Overlapping Onset and Sequential Progression of Vasculopathy in Multiple Organs in Sickle Cell Disease

Background: Sickle cell disease (SCD) is associated with vasculopathy in multiple vital organs, which ultimately leads to complications such as stroke, proliferative retinopathy, chronic kidney disease and pulmonary hypertension. Existing studies focus on single organ specific vasculopathy without an emphasis on shared mechanisms and simultaneous progression of vasculopathy in multiple organs. We conducted this retrospective cohort study to determine the onset and progression, as well as sequence of involvement of vasculopathy in the central nervous system (CNS), eye, kidney and lungs of adults with SCD.

Methods: Our institutional practice is to perform annual magnetic resonance imaging with magnetic resonance angiography (MRI/MRA, for CNS vasculopathy and silent cerebral infarcts), echocardiography (for tricuspidregurgitant jet velocity > 2.5 m/sec, a surrogate of pulmonary hypertension), retinal examination, and measurement of urinaryalbumin:creatinine ratio, and serum creatinine in all adults with SCD. All patients were followed until death or last clinical encounter. Data were summarized as counts and proportions. Multivariable logistic regression was used to identify associations of number of organs affected with mortality.

Results: We identified 280 adults with SCD followed for a median period of 66 months (interquartile range [IQR] 15.7 to 112 months). Median age was 31.1 (IQR 25.4 to 39.7) years and 49.6% were female. Over half (51.8%) were on hydroxyurea therapy. The prevalence of vasculopathy in different organs was: CNS, 37.8%; retinopathy 26.1%, proteinuria, 20.7% (nephropathy 5.71%); and pulmonary hypertension, 15.36%. There was no evidence of vasculopathy in 103 (36.8%) individuals. Of the remaining 177 (63.2%) adults, vasculopathy was present in one, two, three and all four end organs in100, 55, 18, and 4 individuals respectively. Median age of onset was earliest for CNS vasculopathy [25.42 (IQR 19.31, 38.85)] years followed by retinopathy [28.41 (IQR 23.04, 35.79)] years, proteinuria [31.25 (IQR 25.6, 46.0)] years, and pulmonary hypertension [33.08 (IQR 23.83, 47.17)] years (Figure 1). Mortality rate was 1.69 per 100 patient-years. Patients with vasculopathy affecting 3 or 4 organs had a significantly higher mortality rate than those with 0-2 organs affected by vasculopathy [odds ratio 5.50 (95%CI 4.49-20.35), p=0.007], adjusted for phenotype, age, sex, hydroxyurea therapy, and smoking status.

Conclusion: Vasculopathy in SCD occurs in multiple organs simultaneously, with a predisposition to affectthe CNS first. These data strongly support that multiple vasculopathy is common, and when present in at least three organs, is associated with earlier mortality.

View largeDownload slide

View largeDownload slide

Close modal