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

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Endothelial Function in Patients with Sickle Cell Anemia During and After Sickle Cell Crises

Background:Prior studies have demonstrated increased adherence of sickle cell erythrocytes to vascular endothelial cells. While decreased production of nitric oxide and increased production of adhesion molecules have been implicated in this pathophysiology, the relative contribution of these mechanisms during acute sickle cell crises as compared to steady state conditions have not been elucidated.Methods and results: We studied 10 consecutive young adult patients presenting with a sickle cell crisis. Endothelial function was evaluated by a non-invasive brachial artery shear stress method. Serum levels of adhesion molecules were obtained during the crisis. Both brachial artery responsiveness and serum levels of adhesion molecules were then repeated at steady state. Ten age and gender matched volunteers served as a control group. Impaired endothelial function and impaired endothelium-independent vasodilatation were observed in all sickle cell patients during both steady state and during crisis. Flow mediated dilation (FMD)% was 3.25 ± 2.76% during crisis, 4.57 ± 4.11 at steady state, compared with the control group FMD of 11.64 ± 7.69% (p < 0.001). Flow independent dilation was 10.35 ± 11.3% during crisis, 10.03 ± 6.52% at steady state, compared with control group FID of 24.17 ± 11.87% (p < 0.001). Levels of cell adhesion molecules and markers of inflammation were increased in sickle cell crisis patients compared with the control group: sCD40 ligand levels during the acute crisis were over twice the level of normal matched volunteers (p = 0.02), and similarly significant increases were seen for E-selectin (p = 0.008), ICAM-1 (p = 0.037) and VCAM-1 levels (p = 0.01). The levels of each of these biomarkers was not significantly increased during acute crises as compared to patients’ recovery state.Conclusions: Sickle cell anemia patients have severe systemic endothelial dysfunction as demonstrated by both brachial artery assessment and increased serum levels of adhesion molecules. These abnormalities characterize not only the sickle cell crisis but also the steady state pathophysiology of sickle cell anemia.     

Maternal and Perinatal Outcome of Women With Sickle Cell Disease of a Tribal Population in Central India

Pregnancy in sickle cell disease is associated with increased risk of maternal and fetal morbidity and mortality. Sickle cell disease is very common in tribal populations. The objective of this study was to review the maternal and perinatal outcome in patients with sickle cell disease of tribal populations. This is a retrospective study. The data extracted from the patients’ case files included age, gravidity, family history, complications during pregnancy or at time of delivery or postpartum period, mode of delivery, and fetal outcome. There were 25 deliveries to women with sickle cell disease and 54 with sickle cell trait. Preeclampsia and disseminated intravascular coagulation were common problems associated with sickle cell disease as compared to the sickle cell trait and normal groups. No maternal mortality occurred during the period under study. However, a total of five intrauterine fetal deaths and one early neonatal death did occur. The present study confirms the previous reports, the increased risk of fetal death in women with sickle cell disease, however, in contrast to previous studies, no maternal mortality was found.     

Prevalence and Characteristics of Priapism in Sickle Cell Disease

Priapism is a pathological condition of persistent penile erection in the absence of sexual arousal or desire. It is an urological emergency and its identification is important as lack of prompt treatment can result in erectile dysfunction. The aim of this study was to estimate and describe the characteristics (number of episodes, duration, time of occurrence and evolution) of priapism in patients with sickle cell disease. A bibliographical research was carried out in PubMed, searching for papers published in the last 5 years. Thirteen scientific articles were included in this review. The main results were: 1) the highest prevalence of priapism in males reported was 48.0% and the lowest 0.67%; 2) six studies were carried out on the African Continent (46.1%), three in America (23.1%), two in Europe (15.4%) and two in Asia (15.4%); 3) the main goal of ～50.0% of the studies was to determine the rate of priapism in patients with sickle cell disease; 4) there was predominance of sickle cell anemia patients [homozygous Hb S (HBB: c.20A>T) genotype]; 5) the minimum age of patients with priapism was 7 years old and the maximum 30 years. In general, the episodes of priapism occurred during sleep, were recurrent and had variable duration. The prevalence of priapism are not real and the explanations include underreporting by patients, lack of awareness by physicians and lack of proper prospective studies. Priapism is a complication that deserves close attention due to its significant impact on the life of the patient with sickle cell disease and, therefore, should be further clarified.     

Acute Splenic Sequestration Crisis in Adult Sickle Cell Disease: A Report of 16 Cases

Abstract

Acute splenic sequestration crisis (ASSC), characterized by rapidly progressive anemia and circulatory compromise in the setting of sudden splenic enlargement, is an uncommon entity among adult sickle cell patients. We reviewed cases of adult ASSC encountered at our institution to generate insight into the recognition, diagnosis, and treatment of the condition. Cases of adult ASSC during a 10-year period were identified retrospectively. Patient charts were reviewed for laboratory and imaging results; demographic data and clinical course were collected and reviewed. Sixteen cases of adult ASSC were identified. Most patients presented with pain crisis; only four of 16 patients presented with abdominal pain. The maximum decreases in hemoglobin (Hb) (42.0%) and platelets (62.1%) occurred at day 2.9, delaying identification and treatment. Hemodynamic instability played a large role in dictating risk stratification. Therapy consisted of transfusion (14/16) and splenectomy (5/16). No recurrences were noted in a mean follow-up time of 5.3 years but review of patients’ charts demonstrated that at least one of the patients had two prior episodes. Adult ASSC may present with non specific findings and patients may not deteriorate until several days into a previously uneventful hospital course. Changes in platelet counts may be more reliable markers than changes in Hb level since red cell transfusions may interfere with assessments of the sequestration process. This case series of adult ASSC, the largest reported in the literature to date, highlights common clinical, laboratory, radiological, and pathological features of this uncommon entity and helps to guide recognition, diagnosis, and treatment.     

Aging in Sickle Cell Disease: Co-morbidities and New Issues in Management

Abstract

Availability of hydroxyurea (HU) coupled with early therapeutic interventions has increased the life expectancy of patients with sickle cell disease. Hence, the sickle cell community needs to be aware of common diseases of aging that survivors are predisposed to. We chose to investigate the sickle cell disease-related complications as well as non sickle cell disease-related medical problems of aging in 45 sickle cell patients over the age of 40 years. The most frequent chronic complications of sickle cell disease were elevated tricuspid regurgitant jet velocity on echocardiogram, chronic renal disease, iron overload and leg ulcers. Medical co-morbidities in this patient group included hypertension, diabetes mellitus (DM), hypercholesterolemia and symptomatic coronary artery disease (CAD). In our cohort, only 38.0% had a primary care doctor. Only 11.0% over age 50 had a screening colonoscopy, and of the women, 42.0% had a screening mammography. Medical co-morbidities and lack of health maintenance in older sickle cell patients are likely to impact overall health and mortality. Aging patients with sickle cell disease may benefit from a primary medical home for age appropriate comprehensive health care.     

The Assessment and Sustainable Management of Sickle Cell Disease in the Indigenous Tharu Population of Nepal

Sickle cell disease is an inherited hemoglobinopathy associated with significant morbidity and mortality. Reports suggest a high sickle cell disease burden among the indigenous Tharu population of Nepal, who for centuries have inhabited regions where malaria is endemic. Unfortunately, health care resources are limited and often inaccessible for Tharu individuals suffering from sickle cell disease. We conducted a large-scale screening effort to estimate the prevalence of Hb S (HBB: c.20A>T) among the Tharu population and delivered community-based education sessions to increase sickle cell disease awareness. A total of 2899 Tharu individuals aged 6 months to 40 years in the rural district of Dang in Western Nepal were screened using a sickling test, of whom, 271 [9.3%; 95% confidence interval (95% CI): 8.3–10.4%] screened positive for Hb S. Those who screened positive were offered diagnostic gel electrophoresis testing. Of the 133 individuals who underwent diagnostic testing, 75.9% (n?=?101) were confirmed to be Hb AS heterozygotes, 4.5% (n?=?6) were confirmed to be Hb SS homozygotes and 19.5% (n?=?26) were false positives. These findings support a large burden of sickle cell disease among the Tharu population and highlight the importance of appropriate resource allocation and management. With a positive predictive value of 80.0% (95% CI: 73.0-87.0%), the sickling test in conjunction with raising local sickle cell disease awareness may be a simple and sustainable way to promote access to health resources.     

Is the Medical Home for Adult Patients with Sickle Cell Disease a Reality or an Illusion?

Abstract

Recently, the patient-centered medical home (PCMH) emerged as a viable method to improve delivery of medical care. Due to all the promotion about the effectiveness of the PCMH, patients with sickle cell disease, their families and the community hoped that this could be a possible solution to the problems that arise in the treatment of adult patients with sickle cell disease. Review of the literature and review of the criteria for the establishment of a PCMH show that the PCMH is not an ideal model for patients with sickle cell disease because finding a personal physician, which is the first criteria of a functional PCMH, is a major problem in the process of transitioning the care of patients with sickle cell disease from pediatrics to adult care. Moreover, garnering hospital support to defray the initial costs to establish a PCMH for adults with sickle cell disease is unlikely given the already high costs of care for patients with sickle cell disease. Moreover, recent studies have shown insufficient evidence to determine the presumed beneficial effects of the PCMH, especially in patients with chronic disease.     

Erythropoietin Levels in Patients with Sickle Cell Disease Do Not Correlate with Known Inducers of Erythropoietin

Previous studies have suggested that erythropoietin (Epo) levels may be inappropriately low in patients with sickle cell disease compared to the extent of the related anemia they demonstrate. Here, we evaluate Epo level vs. renal function, oxygenation, and markers of inflammation for patients treated for sickle cell disease at our institution. Blood was drawn from 54 patients with sickle cell disease during routine visits to the outpatient hematology office and analyzed for hemoglobin (Hb) level, Epo, markers of inflammation, oxygenation, and renal function. Erythropoietin levels were lower than expected for patients with sickle cell disease, compared to the degree of anemia demonstrated in these patients. In addition, a correlation between Hb level and Epo was not consistently observed. Higher Epo levels were seen in patients receiving hydroxyurea (HU), but no correlation with oxygenation, hemolysis, renal function, or inflammation was observed.     

Patients Welcome the Sickle Cell Disease Mobile Application to Record Symptoms via Technology (SMART)

The widespread use of mobile phones among patients provides a unique opportunity for the development of mobile health intervention designed specifically for sickle cell disease, which will improve self-management as well as health care delivery. Our objective was to determine the receptiveness of patients with sickle cell disease to technology and a mobile application (app) designed for sickle cell disease. Phase I included 100 patients who completed a survey inquiring about receptiveness to technology and use of mobile devices to self-manage and communicate with providers. Phase II surveyed 17 additional patients who tested a newly developed sickle cell disease app, to report its usability and utility. In Phase I, on a 0–10 Likert scale where 0 is not comfortable, and 10 is extremely comfortable, 87.0% of participants reported >5 comfort level using a mobile device for health care management. Participants were comfortable with texting (81.0%) and emailing (77.0%) but not with social media (40.0%). Most participants (84.0%) owned computer devices (desktops, laptops, tablets, or iPads), and 92.0% owned mobile devices. In Phase II, participants reported that the app tested was useful to track pain (88.0%), and 94.0% reported that it was easy to use, practical, and useful for health self-management. All reported that the app was useful to help one communicate with providers. Following the use of our app, patients found it an extremely valuable tool for tracking pain, health management, and communicating with providers. We conclude that mobile technology might provide an appropriate venue for sickle cell disease healthcare management.     

Insulin Secretion and Resistance in Normoglycemic Patients with Sickle Cell Disease

Diabetes mellitus has been described in chronic hemolytic anemias, but data are scarce regarding glucose metabolism in normoglycemic patients. To address this issue, we evaluated insulin sensitivity and secretion in patients with sickle cell disease (SCD) and normal oral glucose tolerance test (OGTT). Forty-five adult patients with homozygous sickle cell disease and Hb S/β-thalassemia (β-thal) (mean age 42.5?±?9.5?years) and 45 healthy individuals matched for age and body mass index (BMI) were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast. All patients had normal OGTT. Fasting glucose values did not differ significantly between groups, however, fasting insulin levels were significantly lower in the patient group compared to the control group (5.1?±?2.7 μUI/mL vs. 11.3?±?6.6 μUI/mL, p?<0.005, respectively). Pancreatic β-cell insulin secretion index in the fasting state was significantly lower in patients with sickle cell disease compared with controls as assessed by calculations of the homeostatic model assessment for β-cell function (HOMA β%) (77.0 vs. 106.0%, respectively, p?<0.001), while HOMA insulin resistance (HOMA IR), was lower in the sickle cell disease patients, albeit not statistically significant (0.8 vs. 1.1, respectively, p?=?0.054). The HOMA β% was significantly correlated with ferritin levels (r?=?–526, p?<0.001) (negative correlation) and with 25-hydroxy (OH)-vitamin D levels (r?=?0.479, p?<0.001) (positive correlation), even when adjusted for serum ferritin levels. Normoglycemic patients with sickle cell disease demonstrated impaired β-cell function with reduced insulin secretion even before OGTT was impaired.     

High Prevalence of Pulmonary Hypertension in Homozygous Sickle Cell Patients with Leg Ulceration

Pulmonary hypertension is a common complication and is a risk factor for death in adult patients with sickle cell disease. Chronic leg ulceration is a major cause of morbidity in homozygous sickle cell disease. We aimed to determine prevalence of pulmonary hypertension in homozygous sickle cell patients and if there is any relation of pulmonary hypertension with leg ulceration.

A total of 88 patients, asymptomatic for pulmonary hypertension, were enrolled in the study. Doppler echocardiography was performed on homozygous sickle cell patients with and without leg ulceration. 12 patients (10 male, 2 female) had active ulcer or healed scar (group I) and 76 patients (40 male, 36 female) had no active leg ulcer or history of (group II). The prevalence of pulmonary hypertension in group I and group II were 91.6% (n = 11) and 31.6% (n = 24), respectively (p = 0.0001). Patients with leg ulceration had increased left atrium and right ventricular diameters at diastole and also had increased left ventricular end-diastolic and end-systolic diameters.

We determined an increased prevalence of pulmonary hypertension in patients with leg ulceration. Patients with homozygous sickle cell disease, especially those with leg ulcers should be screened for pulmonary hypertension, since pulmonary hypertension is a frequent and generally asymptomatic complication and a risk factor of mortality.     

Erythrocyte cAMP in Determining Frequency of Acute Pain Episodes in Sickle Cell Disease Patients from Odisha State,India

Vaso-occlusive crisis (VOC) occurs more frequently during stress in sickle cell disease patients. Epinephrine released during stress increases adhesion of sickled red blood cells (RBCs) to endothelium and to leukocytes, a process mediated through erythrocyte cyclic adenosine monophosphate (cAMP). Increased adhesion of sickled RBCs retards blood flow through the capillaries and promotes vaso-occlusion. Therefore, we examined the association of RBC-cAMP levels with frequency of acute pain episodes in sickle cell disease subjects. Using a case control study design, we measured RBC-cAMP levels, fetal hemoglobin (Hb F), α-thalassemia (α-thal) and other hematological parameters at baseline (sham treated) and after stimulation with epinephrine. The cases consisted of sickle cell disease subjects with three or more acute pain episodes in the last 12 months, and those without a single acute pain episode in the last 12 months were considered as controls. Significantly higher cAMP values were found in cases than the controls, in both sham treated (p?<?0.001) and epinephrine treated RBCs (p?<?0.001) by Wilcoxon Rank Sum test. However, significant association of cAMP values was observed both on univariate [odds ratio (OR): 4.8, 95% confidence interval (95% CI): 1.51-15.19, p?<?0.008) and multivariate logistic regression analyses only in epinephrine treated (OR: 5.07, 95% CI: 1.53-16.82, p?<?0.008) but not in sham-treated RBCs. In the covariates, Hb F consistently showed protective effects in univariate as well as in multivariate analyses. Frequent acute pain episodes are associated with higher cAMP levels than those with less frequent pain episodes, only after stimulation with epinephrine but not with baseline level.     

Phenotypic Diversity of Sickle Cell Disease in Patients with a Double Heterozygosity for Hb S and Hb D-Punjab

Phenotypic heterogeneity for sickle cell disease is associated to several genetic factors such as genotype for sickle cell disease, β-globin gene cluster haplotypes and Hb F levels. The coinheritance of Hb S (HBB: c.20A?>?T) and Hb D-Punjab (HBB: c.364G?>?C) results in a double heterozygosity, which constitutes one of the genotypic causes of sickle cell disease. This study aimed to assess the phenotypic diversity of sickle cell disease presented by carriers of the Hb S/Hb D-Punjab genotype and the Bantu [–?+?– – – –] haplotype. We evaluated medical records from 12 patients with sickle cell disease whose Hb S/Hb D-Punjab genotype and Bantu haplotype were confirmed by molecular analysis. Hb S and Hb D-Punjab levels were quantified by chromatographic analysis. Mean concentrations of Hb S and Hb D-Punjab were 44.8?±?2.3% and 43.3?±?1.8%, respectively. Painful crises were present in eight (66.7%) patients evaluated, representing the most common clinical event. Acute chest syndrome (ACS) was the second most prevalent manifestation, occurring in two individuals (16.7%). Three patients were asymptomatic, while another two exhibited greater diversity of severe clinical manifestations. Medical records here analyzed reported a significant clinical diversity in sickle cell disease ranging from the absence of symptoms to wide phenotypic variety. The sickle cell disease genotype, Bantu haplotype and hemoglobin (Hb) levels did not influence the clinical diversity. Thus, we concluded that the phenotypic variation in sickle cell disease was present within a specific genotype for disease regardless of the β-globin gene cluster haplotypes.     

Amputations in Sickle Cell Disease: Case Series and Literature Review

In this study, we describe four new patients with sickle cell disease who had limb amputations. Two of the patients had sickle cell anemia [Hb S (HBB: c.20A?>?T) (β^S/β^S)] with refractory leg ulcers that required amputations. The third patient had sickle cell trait with an extensive leg ulcer that was associated with epidermoid carcinoma. The fourth patient had amputations of both forearms and feet due to a misdiagnosis of dactylitis. Review of the literature showed that the indications for amputations in sickle cell disease included three distinct categories: mythical beliefs, therapeutic and malpractice. All therapeutic amputations were for severely painful, large, recalcitrant leg ulcers that failed non-interventional therapies. Amputation resulted in pain relief and better quality of life. Phantom neuropathic pain was not a major issue post-operatively. It was absent, transient or well controlled with antidepressants. Limb function was restored post-amputation with prosthetic artificial limbs, wheelchairs or crutches. Malpractice amputations were due to misdiagnosis or to cryotherapy by exposing the painful limb to ice water resulting in thrombosis, gangrene and amputation. We strongly suggest that leg amputations should be considered in the management of certain patients with severe extensive refractory leg ulcers, and topical cryotherapy should never be used to manage sickle cell pain.     

Pulmonary Complications of Sickle Cell Disease

The pulmonary complications of sickle cell disease are a major cause of morbidity and mortality in affected patients. The acute chest syndrome (ACS) is a leading cause of death in patients with sickle cell disease and has a multifactorial etiology. Hydroxyurea (HU), stem cell transplantation (SCT) and chronic transfusions are known to prevent the recurrence of ACS. Careful management of patients admitted for pain crises and surgery including use of incentive spirometry is critical in preventing this complication. Pulmonary hypertension is well known to be associated with sickle cell disease and patients with pulmonary hypertension have increased mortality. Asthma is also commonly seen in patients with sickle cell disease and is associated with a more complicated course. Chronic lung disease develops in a significant proportion of patients with sickle cell disease.     

Comparison of Emergency Department Wait Times in Adults with Sickle Cell Disease Versus Other Painful Etiologies

Sickle cell disease is characterized by intermittent painful crises often requiring treatment in the emergency department (ED). Past examinations of time-to-provider (TTP) in the ED for patients with sickle cell disease demonstrated that these patients may have longer TTP than other patients. Here, we examine TTP for patients presenting for emergency care at a single institution, comparing patients with sickle cell disease to both the general population and to those with other painful conditions, with examination of both institutional and patient factors that might affect wait times. Our data demonstrated that at our institution patients with sickle cell disease have a slightly longer average TTP compared to the general ED population (+16?min.) and to patients with other painful conditions (+4?min.) However, when confounding factors were considered, there was no longer a significant difference between TTP of patients with sickle cell disease and the general population nor between patients with sickle cell disease and those with other painful conditions. Multivariate analyses demonstrated that gender, race, age, high utilizer status, fast track use, time of presentation, acuity and insurance type, were all independently associated with TTP, with acuity, time of presentation and use of fast track having the greatest influence. We concluded that the longer TTP observed in patients with sickle cell disease can at least partially be explained by institutional factors such as the use of fast track protocols. Further work to reduce TTP for sickle cell disease and other patients is needed to optimize care.     

Kidney Disease among Patients with Sickle Cell Disease,Hemoglobin SS and SC

Background and objectives

Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC.

Design, setting, participants, & measurements

Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007–2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299).

Results

In adults with SCD, eGFR was lower among older individuals: −1.78 ml/min per 1.73 m² per year of age (95% confidence interval [95% CI], −2.06 to −1.50; Walk-PHaSST Trial), −1.75 ml/min per 1.73 m² per year of age (95% CI, −2.05 to −1.44; MSH), and −1.69 ml/min per 1.73 m² per year of age (95% CI, −2.00 to −1.38; CSSCD) in HbSS compared with −1.09 ml/min per 1.73 m² per year of age (95% CI, −1.39 to −0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function.

Conclusions

In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.