Dissecting the web of ischemic stroke, sickle cell trait, and chronic kidney disease
Authors: Donna Neuberg
Journal: American Journal of Hematology (2019)

In this issue of the journal, Caughey and colleagues report on the 30-year incidence of ischemic stroke among 3602 black adults who enrolled in the Atheroscloerosis Risk in Communities (ARIC) Study at midlife. Genotyping permits the identification of sickle cell trait (SCT) in this cohort, and SCT is itself associated with hypercoagulability, chronic kidney disease (CKD) and ischemic stroke All patients included in this study had detailed medical history, and CKD was determined based on the eGFR at first or second study visit (CKD defined as eGFR <60 mL/minute/1.73m2). Biomarkers of coagulation obtained at the initial study visit were also available, thereby permitting a detailed consideration of the interplay of SCT, CKD, and hypercoagulability on the subsequent experience of ischemic stroke. This unique cohort contains 236 individuals with SCT, and 468 individuals in the cohort met criteria for CKD at or near study entry. Over a median follow up of 26 years, 555 ischemic strokes were experienced by 436 individuals.1 The authors are to be commended for tackling this important analysis in such a systematic manner. They focus on the modification of the association between SCT and ischemic stroke by CKD, and assess both incident and recurrent ischemic strokes. In support of their primary analyses they have chosen to present the observed data with a granularity that permits the reader to assess directly the results they report. Figure 1 in Caughey et al. shows the unusual pattern of incident and recurrent ischemic stroke seen in SCT participants, involving a noticeable increase in ischemic stroke after 15 years of follow up. This is quite divergent from the pattern observed in individuals without SCT, and is present in participants with CKD as well as in those without CKD. This granularity brings more appreciation of this finding, enhancing the reader's understanding far beyond that which is gained from a simple P value from a test for interaction. Indeed, the P value for interaction of .04 seems modest, but we note that the standard assumption of a constant hazard over time associated with SCT does not appear to be met in SCT participants with or without CKD. This is noted in the similarity of the curves until about 15 years after study entry, and sudden and sharp divergence at that point. The assumptions of modeling guide the narrative; it is not clear that a single hazard ratio estimate captures what is happening with ischemic stroke in SCT patients. Plots for all participants, CKD participants, and participants without CKD are also presented for overall survival and show no divergence between participants with and without SCT, regardless of CKD status. This organizational approach also enhances table 2 in Caughey et al. to help the reader understand how SCT and CKD do, and do not, modulate markers of coagulability. Indeed, the highest values of factor VII activity, factor VIII activity, and von Willebrand factor are found in the SCT participants with CKD. However, none of these measures are statistically significantly higher in SCT participants within the CKD cohort compared to noncarriers with CKD. For Factor VII activity, one could also report this finding emphasizing that the noncarriers without CKD—a group of 2940 participants—had the lowest value, in addition to having the most statistically significant finding associated with SCT. Indeed, the larger differences are associated with the presence or absence of CKD; the magnitudes of difference associated with SCT are smaller. The more compelling associations between the biomarkers and SCT and CKD status are presented through the proportion of participants with elevated levels of each of the markers. This binary variable might be more important in building a model of risk and is certainly easier to interpret. We note only that there are many P-values in table 2, and there is no adjustment of these P-values to reflect multiplicity of testing. Caughey et al. have made an important contribution to the literature but have also revealed aspects of the interplay between ischemic stroke, SCT, and CKD that require further study. We look forward to that future work.