Good outcomes after pediatric intraperitoneal kidney transplant.

BACKGROUND: Kidney transplantation in small children is technically challenging. Consideration of whether to use intraperitoneal versus extraperitoneal placement of the graft depends on patient size, clinical history, anatomy, and surgical preference. We report a large single-center experience of intraperitoneal kidney transplantation and their outcomes. METHODS: We conducted a retrospective review of pediatric patients who underwent kidney transplantation from April 2011 to March 2018 at a single large volume center. We identified those with intraperitoneal placement and assessed their outcomes, including graft and patient survival, rejection episodes, and surgical or non-surgical complications. RESULTS: Forty-six of 168 pediatric kidney transplants (27%) were placed intraperitoneally in children mean age 5.5 ± 2.3 years (range 1.6-10 years) with median body weight 18.2 ± 5 kg (range 11.4-28.6 kg) during the study period. Two patients (4%) had vascular complications; 10 (22%) had urologic complications requiring intervention; all retained graft function. Thirteen patients (28%) had prolonged post-operative ileus. Eight (17%) patients had rejection episodes ≤6 months post-transplant. Only one case resulted in graft loss and was associated with recurrent focal segmental glomerular sclerosis (FSGS). Two patients (4%) had chronic rejection and subsequent graft loss by 5-year follow-up. At 7-year follow-up, graft survival was 93% and patient survival was 98%. CONCLUSIONS: The intraperitoneal approach offers access to the great vessels, which allows greater inflow and outflow and more abdominal capacity for an adult donor kidney, which is beneficial in very small patients. Risk of graft failure and surgical complications were not increased when compared to other published data on pediatric kidney transplants.

Allograft discard risk index for heart transplantation.

BACKGROUND: The numberof patients awaiting heart transplantation (HTx) substantially exceeds the number of donor hearts transplanted each year, yet nearly 65% of eligible donor hearts are discarded rather than transplanted. METHODS: Deceased organ donors listed within the UNOS Deceased Donor Database between 2010 and 2020 were reviewed. Those greater than 10 years old and consented for heart donation were included and randomly separated into training (n = 48 435) and validation (n = 24 217) cohorts. A discard risk index (DSRI) was created using the results of univariable and multivariable analyses. Discard data were assessed at DSRI value deciles, and stratum-specific likelihood ratio (SSLR) analysis and Kaplan-Meier survival function were used for mortality data. RESULTS: Factors associated with higher DSRI values included donor age > 45, LVEF, HBV-core antibodies, hypertension, and diabetes. The DSRI C-statistic was .906 in the training cohort and .904 in the validation cohort. The DSRI did not reliably predict 30-day or 1-year mortality after transplantation (C-statistic .539 and .532, respectively). CONCLUSIONS: The factors leading to heart allograft discard are not correlated to the same degree with post-transplant outcomes. This suggests that optimizing utilization of certain allografts with slightly higher risk of discard could increase the heart donor pool with limited impact on posttransplant mortality.

Elevated serum sodium in recipients of liver transplantation has a substantial impact on outcomes.

Dysnatremias are a rare but significant event in liver transplantation. While recipient pre-transplant hypernatremia has been demonstrated to increase post-transplant mortality, the degree of hypernatremia and the impact of its resolution have been less well characterized. Here, we used multivariate Cox regression with a comprehensive list of donor and recipient factors in order to conduct a robust multivariate retrospective database study of 54,311 United Network for Organ Sharing (UNOS) liver transplant patients to analyze the effect of pre-transplant serum sodium on post-transplant mortality, post-transplant length of hospitalization, and post-transplant graft survival. Mortality and graft failure increased in a stepwise fashion with increasing pre-transplant hypernatremia: 145 -150 mEq/L (HR = 1.118 and HR = 1.113), 150-155 mEq/L (HR = 1.324 and HR = 1.306), and > 155 mEq/L (HR = 1.623 and HR = 1.661). Pre-transplant hypo- and hypernatremia also increased length of post-transplant hospitalization: < 125 mEq/L (HR = 1.098), 125-130 mEq/L (HR = 1.060), 145 -150 mEq/L (HR = 1.140), and 150-155 mEq/L (HR = 1.358). Resolution of hypernatremia showed no significant difference in mortality compared with normonatremia, while unresolved hypernatremia significantly increased mortality (HR = 1.254), including a durable long-term increased mortality risk for patients with creatinine < 2 mg/dL and MELD < 25. Pre-transplant hypernatremia serves as a morbid prognostic indicator for post-transplant morbidity and mortality.

Factors associated with long-term graft survival in pediatric kidney transplant recipients.

Pediatric kidney transplant recipients generally have good outcomes post-transplantation. However, the younger age and longer life span after transplantation in the pediatric population make understanding the multifactorial nature of long-term graft survival critical. This investigation analyzes factors associated with 10-year survival to identify areas for improvement in patient care. Kaplan-Meier with log-rank test and univariable and multivariable logistic regression methods were used to retrospectively analyze 7785 kidney transplant recipients under the age of 18 years from January 1, 1998, until March 9, 2008, using United Network for Organ Sharing (UNOS) data. Our end-point was death-censored 10-year graft survival after excluding recipients whose grafts failed within one year of transplant. Recipients aged 5-18 years had lower 10-year graft survival, which worsened as age increased: 5-9 years (OR: 0.66; CI: 0.52-0.83), 10-14 years (OR: 0.43; CI: 0.33-0.55), and 15-18 years (OR: 0.34; CI: 0.26-0.44). Recipient African American ethnicity (OR: 0.67; CI: 0.58-0.78) and Hispanic donor ethnicity (OR: 0.82; CI: 0.72-0.94) had worse outcomes than other donor and recipient ethnicities, as did patients on dialysis at the time of transplant (OR: 0.82; CI: 0.73-0.91). Recipient private insurance status (OR: 1.35; CI: 1.22-1.50) was protective for 10-year graft survival. By establishing the role of age, race, and insurance status on long-term graft survival, we hope to guide clinicians in identifying patients at high risk for graft failure. This study highlights the need for increased allocation of resources and medical care to reduce the disparity in outcomes for certain patient populations.

The decreasing predictive power of MELD in an era of changing etiology of liver disease.

The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score's concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly-alcoholic liver disease and non-alcoholic fatty liver disease-and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.

The Ryanodine Receptor Contributes to the Lysophosphatidylcholine-Induced Mineralization in Valvular Interstitial Cells.

PURPOSE: Fibrocalcific aortic valve disease (CAVD) is caused by the deposition of calcific nodules in the aortic valve leaflets, resulting in progressive loss of function that ultimately requires surgical intervention. This process is actively mediated by the resident valvular interstitial cells (VICs), which, in response to oxidized lipids, transition from a quiescent to an osteoblast-like state. The purpose of this study was to examine if the ryanodine receptor, an intracellular calcium channel, could be therapeutically targeted to prevent this phenotypic conversion. METHODS: The expression of the ryanodine receptor in porcine aortic VICs was characterized by qRT-PCR and immunofluorescence. Next, the VICs were exposed to lysophosphatidylcholine, an oxidized lipid commonly found in low-density lipoprotein, while the activity of the ryanodine receptor was modulated with ryanodine. The cultures were analyzed for markers of cellular mineralization, alkaline phosphatase activity, proliferation, and apoptosis. RESULTS: Porcine aortic VICs predominantly express isoform 3 of the ryanodine receptors, and this protein mediates the cellular response to LPC. Exposure to LPC caused elevated intracellular calcium concentration in VICs, raised levels of alkaline phosphatase activity, and increased calcific nodule formation, but these changes were reversed when the activity of the ryanodine receptor was blocked. CONCLUSIONS: Our findings suggest blocking the activity of the ryanodine receptor can attenuate the valvular mineralization caused by LPC. We conclude that oxidized lipids, such as LPC, play an important role in the development and progression of CAVD and that the ryanodine receptor is a promising target for pharmacological intervention.

Single amino acid changes in the mumps virus haemagglutinin-neuraminidase and polymerase proteins are associated with neuroattenuation.

It has previously been shown that three amino acid changes, one each in the fusion (F; Ala/Thr-91-->Thr), haemagglutinin-neuraminidase (HN; Ser-466-->Asn) and polymerase (L; Ile-736-->Val) proteins, are associated with attenuation of a neurovirulent clinical isolate of mumps virus (88-1961) following serial passage in vitro. Here, using full-length cDNA plasmid clones and site-directed mutagenesis, it was shown that the single amino acid change in the HN protein and to a lesser extent, the change in the L protein, resulted in neuroattenuation, as assessed in rats. The combination of both amino acid changes caused neuroattenuation of the virus to levels previously reported for the clinical isolate following attenuation in vitro. The amino acid change in the F protein, despite having a dramatic effect on protein function in vitro, was previously shown to not be involved in the observed neuroattenuation, highlighting the importance of conducting confirmatory in vivo studies. This report provides additional supporting evidence for the role of the HN protein as a virulence factor and, as far as is known, is the first report to associate an amino acid change in the L protein with mumps virus neuroattenuation.

Two major histocompatibility complex class I-restricted epitopes of the Borna disease virus p10 protein identified by cytotoxic T lymphocytes induced by DNA-based immunization.

Borna disease virus (BDV) infection of Lewis rats is the most studied animal model of Borna disease, an often fatal encephalomyelitis. In this experimental model, BDV-specific CD8(+) cytotoxic T lymphocytes (CTLs) play a prominent role in the immunopathogenesis of infection by the noncytolytic, persistent BDV. Of the six open reading frames of BDV, CTLs to BDV X (p10) and the L-polymerase have never been studied. In this study, we used plasmid immunization to investigate the CTL response to BDV X and N. Plasmid-based immunization was a potent CTL inducer in Lewis rats. Anti-X CTLs were primed by a single injection of the p10 cDNA. Two codominant p10 epitopes, M(1)SSDLRLTLL(10) and T(8)LLELVRRL(16), associated with the RT1.A(l) major histocompatibility complex class I molecules of the Lewis rats, were identified. In addition, immunization with a BDV p40-expressing plasmid confirmed the previously reported RT1.A(l)-restricted A(230)SYAQMTTY(238) peptide as the CTL target for BDV N. In contrast to the CTL responses, plasmid vaccination was a poor inducer of an antibody response to p10. Three injections of a recombinant eukaryotic expression plasmid of BDV p10 were needed to generate a weak anti-p10 immunoglobulin M response. However, the antibody response could be optimized by a protein boost after priming with cDNA.