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.

Acute Kidney Injury During Treatment with Intravenous Acyclovir for Suspected or Confirmed Neonatal Herpes Simplex Virus Infection.

OBJECTIVE: To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN: We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age <60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS: We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS: Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring.

Post-transplant lymphoproliferative disease after pediatric kidney transplant.

Post-transplant lymphoproliferative disease (PTLD) is the most common malignancy complicating solid organ transplantation (SOT) in adults and children. PTLD encompasses a spectrum of histopathologic features and organ involvement, ranging from benign lymphoproliferation and infectious-mononucleosis like presentation to invasive neoplastic processes such as classical Hodgkin lymphoma. The predominant risk factors for PTLD are Epstein-Barr virus (EBV) serostatus at the time of transplant and the intensity of immunosuppression following transplantation; with EBV-negative recipients of EBV-positive donor organs at the highest risk. In children, PTLD commonly presents in the first two years after transplant, with 80% of cases in the first year, and over 90% of cases associated with EBV-positive B-cell proliferation. Though pediatric kidney transplant recipients are at lower risk (1-3%) for PTLD compared to their other SOT counterparts, there is still a significant risk of morbidity, allograft failure, and an estimated 5-year mortality rate of up to 50%. In spite of this, there is no consensus for monitoring of at-risk patients or optimal management strategies for pediatric patients with PTLD. Here we review pathogenesis and risk factors for the development of PTLD, with current practices for prevention, diagnosis, and management of PTLD in pediatric kidney transplant recipients. We also highlight emerging concepts, current research gaps and potential future developments to improve clinical outcomes and longevity in these patients.

To Be or Not to Be (Inpatient Versus Observation): Improving Admission-Status Assignment.

BACKGROUND: Observation care is frequently indistinguishable from inpatient care. However, the financial burden of inappropriate status assignment for hospitals and patients can be large. Increased awareness of the potential for financial hardships experienced by patients because of status designation spurred interest among physicians in this improvement project. The goal was to improve the percentage of appropriate inpatient-status assignments from 76% to 90% in 2 years and eliminate observation assignments for patients with hospitalizations >48 hours. METHODS: Our multidisciplinary team used the Model for Improvement. Interventions included securing a lead physician advisor to the use-review team, improving the process for status review and adjustment, and creating educational sessions and tools for physicians. Data collected included the percentage of appropriate inpatient assignments, percentage of observation assignments for patients with hospitalizations >48 hours, write-off dollar amount per year from denial of payment due to payer disagreement with inpatient status, and resident physician confidence in assigning status. RESULTS: Appropriate use of inpatient assignments increased from 76% to 84%. Status assignments remaining in observation >48 hours of hospital length of stay decreased by one-half, from 6% to 3%. The write-off dollar amount increased during the study period but decreased by 19% the following calendar year, 2018. Resident self-reported confidence in status designation increased after educational sessions. CONCLUSIONS: Careful selection of admission status by educated providers and a system to identify relevant cases for status changes can increase appropriate status assignment and, potentially, positively affect the economic burden placed on patients and hospitals.

Bartter Syndrome and Gitelman Syndrome.

Bartter and Gitelman syndromes are conditions characterized by renal salt-wasting. Clinical presentations range from severe antenatal disease to asymptomatic with incidental diagnosis. Hypokalemic hypochloremic metabolic alkalosis is the common feature. Bartter variants may be associated with polyuria and weakness. Gitelman syndrome is often subtle, and typically diagnosed later life with incidental hypokalemia and hypomagnesemia. Treatment may involve fluid and electrolyte replenishment, prostaglandin inhibition, and renin-angiotensin-aldosterone system axis disruption. Investigators have identified causative mutations but genotypic-phenotypic correlations are still being characterized. Collaborative registries will allow improved classification schema and development of effective treatments.