provided posttransplant mortality and costs among those receiving HCV-viremic hearts were not >7% higher compared to HCV-negative hearts. Willingness to accept HCV-viremic hearts for transplantation into HCV-negative recipients is cost effective and improves clinical outcomes.     

The burden of cutaneous disease in solid organ transplant recipients of color

Organ transplant recipients (OTRs) are at increased risk of cutaneous malignancy. Skin disorders in OTRs of color (OTRoC) have rarely been systematically assessed. We aimed to ascertain the burden of skin disease encountered in OTRoC by prospectively collecting data from OTRs attending 2 posttransplant skin surveillance clinics: 1 in London, UK and 1 in Philadelphia, USA. Retrospective review of all dermatological diagnoses was performed. Data from 1766 OTRs were analyzed: 1024 (58%) white, 376 (21%) black, 261 (15%) Asian, 57 (3%) Middle Eastern/Mediterranean (ME/M), and 48 (2.7%) Hispanic; and 1128 (64%) male. Viral infections affected 45.1% of OTRs, and were more common in white and ME/M patients (P < .001). Fungal infections affected 28.1% and were more common in ME/M patients (P < .001). Inflammatory skin disease affected 24.5%, and was most common in black patients (P < .001). In addition, 26.4% of patients developed skin cancer. There was an increased risk of skin cancer in white vs nonwhite OTRs (HR 4.4, 95% CI 3.5-5.7, P < .001): keratinocyte cancers were more common in white OTRs (P < .001) and Kaposi sarcoma was more common in black OTRs (P < .001). These data support the need for programs that promote targeted dermatology surveillance for all OTRs, regardless of race/ethnicity or country of origin.     

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.     

Viability assessment and utilization of declined donor kidneys with rhabdomyolysis using ex vivo normothermic perfusion without preimplantation biopsy

The role of ex vivo normothermic perfusion (EVNP) in both organ viability assessment and reconditioning is increasingly being demonstrated. We report the use of this emerging technology to facilitate the transplantation of a pair of donor kidneys with severe acute kidney injury (AKI) secondary to rhabdomyolysis. Donor creatinine was 10.18 mg/dl with protein (30 mg/dl) present in urinalysis. Both kidneys were declined by all other transplantation units and subsequently accepted by our unit. The first kidney was perfused with red cell-based perfusate at 37°C for 75 min, mean renal blood flow was 110 ml/min/100 g and produced 85 ml of urine. Having demonstrated favorable macroscopic appearance and urine output, the kidney was transplanted into a 61-year-old peritoneal dialysis dependent without complication. Given the reassuring information from the first kidney provided by EVNP, the second kidney was not perfused with EVNP and was directly implanted to a 64-year-old patient. The first kidney achieved primary function and the second functioned well after delayed graft function. Recipient eGFR have stabilized at 88.5 and 55.3, respectively (ml/min/1.73 m²), at 2 months posttransplant.     

Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients

Individualized posttransplant immunosuppression is hampered by suboptimal monitoring strategies. To validate the utility of urinary CXCL10/Cr immune monitoring in children, we conducted a multicenter prospective observational study in children <21 years with serial and biopsy-associated urine samples (n = 97). Biopsies (n = 240) were categorized as normal (NOR), rejection (>i1t1; REJ), indeterminate (IND), BKV infection, and leukocyturia (LEU). An independent pediatric cohort of 180 urines was used for external validation. Ninety-seven patients aged 11.4 ± 5.5 years showed elevated urinary CXCL10/Cr in REJ (3.1, IQR 1.1, 16.4; P < .001) and BKV nephropathy (median = 5.6, IQR 1.3, 26.9; P < .001) vs. NOR (0.8, IQR 0.4, 1.5). The AUC for REJ vs. NOR was 0.76 (95% CI 0.66–0.86). Low (0.63) and high (4.08) CXCL10/Cr levels defined high sensitivity and specificity thresholds, respectively; validated against an independent sample set (AUC = 0.76, 95% CI 0.66–0.86). Serial urines anticipated REJ up to 4 weeks prior to biopsy and declined within 1 month following treatment. Elevated mean CXCL10/Cr was correlated with first-year eGFR decline (ρ = −0.37, P ≤ .001), particularly when persistently exceeding ≥4.08 (ratio = 0.81; P < .04). Useful thresholds for urinary CXCL10/Cr levels reproducibly define the risk of rejection, immune quiescence, and decline in allograft function for use in real-time clinical monitoring in children.