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Chronic organ injuries in SCD children
Left ventricular diastolic dysfunction
SCD patients usually exhibit left ventricular (LV) dila- tion, closely correlated to the severity of anemia. Over time, progressive dilation leads to increased wall stress, increased LV mass, and impaired LV filling, which is asso- ciated with increased mortality in SCD adults.23,40 Diastolic dysfunction is linked to microscopic myocardial fibrosis in transgenic SCD mice, and to diffuse myocardial fibrosis on cardiac magnetic resonance imaging (MRI) in patients.40,41
Myocardial ischemia
Myocardial ischemia in SCD patients appears to be related to microvascular perfusion defect rather than to coronary artery occlusion.42 A few cases of acute myocar- dial ischemia or subclinical myocardial injuries have been reported in children with SCD.42,43 In a series of 22 SCD children with chest pain, or ECG or echocardiographic signs (LV dilation or hypokinesis) who underwent single photon emission computed tomography, myocardial hypoperfusion was found in eight of them. Perfusion defects were more frequent in older children. In this study, myocardial perfusion was reassessed in three patients after 6 months of hydroxyurea and was found to be improved.43
Cardiac iron overload
The heart does not appear to be an early target for iron deposition in chronically transfused SCD patients, and this is particularly the case in young patients.44,45 In a mul- ticentric study of regularly transfused SCD patients either on manual exchange transfusion (n=30) or erythrocyta- pheresis (n=11), none had cardiovascular MRI values of T2*<20 ms, in spite of high median ferritin levels (2,700 and 2,400 ng/mL for manual exchange and erythrocyta- pheresis procedures, respectively) and liver iron content (10 and 14 mg/g dry weight for manual exchange and ery- throcytapheresis procedures, respectively).44 The rarity of cardiac iron overload may partly be explained by the fact that, in SCD, iron is efficiently recycled by erythropoiesis or trapped within macrophages because of chronic inflam- mation.44
Lung disease
Respiratory complications were found to be the second cause of death (at 28%) in adults with SCD in the US between 1999 and 2009.22 Chronic complications in SCD include chronic dyspnea, reduced exercise capacity, and loss of lung function. Abnormalities in lung function have frequently been reported in children with SCD, although results remain a subject of debate, both regarding the fre- quency of these abnormalities and the predominant restrictive or obstructive pattern.46-48 A review of 149 chil- dren aged 6-19 years, of whom 139 were followed prospectively for a median of 4.3 years, found normal, obstructive, restrictive, non-specific, and mixed baseline lung function patterns in 70%, 16%, 7%, 6%, and 1% of patients, respectively.49 Baseline lung function patterns were not associated with pain or acute chest syndrome rate either before the pulmonary function tests or during follow-up. In contrast, another study found that occur- rence of acute chest syndrome was associated with a greater decline in lung function.50 In a prospective study of
146 patients with HbSS or HbS/b0 thalassemia, normal, obstructive, restrictive, and non-specific lung function patterns were observed in 61%, 19%, 9%, and 11% of patients, respectively.51 Older age, patient or family histo- ry of asthma or wheezing, and higher lactate dehydroge- nase levels were independent predictors of obstruction. One study reported that 96.5% of patients had normal lung function at eight years of age, but the authors observed a longitudinal decline in lung volumes through adolescence, with a restrictive pattern in 19% of patients by the age of 17.52 Discrepancies between studies may be due to the different thresholds used for defining patterns and to the small numbers of patients, most often ana- lyzed retrospectively in cross-sectional studies. Lung function may also vary depending on geographical area, with a higher reported prevalence of restrictive patterns in patients from sub-Saharan Africa compared to those from high-income countries.48 Overall, obstruction seems to predominate in children whereas restriction is more common in adults.53 Asthma has been found to be associ- ated with acute chest syndrome occurrence and pain54 but its effect on lung function growth is not clear.55 Unresolved issues include the question as to whether there is a link between abnormal lung function and rele- vant outcomes such as progressive dyspnea, pulmonary hypertension, and early mortality.49
Screening and prevention
The question of systematically screening all SCD chil- dren with pulmonary function tests remains a subject of debate.37,38,55 Proponents argue that identifying an undiag- nosed obstructive pattern may help to prevent acute asth- ma crises and therefore reduce the risk of acute chest syn- drome.
Kidney disease
Renal complications in SCD include hyposthenuria, glomerular hyperfiltration, glomerulosclerosis, albumin- uria, and end-stage renal disease. These are responsible for approximately 14-16% of mortality in adults with SCD in the US and are more frequent in patients with HbSS and HbS/b0-thalassemia.56 In addition to the pathophysiologi- cal processes previously described in SCD organ injuries, kidney injury is enhanced by the particularly hypoxic, acidic, and hypertonic environment of the renal medulla which induces red blood cell sickling in the vasa recta, with ischemia and infarction of the tubular cells. The kid- ney is a very good example of the “perfusion paradox” in SCD, with the association of macrovascular whole-kidney hyperhemia, and microvascular medullary blood flow hypoperfusion. In young patients, elevated cardiac output leads to increased renal blood flow, glomerular hypertro- phy, and increased glomerular filtration rate (GFR), the lat- ter being observed as early as childhood.57 GFR then decreases with age, especially in patients developing kid- ney disease. In addition to hyperperfusion, there is a decrease in vascular resistance, which might be related to heme-driven heme oxygenase-1 induction and the release of vasorelaxants such as prostaglandins.56 I/R injuries and heme release seem to play a major role in the develop- ment of acute kidney injury (AKI) and chronic kidney dis- ease (CKD) via oxidative stress, apoptosis induction, and activation of the complement system.58,59
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