Associations between chronic kidney disease, proteinuria, and thrombotic risk in SCD Free

Background: Sickle cell disease (SCD) is characterized by early onset of frailty and age-related complications, including heart disease, hypertension, venous thromboembolism (VTE), and chronic kidney disease (CKD). While recent studies have demonstrated that CKD is a risk factor for thrombosis in SCD, no prior studies have examined the relationship between thrombotic risk and either microalbuminuria or proteinuria in people living with SCD. The ASH Research Collaborative (ASH RC) Data Hub is an excellent resource to examine relationships between advancing age and age-related clinical conditions in people living with SCD. Leveraging from this resource, we examined the prevalence of venous thromboembolic disease, microalbuminuria, and proteinuria by age, and for associations between thrombotic events and the presence of either microalbuminuria or proteinuria in adults living with sickle cell disease.

Methods: We examined diagnoses based on SNOMED data and ICD-10 codes within the ASH RC Data Hub to quantify the prevalence of microalbuminuria, proteinuria, and VTE by age group, with age defined by the difference between date at first diagnosis for each condition and date of birth. Chi-square tests were used to compare the proportion of people with each condition by age group. A repeated measures analysis was conducted using a generalized linear mixed model (GLMM) to determine the association between clinical and demographic covariates and the odds of developing VTE over time. Odds Ratios (ORs) and their 95% Confidence Intervals (CIs) are provided. A 2-sided P value <0.05 was used to determine the significance of variables in all analyses. Data analyses were performed using SAS version 9.4.

Results: We identified 10,749 adults with physician-attested SCD, with a mean age of 23.2 years (SD 16.3). Most participants (93.6%) were Black or African American, 51.7% were women, and 9.4% of participants had Hispanic or Latino ethnicity. Sickle cell subtypes were 65% Hb SS, 24.5% Hb SC, 6.9% Hb Sß⁺ thalassemia, 2.2% Hb Sß⁰ thalassemia, and 1.3% “other” subtype. Within our study population, 27.0% had been diagnosed with VTE, including deep vein thrombosis (DVT) or pulmonary embolism (PE), while 28.1% had been diagnosed with CKD, 24.7% with proteinuria, and 3.3% with microalbuminuria. The prevalence of microalbuminuria, proteinuria, and venous thromboembolism were highest in participants aged 18-39 years (258/5715 (4.3%) with microalbuminuria, 1922/5715 (33.6%) with proteinuria, and 2217/5715 (38.8%) with DVT or PE) compared with older age groups aged 40-79 years (183/5034 (3.6%) with microalbuminuria, 1286/5034 (25.5%) with proteinuria, and 1251/5034 (24.8%) with DVT or PE). In full models, the diagnosis of VTE was associated with CKD and the presence of either microalbuminuria or proteinuria. In multivariable logistic regression analyses including all significant covariates, the diagnosis of VTE was significantly associated with younger age group (18-29 years vs. older age groups, p=0.001), sex (women had 50% higher odds compared with men, p<0.001), Hispanic ethnicity (61% higher odds), SCD subtype (Hb Sß⁺ thalassemia had 87% higher odds and Hb SC had 49% higher odds compared with HbSS / Hb Sß⁰ thalassemia subtypes, p<0.001), and a diagnosis of either microalbuminuria or proteinuria (7% higher odds, p<0.001), and CKD (89% higher odds, p<0.001).

Conclusions: Using coded diagnoses from the ASH RC Data Hub, we confirmed previously identified associations between venous thromboembolic disease and both chronic kidney disease and less severe sickle cell subtypes (Hb SC and Hb Sß⁺ thalassemia). We further found an association between microalbuminuria/proteinuria and venous thromboembolism, even after adjusting for chronic kidney disease. Future directions include analysis of available laboratory albumin:creatinine ratio data to reduce any bias from selective reporting of coded diagnosis. Further studies are needed to examine possible mechanisms underlying increased risk of thrombosis in proteinuria, including inflammation and loss of factors that regulate coagulation pathways, and to examine strategies to prevent thrombosis in high-risk populations.