Allison B. Webber

Novel strategies in immunosuppression: issues in perspective.

Recent findings suggest that a chronic alloimmune response is playing the dominant role in late allograft loss, challenging the notion that most grafts are lost due to the inexorable progression of calcineurin inhibitor (CNI) nephrotoxicity. CNIs have failed to improve long-term outcomes and are associated with multiple metabolic derangements. Thus, improvement in long-term allograft outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities associated with CNIs. To meet this need, inhibitors of novel pathways in B cell and plasma cell activation have emerged to combat the humoral immune response including belimumab and atacicept, both promising targets of B-cell survival factors and bortezomib and eculizumab, agents currently in trials for desensitization protocols and treatment of antibody-mediated rejection. Promising agents for maintenance immunosuppression, used as monotherapy or synergistically, include monoclonal antibodies and fusion receptor proteins targeting the CD40-CD154 pathway (multiple anti-CD40 antibodies), the CD28-CD80/86 pathway (i.e., belatacept), the LFA3-CD2 pathway (i.e., alefacept), and small molecules such as tofacitinib, a janus kinase 1/3 inhibitor. The induction of allograft tolerance has been attempted with some success with simultaneous bone marrow/kidney transplantation from the same donor, albeit, limited by its associated toxicites. Finally, the exciting fields of tissue engineering and stem cell biology with the repopulation of decellularized organs is ushering in a new paradigm for transplantation. The era of simplified immunosuppression regimens devoid of toxicities is upon us with the promise of dramatic improvement in long term survival.

Eculizumab for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas-kidney transplantation--a case report.

A 34-year-old female recipient of a simultaneous pancreas-kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia. Renal biopsy revealed acute antibody-mediated rejection (AMR) and acute thrombotic microangiopathy (TMA). Clinical and laboratory manifestations, which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin, resolved rapidly and completely to eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Cheshire, Conn), a complement factor C5 antibody. De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases. This is the first report of successful treatment of de novo TMA with eculizumab, which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR. Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA, especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease.

Ciprofloxacin prophylaxis in kidney transplant recipients reduces BK virus infection at 3 months but not at 1 year.

Background BK polyomavirus (BKV) infection remains a significant cause of nephropathy and graft loss. Fluoroquinolones inhibit BKV replication in vitro, and small studies suggest in vivo benefit. A strategy of fluoroquinolone prophylaxis directed specifically against BKV has not been formally tested against a control group in kidney transplant recipients. Methods We retrospectively compared the impact of a change in antibiotic prophylaxis practice from no BKV prophylaxis (Group 1, n=106, July–December 2009) to BKV prophylaxis with ciprofloxacin 250 mg twice daily for 30 days (Group 2, n=130, January–June 2010) on the rate of BKV infection during the first 12 months after kidney transplantation. Results Baseline demographics, transplant characteristics, induction immunosuppression, and 1-year incidence of acute rejection were similar between groups. Group 1 had fewer patients on maintenance corticosteroids (65.1% vs. 83.2%, P=0.002). At 3 months, Group 1 had a significantly higher risk of developing BK viremia (0.161 vs. 0.065, P=0.0378) and viruria (0.303 vs. 0.146, P=0.0067) compared with Group 2, but this difference disappeared at 12 months for both viremia (0.297 vs. 0.261, P=0.6061) and viruria (0.437 vs. 0.389, P=0.5363). Adjusting for the difference in steroid use did not change the results. There was a trend toward higher incidence of biopsy-proven BKV nephropathy in Group 1 (4.7% vs. 0.8%, P=0.057). Conclusion Thirty-day ciprofloxacin prophylaxis in kidney transplant recipients is associated with a lower rate of BKV infection at 3 months but not at 12 months. The long-term effectiveness and optimal duration of fluoroquinolone prophylaxis against BKV infection remain unknown.

An Update on Calcineurin Inhibitor-Free Regimens: The Need Persists, but the Landscape has Changed.

Calcineurin inhibitors (CNIs) have failed to improve long-term renal allograft survival. Their association with cardiovascular morbidity in addition to their suboptimal inhibition of a chronic alloimmune response has shifted investigative efforts toward CNI-free regimens. Sotrastaurin, a small molecule targeting protein kinase C isoforms, failed to provide adequate immunosuppression, whereas the Janus kinase 3 inhibitor tofacitinibs success in the treatment of rheumatoid arthritis led to biopharmas abandonment of it as a transplant agent. Like tofacitinib, tocilizumab, a biologic targeting the IL-6 pathway, has been approved for use in rheumatoid arthritis and interest in transplantation has been confined to several investigator-initiated trials. Belatacept, a second-generation, higher avidity variant of CTLA4Ig (abatacept), was approved by the Food and Drug Administration for prophylaxis of transplant rejection in 2011. Long-term follow-up of recipients on belatacept has demonstrated superior glomerular filtration rates as compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing belatacept-inclusive regimens has led to studies using lymphocyte depletion as induction and maintenance therapy with target of rapamycin inhibitors. ASKP1240, the most advanced of the anti-CD40 antibodies targeting the CD40/CD154 costimulatory pathway has just completed a phase II trial with a CNI-free arm. Animal models suggest that its highest efficacy may be in combination with belatacept. Finally, nonagonistic CD28 antibodies, which would allow CTLA4 and PD-LI binding of CD80/CD86 and activation of inhibitory pathways, have re-emerged with 2 anti-CD28 candidates in preclinical development. A reliable nontoxic CNI-free regimen may ultimately require the combination of biologic agents that provide efficacy as well as safety.

Fatal transplant-associated west nile virus encephalitis and public health investigation-california, 2010.

Background In December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified. Methods A public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology. Results Two additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor’s serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified. Conclusions Clinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients.

Mean arterial blood pressure while awaiting kidney transplantation is associated with the risk of primary nonfunction

Background. Primary nonfunction (PNF) is a devastating outcome after kidney transplantation and is more common with kidneys from donors without a heartbeat or expanded criteria donors, or both. We investigated recipient-based risk factors for PNF independent of organ donor source. Methods. We used a case-control study design and matched for the source of organ and year of transplantation; for each recipient with PNF, two recipients without PNF (controls) were randomly selected. We identified 20 PNF cases and 40 controls from our pool of 993 kidney transplant recipients who all received their transplants at our center between 2003 and 2008. The association between PNF and immune risk factors and blood pressure (BP) levels during the 3 months before transplantation was analyzed. Results. Among the factors analyzed, the mean systolic BP (P=0.003, Wilcoxon test), diastolic BP (P=0.02), and mean arterial pressure (MAP) (P=0.006) during the 3 months before transplantation were significantly lower in the PNF cases compared with the controls without PNF. In a multivariable model, only MAP remained as a significant risk factor for PNF and each 10 mm Hg decrease in MAP was associated with a 43% increased odds for PNF (P=0.01). The odds ratio for PNF in those with MAP less than or equal to 80 mm Hg was 4.32 (95% confidence interval, 1.41–13.2, P=0.008), compared with the group with MAP more than 100 mm Hg. Conclusions. Our findings support the hypothesis that the average MAP less than or equal to 80 mm Hg during the 3 months before kidney transplantation is a risk factor for PNF.

Managing the atazanavir–tacrolimus drug interaction in a renal transplant recipient

PURPOSE The management of the drug interaction between atazanavir and tacrolimus in a renal transplant recipient is described. SUMMARY A 53-year-old African-American man with human immunodeficiency virus (HIV) received a renal transplant and was treated in accordance with a corticosteroid-sparing immunosuppressive protocol and maintenance immunosuppression with mycophenolate mofetil and tacrolimus. His highly active antiretroviral therapy included atazanavir 400 mg daily, abacavir 600 mg daily, and lamivudine 100 mg daily. Because of the potential for a significant interaction between tacrolimus and atazanavir, the tacrolimus dosage was to be based on serum tacrolimus concentrations. The patient was initially administered one dose of tacrolimus 0.5 mg on the morning of postoperative day 2. Evaluation of the tacrolimus profiles revealed that a higher dosage was necessary because serum tacrolimus levels decreased to subtherapeutic levels by 6 hours after dose administration. In an attempt to minimize tacrolimus toxicity and limit the duration of a subtherapeutic tacrolimus level, dosing was adjusted to 1 mg every 8 hours. After 48 hours of this regimen, peak serum tacrolimus levels were lower, and the drug concentrations remained at a relatively steady level throughout the dosing interval. One final dosage adjustment (1.5 mg every 12 hours) was performed to optimize serum tacrolimus levels and patient compliance. CONCLUSION In a 53-year-old man with HIV infection who underwent renal transplantation, the drug interaction between atazanavir and tacrolimus was managed by modifying the tacrolimus dosage regimen after determining the patients blood tacrolimus concentration profile.

Prediabetic living kidney donors have preserved kidney function at 10 years after donation.

Background Potential living kidney donors with prediabetes are often excluded from donation because of concerns about the development of type 2 diabetes mellitus (DM) and progression to end-stage renal disease (ESRD). This strategy may be unnecessarily restrictive. Previous studies of living kidney donors have not specifically examined subsets with prediabetes. Methods We ascertained the vital status and development of ESRD in 143 living kidney donors from 1994 to 2007 with predonation impaired fasting glucose (IFG). We then compared the development of DM, the estimated glomerular filtration rate, and the level of albumin excretion in 45 of these IFG donors to 45 matched controls with normal predonation fasting glucose. Results The majority (57.8%) of IFG donors had reverted to normal fasting glucose at a mean follow-up of 10.4 years. Compared with donors with normal fasting glucose, a higher proportion of IFG donors had developed DM (15.56% vs. 2.2%, P=0.06). Predonation characteristics including age, sex, and body mass index did not correlate with the risk of developing DM. At follow- up, estimated glomerular filtration rate by the Modification of Diet in Renal Disease equation (70.7±16.1 mL/min/1.73 m2 vs. 67.3±16.6 mL/min/1.73 m2, P=0.21) and albumin excretion (urine albumin/ creatinine 9.76±23.6 mg/g vs. 5.91±11 mg/g, P=0.29) were similar in IFG and normal glucose donors. Conclusion Carefully screened prediabetic living kidney donors often revert to normal fasting glucose and do not seem to have a significantly increased risk of impaired kidney function in the short term.

Kidney Transplantation for Kidney Failure Due to Multiple Myeloma: Case Reports

Transplantation centers have historically considered a history of multiple myeloma as a contraindication to kidney transplantation due to high recurrence rates and poor transplant survival. However, there have been significant advances in the treatment of multiple myeloma, with improved patient survival, which may allow for successful kidney transplantation in these patients. We report on 4 patients who underwent kidney transplantation at our institution between 2009 and 2015 after having achieved a very good partial response or better with chemotherapy and autologous stem cell transplantation. All 4 patients received kidneys from living donors; 2 underwent induction therapy with basiliximab, and 2, with thymoglobulin. One patient had progression of myeloma, which responded well to therapy. All had functioning transplants at 1 year after kidney transplantation. No patients experienced a rejection episode or infections with BK polyomavirus or cytomegalovirus, with follow-up ranging from 16 to 58 months after kidney transplantation. Our experience suggests that kidney transplantation is feasible in a subset of patients with multiple myeloma. Future studies are necessary to compare outcomes in these patients with other high-risk patients undergoing kidney transplantation.