initially used because of the high rate of concomitant ischemic stroke. Standard American Heart Association guidelines for hemorrhagic stroke are followed for sickle cell patients. Vascular imaging is important to detect associated aneurysms that may require surgical planning. Long-term management of ischemic stroke in adults has not been prospectively studied, but indefinite transfusions, usually with antiplatelet therapy, are standard. Many pediatric patients have been transitioned off transfusion to hydroxyurea as adults, but a high recurrence rate has been reported.26 Combination hydroxyurea and transfusions may be beneficial in recurrent episodes.27 Encephaloduroarteriosynangiosis is increasingly used in patients with moyamoya to improve cerebral oxygenation and decrease recurrent infarction and intracerebral hemorrhage.28 The management of silent infarctions is not standardized. Transfusion therapy may be beneficial and, at a minimum, hydroxyurea therapy is indicated. Most adult patients have hemosiderosis, and early chelation therapy is indicated in chronic as well as intermittently transfused patients. The management of neurocognitive impairment requires aggressive treatment of comorbid factors in SCD and the general population, such as nocturnal hypoxemia.29 Physical exercise improves memory in infrared spectroscopy measurements in older adults as well as those poststroke.30 In addition, it appears that, in transgenic sickle cell mice and patients, moderate exercise training decreases inflammation and may even improve sickle cell biology.31,32 However, exercise is not often included in the health maintenance programs for sickle cell patients with and without stroke because of theoretical concerns that metabolic changes imposed by exercise may initiate sickling and clinical events.32 Rapid advances in gene therapy and stem cell transplantation may soon be available to neurocognitively injured adult sickle cell patients. Preliminary results indicate gene therapy, nonmyeloablative, haploidentical stem cell transplantation, and BCL11A gene editing therapy are promising options. Ongoing trials will determine their safety and efficacy in this adult population.33-35 Chronic renal disease Chronic renal disease is a major cause of morbidity and mortality in aging sickle cell patients. At least 25% of older sickle cell adults have chronic kidney disease, which accounts for half the deaths in this older population.36 In the SCD surveillance project in California, pulmonary and renal failure were the leading complications in hospitalized patients older than 50 years of age.14 The 5-year survival following the diagnosis of renal failure is variable but is approximately 55% and is remarkably shorter than for nonsickle cell patients.37,38 A multidisciplinary approach addressing early prevention, early identification, access to treatment, and new therapies are needed. As sickle cell patients age, they experience repeated multifactorial renal injuries, often undiagnosed, that lead to the insidious presentation of renal failure.36,38-42 An acute kidney injury often accompanies serious sickle cell events that may not be reflected in creatinine levels.40,43,44 Red cell hemolysis with nitric oxide deficiency and endothelial dysfunction results in chronic renal ischemia and is a major cause of renal pathophysiology in SCD.41,45-47 The downstream effect of the ischemia leads to inflammation, elevation of tyrosine kinase-1 and other promotors of angiogenesis, activation of hypoxia-inducible factor 1a and endothelin-1, as well as oxidative stress.38,41,48,49 Therefore, patients with renal disease often have other characteristics of the hemolysis phenotype, including pulmonary hypertension, CNS injury, and severe anemia. In several multicenter trials, albuminuria is associated with hemolysis, low hemoglobin, elevated blood pressure, and pulmonary hypertension.39,45,50 Screening and early diagnosis of renal disease should be part of the ongoing, periodic care of all sickle cell patients and is essential to improving outcome. Relative hypertension and elevated pulse pressure are high-risk factors for renal disease.50 Periodic screening for microalbuminuria, hematuria, and estimated glomerular filtration rate are standard. Early detection of renal disease by using surrogate markers of renal disease (including serum cystatin C, urine N-acetylb-D-glucosaminidase, urinary b2-microglobin, and hemoglobinuria) may be beneficial but are not yet validated.36,38,47,51 Deteriorating trends in laboratory screening tests, rather than just absolute amounts, should prompt nephrology involvement. Therapies There are multiple therapeutic interventions that may decrease chronic renal disease.36,42,52 Early initiation of hydroxyurea therapy is renal protective, as is chronic transfusion therapy.36,53,54 The early treatment of proteinuria with inhibitors of the renin angiotensin system may prevent progressive disease. Recently, an angiotensin-II Hematology 2017 437 receptor-1 blocker may be more beneficial than an angiotensinconverting enzyme inhibitor.52 Because endothelin-1 is a cause of progression of renal disease, research data suggest that endothelin A receptor antagonism therapy was beneficial in hemoglobin S transgenic mice.42,48 Because hemolysis with free hemoglobin is