Urine concentration impairment in sickle cell anemia: genuine nephrogenic diabetes insipidus or osmotic diuresis?

The urine concentration impairment responsible for hyposthenuria in sickle cell nephropathy is currently thought to be a consequence of renal medulla lesions, which lead to nephrogenic diabetes insipidus. The objective of the present study was to investigate the mechanism of hyposthenuria in patients with sickle cell anemia. We performed an observational study of patients with homozygous SS sickle cell anemia and data available on the fasting plasma antidiuretic hormone (ADH) concentration. A total of 55 patients were analyzed. The fasting plasma ADH values ranged from 1.2 to 15.4 pg/mL, and 82% of the patients had elevated ADH values and low fasting urine osmolality (<505 mosmol/kgH2O). Plasma ADH was positively associated with plasma tonicity and natremia (P < 0.001). None of the patients experienced polyuria and fasting free water clearance was negative in all cases, thus, ruling out nephrogenic diabetes insipidus. The tertile groups did not differ with regard to fasting urine osmolality, plasma renin level, mGFR, or several hemolysis biomarkers. The negative fasting free water clearance in all cases and the strong association between 24-h osmolal clearance and 24-h diuresis favors the diagnosis of osmotic diuresis due to an impaired medullary gradient, rather than lesions to collecting tubule.NEW & NOTEWORTHY The urine concentration impairment in sickle cell anemia is an osmotic diuresis related to an impaired renal medullary gradient leading to an ADH plateau effect. The fasting plasma ADH was high in the context of a basic state of close-to-maximal urine concentration probably driven by short nephrons maintaining a cortex-outer medullary gradient (about 400 milliosmoles). The patients had a low daily osmoles intake without evidence of thirst dysregulation so no one experienced polyuria.

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

Diffuse cystic lung disease in sickle cell anaemia: a series of 22 cases and a case-control study.

Chronic interstitial lung abnormalities have been described in sickle cell disease (SCD) and attributed to repetitive episode of acute chest syndrome. We report a series of 22 cases of diffuse cystic lung disease in SCD with a case-control study to hunt for mechanism. On pathological analysis of a surgical lung biopsy of the index case, the bronchioles had the appearance of constrictive bronchiolitis. Pulmonary function test results revealed lower forced expiratory flow from 25% to 75% of vital capacity in cases versus controls. These findings suggest a bronchiolar mechanism that was not associated with more acute chest syndrome.

Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study.

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

Altered cardiac reserve is a determinant of exercise intolerance in sickle cell anaemia patients.

BACKGROUND: The underlying mechanisms of exercise intolerance in sickle cell anaemia (SCA) patients are complex and not yet completely understood. While latent heart failure at rest could be unmasked upon exercise, most previous studies assessed cardiac function at rest. We aimed to investigate exercise cardiovascular reserve as a potential contributor to exercise intolerance in adult SCA patients. METHODS: In this observational prospective study, we compared prospectively 60 SCA patients (median age 31 years, 60% women) to 20 matched controls. All subjects underwent symptom-limited combined exercise echocardiography and oxygen uptake (VO2 ) measurements. Differences between arterial and venous oxygen content (C(a-v)O2 ) were calculated. Cardiac reserve was defined as the absolute change in cardiac index (Ci) from baseline to peak exercise. RESULTS: Compared to controls, SCA patients demonstrated severe exercise intolerance (median peakVO2 , 34.3 vs. 19.7 ml/min/kg, respectively, p < .0001). SCA patients displayed heterogeneously increased Ci from rest to peak exercise (median +5.8, range 2.6 to 10.6 L/min/m²) which correlated with peakVO2 (r = 0.71, p < .0001). In contrast, the C(a-v)O2 exercise reserve was homogenously reduced and did not correlate with peakVO2 (r = 0.18, p = .16). While haemoglobin level and C(a-v)O2 were similar in SCA subgroups, SCA patients in the lower VO2 tertile had chronotropic incompetence and left ventricular diastolic dysfunction (left atrial peak longitudinal strain was reduced, and both E/e' ratio and left atrial volume index were increased) and were characterized by a reduced cardiac reserve, +5.0[4.2-5.5] compared to +6.7[5.5-7.8] L/min/m² for the rest of the patient cohort, p < .0001. CONCLUSIONS: Altered cardiac reserve due to chronotropic incompetence and left ventricular diastolic dysfunction seems to be an important determinant of exercise intolerance in adult SCA patients.

Pregnancy outcome in women with transfused beta-thalassemia in France.

Because of chronic anemia, hypogonadotropic hypogonadism, and iron chelation, pregnancy in homozygous and heterozygous compound beta-thalassemia patients stays a challenge. Pregnancies of transfused beta-thalassemia women registered in the French National Registry, conducted between 1995 and 2015, are described. These pregnancies were compared with pregnancies in healthy women and to data previously published in the literature. Fifty-six pregnancies of 37 women were studied. There were 5 twin pregnancies. Assisted reproductive technologies (ART) were used in 9 pregnancies. Median term at delivery was 39 amenorrhea weeks, and median weight at birth was 2780 g. Cesarean section was performed in 53.6% of the pregnancies. There were 6 thromboembolic events, 6 serious infections, 6 pregnancy-induced hypertensions (PIH), 6 intrauterine growth retardations (IUGR), 5 severe hemorrhages, 4 gestational diabetes, 3 alloimmunizations, 2 heart diseases, and 1 pre-eclampsia. There were 5 infections and 4 osteoporosis in the first year of post-partum. ART and cesarean sections were more often used in the beta-thalassemia group, compared to control subjects. Thromboembolic events, PIH, hemorrhage at delivery, and IUGR were more frequent in the beta-thalassemia group. Time to delivery was not different, but infant weight at birth was significantly smaller in the beta-thalassemia group. In the post-partum period, global maternal complications were more frequent in the beta-thalassemia group. Pregnancy in transfused beta-thalassemia women is safe with rare obstetrical and fetal complications. Cesarean section remains often chosen, and infant weight at birth remains smaller than that in the general population, despite delivery at full term.

Impact of pre-eclampsia on renal outcome in sickle cell disease patients.

The long-term consequences of pre-eclampsia (PrE) for renal function have never been determined in patients with sickle cell disease (SCD). Between 2008 and 2015, we screened 306 pregnancies in women with SCD and identified 40 with PrE (13%). The control group consisted of 65 pregnant SCD patients without PrE. In multivariable analysis, PrE events were associated with an increase of 1 log of lactate dehydrogenase level (adjusted odds ratio, aOR = 3·83, P = 0·05), a decrease of 10 g/l of haemoglobin levels (aOR = 2·48, P = 0·006) and one or more vaso-occlusive crisis during pregnancy (aOR = 16·68, P = 0·002). Estimated glomerular filtration rate (eGFR) was similar in the two groups at steady state but was significantly lower in the PrE group after one year of follow-up and at last follow-up (130 vs 148 ml/min/1·73 m2 , P < 0·001 and 120 vs 130 ml/min/1·73 m2 , P < 0·001, respectively). In multivariable analysis, eGFR had returned to steady-state levels one year after pregnancy in patients without PrE but continued to decrease in patients with PrE (ß = -18·15 ml/min/1·73 m2 , P < 0·001). This decline was more marked at the end of follow-up (ß = -31·15 ml/min, P < 0·001). In conclusion, PrE episodes are associated with a significant risk of subsequent renal function decline in SCD patients.

Risk factors for CKD stage II onset in a prospective cohort of homozygous sickle cell adults.

Prevalence of renal impairment is increasing with aging in sickle cell anemia (SCA) patients, and is responsible for a high morbidity and mortality. However, sickle cell nephropathy's natural course remains mostly unknown. We conducted a prospective observational cohort study aimed to identify risk factors for CKD stage II in a cohort of SCA patients. Baseline clinical and biological parameters were collected. Renal parameters were updated at each visit. Risk factors were analyzed using the Cox model. Five-hundred and thirty-five SCA patients were included with a median follow-up of 5.33 (IQR:2.10-8.13) years. Median age was 22 (IQR:19-30) years old. Glomerular hyperfiltration was detected in 299 (55.9%) patients, microalbuminuria and macroalbuminuria in 180 (34%) and 67 (12.7%) patients respectively. During follow up, CKD stage II onset was detected in 39 patients (7.3%). Risk factors for CKD stage II after adjustment on baseline eGFR and age were macroalbuminuria HR: 3.89 [95% CI: 1.61;9.43], diastolic blood pressure (DBP) above 70 mm Hg HR: 2.02 [1.02-3.971], LDH (for 100 IU/L increase) HR: 1.28 [1.12;1.48] and tricuspid regurgitation velocity >2.5 m/sec HR: 2.89 [1.20-6.99]. Multivariate analysis also found age as a strong independent risk factor with HR: (per year increase) 1.13 [1.09;1.16] and a 13.3-fold increase above 30 years (p < 0.001). Our results show a high incidence of CKD stage II with aging, with a strong significant risk increase after 30-years-old, and pinpoint baseline DBP, macroalbuminuria and increased LDH as independent risk factors raising the issue of optimal blood pressure targets for SCA patients.

Cardiovascular phenotypes predict clinical outcomes in sickle cell disease: An echocardiography-based cluster analysis.

This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.

Severe COVID-19 with acute respiratory distress syndrome (ARDS) in a sickle cell disease adult patient: case report.

BACKGROUND: Sickle-cell anaemia is a widespread genetic disease prevalent worldwide among African and African-American populations. The pathogenesis is most often revealed by pulmonary conditions, including acute thoracic syndrome, which is affecting the life expectancy of these populations. The global spread of CoV2-SARS infection with a respiratory tropism, endothelial damages and procoagulant status endangers the SCD population. However, with only a few case reports, consequences of the Covid-19 pandemic on SCD population remain poorly known. CASE PRESENTATION: We report a case of a 33-year-old man with a history of homozygous SS homozygous sickle cell anemia who consulted on March 24, 2020 for febrile dyspnea 11 days after the onset of symptoms. A nasopharyngeal swab was positive for SARS-CoV-2. His respiratory status worsened rapidly in the emergency room and then in ICU leading to severe ARDS requiring intubation, curarization, and venovenous ECMO. Hematologically, severe hemolysis associated with major thrombocytopenia without documented spinal cord injury was noted. Several transfusion exchanges are performed. The evolution was finally slowly favorable and led to discharge from the intensive care unit and then from the hospital. CONCLUSIONS: This case recalls the importance of an increased prevention policy against COVID-19among the SCD population. In addition, from a therapeutic point of view, it advocates (1) a high preventive anticoagulation from the outset according to the level of D-dimers (2) the use of venovenous ECMO in this particular case, whereas this technique has had rather disappointing results in acute chest syndromes. (3) Unexpectedly, our patient did not develop pulmonary arterial hypertension (PAH) and acute cor pulmonale (ACP), whereas this is a common feature of ARDS during SCD. These last two observations suggest a different pathophysiology of pulmonary disorders in SCD patients in the case of SARS COv2. It could be associated with marked hypoxemia secondary to pulmonary vascular vasodilation.

Cardiovascular manifestations of sickle cell disease.

Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.

Plasma histamine elevation in a large cohort of sickle cell disease patients.

The role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso-occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0-45·0] vs 9·6 [6·2-14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.

Clinical phenotypes and outcomes of precapillary pulmonary hypertension of sickle cell disease.

RATIONALE: Precapillary pulmonary hypertension (PH) is a devastating complication of sickle cell disease (SCD). Little is known about the influence of the SCD genotype on PH characteristics. OBJECTIVES: To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. METHODS: A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. RESULTS: 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-ß0 thalassaemia (S-ß0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-ß0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-ß0 thal patients, respectively, and 50% of SS/S-ß0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. CONCLUSIONS: Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.

Cardiac manifestations in sickle cell disease varies with patient genotype.

Cardiac involvement is well characterized in sickle cell anaemia (SCA) but cardiac features associated with Haemoglobin SC (HbSC) disease are mostly unknown. We compared 60 patients with HbSC disease (median age 31 years, 25 men) to 60 SCA patients and 60 controls matched for age and gender. Left ventricular ejection fraction (LVEF), left ventricle (LV) mass index (LVMi), cardiac index and peak tricuspid regurgitation velocity (TRV) were measured using echocardiography. LV filling pressures were assessed using the ratio of early diastolic transmitral velocity to tissue velocity (E/e' ratio). The LVMi was higher in both genotypes compared to controls. However, whereas LV hypertrophy was observed only in 3(5%) HbSC patients, this condition was diagnosed in 27(45%) SCA patients (P < 0·0001). While cardiac index and TRV were similar in HbSC compared to controls, SCA patients exhibited elevated cardiac output and TRV. LVEF was similar in the 3 groups. However, both genotypes had a higher E/e' ratio compared to controls. Cardiac involvement in SCA was related to anaemia and haemolysis, while LV diastolic dysfunction and TRV in HbSC disease patients were related to arterial hypertension and overweight comorbidities. In summary, cardiac involvement and its determinants are different in HbSC disease and SCA. Patient's genotype should be considered with regard to the echocardiographic indications and findings.

Chronic blood exchange transfusions in the management of pre-capillary pulmonary hypertension complicating sickle cell disease.

The long-term effects of chronic blood exchange transfusions (BETs) on pre-capillary pulmonary hypertension complicating sickle cell disease (SCD) are unknown.13 homozygous SS SCD patients suffering from pre-capillary pulmonary hypertension and treated by chronic BETs were evaluated retrospectively. Assessments included haemodynamics, New York Heart Association Functional Class (NYHA FC), 6-min walk distance (6MWD) and blood tests.Before initiating BETs, all patients were NYHA FC III or IV, median (range) 6MWD was 223 (0-501) m and median (range) pulmonary vascular resistance (PVR) was 3.7 (2-12.5) Wood Units. After a median number of 4 BET sessions, all patients had improved to NYHA FC II or III. Significant improvements in haemodynamics were observed, including a decrease in PVR (p=0.01). There was a trend to higher 6MWD (p=0.09). Median (range) follow-up time after initiation of BETs was 25 (6-53) months. During this period, two patients decided to stop BETs. One of them died from acute right heart failure and the other experienced worsening pulmonary hypertension. Two other patients died during follow-up at 25 and 54 months after BET initiation.Chronic BETs may be a potential therapeutic option in pre-capillary pulmonary hypertension complicating SCD, leading to significant clinical and haemodynamic improvements. These data must be confirmed in a prospective study.

Renin-angiotensin system blockade promotes a cardio-renal protection in albuminuric homozygous sickle cell patients.

The management of sickle cell nephropathy (SCN) at an early stage is an important issue to prevent renal and cardiovascular morbidity and mortality. This study aimed to evaluate in this population, whether angiotensin converting enzyme inhibitors (ACEIs) treatment could exert a cardio-renal protection in a SCN cohort. Forty-two SCN patients (urine albumin:creatinine ratio (ACR) > 10 mg/mmol) were treated with ACEIs for 6 months, then evaluated for ACR, measured glomerular filtration rate (mGFR) together with haematological and cardiovascular parameters. A 1-month washout was also performed in order to differentiate short- and long-term ACEIs effects. A decrease in ACR baseline value (>30%) was detected in 62% of cases (mean ACR: 46·4 ± 7·6 and 26·4 ± 3·9 mg/mmol at baseline and 6 months respectively; P = 0·002), whereas mGFR values were unchanged. ACR decrease was detected at 1 month following ACEI initiation (32·9 ± 6·9, P = 0·02) with a persistent trend after withdrawal (P = 0·08). ACEIs also decreased diastolic blood pressure (P = 0·007), pulse wave velocity (P = 0·01), tricuspid regurgitation velocity (TRV; P = 0·04), asymmetric dimethyl arginine (ADMA: P = 0·001) and haemoglobin (P = 0·01) while conventional haemolytic biomarkers were unchanged. Our data suggest that ACEIs are safe and effective at decreasing albuminuria in sickle cell patients with a beneficial effect on specific mortality risk factors, such as TRV and asymmetric dimethyl arginine.

Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease.

Intravascular hemolysis describes the relocalization of heme and hemoglobin (Hb) from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MPs) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MPs have a physiopathological impact. Up to one-third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MPs. Erythrocyte vesiculation in vitro produced MPs loaded with heme. In silico analysis predicted that externalized phosphatidylserine (PS) in MPs may associate with and help retain heme at the cell surface. Immunohistology identified Hb-laden MPs adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MPs adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MPs triggered rapid vasoocclusions in kidneys and compromised microvascular dilation ex vivo. These vascular effects were largely blocked by heme-scavenging hemopexin and by the PS antagonist annexin-a5, in vitro and in vivo. Adversely remodeled MPs carrying heme may thus be a source of oxidant stress for the endothelium, linking hemolysis to vascular injury. This pathway might provide new targets for the therapeutic preservation of vascular function in SCD.