Immunosuppression Exposure and Risk of Infection-Related Acute Care Events in Patients With Glomerular Disease: An Observational Cohort Study

Abstract

Rationale & objective: Infections cause morbidity and mortality in patients with glomerular disease. The relative contributions from immunosuppression exposure and glomerular disease activity to infection risk are not well characterized. To address this unmet need, we characterized the relationship between time-varying combinations of immunosuppressant exposure and infection-related acute care events while controlling for disease activity, among individuals with glomerular disease.

Study design: Prospective, multicenter, observational cohort study.

Setting & participants: Adults and children with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or immunoglobulin A nephropathy/vasculitis were enrolled at 71 clinical sites in North America and Europe. A total of 2,388 Cure Glomerulonephropathy Network participants (36% aged <18 years) had at least 1 follow-up visit and were included in the analysis.

Exposures: Immunosuppression exposure modeled on a weekly basis.

Outcome: Infections leading to an emergency department visit or hospitalization.

Analytical approach: Marginal structural models were used to estimate the effect of time-varying immunosuppression exposure on hazard of first infection-related acute care event while accounting for baseline sociodemographic and clinical factors, and time-varying disease activity.

Results: A total of 2,388 participants were followed for a median of 3.2 years (interquartile range, 1.6-4.6), and 15% experienced at least 1 infection-related emergency department visit or hospitalization. Compared to no immunosuppression exposure, steroid exposure, steroid with any other immunosuppressant, and nonsteroid immunosuppressant exposure were associated with a 2.65-fold (95% CI, 1.83-3.86), 2.68-fold (95% CI, 1.95-3.68), and 1.7-fold (95% CI, 1.29-2.24) higher risk of first infection, respectively.

Limitations: Absence of medication dosing data, lack of a control group, and potential bias in ascertainment of outcome events secondary to the coronavirus 2 pandemic.

Conclusions: Corticosteroids with or without concomitant additional immunosuppression significantly increased risk of infection leading to acute care utilization in adults and children with glomerular disease.

Keywords: Corticosteroids; glomerular disease; glomerulonephritis; hospitalization; immunosuppression; infection.

Graphical abstract

Figure 1

Illustration of time-dependent confounding by Disease Activity (DzA) of the relationship between Immunosuppression Exposure (IS) and Infection (INF) over longitudinal follow-up. Solid arrows demonstrate effects of interest and standard confounding typically found in observational studies, dashed arrows represent correlations within a variable over time, and dotted arrows represent time-dependent confounding affected by previous exposure.

Figure 2

Cohort assembly. Abbreviations: eGFR, estimated glomerular filtration rate; UPCR, urinary protein-creatinine ratio.

Figure 3

Scatterplot of infection-related acute care events by year. Linear regression model using the interaction between time and coronavirus disease 2019 (COVID-19) era indicator was used to compare regression slopes before vs during the COVID-19 pandemic (P = 0.08).

Figure 4

Marginal structural Cox models assessing the relationship between immunosuppression exposure and risk of first infection. Hazard ratio estimates and corresponding 95% CIs depicted as diamonds and horizontal bars, respectively. Full model results are provided in Tables S2-S4. Abbreviations: CNI, calcineurin inhibitor; MMF, mycophenolic acid; ref, reference.