Page 36 - 2021_06-Haematologica-web

S. Allali et al.
Renal manifestations vary greatly depending on the patient and his or her age. Hyposthenuria is observed from infancy in the majority of children. Enuresia is very frequent and may have a severe psychological impact. Hyperfiltration occurs very early, as evidenced by 99-tech- netium diethylenetriaminepentaacetate (DTPA) plasma clearance measurements in infants with SCD aged 9-19 months enrolled in the BABY HUG trial.57 Baseline DTPA glomerular filtration rate (GFR) was 125±34 mL/min/1.73 m2 (range: 40-300 mL/min/1.73 m2) compared with the published normal value of 91±18 mL/min/1.73 m2 (10- 90% range: 60-120 mL/min/1.73 m2) for this age group.57 On average, baseline DTPA GFR increased by 3 mL/min/1.73 m2 for every one month increase in age.57 Hyperfiltration, defined as estimated GFR (eGFR) >180 mL/min/1.73 m2, was also evidenced using cystatin C measurement in a cohort of 91 children with HbSS and HbS/b0-thalassemia aged 5-21 years.60 Thirty-nine patients (43%) had hyperfiltration and nine of them (23%) pro- gressed to microalbuminuria, defined as albumin to crea- tinine ratio 30-300 mg/g, compared with three of the 52 patients (6%) without hyperfiltration. Several studies have demonstrated that hyperfiltration increases during early childhood, remains stable before adolescence, then decreases as progressive CKD continues.60-62 eGFR <90 mL/min/1.73 m2 is seen in 8-21% of adolescents.61-63 Albuminuria may develop in some children. In a series of 410 SCD patients aged 2-21 years, microalbuminuria was found in 21% (70% of them were HbSS and HbS/b0-tha- lassemics); macroalbuminuria (defined as albumin to crea- tinine ratio ≥300 mg/g creatinine) was presented in three HbSS patients. In HbSS and HbS/b0-thalassemics, abnor- mal albuminuria was associated with older age and lower baseline hemoglobin level.61
SCD patients with CKD may have a stable renal func- tion but are at risk of AKI during vaso-occlusive crisis or other concomitant illness.64 In a retrospective study, AKI was found in 17% of 197 admissions for vaso-occlusive pain.64 At admission, every ‘one unit’ drop in hemoglobin levels compared to patients’ baseline values increased the risk of AKI by 49%. Ketorolac administration (in terms of total days and doses) was also associated with AKI but the role of non-steroidal anti-inflammatory drugs (NSAID) could not be formally confirmed because of the retrospec- tive nature of the study. The impact of the decrease in hemoglobin levels on the occurrence of AKI compared to baseline values has also been observed in children during acute chest syndrome,65 and may reflect a direct toxic effect of free heme or hemoglobin released during hemol- ysis on the kidney.
Renal dysfunction is more severe and frequent in patients with HbSS and HbS/b0-thalassemia, and is associ- ated with anemia.66 As in other diseases, nocturnal hyper- tension and hyperuricemia have been associated with lower eGFR.67 The predictive value of an APOL1 genetic profile has recently been suggested for onset of renal dis- ease in children with SCD.68
Screening and prevention
Screening for kidney disease should not be based on serum creatinine level in children with SCD because of increased eGFR, often lower muscle mass, and increased tubular secretion of creatinine.61 Albuminuria is a good predictor of risk for CKD and can be used for routine screening. The National Heart Lung and Blood Institute
recommends screening for albuminuria starting at ten years of age for all SCD patients.68 The gold standard for measuring GFR is inulin clearance but this is costly. Therefore, cystatin C and creatinine-based estimations of GFR (Schwartz equation using patient height and creati- nine value) may be more relevant for annual screening.60 In children, it must be remembered that a normal GFR is an alarm signal as it should, in fact, be elevated in the context of initial hyperfiltration.
Hydroxyurea may be considered in patients with elevat- ed microalbuminuria but the results of existing studies are controversial. Hydroxyurea was not superior to placebo in the prevention of hyperfiltration in the BABY-HUG trial, although it was associated with a better concentrating ability and less renal enlargement.69,70 In pediatric series, hydroxyurea was associated with a trend for a decrease in the frequency of microalbuminuria71-73 and with a signifi- cant decrease in DTPA GFR in 23 children with a median age of 7.5 years.74
Very few studies have reported the use of angiotensin converting enzyme inhibitors (ACE I), combined or not with hydroxyurea, in SCD children with albuminuria.71,75 Albuminuria decreased in some children treated with ACE I but some patients experienced hyperkalemia, prompting interruption of ACE I therapy.
Cerebrovascular disease
Patients affected with SCD may suffer from ischemic and hemorrhagic stroke, silent cerebral infarction, and neurological decline. Cerebrovascular events account for approximately 12% of SCD-related mortality in the US.22 In children, these represent the third cause of death after infections and hematologic complications (acute splenic sequestration and other causes of acute anemia).76 Furthermore, cerebrovascular events are responsible for a high rate of motor and cognitive disabilities.77 The brain provides a good illustration of the “perfusion paradox” of SCD, combining hyperperfusion within the arteries of the circle of Willis and microvascular hypoperfusion. Hemolysis and I/R injuries generate inflammation, endothelial dysfunction, and intimal hyperplasia. The roles of hemodynamic changes and procoagulant status are still under investigation.18,77
Cerebral vasculopathy mostly affects HbSS and HbS/b0- thalassemia patients. Events may be overt or so-called 'silent', which is an inappropriate term since silent cerebral infarcts (SCI) were found to be associated with cognitive defects.78 Overt events are mostly ischemic, occurring with two peaks of frequency either before the age of ten or after 40 years of age, but may also be hemorrhagic with an increasing incidence associated with age. Risk factors include a lower steady-state Hb level, prior transient ischemic attack, recent or frequent acute chest syndromes, high systolic blood pressure,11 nocturnal hypoxemia,79 a past history of bacterial meningitis,11 and the presence of silent infarcts on MRI.80 The role of co-existent G6PD deficiency is controversial, as it was found to increase the risk of stroke in one,81 but not all, studies.82 Increased HbF level and pres- ence of α-thalassemia may have a protective effect.81 Hemorrhagic strokes may complicate moya-moya syn- dromes or may be related to ruptured aneurysm, the preva- lence of which is increased in SCD patients, most likely due to the effect of flow disturbances on the vascular wall.77
1538
haematologica | 2021; 106(6)