The morbidity and mortality of end stage renal disease in sickle cell disease
Authors: Maya Viner, Jifang Zhou, David Allison, Jin Han, Robert E. Molokie, Shivi Jain, Michel Gowhari, Victor R. Gordeuk, Gregory Calip, Santosh L. Saraf
Journal: American Journal of Hematology (2019)

Chronic kidney disease occurs in more than half of adults with sickle cell disease (SCD)1 and is an independent predictor for early death.2 SCD patients that progress to end-stage renal disease (ESRD) have an especially poor prognosis, with 26% mortality within the 1st year of initiating renal replacement therapy.3 In non-SCD ESRD patients, high rates of cardiovascular, infectious, and nutritional complications are observed,4, 5 but the morbidity of ESRD in SCD patients is unclear. We conducted a retrospective analysis comparing these complications among SCD patients with versus without ESRD. We also analyzed the morbidity of ESRD in a cohort of SCD patients from the Truven Health MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. Thirty-two SCD patients, all Hb SS genotype, were treated for ESRD at the University of Illinois at Chicago (UIC) between January 1998 and December 2018. Clinical and laboratory data within 12 months of initiating renal replacement therapy and clinical complications during renal replacement therapy were obtained from the electronic medical charting system. Thirty-two age, sex, hemoglobin genotype, and hydroxyurea therapy-matched SCD patients without ESRD were randomly selected from a prospective registry at UIC. The protocol was approved by the Institutional Review Board prior to data collection. Linear and categorical variables were compared using the Kruskal-Wallis and Chi square test, respectively. Survival patterns were compared using the log-rank test and the Cox proportional hazards models adjusting for age and sex. Median and interquartile ranges (IQRs) are provided. Of the 32 SCD patients with ESRD, 21 were treated with hemodialysis, six with peritoneal dialysis, and five with kidney transplantation. The median age at the time renal replacement therapy was initiated was 44 years old and 59% were male. Twenty-two of 30 (73%) patients with medical records available pre-ESRD had established nephrology care prior to progressing to ESRD. At the time renal replacement therapy was initiated, 21 (70%) had hemodialysis performed through a central venous catheter, six (20%) had peritoneal dialysis performed through a peritoneal catheter, two (7%) had hemodialysis performed through an AV fistula, and one (3%) went directly to a living related-donor kidney transplantation. SCD patients with ESRD had a greater proportion diagnosed with hypertension, a higher serum ferritin concentration and systolic blood pressure, and lower hemoglobin F%, platelet count, and reticulocyte percentage at the time renal replacement therapy was initiated compared to matched non-ESRD SCD patients at the time of entry into the registry (P ≤ 0.008) (Supporting Information Table S1). Greater prevalences of an elevated tricuspid regurgitant jet velocity (defined as >3.0 m/s) and left ventricular dysfunction (defined as ejection fraction <50%) were observed in the ESRD SCD patients (P ≤ 0.03) (Figure 1A). Phosphorous levels, which rise due to a reduction in the filtered phosphate load and then lead to secondary hyperparathyroidism in kidney disease,5 were higher in the ESRD SCD patients (ESRD: 6.0 mg/dL, IQR 5.1-7.3 mg/dL versus non-ESRD: 4.3 mg/dL, IQR 3.7-4.9 mg/dL) (P < 0.0001). Parathyroid hormone levels were also significantly higher in the ESRD SCD patients (P = 0.0003) (Figure 1B). During renal replacement therapy, greater rates of atrial flutter/fibrillation, congestive heart failure exacerbation, bacteremia, and sepsis were observed in the ESRD SCD patients compared to rates observed in the non-ESRD SCD patients during longitudinal follow up (Table 1). Higher rates of deep vein thrombosis and hemorrhage requiring red blood cell (RBC) transfusion and lower rates of acute chest syndrome were also observed in the ESRD patients (Table 1). A higher annual RBC transfusion requirement was observed in the ESRD patients after starting renal replacement therapy (8.7 units/year, IQR 2.5-17.8 units/year) versus non-ESRD (1.1 units/year, IQR 0-7.0 units/year) SCD patients (P = 0.005). The RBC transfusion burden was highest in ESRD patients not treated with an erythroid stimulating agent (ESA) and lowest in those treated with an ESA and hydroxyurea (Figure 1C). With a median follow up of 6.8 years (IQR, 2.2-7.7 years), 24 (75%) deaths were observed in the ESRD group versus 5 (16%) deaths in the non-ESRD group (log-rank P < 0.0001; age and sex-adjusted HR 8.4, 95% CI: 3.2-23.5). Survival was improved in those ESRD patients that went on to kidney transplantation compared to the non-transplanted ESRD group (log-rank P = 0.02; age and sex-adjusted HR 0.1, 95% CI: 0.03-0.6) (Figure 1D). To further evaluate the morbidity of ESRD in SCD, we analyzed data from the Truven Health MarketScan Research Databases between January 2009 and December 2014. Detailed cohort selection criteria are provided in Supporting Information Table S2. Seventy-eight SCD patients with ESRD (hemodialysis: n = 54, peritoneal dialysis: n = 17, kidney transplantation: n = 7) were identified. The median age of this cohort was 48 years and 42% were male. Consistent with the UIC cohort, a higher prevalence of hypertension, iron overload, and heart failure were observed in the ESRD SCD patients compared to age-matched and sex-matched non-ESRD SCD patients (P ≤ 0.002) (Supporting Information Table S3). During the follow up period, greater rates of congestive heart failure exacerbation, bacteremia, and sepsis were observed in the patients with ESRD relative to non-ESRD controls (Table 2). Also consistent with the UIC cohort, higher rates of thromboembolic events (deep vein thrombosis, pulmonary embolus, and stroke) were observed in the ESRD versus non-ESRD SCD patients. In two cohorts, we highlight the morbidity of ESRD in SCD patients. The high rates of cardiovascular complications, infection, and thromboembolism are consistent with what has been observed in other SCD ESRD cohorts3, 6 and significantly greater than in matched non-ESRD SCD patients. Our findings suggest that initiatives that have been implemented in the general ESRD population, such as establishing nephrology care prior to renal replacement therapy, replacing catheter use with AV fistulas and grafts to reduce thrombosis and infection, nutritional care to prevent hyperphosphatemia and secondary hyperparathyroidism, preemptive kidney transplant evaluation, and cardiovascular risk assessment,4 are all relevant in SCD patients with advanced kidney disease. This work was supported by the National Heart, Lung, Blood Institute through grants K23-HL125984 (S.L.S). M.V., J.Z., D.A., J.H., V.R.G., G.C. and S.L.S. designed and performed research, analyzed the data, and wrote the article. R.E.M., S.V., and M.G. designed the research and wrote the article. There are no relevant conflicts of interest to disclose. Supplementary Table 1 Baseline clinical variables of sickle cell disease adults at the time of initiating renal replacement therapy compared to 32 age, sex, hemoglobin genotyped, and hydroxyurea therapy-matched sickle cell disease adults not on renal replacement therapy from the University of Illinois at Chicago. Supplementary Table 2: Attrition table from the Truven Health MarketScan Databases Supplementary Table 3: Baseline clinical variables of sickle cell disease adults at the time of initiating renal replacement therapy from the Truven cohort* Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.