Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients.

Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti-IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.

Variables affecting estimated glomerular filtration rate after renal transplantation in children: a NAPRTCS data analysis.

Short-term graft survival has improved in renal transplants without significant effect on long-term graft survival. As GFR decline precedes graft loss, an understanding of variables affecting eGFR after TX may help improve graft survival. NAPRTCS data were analyzed to assess effects of donor, recipient, and other variables on Schwartz eGFR after transplantation. For 8438 children with a functioning graft at day 30, data were censored for children dying with a functioning graft, and those with <3 yr follow-up. Multivariate linear regression and repeated measures analyses identified factors related to eGFR at day 30 after TX and during follow-up. Young, female, non-black, children without ATN and acute rejection in the first 30 days, TX after 1995, those with better eGFR at day 30, and receiving tacrolimus had better long-term eGFR. Transplant from ideal (6-35 yr) donors had best short-term eGFR, young donors (<5 yr) had lower eGFR and poor graft survival. After one yr, eGFR improved in surviving grafts of young donors and matched ideal donors. Acute rejection, BP medications, and hospitalizations in prior six months had negative association with subsequent eGFR. Regardless of variables, eGFR deteriorated with time. Slope of eGFR decline has not changed in the recent era indicating the need for innovative therapies.

The onset of rapidly progressive neurologic deterioration after a brief gastrointestinal illness in a renal allograft recipient.

Renal transplant recipients are at increased risk for life-threatening complications, most commonly infections. Because of their impaired cell-mediated immunity, these patients are particularly susceptible to organisms that rely on intracellular survival and spread, such as Listeria monocytogenes. Despite being a food-borne pathogen, L. monocytogenes is associated with significant morbidity and mortality. Here we report the case of a renal transplant recipient who developed rapidly progressive neurological symptoms after a brief gastrointestinal illness. Magnetic resonance imaging scan of the brain showed a large mass that was identified as an abscess due to L. monocytogenes. Timely aspiration and antibiotic treatment resulted in complete recovery, as opposed to worse outcomes in the available case reports. We further review the epidemiology, microbiology, clinical presentation, and therapeutic options for listerial brain abscess.

Younger age and antibody induction increase the risk for infection in pediatric renal transplantation: a NAPRTCS report.

UNLABELLED: Infections now exceed rejection as a cause of hospitalization in the first 2 years post-renal transplantation. We analyzed data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) to determine risks for hospitalization for infection (HI), either bacterial (HBI) or viral (HVI). 3106 children transplanted between 1996 and 2002 with 2-year follow-up were analyzed. Univariate and multivariate logistic regression analyses identified factors for cause-specific hospitalization. RESULTS: 23.4% experienced HBI, 23.9% HVI; 8.9% were hospitalized for both. Children 0-1 years age at transplant had higher rates of HI (64.2%), HBI (40.3%) and HVI (43.3%) compared to >12 years (31%, 17.5% and 18.9%, p < 0.0001). In comparison to no induction, patients receiving monoclonal or polyclonal antibody were more likely to have HI (>42% vs. 34.0%), HBI (>24% vs. 21%) or HVI (>29% vs. 21%, all p < 0.003) but had equivalent graft survival (p = NS). Higher rates of HI, HBI and HVI were also seen with prophylactic antimicrobial use and with >5 transfusions pretransplant. Since antibody induction in recent era was not associated with better graft or patient survival but was associated with more HI and HVI, the need for routine antibody induction in children needs to be reassessed.

Successful use of oral ganciclovir for the treatment of intrauterine cytomegalovirus infection in a renal allograft recipient.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns and is the leading infectious cause of congenital birth defects. Female renal allograft recipients who develop CMV infection during pregnancy are at risk for both graft dysfunction and fetal morbidity. DNA-based analysis of amniotic fluid (AF) from at-risk pregnancies has been suggested as an adjunct/substitute for traditional culture. We have shown that CMV-polymerase chain reaction of AF is a useful diagnostic test for congenital CMV infection. Using this test we diagnosed CMV infection in the fetus of a 30-year-old renal transplant recipient. As termination was not an option for the family, the patient was extensively counseled and treated with oral ganciclovir. This resulted in clearance of the virus from the AF and the delivery of a healthy newborn girl, free of CMV disease. This is the first reported case to our knowledge of successful use of maternal ganciclovir to treat intrauterine CMV infection in a pregnant renal transplant recipient.

Intravenous immune globulin treatment inhibits crossmatch positivity and allows for successful transplantation of incompatible organs in living-donor and cadaver recipients.

BACKGROUND: Sensitization to human leukocyte antigens (HLA) is a significant barrier to transplantation. Currently, no proven therapy exists to improve access to transplantation for highly sensitized patients. Here, we report a novel approach using intravenous immune globulin to modulate anti-HLA antibody and improve the chances for successful transplantation. PATIENTS AND METHODS: Forty-five highly HLA-sensitized patients presented as candidates for living-donor kidney transplantation (n=28), cadaveric kidney transplantation (n=15), or heart transplantation (n=2). All patients had a positive CDC crossmatch (CMX) with their donors. In living-donor recipients, intravenous immune globulin (IVIG) was added to the CMX evaluation to determine whether blocking antibodies present in IVIG could inhibit cytotoxicity. For those who showed in vitro inhibition with IVIG (n=26), IVIG was administered (usually as a single dose, 2 g/kg) and the CDC CMX was repeated against the prospective donor immediately after IVIG infusion. If negative, the patient underwent transplantation with their living-donor kidney within 24 to 72 hr. A similar but modified protocol was performed for cadaver donor candidates, all of whom were highly sensitized and had had CMX positivity with multiple donors, negating transplantation. Reductions in CMX positivity, posttransplantation serum creatinine level, number and severity of rejection episodes, and patient and graft survival rates were determined. RESULTS: Forty-two patients underwent transplantation. IVIG treatment completely abrogated the donor-specific CMXs in 35 of 42 patients. In the remaining 7 patients, the CDC CMX was inhibited, but flow cytometry CMXs remained positive. A total of 13 (31%) of 42 recipients developed rejection episodes 3 to 49 days after transplantation. Three grafts (7%) were lost to rejection. Mean serum creatinine level at 24 months was 1.4+/-0.4 mg/dL. Patient and graft survival rates were 97.6% and 89.1%, respectively, at 24 months. CONCLUSIONS: The in vitro IVIG CMX technique predicts the ability of IVIG to reduce anti-HLA antibody levels in highly sensitized patients. Subsequent in vivo IVIG treatment of responders eliminates the positive CDC CMX and allows for successful transplantation. Thus a positive CMX result is not necessarily a contraindication for transplantation and allows access to transplantation for patients for whom it was previously contraindicated.