Parental experiences of adopting healthy lifestyles for children with disabilities living with overweight and obesity

BackgroundChildren with disabilities present with high obesity rates.ObjectiveThis study explored the parental experience of adopting healthy lifestyle choices, for children with disabilities, who received dietetic weight management advice.MethodsSemi-structured qualitative interviews were carried out with eight parents/carers in their own homes or healthcare setting in an inner London locality, or by telephone. Data was analyzed using an interpretative phenomenological analysis (IPA) approach.ResultsFive superordinate themes emerged: 1. Strategies to promote healthy lifestyles: encouraging physical activity, limiting access to food and taking a gradual approach to making lifestyle changes. 2. Challenges to adopting healthy lifestyles: selective eating patterns, the high cost of healthy foods and parental/carer lack of time. 3. The role of healthcare professionals (HCPs): revealed that not all parents/carers received advice or support, prior to dietetic referral, when managing their child's weight. Feeling reassured by HCPs was valued. Parents/carers reported a positive experience of seeing the dietitian, as they appreciated receiving practical and individualized advice. 4. Support needs: family support and support from families with children with disabilities was explored. 5. Parent/carer wellbeing: such as stress was found to have a detrimental impact on parents making healthy lifestyle changes.ConclusionsAdopting a healthy lifestyle involved a variety of strategies and challenges, some of which are specific to this population group and should be considered by HCPs, when having weight-related discussions and offering advice. Parental/carer support needs and wellbeing should also be taken into consideration when planning weight management services for this population group.     

肾移植术后巨细胞病毒感染与急性排斥反应

目的 :探讨肾移植术后活动性巨细胞病毒 (CMV)感染的发生率、原因以及对急性排斥反应的影响。方法 :检测 182例肾移植受者及其供者术前血清抗CMV抗体 ,受者术后定期PCR法检测体内CMVDNA ,对CMVDNA阳性的部分患者给予抗CMV治疗 ,并比较各组排斥反应的发生率。结果 :无论是供者还是受者 ,术前如血清抗CMV抗体阳性 ,受者术后发生活动性CMV感染者明显增多 ,且急性排斥反应的发生率亦明显增加 ;接受抗病毒治疗急性排斥反应明显减少。结论 :CMV感染是肾移植术后急性排斥反应的原因之一 ,预防和治疗CMV感染对肾移植术后急性排斥反应的防治具有重要意义。     

Short- and long-term impact of neutropenia within the first year after kidney transplantation

The aim of this retrospective single-center study was to investigate the short- and long-term impact of neutropenia occurring within the first year after kidney transplantation, with a special emphasis on different neutropenia grades. In this unselected cohort, 225/721 patients (31%) developed 357 neutropenic episodes within the first year post-transplant. Based on the nadir neutrophil count, patients were grouped as neutropenia grade 2 (<1.5–1.0*10⁹/l; n = 105), grade 3 (<1.0–0.5*10⁹/l; n = 65), and grade 4 (<0.5*10⁹/l; n = 55). Most neutropenia episodes were presumably drug-related (71%) and managed by reduction/discontinuation of potentially responsible drugs (mycophenolic acid [MPA] 51%, valganciclovir 25%, trimethoprim/sulfamethoxazole 19%). Steroids were added/increased as replacement for reduced/discontinued MPA. Granulocyte colony-stimulating factor was only used in 2/357 neutropenia episodes (0.6%). One-year incidence of (sub)clinical rejection, one-year mortality, and long-term patient and graft survival were not different among patients without neutropenia and neutropenia grade 2/3/4. However, the incidence of infections was about 3-times higher during neutropenia grade 3 and 4, but not increased during grade 2. In conclusion, neutropenia within the first year after kidney transplantation represents no increased risk for rejection and has no negative impact on long-term patient and graft survival. Adding/increasing steroids as replacement for reduced/discontinued MPA might supplement management of neutropenia.     

Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.     

Early steroid withdrawal in HIV-infected kidney transplant recipients: Utilization and outcomes

Kidney transplant (KT) outcomes for HIV-infected (HIV+) persons are excellent, yet acute rejection (AR) is common and optimal immunosuppressive regimens remain unclear. Early steroid withdrawal (ESW) is associated with AR in other populations, but its utilization and impact are unknown in HIV+ KT. Using SRTR, we identified 1225 HIV+ KT recipients between January 1, 2000, and December 31, 2017, without AR, graft failure, or mortality during KT admission, and compared those with ESW with those with steroid continuation (SC). We quantified associations between ESW and AR using multivariable logistic regression and interval-censored survival analysis, as well as with graft failure and mortality using Cox regression, adjusting for donor, recipient, and immunologic factors. ESW utilization was 20.4%, with more zero HLA mismatch (8% vs 4%), living donors (26% vs 20%), and lymphodepleting induction (64% vs 46%) compared to the SC group. ESW utilization varied widely across 129 centers, with less use at high- versus moderate-volume centers (6% vs 21%, P < .001). AR was more common with ESW by 1 year (18.4% vs 12.3%; aOR: _1.081.61_2.41, P = .04) and over the study period (aHR: _1.021.39_1.90, P = .03), without difference in death-censored graft failure (aHR _0.600.91_1.36, P = .33) or mortality (aHR: _0.751.15_1.77, P = .45). To reduce AR after HIV+ KT, tailoring of ESW utilization is reasonable.     

TLR-MyD88 signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens

Refractory B cell responses to T cell–independent (TI) carbohydrate antigens (Ags) are critical drivers of rejection reactions to ABO-incompatible allogeneic grafts and xenogeneic grafts from other species. To explore the biological significance of crosstalk between Toll-like receptors (TLRs) and B cell receptors (BCRs) in the TI B cell immunity, we here used MyD88-, TRIF-, and α-galactosyltransferase-deficient mice to study B cell phenotypes and functional properties during TI transplant–related glycan Ag exposure. BCR stimulation alone induced differentiation into CD5^high (B-1a) cells, which were highly sensitive to a calcineurin inhibitor (CNI), while co-stimulation of TLRs and BCRs induced differentiation into CD5^dim (B-1b) cells in MyD88-dependent and CNI-resistant manner. MyD88-dependent TLR stimulation in B-1b cells enhanced downstream factors in the BCR-calcineurin pathway, including a nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). TLR inhibitor together with CNI abrogated refractory B-1b cell immune responses against the ABO-blood group Ags, while blocking both BCRs and TLR-MyD88 by using Bruton's tyrosine kinase inhibitor and histone deacetylase inhibitor abrogated refractory B-1b cell immune responses against Gal-glycan Ags. Thus, this study provides a rationale for a novel therapeutic approach to overcome refractory transplant-related anti-glycan Ab production by blocking both BCR and TLR-MyD88 signals.     

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.     

Immune checkpoint inhibitor therapy-associated graft intolerance syndrome in a failed kidney transplant recipient

Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies against inhibitory receptors on T cells resulting in anticancer activity. In kidney transplant (KT) recipients, ICPI use has been associated with acute allograft rejection. In failed allografts, however, the effects of ICPIs are unknown. We present a case of a 66-year-old man with a history of diabetes, renal cell cancer, left native nephrectomy, and end-stage kidney disease. He received a deceased donor KT which failed after 6 years due to biopsy-proven recurrent diabetic nephrosclerosis. He was started on hemodialysis and his immunosuppression was gradually weaned off. A year later, he was diagnosed with renal cell cancer in his right native kidney requiring nephrectomy. He later developed metastasis and was started on combination ICPIs. He developed hematuria, allograft pain, and malaise consistent with graft intolerance syndrome 28 days after starting ICPIs. Urine culture and cystoscopy were normal. A computed tomography scan of his abdomen revealed an enlarged allograft with patchy enhancement. After a multidisciplinary discussion, he underwent transplant nephrectomy. Histopathology showed chronic active T cell–mediated rejection. As ICPI use becomes prevalent, practitioners need to be aware of its potential complications among KT recipients both with functioning and failed allografts.     

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre–formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%–97%) and 6250 (5000–10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14–0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.