HMOX1 and acute kidney injury in sickle cell anemia.
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ABSTRACT:
SUBMITTER: Saraf SL
PROVIDER: S-EPMC6182266 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Publications
<i>HMOX1</i> and acute kidney injury in sickle cell anemia.
Saraf Santosh L SL Viner Maya M Rischall Ariel A Raslan Rasha R Shah Binal N BN Zhang Xu X Han Jin J Gowhari Michel M Jain Shivi S Molokie Robert E RE Machado Roberto F RF Lash James P JP Gordeuk Victor R VR
Blood 20180823 15
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Project description:Background and objectivesSickle cell trait and sickle cell disease are associated with faster GFR decline compared with normal hemoglobin phenotypes. We sought to compare the AKI risk in sickle cell trait/disease to normal hemoglobin phenotypes and investigate the association between AKI and GFR decline in sickle cell trait/disease.Design, setting, participants, & measurementsThis multicenter observational study used registry data (January 2005-June 2018) of adult Black patients with sickle cell trait/disease (exposures) and normal hemoglobin phenotype (reference) ascertained by hemoglobin electrophoresis. Outcomes of interest (incident AKI [1.5 times baseline serum creatinine or higher], incident severe AKI [doubling of baseline serum creatinine or higher], and incident sustained AKI [AKI persisting for ≥72 hours]) were adjudicated by chart review and evaluated by Cox regression. The association between AKI and GFR decline (linear mixed models) was also investigated.ResultsWe identified 8968 reference patients, 1279 patients with sickle cell trait, and 254 patients with sickle cell disease with a median follow-up of 7.6 years and mean baseline serum creatinine of 0.8 mg/dl. We observed 796 AKI events, 452 sustained AKI events, and 466 severe AKI events. Compared with people with a normal hemoglobin phenotype, sickle cell trait was associated with higher risk for sustained AKI (adjusted hazard ratio, 1.64; 95% confidence interval, 1.27 to 2.11), but not AKI (adjusted hazard ratio, 1.11; 95% confidence interval, 0.91 to 1.36) or severe AKI (adjusted hazard ratio, 1.26; 95% confidence interval, 0.96 to 1.64). Sickle cell disease was associated with AKI (adjusted hazard ratio, 2.85; 95% confidence interval, 2.13 to 3.81), severe AKI (adjusted hazard ratio, 2.38; 95% confidence interval, 1.65 to 3.42), and sustained AKI (adjusted hazard ratio, 2.50; 95% confidence interval, 1.68 to 3.71). Post-AKI GFR decline was significantly faster in sickle cell trait (0.37 ml/min per 1.73 m2 per year faster, P<0.01) and disease (1.69 ml/min per 1.73 m2 per year faster, P<0.01) compared with the reference.ConclusionsSickle cell trait and disease are associated with higher risk of AKI, which is associated with accelerated decline in eGFR.
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Project description:Acute kidney injury (AKI) is a major clinical concern in sickle cell disease (SCD). Clinical evidence suggests that red cell alarmins may cause AKI in SCD, however, the sterile inflammatory process involved has hitherto not been defined. We discovered that hemopexin deficiency in SCD is associated with a compensatory increase in α-1-microglobulin (A1M), resulting in an up to 10-fold higher A1M-to-hemopexin ratio in SCD compared with healthy controls. The A1M-to-hemopexin ratio is associated with markers of hemolysis and AKI in both humans and mice with SCD. Studies in mice showed that excess heme is directed to the kidneys in SCD in a process involving A1M causing AKI, whereas excess heme in controls is transported to the liver as expected. Using genetic and bone marrow chimeric tools, we confirmed that hemopexin deficiency promotes AKI in sickle mice under hemolytic stress. However, AKI was blocked when hemopexin deficiency in sickle mice was corrected with infusions of purified hemopexin prior to the induction of hemolytic stress. This study identifies acquired hemopexin deficiency as a risk factor of AKI in SCD and hemopexin replacement as a potential therapy.
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Project description:Though the patients with sickle cell anemia (SCA) inherit same genetic mutation, they show considerable phenotypic heterogeneity. It has been observed that patients with elevated fetal hemoglobin (HbF) levels have a relatively mild clinical course. There is sparse literature on the association of higher HbF levels leading to reduction in the oxidative stress in SCA patients. Hence in this study, the significance between the HMOX1 gene polymorphisms and the HbF levels has been studied. Preliminary screening was carried out. Genotyping of 3 variants in the HMOX1 gene was performed in 90 SCA patients and 50 healthy controls by PCR-RFLP, GeneScan and direct DNA sequencing. It was observed that SCA patients with higher HbF levels, showed improved hematological indices with an inverse effect on HbS levels. The TT genotype of rs2071746 (A→T) polymorphism was found to be associated with elevated HbF levels (P: 0.012). Also, the long form (> 25 GT repeats) of rs3074372 (GT)n repeats was found to be linked with increased HbF levels. We could not find any association of rs2071749 (A→G) polymorphism with the HbF levels. As, the sickle cell anemia patients show significant oxidative stress due to hemolysis, the study of polymorphisms in the HMOX1 gene may act as a potential independent marker for elevated HbF levels.
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Project description:Spleen dysfunction is central to morbidity and mortality in children with sickle cell anemia (SCA). The initiation and determinants of spleen injury, including acute splenic sequestration (ASS) have not been established. We investigated splenic function longitudinally in a cohort of 57 infants with SCA enrolled at 3 to 6 months of age and followed up to 24 months of age and explored the respective contribution of decreased red blood cell (RBC) deformability and increased RBC adhesion on splenic injury, including ASS. Spleen function was evaluated by sequential 99mTc heated RBC spleen scintigraphy and high-throughput quantification of RBCs with Howell-Jolly bodies (HJBs). At 6 and 18 months of age, spleen filtration function was decreased in 32% and 50% of infants, respectively, whereas the median %HJB-RBCs rose significantly (from 0.3% to 0.74%). An excellent correlation was established between %HJB-RBCs and spleen scintigraphy results. RBC adhesion to laminin and endothelial cells increased with time. Adhesion to endothelial cells negatively correlated with splenic function. Irreversibly sickled cells (ISCs), used as a surrogate marker of impaired deformability, were detected at enrollment and increased significantly at 18 months. %ISCs correlated positively with %HJB-RBCs and negatively with splenic uptake, indicating a relationship between their presence in the circulation and spleen dysfunction. In the subgroup of 8 infants who subsequently experienced ASS, %ISCs at enrollment were significantly higher compared with the asymptomatic group, suggesting a major role of impaired deformability in ASS. Higher levels of %HJB-RBCs were observed after the occurrence of ASS, demonstrating its negative impact on splenic function.
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Project description:Abstract Despite a high occurrence of acute kidney injury (AKI) with COVID‐19 infection, there are no data on its incidence in sickle cell disease (SCD). We performed a single‐center retrospective chart review of persons aged >1 year with SCD, COVID‐19 infection and no prior dialysis requirement hospitalized from June 1, 2020 to May 31, 2022. Demographics, clinical, laboratory characteristics and outcomes were abstracted. AKI was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of 38 patients meeting study criteria (60.6% female, mean age ± SD 38.6 ± 15.9 years), 3 (7.9%) were COVID vaccinated. Fifty‐five percent (55%) developed AKI with 7.9% (n = 3) requiring dialysis. Participants with AKI were older (44.9 versus 30.8 years, p = 0.005), with a higher proportion having baseline chronic kidney disease (52% versus 0%, p = 0.001). Severe COVID infection [age‐adjusted odds ratio (aOR): 8.93, 95%CI: 1.73‐45.99, p = 0.033], red cell transfusion (aOR 7.92, 1.47‐42.69) and decrease in hemoglobin per unit from baseline (aOR 2.85, 1.24‐2.28) were associated with AKI. Five persons died in hospital, with AKI resulting in higher median length of stay (12 versus 5 days, p = 0.007). Targeted COVID‐19 preventative measures and multinational longitudinal studies to ascertain the impact of AKI and COVID‐19 infection in SCD are needed.
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Project description:BackgroundIrregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.ObjectiveTo test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.DesignCross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.SettingClinical trial setting in tertiary care centers.PatientsAsymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.Main outcome measureIncidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).ResultsAcute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.ConclusionsChildren with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
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Project description:BackgroundPatients with sickle cell anemia (SCA) have an increased prevalence of nephropathy and mortality from chronic kidney disease (CKD).MethodsWe evaluated the association of hyperuricemia and nocturnal hypertension with lower estimated glomerular filtration rate (eGFR) using cystatin-C in patients aged 10-21 years with the HbSS or HbSB0 form of the disease during a non-acute clinic visit. eGFR and uric acid measurements were obtained in 83 and 81 participants, respectively, and 24-h ambulatory blood pressure monitoring (ABPM) was performed in 44 participants. Annual testing included vital signs, complete blood count, comprehensive metabolic panel, medications, urine microalbumin/creatinine, and lactate dehydrogenase measurements. Hyperuricemia was defined as a uric acid level of ≥5.5 mg/dL. Nocturnal hypertension was defined as >25% of nocturnal readings at >95th percentile according to norms established by the American Heart Association Statement on ABPM in children and adolescents.ResultsThe mean eGFR was statistically significantly lower in patients with hyperuricemia than in those with normal uric acid levels (143 vs. 161 mL/min/1.73 m2, respectively). Of the 44 participants for whom ABPM data were available, 14 (32%) had systolic nocturnal hypertension and 12 (27%) had diastolic nocturnal hypertension. The mean eGFR was statistically significantly lower in participants with nocturnal systolic and diastolic hypertension than in those with normal nocturnal blood pressure. In a regression model, nocturnal hypertension and hyperuricemia were associated with a lower eGFR.ConclusionsTwo risk factors for CKD, i.e., nocturnal hypertension and hyperuricemia, were associated with lower eGFR in older children and adolescent patients with SCA. Long-term studies on their association with progression to CKD in this population are warranted.Key pointNocturnal hypertension and hyperuricemia are established risk factors for nephropathy in other diseases and may play a role in SCA nephropathy.
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