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 m(2) per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m(2) per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m(2) per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m(2) 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.

Acidente vascular cerebral na hemoglobinopatia SC(HBB glu6val e glu6lys): avaliação de marcadores de prognóstico / hemoglobinopathy (HBB glu6val and glu6lys): evaluation of prognostic markers

O acidente vascular cerebral (AVC) é uma complicação clínica grave da doença falciforme (DF). Poucos estudos avaliaram a velocidade do fluxo sanguíneo cerebral utilizando o Doppler transcraniano (DTC) e marcadores preditores do AVC na hemoglobinopatia SC (HbSC) e, desta forma, as velocidades consideradas de risco para os indivíduos com esta hemoglobinopatia são baseadas em velocidades descritas para a anemia falciforme (AF) e para a Sβ talassemia (HbS/β). Assim, o objetivo do presente estudo foi identificar marcadores preditores do AVC em indivíduos com HbSC, estabelecendo subfenótipos da doença pela associação de biomarcadores genéticos, hematológicos, bioquímicos e imunológicos com o valor da velocidade do fluxo sanguíneo cerebral. Para tanto, foi realizado um estudo transversal, onde foram investigados 68 indivíduos com HbSC. A velocidade média máxima do fluxo sanguíneo cerebral nas artérias cerebral média, carótida anterior e cerebral anterior foi determinada utilizando o DTC...

Stroke is a serious clinical complication of sickle cell disease (SCD). Only few studies have evaluated the rate of cerebral blood flow by transcranial Doppler (TCD) and stroke predictor markers on hemoglobinopathy SC (HbSC), thus, velocity considered as risk for stroke that is used to diagnose HbSC individuals are based on velocities described for the sickle cell anemia (SCA) and Sβ thalassemia. The objective of this study was to identify predictors markers of stroke in individuals with HbSC, establishing subphenotypes disease by the association of genetic biomarkers, hematological, biochemical and immunological with the value of the velocity of cerebral blood flow. For that, we conducted a cross-sectional study, which were investigated 68 HbSC individuals. The average maximum rate of cerebral blood flow in the middle cerebral artery, anterior cerebral artery and anterior carotid artery was determined using the DTC...

Cohort study of adult patients with haemoglobin SC disease: clinical characteristics and predictors of mortality.

Haemoglobin (Hb) SC disease is the second most common subtype of sickle cell disease and is potentially fatal. This study aimed to determine the clinical characteristics, outcome and predictors of mortality in HbSC disease patients, and to compare these findings with patients followed-up in different centres. Clinical, laboratory and outcome data were collected from a cohort of adult patients with HbSC disease followed between 1991 and 2103. Cox regression multivariate analysis was used to determine predictors of mortality. One hundred and fifty-five patients were followed-up over 20 years: 9% died and 70·8% had at least one complication. The most common complications were: painful crises (38·3%), retinopathy (33·8%), cholelithiasis (30·3%), osteonecrosis (24·8%) and sensorineural hearing disorders (9·7%). Frequency of chronic complications was similar in most studies. In multivariate analysis, hearing disorders remained an independent predictor of mortality (Odds Ratio 9·26, 95% confidence interval 1·1-74·8; P = 0·03). It was concluded that patients with HbSC disease receive a late diagnosis and there is remarkable similarity between the studies conducted in different centres around the world. Sensorineural hearing disorders were an independent predictor of mortality, suggesting that it may be useful to implement routine diagnostic screening.

Mortality rate in Sickle Cell Disease Patients in Crisis at a Haematology Day Care Unit (HDCU) in Nigeria

The Haematology Day Care Unit (HDCU) of the University College Hospital; Ibadan; Nigeria was established in 1975 with the main goal of providing immediate and specialized care to haematological emergencies; particularly sickle cell disease (SCD) patients. Since inception; a systematic analysis of its effectiveness has not been done; hence this study. A retrospective study of all registered patients attending the Haematology Day Care Unit of the University College Hospital; Ibadan; over a one-year period was conducted and analyzed. Demographic data; diagnosis; treatment received; outcome of such treatment as well as laboratory parameters were extracted from HDCU register and the data were then analysed using descriptive statistics. A total of 890 patients were seen during the period; January and December 2001; out of which 520 were sickle cell disease patients (HbSS accounted for 508 (92.7) cases and HbSC; 40 (7.3) cases). The mean age of the SCD patients was 25.8years; the median; 23years and the mode; 18years. The mean PCV was 21.2; median; 21.0 and mode; 20. Majority (246 or 47.3) of the patients were between 20 and 30 years; the lowest frequency being in the 50years group (14 or 2.7). One patient died during the period under review (31year old female with HbSC disease); giving a mortality rate of 2 per 1000 patients

Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors.

Over the past 40 years, we observed 284 subjects with hemoglobin SC disease (Hb SC) for 2,837 person-years. We examined the association of the course of clinical events with hematologic and genetic factors. The mean entry age was 21 years, although 15% entered before one year of age. The mean Hb concentration was 11.3 g/dL, the mean fetal hemoglobin was 2.5%, and the mean MCV was 84.4 fL. Twenty-five subjects died at a median age of 37 years. Chronic organ-specific complications occurred in 112 subjects (39.4%), with advanced retinopathy in 65 subjects (22.9%) and osteonecrosis (avascular necrosis) in 42 subjects (14.8%). We identified the beta-globin haplotypes in 82 subjects and the alpha-gene status in 79. Twenty-nine percent had alpha-thalassemia-2. The beta(CI) haplotype was present in 85.4%. We found a decreased incidence of retinopathy in the beta(CI) subjects compared to the non-beta(CI) subjects (33% vs. 67%; P = 0.049) with a later mean onset age (29 years vs. 21 years; log-rank test, P= 0.026). We also found a consistent pattern of decreased morbidity in subjects who had alpha-thalassemia-2 in comparison to those who did not. We found a reduced risk of chronic organ-specific complications (log-rank test, P= 0.003), lower incidence of sickle crisis (48% vs. 80%, P= 0.001), later onset of gallbladder disease (age of onset: 55 years vs. 34 years; P= 0.055), and lower risk of osteonecrosis (log-rank test, P= 0.024). Our findings suggest that Hb SC subjects who have not inherited alpha-thalassemia-2 might benefit from erythrocyte rehydration therapy.

Major changes in sickle cell disease.

Clinical, molecular, and genetic advances have revealed new pathophysiologic insights and treatments for the growing number of recognized hematologic and nonhematologic abnormalities in sickle cell disease. Treatment targets of cellular dehydration, sickle hemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation have been validated as potential therapy. New uses for transfusion therapy hold the promise of decreased major symptoms of acute chest syndrome, stroke, and severe pain crises, but at the expense of increased risk for transfusion reactions, infections, and iron overload. Accumulated experience with autologous, chimeric, and stem cell bone marrow transplantation holds promise for a small percentage of patients with disease. Patient selection, suitable donors, and early mortality are still limiting factors. Genetic manipulation, which offers hope for ameliorating the disease in a larger percentage of patients, is progressing slowly. Combination and staged therapies will be developed and matched to the severity and progression of the patient's disease. Strategies for prevention of major organ damage to the brain, heart, lungs, and kidneys will be prospectively evaluated and refined.

Gallstones in sickle cell disease: observations from The Jamaican Cohort study.

The prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones were studied in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort study from birth. Gallstones developed in 96 patients with homozygous sickle cell disease and 18 patients with sickle cell-hemoglobin C disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.

Gallstones in sickle cell disease: observations from the Jamaican Cohort study

The prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones were studied in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort study from birth. Gallstones developed in 96 patients with homozygous sickle cell disease and 18 patients with sickle cell-hemoglobin C disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.(AU)

National trends in the mortality of children with sickle cell disease, 1968 through 1992.

OBJECTIVES: This paper describes national trends in mortality of children with sickle cell disease and the settings in which death occurred. METHODS: United States death certificate data from 1968 through 1992 were used to calculate mortality rates of Black children with sickle cell disease 1 to 14 years old. Deaths from trauma, congenital anomalies, and perinatal conditions were excluded. RESULTS: Between 1968 and 1992, mortality rates of Black children with sickle cell disease decreased 41% for 1- to 4-year-olds, 47% for 5- to 9-year-olds, and 53% for 10- to 14-year-olds. During 1986 through 1992, children who died before hospital admission accounted for 41% of deaths among 1- to 4-year-olds, 27% among 5- to 9-year-olds, and 12% among 10- to 14-year-olds. CONCLUSIONS: Survival of Black children with sickle cell disease has improved markedly since 1968. A substantial proportion of deaths continue to occur prior to hospital admission. Trends in sickle cell mortality can be monitored inexpensively with death-certificate data.

Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia.

PURPOSE: Blood pressure in individuals who have sickle cell disease has been reported to be lower than published normal values. We determine whether and to what degree this is true, using data obtained as part of a large natural history study. PATIENTS AND METHODS: Blood pressure was measured annually for 3,317 subjects with sickle cell disease who were 2 years old or older. Values obtained were compared with those reported by the National Health and Nutrition Examination Survey I and II (NHANES I and II). They were further analyzed with respect to age, sex, height, weight, hematologic diagnosis, blood urea nitrogen and creatinine, stroke, and death. RESULTS: Blood pressure was significantly lower in subjects with sickle cell anemia than published norms for age, race, and sex, a difference that increased with age. It correlated with body mass index, hemoglobin, measures of renal function and age, but the strength of the correlation varied among age and sex subgroups. The risk for occlusive stroke increased with systolic but not diastolic pressure. Mortality was related to elevated blood pressure in males (P < 0.05) and to a lesser extent in females (P = 0.10). In subjects with hemoglobin SC disease, blood pressure also deviated from normal but to a lesser degree. CONCLUSION: Blood pressure is generally lower than normal in individuals with sickle cell anemia. Those with high values relative to this population had an increased risk of stroke and death. Blood pressure should be monitored but values obtained must be assessed relative to the lower values expected for patients with this disease. Those with blood pressure values above 140/90 mm Hg should be evaluated and considered for treatment.

Fetal outcome and childhood mortality in offspring of mothers with sickle cell trait and disease.

The sickle cell hemoglobinopathy is a major public health problem which causes high morbidity and mortality in India. Although the hematological and clinical profile of the patients is extensively studies. The reproductive outcome of mothers afflicted with sickle cell trait and disease is still unknown in India. In a retrospective study, we have examined the reproductive profile of 190 mothers afflicted with sickle cell, attending Medical Out-Patient Department at V.S.S. Medical College Hospital, Burla in Western Orissa, India during the year 1991-1992. Seventy-three mothers who were found normal after medical examination and were free from hemoglobinopathic disorders, anemia, jaundice, iron deficiency, etc. constituted the control group and 66 mothers with sickle cell trait and 51 with sickle cell disease formed the study group. The reproductive history was recorded for number of conceptions, fate of offspring, live birth, surviving children and childhood mortality. Hematological investigations and hemoglobin electrophoresis were done as per the standard procedure. There was no difference in mean number of livebirths per mother between controls and sickle cell trait mothers. But between the controls and sickle cell homozygotes (p < 0.01), and sickle cell trait and disease (p < 0.01) mothers, this mean number was significant. For abortions/miscarriages, the difference between controls and sickle cell homozygotes (p < 0.001), and sickle cell trait and disease (p < 0.01) mothers was highly significant. The number of stillbirths per mother in homozygous sickle cell mothers was higher (p < 0.01) as compared to controls. There were significantly higher childhood deaths in sickle cell trait (p < 0.05) and disease (p < 0.05) mothers than in the controls. It seems that the sickle cell heterozygote and hemoglobin E heterozygote mothers are genetically better fit than the sickle cell homozygotes. Further, the sickle cell disease is clinically severer than the hemoglobin E disease in India probably due to molecular diversity.

Mortality in sickle cell disease. Life expectancy and risk factors for early death.

BACKGROUND: Information on life expectancy and risk factors for early death among patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and the sickle cell-beta-thalassemias) is needed to counsel patients, target therapy, and design clinical trials. METHODS: We followed 3764 patients who ranged from birth to 66 years of age at enrollment to determine the life expectancy and calculate the median age at death. In addition, we investigated the circumstances of death for all 209 adult patients who died during the study, and used proportional-hazards regression analysis to identify risk factors for early death among 964 adults with sickle cell anemia who were followed for at least two years. RESULTS: Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Among adults with sickle cell disease, 18 percent of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis (78 percent had pain, the chest syndrome, or both; 22 percent had stroke). Modeling revealed that in patients with sickle cell anemia, the acute chest syndrome, renal failure, seizures, a base-line white-cell count above 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death. CONCLUSIONS: Fifty percent of patients with sickle cell anemia survived beyond the fifth decade. A large proportion of those who died had no overt chronic organ failure but died during an acute episode of pain, chest syndrome, or stroke. Early mortality was highest among patients whose disease was symptomatic. A high level of fetal hemoglobin predicted improved survival and is probably a reliable childhood forecaster of adult life expectancy.

Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality.

OBJECTIVE: To determine the incidence, clinical course, and risk factors associated with the onset of chronic renal failure in sickle cell anemia and sickle C disease. DESIGN: A prospective, 25-year longitudinal demographic and clinical cohort study. A matched case-control study was conducted to determine risk factors. PATIENTS: A total of 725 patients with sickle cell anemia and 209 patients with sickle C disease who received medical care from the hematology service in a large municipal hospital. Most were observed from birth or early childhood. MEASUREMENTS: Thirty-six patients developed sickle renal failure: 4.2% of patients with sickle cell anemia and 2.4% of patients with sickle C disease. The median age of disease onset for these patients was 23.1 and 49.9 years, respectively. Survival time for patients with sickle cell anemia after the diagnosis of sickle renal failure, despite dialysis, was 4 years, and the median age at the time of death was 27 years. Relative risk for mortality was 1.42 (95% Cl, 1.12 to 1.81; P = 0.02) compared with patients who did not develop renal insufficiency. MAIN RESULTS: Histopathologic studies showed characteristic lesions of glomerular "drop out" and glomerulosclerosis. Case-control analysis showed that ineffective erythropoiesis with increasingly severe anemia, hypertension, proteinuria, the nephrotic syndrome, and microscopic hematuria were significant pre-azotemic predictors of chronic renal failure. The risk for sickle renal failure was increased in patients who had inherited the Central African Republic beta s-gene cluster haplotype. CONCLUSIONS: The pre-azotemic manifestations of hypertension, proteinuria, and increasingly severe anemia predict end-stage renal failure in patients with sickle cell disease. The rate of progression of renal insufficiency is genetically determined. Treatment of the uremic phase has been dismal, underscoring the need for the development of useful pre-azotemic therapeutic modalities.

Mortality in children and adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease.

A study of the natural history of sickle hemoglobinopathies was begun in March 1979. By August 1987, a total of 2824 patients less than 20 years of age were enrolled. There have been 14,670 person-years of follow-up. Seventy-three deaths have occurred. Most of the deaths were in patients with hemoglobin SS. The peak incidence of death was between 1 and 3 years of age, and the major cause in these young patients was infection. Cerebrovascular accidents and traumatic events exceeded infections as a cause of death in patients greater than 10 years of age. There was limited success in identifying risk factors for death. Comparison of this study's overall mortality of 2.6% (0.5 deaths per 100 person-years) with previous reports indicates improvement of survival in US patients less than 20 years of age with sickle hemoglobinopathies. This improvement is most likely due to parental education and counseling about the illness and the early institution of antibiotics in suspected infections.

The cohort study of sickle cell disease - abstract

Most observations on sickle cell disease have been made on symptomatically selected hospital-based populations. As such, they represent a group of patients who are benign enough to have survived, but severe enough to have come to medical attention. Traditional medical descriptions have therefore emphasised only the severe end of what is now recognised to be a wide clinical spectrum. Documentation of this spectrum is important to an understanding of the natural history of the disease and to the determinants of severity. The cohort study was an attempt to define a large representative group of patients with sickle cell disease where there had been no element of symptomatic selection and to follow them prospectively. Between June 1973 and December 1981, 100,000 consecutive normal deliveries were screened at Victoria Jubilee Hospital, Kingston with the detection of 315 children with homozygous sickle cell (SS) disease. 201, with sickle cell-haemoglobin C (SC) disease, 33 with sickle cell cell-beta+ thalassaemia, and 14 with sickle cell-beta§ thalassaemia. Among the SS group, there have been 56 deaths, nearly 10 percent dying in the first year of life. Although symptoms are rare in the first six months of life because of high levels of HbF, the second 6 months of life is the highest risk period at any time in the life of the child, the mortality rate falling for each individual year subsequently. Thus, life-threatening complications occur in SS disease at an age when the underlying haemoglobinopathy may not be suspected. Principle causes of early mortality included acute chest syndrome, acute splenic sequestration and pneumococcal septicaemia. Since the frequency and outcome of these complications may be affected by prophylaxis or early intervention, it is essential that the diagnosis of the underlying haemoglobinopathy be made early. Neonatal diagnosis of sickle cell disease is simple and cost-effective and allows prophylaxis and education programmes to be instituted early (AU)

Is pain crisis a cause of death in sickle cell disease?

It has been a matter of controversy as to whether patients with sickle cell disease die of crisis or merely in crisis. The authors reviewed the 74 patients with sickle cell disease autopsied at The Johns Hopkins Hospital. From clinical review, there were 20 (27%) who died with pain crisis, 51 (69%) who died without pain crisis, and 3 (4%) for whom documentation was insufficient. On pathology review, death was attributable to infection in 19 (26%), uremia in 9 (12%), sequestration crisis in 9 (12%), necrotic bone marrow emboli in 7 (9%), and miscellaneous causes in 14 (19%); in 16 (22%) patients no cause of death could be identified. Death was explained in 47/51 (92%) patients without pain crisis; but only in 11/20 (55%, P less than 0.01) patients dying in pain crisis. The disproportionately large number of patients dying in pain crisis with an unexplained cause of death suggests that pain crisis may account for the death of some patients with sickle cell disease.