GFR in Patients with β-Thalassemia Major

Background and objectives

Patients with β-thalassemia major (TM) may have tubular dysfunction and glomerular dysfunction, primarily hyperfiltration, based on eGFR. Assessment of GFR based on serum creatinine concentration may overestimate GFR in these patients. This study sought to determine GFR by using inulin clearance and compare it with measured creatinine clearance (Ccr) and eGFR.

Design, setting, participants & measurements

Patients followed up in an Israeli thalassemia clinic who had been regularly transfused for years and treated with deferasirox were included in the study. They were studied by inulin clearance, Ccr, the CKD Epidemiology Collaboration and the Modification of Diet in Renal Disease equations for eGFR, and the Cockcroft–Gault estimation for Ccr. Expected creatinine excretion rate and tubular creatinine secretion rate were calculated.

Results

Nine white patients were studied. Results, given as medians, were as follows: serum creatinine was 0.59 mg/dl (below normal limits); GFR was low (76.6 ml/min per 1.73 m²) and reached the level of CKD; Ccr was 134.9 ml/min per 1.73 m², higher than the GFR because of a tubular creatinine secretion rate of 30.3 ml/min per 1.73 m² (this accounted for 40% of the Ccr); and eGFR calculated by the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease equations and Cockcroft–Gault–estimated Ccr were 133, 141, and 168 ml/min per 1.73 m², respectively. These latter values were significantly higher than the GFR, reaching the hyperfiltration range, and indicated that the estimation techniques were clinically unacceptable as a method for measuring kidney function compared with the GFR according to Bland and Altman analyses.

Conclusions

Contrary to previous reports, patients in this study with TM had normal or reduced GFR. The estimating methods showed erroneous overestimation of GFR and were clinically unacceptable for GFR measurements in patients with TM by Bland and Altman analysis. Therefore, more accurate methods should be used for early detection of reduced GFR and prevention of its further decline toward CKD in these patients.     

Correlation of Iron Overload and Glomerular Filtration Rate Estimated by Cystatin C in Patients with β-Thalassemia Major

Historically, renal involvement has not been a commonly recognized complication in patients with β-thalassemia major (β-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with β-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3?±?9 years (range 2.5–38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient ?0.25). In the univariable analyses, serum ferritin (p?=?0.004), diabetes status (p?p?p?=?0.033), chelation with DFX (p?=?0.05) and diabetes status (p?相似文献   

Life-Threatening Drug-Induced Liver Injury in a Patient with β-Thalassemia Major and Severe Iron Overload on Polypharmacy

Abstract

A 20-year-old male affected by transfusion-dependent β-thalassemia (β-thal), was prescribed intensive chelation therapy with deferoxamine (DFO) and deferiprone (DFP) because of severe hepatic and cardiac iron overload and β-blocker and warfarin to manage a previous event of atrial fibrillation (AFib) and heart failure. After a few months, he developed critical liver failure, renal tubulopathy and severe electrolyte imbalance. Laboratory and instrumental evaluations were performed to carry out differential diagnosis of acute liver failure and an exclusion diagnosis of drug induced liver injury (DILI) was made. The cholestatic pattern suggested warfarin as the main causative agent and polypharmacy, liver iron overload and heart failure as aggravating factors. Warfarin is a drug commonly prescribed in thalassemia patients who often need polypharmacy for the management of anemia- and iron-related complications. Strict monitoring and multidisciplinary approaches are mandatory to avoid preventable mortality in this fragile population.     

Correlation of Pancreatic Iron Overload Measured by T2*-Weighted Magnetic Resonance Imaging in Diabetic Patients with β-Thalassemia Major

Diabetes mellitus (DM) is one of the potential complications in patients with transfusion-dependent β-thalassemia major (β-TM). In this case-controlled study, we examined the pancreatic iron levels in outpatients with β-TM. In this study, cases of patients with β-TM and DM were gender- and age-matched with control subjects, who were non-diabetic and had normal blood glucose on standard oral glucose tolerance (OGTT) tests. One of four diagnoses [normal, pre-diabetes, impaired glucose tolerance (IGT), DM] was made according to the American Diabetes Association (ADA) criteria. The T2*-weighted magnetic resonance imaging (T2*-weighted MRI) of the heart, liver, and pancreas was performed using a 1.5 Tesla scanner. The study enrolled 26 diabetic cases, 17 non-diabetic cases, and eight cases of IGT or pre-diabetes cases. The severity of pancreatic and cardiac iron siderosis was significantly different between the groups. We found a statistically significant difference at 5.6?ms in the T2*-weighted MRI values for the pancreas between patients with normal vs. abnormal glucose metabolism [p?p?r?=?0.4; p?r?=?0.38; p?相似文献   

Glutathione S-Transferase M1 Gene Polymorphisms are Associated with Cardiac Iron Deposition in Patients with β-Thalassemia Major

Patients with β-thalassemia (thal) major are subject to peroxidative tissue injury by iron overload. Glutathione S-transferases work as antioxidants, and their activity is determined genetically. In this study, we used multiplex polymerase chain reaction (m-PCR) to analyze polymorphisms of two endogenous antioxidant agents, glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1), and to determine their roles in 41 patients with β-thal major. Our results showed that the GSTM1 and GSTT1 null genotypes were not associated with any incidence of endocrine dysfunction (including diabetes mellitus, hypogonadism, hypothyroidism, and growth hormone deficiency), liver function, or impaired left ventricular ejection fraction (LVEF). The GSTM1 null genotype, but not the GSTT1 null genotype, was associated with a decreased signal intensity ratio on cardiac magnetic resonance imaging (MRI). Our results suggest that genetic variations of the GSTM1 enzyme are associated with cardiac iron deposition in patients with β-thal major.     

Comparison of Quality of Life in Patients with β-Thalassemia Intermedia and β-Thalassemia Major in Southern Iran

Increased life expectancy in patients with β-thalassemia (β-thal) requires healthcare professionals to give greater attention to improving their quality of life (QoL). We aimed to evaluate health-related QoL (HRQoL) and its determinants in patients with β-thal intermedia (β-TI) compared with β-thal major (β-TM). In this cross sectional study, 118 patients with β-TI, referred to the Thalassemia Clinic of Shiraz University of Medical Sciences, Shiraz, Iran, were investigated by convenience sampling from January to June 2014 in southern Iran. A Short Form-36 (SF36) questionnaire was used. We had previously conducted a similar study in 101 patients with β-TM (12 to 38 years). Compared data of the two studies were analyzed. Mean age was 26.5?±?6.5 (12 to 48) years in β-TI and 19.5?±?4.4 (12–38) years in the β-TM group. The best scales of HRQoL were physical functionin (PF) (76.8?±?26.6) and bodily pain (BP) (70.1?±?24.8) in the β-TI group. Males had significantly better score only in vitality dimension compared to females (p?=?0.020). Higher education (p?=?0.023) in univariate analysis and age ≤20 years (B coefficient?=?13, p?=?0.008) in multivariate analysis showed significant relationships with higher total HRQoL score in β-TI. Comparison of β-TI and β-TM, after adjusting for covariates, total HRQoL was similar between the two groups. In evaluating the subscales, only PF showed a better condition in patients with β-TM [adjusted mean difference?=?12.5, 95% confidence interval (95% CI): 5.6–19.3, p?相似文献   

Marital Status and Fertility in Adult Iranian Patients with β-Thalassemia Major

Expecting a family is an important component and a great goal for better quality of life for most of adults with β-thalassemia major. The aim of the present study was to examine the marital status of adults with β-thalassemia major. This cross-sectional study examined the marital status of patients with transfusion-dependent β-thalassemia aged over 15 years. Patients’ demographic characteristics including age, gender, marital status, duration of marriage, divorce, having or not having children and spouse’s health status were recorded. Information about the disease including cardiac and endocrine complications, ferritin level, splenectomy and viral hepatitis were also recorded. Of 228 patients with transfusion-dependent β-thalassemia major aged over 15 years who were treated at this medical center, 32 (14 %) were married. The mean age of married patients was 25.18 ± 4.74 years. Among the married patients, 8 (25 %) were females and 24 (75 %) patients were males. The mean age of marriage was 22.76 ± 4.16 years. The minimum and maximum marriage age was 15 and 33 years, respectively. The median duration of marriage was one year with the range from 3 months to 11 years. Only 8 (25 %) patients (one female and seven males) had children. Therapeutic advances have led to significantly increased survival and improved quality of life and fertility of patients with β-thalassemia major. According to the results, 14 % of patients over 15 years were married which was slightly higher as compared with other similar studies.     

Comparison of Oral and Subcutaneous Iron Chelation Therapies in the Prevention of Major Endocrinopathies in β-Thalassemia Major Patients

While hypertransfusion and subcutaneous iron chelation therapy have increased longevity of patients with β-thalassemia (thal) major, endocrinopathies have become more common and impair the quality of their lives. Additionally, subcutaneous iron chelation therapy is an uncomfortable experience and can prevent patients from regular compliance with iron chelation therapy. We compared the efficacy of oral deferiprone (L1) to subcutaneous desferrioxamine (DFO) chelation therapy for the prevention of major endocrinopathies (growth hormone insufficiency, diabetes mellitus and gonadal dysfunction) among patients with β-thal major to see if we could offer these patients an easier and more painless way to reduce their body iron load and related endocrine complications.     

Compliance with Deferoxamine Therapy and Thyroid Dysfunction of Patients with β-Thalassemia Major in Syria

Abstract

Hypothyroidism is one of the common endocrine complications described in patients with β-thalassemia major (β-TM). Studies have reported its incidence and severity depending on the region, quality of management and treatment protocols. The reported thyroid dysfunction includes overt hypothyroidism, subclinical hypothyroidism and rarely, central hypothyroidism. The main aims of this study were to identify the incidence of hypothyroidism in 82 patients with β-TM in Syria, and also to evaluate the effect of compliance with deferoxamine (DFO) therapy on the patients’ thyroid function. Out of the 82 patients included in this study, 24 had subclinical hypothyroidism (29.27%) and one patient had overt hypothyroidism (1.22%). It was demonstrated by this study that noncompliance with DFO therapy increases the risk of thyroid dysfunction 6.38-times compared to compliance with DFO [risk ratio (RR) = 6.385; 95% confidence interval (95% CI) 2.40-16.95)]. These results emphasize the importance of compliance with chelation therapy to minimize the burden of thyropathy on patients’ quality of life, and also augment the rationale for a routine follow-up and endocrine evaluation for early detection and management of these complications.     

Is Vitamin C Supplementation in Patients with β-Thalassemia Major Beneficial or Detrimental?

Globally, β-thalassemia major (β-TM) is one of the most common hereditary disorders. Multiple blood transfusions, that are a life-saving therapy in patients with β-TM, is a major source of iron overload. Iron overload can lead to significant morbidity and mortality. Research evidence indicates that oxidative stress induced by iron overload, is one of the major precipitating causes of vitamin C deficiency in β-TM patients. It has previously been shown that patients with β-TM have significantly lower levels of vitamin C as compared to healthy individuals. It is believed that vitamin C can reduce both ferric (Fe³⁺) and ferrous (Fe²⁺) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system. Despite the potential benefits of vitamin C in patients with β-TM, several areas of concern exist that should be addressed by high quality research designs. Some recommendations have been provided through this study.     

A Systematic Review and Meta-Analysis of Deferiprone Monotherapy and in Combination with Deferoxamine for Reduction of Iron Overload in Chronically Transfused Patients with β-Thalassemia

β-Thalassemia major (β-TM) patients require life-long blood transfusions, resulting in iron overload with multi-organ morbidity and mortality. Evidence from small randomized controlled trials (RCTs) published to date for deferiprone (DFP) monotherapy or in combination with deferoxamine (DFO) is unclear. We summarized evidence on the efficacy of DFP monotherapy compared to DFO, and DFP-DFO combination therapy compared to DFP or DFO monotherapy in chronically transfused β-TM. We searched four electronic databases and examined the grey literature. Two authors independently assessed trial quality and extracted data. We calculated the relative risk for dichotomous outcomes and mean difference (MD) for continuous outcomes. We identified 15 RCTs (1003 participants) that met the inclusion criteria. Deferiprone was more efficacious than DFO in improving cardiac ejection fraction [MD 2.88, 95% CI (95% confidence interval) 1.12 to 4.64, p?=?0.001) and endocrine dysfunction (MD 0.09, 95% CI 0.08 to 0.10, p?p?=?0.008). There was no significant difference in all other outcomes examined. Meta-analysis on changes in myocardial iron content was not possible due to differences in data presentation. The quality of evidence for all outcomes was low. There is currently insufficient evidence to show that DFP is superior to DFO in the treatment of iron overload. The use of DFP must be weighed against the potential side-effects, patient compliance and preference. Large RCTs with clinically relevant outcomes are required.     

Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major

Abstract

Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30?mg/kg/day and never increased to more than 40?mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82?±?10.86?ms, and after 32.13?±?7.74?ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23?ms). The mean LVEF value was 68.43?±?7.08% before treatment with DFX and 67.95?±?5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.     

Evaluation of Mental Health and Physical Pain in Patients with β-Thalassemia Major in Northern Greece

Abstract

β-Thalassemia major (β-TM) is a chronic, genetic blood disorder. Patients are considered to be vulnerable to emotional and behavioral problems. The aim of this study was to assess mental health and somatic pain of patients with homozygous β-TM, who are systematically transfused in our unit. In this survey, 54 adult patients were studied. The general health questionnaire (GHQ-28) was used as mental health assessment model aimed at detecting mental disorders. The model of Binary was used as scoring method of GHQ-28. Overall ratings below 5 indicate no psychiatric problem, while a total score over or equal to 5 indicated the likelihood of a psychiatric disorder. The visual analogue scale (VAS) of pain was used as model for pain evaluation. One out of four examined patients who presented with a GHQ-28 score above or equal to 5 had an increased chance of being diagnosed with a psychiatric disorder. Concerning the pain, the majority of the studied patients scored between 1 and 3, meaning that they were feeling mild pain. There was no statistical significant correlation between age and GHQ-28 score. There was a statistical significant correlation between age and somatic symptoms (p?=?0.026), anxiety and somatic symptoms (0.004) as well as anxiety and depression (p?=?0.022). Thalassemic patients tend to be diagnosed with psychiatric disorders and it seems that they do not feel severe pain. More quantitative and comprehensive studies have to be conducted in order to estimate specific effective factors in psychosocial health.     

The Assessment of Skin Color and Iron Levels in Pediatric Patients with β-Thalassemia Major Using a Visual Skin Color Chart

Patients with β-thalassemia major (β-TM), a disease that emerges due to disorder of hemoglobin (Hb) synthesis, require life-long erythrocyte transfusion. The purpose of this study was to evaluate skin color and iron levels of patients with β-TM using a visual skin color chart. Each patient’s skin color was matched on a skin color chart under a fluorescent lamp by the same physician on each occasion. Iron, iron binding capacity, ferritin and complete blood count (CBC) were studied for each patient enrolled. Colors marked on the visual skin color chart were compared with the laboratory results. Thirty-five patients being monitored at our hospital were included, 19 (54.3%) males and 16 (45.7%) females. The colors marked on the chart darkened as patients aged (p?=?0.002, r?=?0.49), the frequency of annual transfusions (p?=?0.022, r?=?0.385), ferritin levels (p?r?=?0.72) and iron levels increased (p?=?0.001, r?=?0.538) and as total iron binding capacity (TIBC) decreased (p?r?=?–0.709). On the basis of this study, iron deposition in patients with β-TM was correlated with the colors on the chart.     

Quality of Life and Depression in Turkish Patients with β-Thalassemia Major: A Cross-Sectional Study

Abstract

Thalassemias are the most common monogenic disorders worldwide. Thalassemia patients experience difficulties in their schooling, finding jobs and/or marriage because of functional and physical limitations caused by this disease. It is expected that the quality of life (QoL) of patients with thalassemia will be lower than those without this disease. The aim of this study was to benefit worldwide thalassemia patients in terms of QoL and mental health. This cross-sectional study was performed in Turkey. The study population consisted of of 57 β-thalassemia major (β-TM) patients and the control group. The short form-36 (SF-36) questionnaire and Beck depression inventory (BDI) were used. The mean age of the patients was 21.6?±?6.6 (age range 15-39) and the male-to-female ratio was 0.7. The mean SF-36 scores of the patient and the control groups were 59.2?±?12.4 and 75.7?±?11.8, and the mean BDI scores of the patients and controls were 13.5?±?6.4 and 6.1?±?3.7, respectively. There was a statistically significant difference between the total SF-36 and BDI scores of patients and controls. We aimed to investigate the effects of the decrease in morbidity and mortality of β-thalassemia (β-thal) due to regular transfusions and chelation therapy on the QoL and mental health of patients. The β-TM patients have a comparatively worse QoL score than the normal population. Improving QoL should be the target of clinicians who are monitoring adolescent or young adult β-TM patients.     

Left Ventricular Diastolic Dysfunction in β-Thalassemia Major with Heart Failure

We studied the clinical, electrocardiographic, echocardiographic, Doppler and T2* cardiac magnetic resonance (CMR) data of all adult β-thalassemia major (β-TM) patients with heart failure (HF) consecutively observed at our referral center of the Sicilian region between 2008 and 2016. There were 16 patients enrolled in the study. Echocardiographic examination showed that only one patient had HF with systolic dysfunction of the left ventricle (HFrEF), whereas the others had HF with preserved systolic function of the left ventricle (HFpEF). Systolic dysfunction of the right ventricle (RV) was observed in 13 cases. Furthermore, 30.0% of the patients presented T2* CMR values consistent with intermediate risk of systolic dysfunction of the left ventricle (LV) due to iron overload, whereas 70.0% had normal values. Typical electrocardiographic abnormalities (wide T wave inversion and low voltages) were observed in 11 out of 16 patients. In conclusion, in the adult β-TM patients with HF recently observed at our center, the predominant form was that with diastolic dysfunction of the LV, and with systolic dysfunction of the RV. Only 30.0% had low values of T2* CMR. Typical electrocardiographic abnormalities were found in 69.0%.     

Elevated Serum Levels of Cell Death Circulating Biomarkers,M30 and M65, In Patients with β-Thalassemia Major

Deposition of iron in visceral organs, mainly in the liver, causes tissue damage in β-thalassemia major (β-TM) patients. Keratin 18 (K18) represents one of the major caspase substrates during apoptosis of hepatocytes. To better characterize the hepatic apoptosis and/or necrosis in β-thal patients, the circulating levels of M65 (soluble intact K18) and M30 (the caspases-generated K18 fragment) were measured in 40 β-TM patients and compared with 40 healthy controls. The ratio of M30/M65 (caspase-cleaved to total K18) was also determined in thalassemic and normal subjects. Results of the ELISA assays revealed that the serum levels of hepatocyte death markers, M65 and M30, were significantly increased in β-thal patients compared to healthy controls (p <0.0001). M30 serum levels were also positively correlated with the serum levels of liver transaminases including aspartate aminotransferase (AST) (r = 0.337, p = 0.047) and alanine aminotransferase (ALT) (r =0.391, p = 0.02).     

Assessment of Peripheral Neuropathy in Patients with β-Thalassemia via Electrophysiological Study: Reevaluation in the Era of Iron Chelators

Peripheral neuropathy is one of the complications of β-thalassemia (β-thal) that has been investigated in limited reports. We aimed to detect the rate of peripheral neuropathy and risk factors for neuropathy development in patients with β-thal. The study was performed in patients with β-thal intermedia (β-TI) or β-thal major (β-TM). Prospective electrophysiological studies were achieved via standard procedures. A total of 27 patients were enrolled in the study. Electrophysiological studies for both motor and sensory nerves were within normal range. In motor nerve studies, delayed peroneal nerve latency was found in patients with high ferritin levels, increased ulnar nerve amplitude was detected in patients ≥20 years old, and increased tibial nerve amplitude was seen in patients with low copper levels. We could not show peripheral neuropathy in our patients. Increased ferritin level, older age, and copper deficiency may cause mild changes in electrophysiological studies of motor nerves.     

Molecular Heterogeneity of β-Thalassemia Alleles in Spain and its Importance in the Diagnosis and Prevention of β-Thalassemia Major and Sickle Cell Disorders

In the last 20 years, migratory flows have changed the pattern of β-thalassemia (β-thal) mutations in Catalonia and have also increased β^S prevalence, either alone or in association with β-thal alleles. Characterization of the β gene is needed for genetic counseling for β-thal major and also for sickle cell diseases. The purpose of this study was to investigate the current distribution pattern of β‐thal mutations. Seventy nine individuals were characterized at the molecular level. As a first step, frequent mutations in the Mediterranean region were screened and when none of these mutations were identified, the β-globin gene was sequenced. Screening for common mutations allowed the characterization of 60 individuals. In the remaining 19 cases, 11 different mutations were identified. β-Thalassemia heterogeneity in Spain has markedly increased, leading to the requirement of including new methods for genetic diagnosis. Prevention of β-thal major and sickle cell disease are necessary since their prevalence in Spain is increasing dramatically.