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Letters to the Editor
threshold of >3.0 mL/min/1.73 m2 per year, multivari- able analysis showed significant associations of rapid decline with age (odds ratio [OR]: 1.03, 95%CI: 1.01- 1.04; P=0.003), male sex (OR: 1.58, 95%CI: 1.09-2.29; P=0.016), and history of stroke (OR: 1.99, 95%CI: 1.25- 3.15; P=0.004). Using a threshold of >5.0 mL/min/1.73 m2 per year, significant associations were observed between rapid decline and hemoglobin (OR: 0.83, 95%CI: 0.72-0.96; P=0.009) as well as history of stroke (OR: 1.72, 95%CI: 1.03-2.86; P=0.038).
Ninety-eight of 605 patients died during the observa- tion period. Adjusted for age, sex, white blood cell count, hemoglobin, baseline eGFR and use of hydroxyurea, rapid eGFR decline, at thresholds of >3.0 mL/min/1.73 m2 per year and >5.0 mL/min/1.73 m2 per year, was associ- ated with increased mortality risk (hazard ratio [HR]: 2.41, 95%CI: 1.57-3.69; P<0.0001 and HR: 2.90, 95%CI: 1.87-4.48; P<0.0001, respectively). Kaplan-Meier esti- mates showed significantly lower survival probabilities for patients with rapid eGFR decline using both decline thresholds (log-rank test; P<0.0001) (Figures 1B and C).
In this multicenter analysis, we confirm accelerated eGFR loss over time in adults with sickle cell anemia, with an average eGFR loss of 2.36 mL/min/1.73 m2 per year, representing a faster kidney function decline than is reported in African American adults.13 The observed decline in this pooled cohort is similar to that in patients with diabetes, who have reported eGFR declines of 2.1 and 2.7 mL/min/1.73 m2 per year, respectively, for women and men.14 We also confirm the high prevalence of rapid eGFR decline, as well as its impact on survival. Regardless of the threshold, >3.0 mL/min/1.73 m2 or >5.0 mL/min/1.73 m2 per year, rapid decline is more frequent in sickle cell anemia than the reported prevalence of 10.5% after 12 years in the African American population.13 Much like in patients with diabetes,15 male sex was a significant risk factor for rapid eGFR decline. This is consistent with the finding in a multicenter, obser- vational study, which reported faster kidney function decline in males with SCD.16
In age-, sex- and cohort-adjusted analysis, we observed an association of proteinuria with rapid decline of kidney function. However, proteinuria was not included in the multivariable analysis due to severe lack of data. Albuminuria is a known risk factor for progression of CKD.2
Increased hemoglobin was associated with a lower risk of rapid eGFR decline. Although not evaluated in the multivariable analysis due to substantial missing data, hemoglobinuria has previously been shown to be associ- ated with albuminuria and CKD progression, suggesting an important role for intravascular hemolysis in the pathogenesis of SCD-related kidney disease.17 Based on the role of intravascular hemolysis, drugs that decrease hemolysis may prevent or slow the progression of kidney disease in SCD.
Our study is limited by lack of data for several impor- tant variables. Approximately 40% of patients had only two eGFR evaluations, which may have had an impact on the estimated change in eGFR over time. Most patients did not have urine albumin-creatinine ratios, limiting assessment of the role of albuminuria.
In conclusion, this pooled analysis confirms the high prevalence of rapid decline in kidney function in adults with sickle cell anemia. The association of rapid decline in kidney function with increased mortality highlights the need for early identification of individuals at risk for such decline.
Kenneth I. Ataga,1 Qingning Zhou,2 Vimal K. Derebail,3 Santosh L. Saraf,4 Jane S. Hankins,5 Laura R. Loehr,6 Melanie E. Garrett,7 Allison E. Ashley-Koch,7 Jianwen Cai8 and Marilyn J. Telen9
1Center for Sickle Cell Disease, University of Tennessee Health Scienter Center, Memphis, TN; 2Department of Mathematics and Statistics, University of North Carolina, Charlotte, NC; 3Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC; 4Division of Hematology/Oncology, University of Illinois, Chicago, IL; 5Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN; 6Division of General Medicine and Clinical Epidemiology, University of North Carolina, Chapel Hill, NC; 7Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC; 8Department of Biostatistics, University of North Carolina, Chapel Hill, NC and 9Division of Hematology, Duke University Medical Center, Durham, NC, USA
Correspondence: KENNETH I. ATAGA - kataga@uthsc.edu doi:10.3324/haematol.2020.267419
Received: July 17, 2020.
Accepted: October 23, 2020.
Pre-published: November 12, 2020.
Disclosures: KIA has received funding from the US FDA (R01FD006030), Novartis, and Global Blood Therapeutics, served on advisory boards for Novartis, Global Blood Therapeutics, Novo Nordisk and Editas Medicine, and as a consultant for Roche. Dr. Derebail has received funding from the US FDA (R01FD006030), has served on advisory boards for Novartis and Retrophin.
SLF has received research funding from Novartis, Global Blood Therapeutics and Pfizer and served as a consultant role for Global Blood Therapeutics and advisory board for Novartis. JSH receives research funding from Global Blood Therapeutics, and
consultant fees from Global Blood Therapeutics and MJ Lifesciences. MJT has served on steering committees and advisory committees
for Pfizer, GlycoMimetics, Novartis, and Forma Therapeutics.
JC has received funding from the FDA (R01FD006030).
KIA, VKD, LL, JC received funding for the study from the US Food and Drug Administration (R01FD006030).
Contributions: KIA designed the study, analyzed the data and wrote the manuscript; QZ and JC analyzed the data, and assisted in study design and manuscript preparation; MEG assisted in data analysis and manuscript preparation; VKD, SLS, JSH, LRL, AEA-K and MJT assisted in study design, data analysis and manuscript preparation.
Funding: funding for the study was provided by the US Food and Drug Administration, R01FD006030 (KIA, VKD, LL, JC).
References
1. Ataga KI, Derebail VK, Archer DR. The glomerulopathy of sickle cell disease. Am J Hematol. 2014;89(9):907-914.
2. Gosmanova EO, Zaidi S, Wan JY, Adams-Graves PE. Prevalence and progression of chronic kidney disease in adult patients with sickle cell disease. J Investig Med. 2014;62(5):804-807.
3. Thrower A, Ciccone EJ, Maitra P, et al. Effect of renin-angiotensin- aldosterone system blocking agents on progression of glomerulopa- thy in sickle cell disease. Br J Haematol. 2019;184(2):246-252.
4. Xu JZ, Garrett ME, Soldano KL, et al. Clinical and metabolomic risk factors associated with rapid renal function decline in sickle cell dis- ease. Am J Hematol. 2018;93(12):1451-1460.
5. Derebail VK, Ciccone EJ, Zhou Q, et al. Progressive decline in esti- mated GFR in patients with sickle cell disease: an observational Cohort Study. Am J Kidney Dis. 2019;74(1):47-55.
6. Derebail VK, Zhou Q, Ciccone EJ, et al. Rapid decline in estimated glomerular filtration rate is common in adults with sickle cell disease and associated with increased mortality. Br J Haematol. 2019;186(6):900-907
7. Saraf SL, Viner M, Rischall A, et al. HMOX1 and acute kidney injury in sickle cell anemia. Blood. 2018;132(15):1621-1625.
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