Evaluation of serial monitoring of donor-specific antibodies in pediatric and adult intestinal/multivisceral transplant recipients.

BACKGROUND: The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring. METHODS: This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed. RESULTS: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II. CONCLUSION: Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients.

Chronic Allograft Injury.

With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.

Current State of Multiorgan Transplantation and Implications for Future Practice and Policy.

The incidence of kidney dysfunction has increased in liver transplant and heart transplant candidates, reflecting a changing patient population and allocation policies that prioritize the most urgent candidates. A higher burden of pretransplant kidney dysfunction has resulted in a substantial rise in the utilization of multiorgan transplantation (MOT). Owing to a shortage of available deceased donor kidneys, the increased use of MOT has the potential to disadvantage kidney-alone transplant candidates, as current allocation policies generally provide priority for MOT candidates above all kidney-alone transplant candidates. In this review, the implications of kidney disease in liver transplant and heart transplant candidates is reviewed, and current policies used to allocate organs are discussed. Important ethical considerations pertaining to MOT allocation are examined, and future policy modifications that may improve both equity and utility in MOT policy are considered.

The impact of multi-organ transplant allocation priority on waitlisted kidney transplant candidates.

Kidney-alone transplant (KAT) candidates may be disadvantaged by the allocation priority given to multi-organ transplant (MOT) candidates. This study identified potential KAT candidates not receiving a given kidney offer due to its allocation for MOT. Using the Organ Procurement and Transplant Network (OPTN) database, we identified deceased donors from 2002 to 2017 who had one kidney allocated for MOT and the other kidney allocated for KAT or simultaneous pancreas-kidney transplant (SPK) (n = 7,378). Potential transplant recipient data were used to identify the "next-sequential KAT candidate" who would have received a given kidney offer had it not been allocated to a higher prioritized MOT candidate. In this analysis, next-sequential KAT candidates were younger (p < .001), more likely to be racial/ethnic minorities (p < .001), and more highly sensitized than MOT recipients (p < .001). A total of 2,113 (28.6%) next-sequential KAT candidates subsequently either died or were removed from the waiting list without receiving a transplant. In a multivariable model, despite adjacent position on the kidney match-run, mortality risk was significantly higher for next-sequential KAT candidates compared to KAT/SPK recipients (hazard ratio 1.55, 95% confidence interval 1.44, 1.66). These results highlight implications of MOT allocation prioritization, and potential consequences to KAT candidates prioritized below MOT candidates.

Cytomegalovirus serologic matching in deceased donor kidney allocation optimizes high- and low-risk (D+R- and D-R-) profiles and does not adversely affect transplant rates.

Cytomegalovirus (CMV) is a major cause of infection-related morbidity and mortality in kidney transplantation. The most significant risk for developing CMV infection after transplant depends upon donor (D) and recipient (R) CMV serostatus. In 2012, our Organ Procurement Organization (OPO) began a novel pretransplant CMV prevention strategy via matching deceased kidney donors and recipients by CMV serostatus. Prior to the matching protocol, our distribution of seropositive and seronegative donors and recipients was similar to the United States at large. After the matching protocol, high-risk D+R- were reduced from 18.5% to 2.9%, whereas low-risk D-R- were increased from 13.5% to 24%. There was no adverse effect on transplant rates and no differential effect on waiting times for R+ vs R- after the protocol was implemented. This protocol could be implemented on a regional or national level to optimize low and high-risk CMV seroprofiles and potentially improve CMV-related outcomes in kidney transplantation.

Chronic systemic capillary leak syndrome treatment with intravenous immune globulin: Case report and review of the literature
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Systemic capillary leak syndrome (SCLS) is a disorder characterized by increased vascular permeability with intermittent acute episodes of profound capillary leak that may result in hypotension or shock. A rarely described chronic form of SCLS (cSCLS) presents as refractory edema, with pleural and/or pericardial effusions and hypoalbuminemia. These entities are differentiated by massive and periodic episodes of capillary leak, which can result in shock in SCLS, and chronic refractory edema in cSCLS. The etiologies of these disorders are poorly understood, but both acute and chronic forms often present with an associated monoclonal gammopathy. Flares of the SCLS have been reduced by treatment with intravenous immune globulin (IVIG). Only six cases of cSCLS have been reported, and previous treatments have included steroids, terbutaline, and theophylline. Based upon the reported responses of SCLS to IVIG, we present the case of a 54-year-old man with cSCLS where ongoing treatment with IVIG resulted in a marked and sustained improvement in the signs and symptoms of the capillary leak syndrome.
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BK viremia surveillance and outcomes in simultaneous pancreas-kidney transplant recipients.

BACKGROUND: While screening for asymptomatic BK viremia (BKV) has been well studied in isolated kidney transplant recipients, there is a paucity of published outcomes in simultaneous pancreas-kidney (SPK) transplant recipients who underwent BKV screening followed by pre-emptive reduction in immunosuppression. METHODS: This is a single-center, retrospective review of 31 consecutive SPK recipients who were transplanted over a 5-year period following the initiation of a serum BKV screening protocol. RESULTS: BK viremia developed in 11 (35.5%) patients, and all patients achieved complete viral clearance following reduction in immunosuppression. Two patients (6.5%) developed BK virus nephropathy, but both had preserved allograft function. One patient developed mild rejection of the kidney allograft following clearance of BKV, and two patients developed mild rejection of the pancreas allograft after reduction in immunosuppression, but there were no kidney or pancreas allograft losses due to rejection. The development of BK viremia did not impact overall patient survival or kidney and pancreas allograft survival. CONCLUSION: Screening asymptomatic SPK recipients for BKV followed by reduction in maintenance immunosuppression appears to be an effective strategy to prevent kidney allograft dysfunction and graft loss due to BK virus nephropathy, without compromising pancreas allograft outcomes.

Hypercoagulability in Kidney Transplant Recipients.

Thrombosis remains an important complication after kidney transplantation. Outcomes for graft and deep vein thrombosis are not favorable. The majority of early kidney transplant failure in adults is due to allograft thrombosis. Risk stratification, early diagnosis, and appropriate intervention are critical to the management of thrombotic complications of transplant. In patients with end-stage renal disease, the prevalence of acquired risk factors for thrombosis is significantly high. Because of hereditary and acquired risk factors, renal transplant recipients manifest features of a chronic prothrombotic state. Identification of hereditary thrombotic risk factors before transplantation may be a useful tool for selecting appropriate candidates for thrombosis prophylaxis immediately after transplantation. Short-term anticoagulation may be appropriate for all patients after kidney transplantation.

Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations.

SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities. To study how SHP-2 regulates tissue homeostasis in normal adults, we used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality. Most strikingly, induced SHP-2-deficient mice developed severe skeletal abnormalities, including kyphoses and scolioses of the spine. Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass. Osteoclasts were essentially absent from the bones of SHP-2-deficient mice, thus accounting for the osteopetrotic phenotype. Studies in vitro revealed that osteoclastogenesis that was stimulated by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) was defective in SHP-2-deficient mice. At least in part, this was explained by a requirement for SHP-2 in M-CSF-induced activation of the pro-survival protein kinase AKT in hematopoietic precursor cells. These findings illustrate an essential role for SHP-2 in skeletal growth and remodeling in adults, and reveal some of the cellular and molecular mechanisms involved. The model is predicted to be of further use in understanding how SHP-2 regulates skeletal morphogenesis, which could lead to the development of novel therapies for the treatment of skeletal malformations in human patients with SHP-2 mutations.

Topics in transplantation medicine for general nephrologists.

Before transplantation, the general nephrologist is the primary resource for potential kidney transplantation recipients. After transplantation, the general nephrologist is increasingly managing transplant medications and complications. We provide evidence-based management strategies for common clinical issues. Linking our approach with the data allows the clinician to explore each subject in greater depth to tailor care to individual patients.

Metabolic syndrome and new onset diabetes after transplantation in kidney transplant recipients.

BACKGROUND: Metabolic syndrome (MS) and new onset diabetes after transplant (NODAT) are common in kidney transplant patients. We studied the relationship between the two conditions and their impact on metabolic and cardiovascular risk profiles. METHODS: All non-diabetic patients transplanted between 1999 and 2005 who were followed up to 2006 were included. MS and NODAT were determined. Kaplan-Meier survival and various regression analyses were performed to determine the clinical correlates for both conditions and their association with various cardiovascular risk factors. RESULTS: Among 591 patients, 314 (53.1%) had MS and 90 (15.2%) developed NODAT. The two conditions were highly associated with each other as 84 patients with NODAT also had MS (14.2%). Elevated body mass index and fasting glucose levels at transplant were risk factors for both conditions, whereas weight gain after transplant was associated only with MS. African American, old age, and hypertension-related ESRD were risk factors for NODAT. Finally, the presence of MS was associated with reduced kidney function and elevated uric acid levels, whereas the presence of NODAT with elevated pulse pressure. CONCLUSIONS: MS and NODAT are highly prevalent and significantly associated with impaired metabolic and cardiovascular risk profiles. Early identification of such conditions may facilitate targeted therapeutic intervention.