Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease.

Glomerular hyperfiltration is common in sickle cell disease (SCD) and precedes proteinuria and declining kidney function. We evaluated hyperfiltration in SCD patients and its "normalization." Routine visit data were collected retrospectively from adult SCD patients in a single centre from 2004 to 2013. Baseline was defined as first available serum creatinine and hyperfiltration as estimated glomerular filtration rates (eGFR) >130 ml/min/1·73 m2 for women and >140 ml/min/1·73 m2 for men. Normalization of hyperfiltration was eGFR reduction to 90-130 ml/min/1·73 m2 for women or 90-140 ml/min/1·73 m2 for men. Among 292 patients, median age was 27 years [interquartile range (IQR):20·0-38·0], and 56·8% had baseline hyperfiltration. Baseline hyperfiltration was inversely associated with age [odds ratio (OR):0·86, 95% confidence interval (CI): 0·82-0·90; P < 0·0001], male sex (OR:0·16, 95% CI: 0·07-0·41; P = 0·0001), haemoglobin (OR:0·76, 95% CI 0·61-0·94; P = 0·01), weight (OR:0·96, 95% CI: 0·93-0·99; P = 0·004), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) use (OR:0·08, 95% CI: 0·01-0·75; P = 0·03), and positively with hydroxycarbamide use (OR:2·99, 95% CI: 1·18-7·56; P = 0·02). Of 89 hyperfiltration patients without baseline proteinuria, 10 (11·2%) developed new-onset proteinuria [median 1·05 years (IQR:0·63-2·09)]. Normalization of hyperfiltration was less likely with higher baseline eGFR [hazard ratio (HR):0·90, 95% CI: 0·86-0·95; P < 0·0001] and more likely in males (HR:6·35, 95% CI:2·71-14·86, <0·0001). Hyperfiltration is common in adult SCD patients, particularly when younger. Decline to normal values is more likely in males, possibly representing kidney function loss rather than improvement in hyperfiltration.

Acute Kidney Injury among Black Patients with Sickle Cell Trait and Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: Sickle 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, & MEASUREMENTS: This 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. RESULTS: We 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. CONCLUSIONS: Sickle cell trait and disease are associated with higher risk of AKI, which is associated with accelerated decline in eGFR.

Kidney Function Decline among Black Patients with Sickle Cell Trait and Sickle Cell Disease: An Observational Cohort Study.

BACKGROUND: Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. METHODS: Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. RESULTS: We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. CONCLUSIONS: Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.

Altered blood rheology and impaired pressure-induced cutaneous vasodilation in a mouse model of combined type 2 diabetes and sickle cell trait.

OBJECTIVE: Type 2 diabetes (T2D)-related vascular dysfunction and hemorheological abnormalities could possibly be amplified by sickle cell trait (SCT). These alterations could potentially increase the risk of vascular complications in individuals with combined T2D and SCT. Therefore, this study used a mouse model to determine whether vascular function and blood rheology were more severely altered in combined T2D and SCT than in T2D or SCT alone. METHODS: Townes transgenic mice with or without SCT received a 12-week high fat high sucrose or standard diet to create models of combined T2D-SCT, T2D, SCT, and controls. Pressure-induced vasodilation (PIV) and sodium nitroprusside (SNP)-mediated vasodilation in-vivo, and hemorheological parameters were measured. RESULTS: No significant differences in blood viscosity, hematocrit, erythrocyte deformability, or PIV were observed between the control and T2D mice, or the control and SCT mice. However, blood viscosity, erythrocyte deformability, and PIV were significantly altered in the T2D-SCT mice compared to the control mice. There were no differences in SNP response between the groups. CONCLUSIONS: Although neither T2D nor SCT alone had significant effects on blood rheology parameters or vascular function, combined T2D-SCT mice had significantly altered blood rheology and significantly impaired vascular function.

Increasing Wellness Through Physical Activity in Children With Chronic Disease and Disability.

Children with chronic medical conditions face many challenges when considering sport participation. Compared with their healthy counterparts, they are often discouraged from physical activity or sports participation because of real or perceived limitations imposed by their condition. Prescribed exercise should be based on the demands of the sport, the effect of the disease on performance, and the potential for exercise-induced acute or chronic worsening of the illness or disability. This article will focus on several examples of chronic medical conditions and the clinician's role in providing advice about sport participation.

Balancing exercise risk and benefits: lessons learned from sickle cell trait and sickle cell anemia.

Development of exercise guidelines for individuals with sickle cell trait (SCT) and sickle cell anemia (SCA) is hampered by the need to weigh the benefits against risks of exercise in these populations. In SCT, concern for exercise collapse associated with sickle cell trait has resulted in controversial screening of student athletes for SCT. In SCA, there exists unsubstantiated concerns that high-intensity exercise may result in pain and other complications. In both, finding the "right dose" of exercise remains a challenge for patients and their providers. Despite assumptions that factors predisposing to adverse events from high-intensity exercise overlap in SCT and SCA, the issues that frame our understanding of exercise-related harms in both are distinct. This review will compare issues that affect the risk-benefit balance of exercise in SCT and SCA through these key questions: (1) What is the evidence that high-intensity exercise is associated with harm? (2) What are the pathophysiologic mechanisms that could predispose to harm? (3) What are the preventive strategies that may reduce risk? and (4) Why do we need to consider the benefits of exercise in this debate? Addressing these knowledge gaps is essential for developing an evidence-based exercise prescription for these patient populations.

Association of Sickle Cell Trait and Hemoglobin S Percentage with Physical Fitness.

PURPOSE: This study aimed to determine the association between sickle cell trait (SCT) as a binary variable and hemoglobin S percentage as a stratified categorical variable with aerobic and anaerobic fitness. METHODS: This retrospective cohort study included all recruits who entered US Air Force Basic Training between January 2009 and December 2014. Fitness parameters among recruits with and without SCT were compared using a standardized fitness assessment of a 1.5-mile timed run, 1 min of push-ups, and 1 min of sit-ups. Performance was further compared by stratifying those with SCT by their hemoglobin S percentage (20%-29.99%, 30%-39.99%, and ≥40%). RESULTS: Of all recruits (N = 210,461) who entered training during the surveillance period, 2161 (1.0%) had SCT. After adjusting for age, sex, race, body mass index, and ambient temperature while conducting the fitness assessment, recruits with SCT were slower on their initial run than their peers without SCT by a mean (standard error) of 9.4 s (2.6 s) (P < 0.001) and completed 0.5 (0.3) fewer push-ups (P < 0.05); sit-up completion was statistically equivalent between the two groups. When retested 6 wk later, recruits with SCT improved their run time by a margin of 4.3 s (2.1 s) over their counterparts without SCT (P < 0.05). Baseline physical fitness was largely consistent across strata of hemoglobin S percentages; increased percentages were modestly correlated with faster run times (R = 0.374) and fewer push-ups (R = 0.339). CONCLUSIONS: As compared with their peers, recruits with SCT had slightly inferior aerobic fitness and similar anaerobic fitness at the outset of basic training, and gaps further narrowed over 6 wk of training. Stratifying recruits by their hemoglobin S percentage did not dramatically change the strength or direction of association.

Cistatina C: marcador de laboratorio precoz de enfermedad renal en pacientes con depranocitosis / Cystatin C: early laboratory marker of renal disease In sickle cell disease

La enfermedad renal en el paciente con drepanocitosis es una consecuencia de su complejo proceso fisiopatológico, por lo que es importante disponer de un grupo de parámetros de laboratorio que, junto a la evaluación clínica, permita determinar de forma precoz la presencia de esta complicación. La cistatina C ha demostrado ser uno de los parámetros que con mayor exactitud aporta evidencia temprana de daño renal en este grupo de pacientes y al mismo tiempo constituye un posible indicador de pronóstico de gran importancia(AU)

Renal disease in patients with sickle cell disease is a consequence of its complex pathophysiological process, so it is important to have a set of laboratory parameters that, together with the clinical evaluation, allow the early detection of this complication. Cystatin C has been shown to be one of the parameters that provides, with greater accuracy, early evidence of kidney damage in this group of patients and at the same time constitutes a possible indicator of prognosis of great importance(AU)

Cistatina C: marcador de laboratorio precoz de enfermedad renal en pacientes con depranocitosis / Cystatin C: early laboratory marker of renal disease In sickle cell disease

La enfermedad renal en el paciente con drepanocitosis es una consecuencia de su complejo proceso fisiopatológico, por lo que es importante disponer de un grupo de parámetros de laboratorio que, junto a la evaluación clínica, permita determinar de forma precoz la presencia de esta complicación. La cistatina C ha demostrado ser uno de los parámetros que con mayor exactitud aporta evidencia temprana de daño renal en este grupo de pacientes y al mismo tiempo constituye un posible indicador de pronóstico de gran importancia(AU)

Renal disease in patients with sickle cell disease is a consequence of its complex pathophysiological process, so it is important to have a set of laboratory parameters that, together with the clinical evaluation, allow the early detection of this complication. Cystatin C has been shown to be one of the parameters that provides, with greater accuracy, early evidence of kidney damage in this group of patients and at the same time constitutes a possible indicator of prognosis of great importance(AU)

Age is a predictor of a small decrease in lung function in children with sickle cell anemia.

The longitudinal pattern of lung function in children with sickle cell anemia (SCA) has shown a decrease in FEV1 % predicted, a risk factor for death in adults with SCA, but predictors for this decline are poorly characterized. In a prospective longitudinal multi-center cohort of children with SCA, we tested the hypotheses that: (1) FEV1 % predicted declines over time; and (2) SCA-specific characteristics and therapy predict this decline. At three clinical centers, children with SCA (HbSS or HbSß0 thalassemia), unselected for respiratory disease, were enrolled in the Sleep and Asthma Cohort (SAC) study. Study-certified pulmonary function technicians performed spirometry and lung volumes. Each assessment was reviewed centrally. Predicted values were determined for TLC, FEV1 , FVC, and FEV1 /FVC ratio. A total of 197 participants, mean age 11.0 years at first testing (range 4-19.3 years), had a minimum of three spirometry measurements, over an average of 4.4 years (range 1.1-6.5 years) from baseline to endpoint. In a multivariable model, FEV1 % predicted declines by 0.3% for every additional year of age (95% CI -0.56 to -0.05, P = .020). Sex, asthma history, hemoglobin, reticulocyte count, white blood cell count, incidence rate of severe acute pain and acute chest syndrome episodes, and hydroxyurea therapy were not associated with a decline in FEV1 % predicted. In a large, rigorously evaluated, prospective cohort of an unselected group of children with SCA, FEV1 % predicted declines minimally over an average of 4 years, and none of the examined disease features predict the decline.

Blood Pressure and Arterial Stiffness in Kenyan Adolescents With the Sickle Cell Trait.

The potential association between sickle cell trait (SCT) and increased arterial stiffness/blood pressure (BP) has not been evaluated in detail despite its association with stroke, sudden death, and renal disease. We performed 24-hour ambulatory BP monitoring and arterial stiffness measurements in adolescents raised in a malaria-free environment in Kenya. Between December 2015 and June 2016, 938 randomly selected adolescents (ages 11-17 years) who had been continuous residents of Nairobi from birth were invited to participate in the study. Standard clinic BP measurement was performed, followed by 24-hour ambulatory BP monitoring and arterial stiffness measurement using an Arteriograph24 (TensioMed Ltd., Budapest, Hungary) device. SCT status was determined using DNA genotyping in contemporaneously collected blood samples. Of the 938 adolescents invited to participate, 609 (65%) provided complete data for analysis. SCT was present in 103 (15%). Mean 24-hour systolic and diastolic BPs were 116 (standard deviation (SD), 11.5) mm Hg and 64 (SD, 7) mm Hg, respectively, in children with SCT and 117 (SD, 11.4) mm Hg and 64 (SD, 6.8) mm Hg, respectively, in non-SCT children. Mean pulse wave velocity (PWV) was 7.1 (SD, 0.8) m/second and 7.0 (SD, 0.8) m/second in SCT and non-SCT children, respectively. We observed no differences in PWV or in any clinic or ambulatory BP-derived measures between adolescents with and without SCT. These data suggest that SCT does not independently influence BP or PWV.

Characterization of a mouse model of sickle cell trait: parallels to human trait and a novel finding of cutaneous sensitization.

Sickle cell trait (SCT) has classically been categorized as a benign condition except in rare cases or upon exposure to severe physical conditions. However, several lines of evidence indicate that individuals with SCT are not always asymptomatic, and additional physiological changes and risks may remain unexplored. Here, we utilized mice harbouring one copy of normal human ß globin and one copy of sickle human ß globin as a model of SCT to assess haematological, histopathological and somatosensory outcomes. We observed that SCT mice displayed renal and hepatic vascular congestion after exposure to hypoxia. Further, we observed that SCT mice displayed increased cold aversion as well as mechanical and heat sensitivity, though to a lesser degree than homozygous sickle cell disease mice. Notably, mechanical hypersensitivity increased following hypoxia and reoxygenation. Overall our findings suggest that SCT is not entirely benign, and further assessment of pain and cutaneous sensitization is warranted both in animal models and in clinical populations.