Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease

Abstract

Background and objectives: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome.

Design, setting, participants, & measurements: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties.

Results: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival.

Conclusions: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.

Keywords: ANCA; anti-glomerular basement membrane disease; autoantibodies; cluster analysis; epidemiology; follow-up studies; humans; incidence; kidney; kidney failure, chronic.

Figure 1.

Flowchart of case ascertainment. A total of 97 individuals had either a positive result for anti-glomerular basement membrane (anti-GBM) antibody, or a biopsy-proven diagnosis of anti-GBM disease. Of those excluded from the final analysis, most (n=11) had a modest rise in antibody level with no evidence of clinical disease. Three double-positive cases had symptoms and signs consistent with multisystem ANCA-associated vasculitis (AAV). Three patients did not reside in Ireland at the time of diagnosis. One case had antibody positivity and reduced kidney function but did not meet our inclusion criteria.

Figure 2.

Incidence and temporal clustering. (A) Annual incidence rates (with 95% confidence intervals [95% CIs]) for each year of the study period, expressed as per million population (pmp). (B) The location of cases diagnosed in the temporal cluster (represented by black stars). Six cases were resident in the southeast of the country (area shaded in dark gray).

Figure 3.

Spatial clustering. Results of spatial analysis showing standardized incidence ratios (SIR) with 95% confidence intervals (95% CIs) for each county (A), a country-wide spatial map of SIR (B), and the location of all seven cases encountered in County Donegal (C).

Figure 4.

Effect of clustering on outcome. Kaplan–Meier curves demonstrating renal survival (A) and patient survival (B) according to distance in kilometers from specialist referral center (above or below the median distance traveled).