Bortezomib for antibody-mediated rejection of kidney transplant in youth: Associations with donor-specific antibody.

BACKGROUND: Antibody-mediated rejection is one of the most significant risk factors for allograft dysfunction and failure in children and adolescents with kidney transplants, yet optimal treatment remains unidentified. To date, there are mixed findings regarding the use of Bortezomib, a plasma cell apoptosis inducer, as an adjunct therapy in the treatment of antibody-mediated rejection. METHODS: In a retrospective single center study, we reviewed the efficacy and tolerability of bortezomib as adjunct therapy for treatment-refractory antibody-mediated rejection. RESULTS: Six patients with a median age of 14.6 years (range 6.9-20.1 years) received bortezomib at a mean of 71 months (range 15-83 months) post-kidney transplant. Four patients experienced decline in estimated glomerular filtration rate (eGFR) from 4% to 42%. One patient started bortezomib while on hemodialysis and did not recover graft function, and another patient progressed to hemodialysis 6 months after receiving bortezomib. Although DSA did not completely resolve, there was a statistically significant decline in DSA MFI pre and 12-months post-BZ (p = .012, paired t-test) for the subjects who were not on dialysis at the time of bortezomib. Chronic Allograft Damage Index (CADI) score of ≥3 was seen in all six subjects at their biopsy prior to therapy. No adverse effects were reported. CONCLUSIONS: Bortezomib was well tolerated and resulted in improvements in MFI of DSA among four pediatric subjects without allograft failure, although no effects were observed on eGFR trajectory. Further studies are needed to clarify whether earlier intervention with bortezomib could prevent renal failure progression.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Living-Related Donor Kidney Transplant in a Patient With Single Ventricle and Fontan Circulation.

The hemodynamic profile of the Fontan circulation presents challenges that raise questions about candidacy for organ transplantation. We report a case of a 24-year-old male with double-inlet right ventricle and aortic atresia, who suffered bilateral renal cortical necrosis due to neonatal cardiovascular shock, received a live-donor kidney transplant from his mother at age 17, and has diminished yet stable renal function seven years posttransplant.

18-month outcomes of heterologous bilateral hand transplantation in a child: a case report.

BACKGROUND: Although heterologous vascular composite allotransplantation has become a burgeoning treatment option for adult amputees, there have been no successful cases previously reported in children. Here, we describe the surgical, immunological, and neurorehabilitation details with functional outcomes 18 months after heterologous bilateral hand and forearm transplantation in an 8-year-old child with quadrimembral amputations and a previous kidney transplant. METHODS: 2 years of extensive preparation by medical and surgical teams preceded the hand-forearm transplantation of this child. The initial immunosuppressive protocol included thymoglobulin, tacrolimus, prednisone, and mycophenolate mofetil. In July, 2015, our vascularised composite allotransplantation team did the first bilateral hand and forearm transplantation in a child, an 8-year-old boy with previous living-related kidney transplantation. The surgery included four teams working simultaneously on the donor and recipient limbs, aided by customised cutting guides that aimed to reduce ischaemia time. Following an extended length of time in hospital, skin biopsies and close monitoring of renal function and drug concentrations occurred weekly for the first 3 months and were slowly tapered to monthly, and then quarterly. Skin biopsies were also done when tissue rejection was suspected. Paediatric-specific rehabilitation techniques were applied to promote patient engagement during rehabilitation. Progress was assessed by monthly sensory and motor function tests during routine clinic visits and with serial functional brain imaging studies, including structural brain MRI, magnetoencephalography and transcranial magnetic stimulation. FINDINGS: The surgery lasted 10 h and 40 min. Vascular revision of the ulnar artery was required a few hours postoperatively. There were no further immediate postsurgical complications. Rejection episodes occurred throughout the first year but were reversed. An increase in serum creatinine led to the addition of sirolimus at 3 months after transplantation with concomitant reduction in tacrolimus targets. Sensibility to light touch was present by 6 months after transplantation. Intrinsic hand muscle innervation was present by 7-10 months after transplantation. At 18 months, the child had exceeded his previous adapted abilities. As of 18 months after transplantation surgery he is able to write and feed, toilet, and dress himself more independently and efficiently than he could do before transplantation. He remains on four immunosuppressive medications and functional neuroimaging studies have shown motor and somatosensory cortical reorganisation. INTERPRETATION: Hand transplantation in a child can be surgically, medically, and functionally successful under carefully considered circumstances. Long-term data on the functional trajectory, neurological recovery, psychological sequelae, and the potential late effect of immunosuppression are still needed to support broader implementation of paediatric vascular composite allotransplantation. FUNDING: The Children's Hospital of Philadelphia.

Use and Predictors of End-of-Life Care Among HIV Patients in a Safety Net Health System.

CONTEXT: Although highly active antiretroviral therapy has improved survival among many HIV patients, there are still those with advanced illness and limited access to care who may benefit from palliative care and hospice. OBJECTIVES: To examine completion of advance directives, use of palliative care, and enrollment in hospice among HIV patients who receive care at an urban safety net hospital. METHODS: This was a retrospective cohort study of HIV patients in a large, urban safety net hospital in 2010. Physicians abstracted data from the electronic medical record on patient and clinical factors and end-of-life care use. Logistic regression examined predictors of hospice use. RESULTS: Overall, 367 HIV patients identified electronically by International Classification of Disease (ICD)-9 code were hospitalized in 2010. The mean age was 42 years, and 57% were African American. Although 28% died, only 6% of the sample received palliative care consultation, and 6% of the sample enrolled in hospice. Those who received hospice had lower albumin levels (adjusted odds ratio [AOR] 4.53, 95% CI 1.19-17.34) had received palliative care (AOR 9.73, 95% CI 2.10-45.09) and completed an advance directive (AOR 16.33, 95% CI 4.23-61.68). Of those patients who received hospice, the mean time to death after enrollment was 11 days. CONCLUSION: Among an urban cohort of HIV patients, the rates of advance directive completion, palliative care use, and hospice use were low. Despite advancements in the treatment of HIV, many patients with advanced illness may benefit from palliative care and hospice services. Advances should be made in identifying those patients earlier in their disease trajectories.