Influence of epidemiology, immunosuppressive regimens, clinical presentation, and treatment on kidney transplant outcomes of patients diagnosed with tuberculosis: A retrospective cohort analysis

Abstract

Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients. Although local epidemiology is an important factor, diagnostic/therapeutic challenges and immunosuppressive therapy (ISS) may influence outcomes. We analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a variety of ISS with long-term follow-up. Our retrospective single-center cohort study included all KT procedures performed between January 1, 1998, and August 31, 2014, with follow-up until August 31, 2014. Induction therapy was based on perceived immunological risk; maintenance ISS included prednisone and calcineurin inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or mechanistic target of rapamycin inhibitor (mTORi). Thirty-four patients received belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR 932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%). Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients diagnosed after the first year. Unadjusted analysis revealed an increasing confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI = 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32, P < .001] vs 14.7% belatacept/MPA [HR = 13.14, 95% CI = 5.27 to 32.79, P < .001]). Thirty-seven (24%) patients died, and 39 (25.6%) patients experienced graft loss. Cytomegalovirus infection (P = .02) and definitive ISS discontinuation (P < .001) were associated with death. Rejection (P = .018) and ISS discontinuation (P = .005) occurred with graft loss. TB occurred at any time after KT and was influenced by ISS. K E Y W O R D S clinical research/practice, complication: infectious, immunosuppressant -fusion proteins and monoclonal antibodies: belatacept, infection -mycobacterial, infection and infectious agents, infectious disease, kidney transplantation/nephrology

An Inflammatory Story: Antibodies in Tuberculosis Comorbidities

“…A recent retrospective analysis discovered that kidney transplant recipients receiving the immunotherapy Belatacept, a fusion protein of anti-CTLA-4 and the Fc-portion of IgG1 (CTLA4-Ig), had a significantly higher incidence of TB reactivation and infection (279). The incidence of TB in the group receiving Belatacept was higher at 17.6% compared to other immunosuppressive drugs where the incidence was <2.5% indicating that the immunosuppressive actions of these drugs may not have been the root cause for TB reactivation in these groups (279). This is interesting given the previous studies discussed above provide some evidence to support the proinflammatory actions of IgG1 may worsen TB disease prognosis.…”

Mycobacterium tuberculosis in transplantation: Immunity sufficient to perpetuate disease?

“…In normal hosts, the risk of active TB is ~5% in the first 5‐7 years after infection and ~0.1% per year thereafter. After transplant, most cases occur in the first 6 months except in renal recipients, where onset is typically later as observed by Viana et al (median 18.8 months, IQR 7.2‐60) . Late TB might be anticipated if primary infection occurred after transplant due to local exposure.…”

“…In this series, the absence of “immune reconstitution” following reduced immunosuppression may reflect continuation of prednisone; still, 25.6% of patients had graft loss, half with rejection. Mortality of 57%‐83% is largely attributable to TB and is increased by delayed clinical recognition and therapy . Antibiotic susceptibility testing is a cornerstone of management for TB; resistance is a major factor in management in endemic regions but was not identified as a major factor in this series.…”

Latent tuberculosis infection and renal transplantation – Diagnosis and management

“…TB is also responsible for loss of the renal allograft (transplanted kidney) in approximately one third of cases. Most of the TB cases in renal transplant recipients are due to re-activation of LTBI in the recipient or from donor kidney (Viana et al, 2018;Abad and Razonable, 2018a,b). TB can also occur due to increased susceptibility to acquiring new M.tb infection which rapidly progresses to miliary TB because of immunosuppressive therapy.…”

“…The diagnosis and treatment of LTBI and active TB disease in donors and transplant recipients can be quite challenging since the presentation is cryptic with non-specific symptoms and signs, and the diagnosis can easily be missed unless there is a high degree of awareness of the possibility of TB. The clinical presentation of TB occurring in transplant recipients is said to differ from that in the general population and an increased frequency of extrapulmonary TB is seen (Viana et al, 2018;Abad and Razonable, 2018a,b).…”