镰状细胞性贫血患儿造血干细胞移植后肾小球高滤过的逆转。

IF 9.9 1区 医学 Q1 HEMATOLOGY
Stella Huet, Annie Kamdem, Valentine Beaufront, Karima Yakouben, Nathalie Dhedin, Catherine Paillard, Isabelle Hau, Claire Falguière, Aoufa Dahmani, Bassem Khazem, Ekaterina Belozertsteva, Céline Delestrain, Stéphane Bechet, Cécile Arnaud, Corinne Pondarré
{"title":"镰状细胞性贫血患儿造血干细胞移植后肾小球高滤过的逆转。","authors":"Stella Huet,&nbsp;Annie Kamdem,&nbsp;Valentine Beaufront,&nbsp;Karima Yakouben,&nbsp;Nathalie Dhedin,&nbsp;Catherine Paillard,&nbsp;Isabelle Hau,&nbsp;Claire Falguière,&nbsp;Aoufa Dahmani,&nbsp;Bassem Khazem,&nbsp;Ekaterina Belozertsteva,&nbsp;Céline Delestrain,&nbsp;Stéphane Bechet,&nbsp;Cécile Arnaud,&nbsp;Corinne Pondarré","doi":"10.1002/ajh.70004","DOIUrl":null,"url":null,"abstract":"<p>Glomerular hyperfiltration is one of the earliest manifestations of sickle nephropathy, preceding the development of albuminuria and, ultimately, renal failure [<span>1</span>]. Among sickle genotypes, the sickle cell anemia (SCA) subgroup (HbSS and HbSβ<sup>0</sup> thalassemia) is associated with a higher estimated glomerular filtration rate (eGFR) [<span>2</span>], that may begin in infancy, as described in the BABY-HUG trial [<span>3</span>]. The pathogenesis of glomerular hyperfiltration in SCA remains unclear, but it involves chronic hemolysis and anemia resulting in a high renal plasma flow, with sickling of the red blood cells in the hypertonic, hypoxic, and acidic environment of the renal medulla leading to vaso-occlusion (VO), ischemia, and infarction of the vasa recta.</p><p>In our recently published regional newborn sickle cell disease (SCD) cohort study, we described substantial persistent morbidity due to acute complications and chronic organ damage in the SCA subgroup, providing a rationale for the earlier introduction of disease-modifying therapies (DMTs) [<span>4</span>]. However, there have been few investigations of the ability of DMTs to normalize eGFR in children with SCA [<span>3, 5</span>].</p><p>Our main objective was to study the impact of therapeutic intensification, such as hydroxyurea (HU), chronic transfusion program (TP) and hematopoietic stem cell transplantation (HSCT), on eGFR, using prospectively collected longitudinal data from our sickle cell disease (SCD) cohort.</p><p>This study was approved by our institutional ethics committee (no. 2021-07-09). We included only children diagnosed with SCD by newborn screening. Serum creatinine concentration and height data were collected prospectively during complete annual check-ups as part of standard patient management and were recorded in our database, allowing longitudinal GFR estimation. We used the pediatric under-25 formula, a method derived from the CKiD Schwartz formula for use in children and young adults up to 25 years old, to provide an estimate of kidney function adjusted for age and sex. In addition, patient and treatment characteristics such as age, DMT, routine blood count, hemoglobin (Hb), HbF, and HbS levels and hemolytic parameters were also monitored, making it possible to assess eGFR changes following DMT.</p><p>In accordance with national guidelines, at our regional center, HU is introduced after the recurrence of VO complications and/or low Hb levels, and TP, mainly for stroke prevention. Our center also specifically offers HSCT to patients with cerebral vasculopathy or frequent VO complications with a human leukocyte antigen-identical sibling [<span>4</span>].</p><p>Statistical analysis was conducted with STATA v17. The eGFR values (mL/min/1.73 m<sup>2</sup>) were described with mean, standard deviation (SD), median, interquartile range (IQR) and comparisons between sickle genotype groups were performed with non-parametric Wilcoxon–Mann–Whitney tests. For comparisons of eGFR and other biological parameters before therapeutic intensification with those obtained after DMT, we restricted the analysis to patients with both pre- and post-DMT eGFR values. Time-based groups were compared in non-parametric Kruskal–Wallis tests. Values of <i>p</i> &lt; 0.05 in two-tailed tests were considered statistically significant.</p><p>From 1993 to 2021, 606 children aged two to 18 years—474 with severe SCA genotypes and 132 with milder genotypes (HbSC and HbSβ<sup>+</sup> thalassemia)—had at least one complete clinical and biological check-up. In total, 3795 (mean 6.4 ± 3.8 per child) eGFR values were collected and analyzed.</p><p>We first investigated the natural course of eGFR values in patients with SCD, by restricting our analysis to data collected before any therapeutic intensification. The differences between the SCA and milder subgroups are shown in Figure S1. All the comparisons were statistically significant, indicating that eGFR was higher in the SCA subgroup for children of all age groups considered. Significantly higher eGFR values for this subgroup became apparent very early, in children as young as 2 years of age, consistent with the BABY-HUG results showing early hyperfiltration according to measured DTPA GFR [<span>3</span>]. Interestingly, estimation with the U25 formula, which is more accurate for young patients than adult-based equations, revealed that eGFR remained significantly higher in this subgroup until the age of 18 years.</p><p>To evaluate the impact of therapeutic intensification on eGFR, we limited our analysis to children with SCA. We compared eGFR values obtained close to the date of treatment modification: the last value obtained before and the first value obtained after treatment intensification. We also evaluated eGFR at the last check-up. To evaluate the impact of HU and TP on eGFR, only data for children for whom these treatments were the first therapeutic intensification were analyzed. To assess changes in renal function associated with HSCT, given that most children received some DMT before undergoing HSCT, post-transplant eGFRs were compared to pre-transplant levels, regardless of whether the patients were on HU or TP before transplantation.</p><p>We investigated the mechanisms contributing to changes in eGFR after therapeutic intensification by analyzing Hb, HbF, and HbS levels; reticulocyte, absolute leukocyte, and neutrophil counts (ANC); total bilirubin levels; and lactate dehydrogenase (LDH) activity immediately before and after therapeutic intensification.</p><p>No modification of eGFR was observed following the introduction of either HU (106 children, median 123.8 [IQR 110.1–145.6] after vs. 120.7 [IQR 102.9–138.9] mL/min/1.73 m<sup>2</sup> before HU), or a TP (74 children, 128.5 [IQR 107.4–148.1] after vs. 121.1 [IQR 104.3–142.5] mL/min/1.73 m<sup>2</sup> before TP). Conversely, both these treatments significantly improved Hb levels and decreased hemolysis (Table S1A,B). After a mean duration between HU initiation and last eGFR assessment of 5.8 ± 2.1 years, we observed no significant change in eGFR. Our data for HU therapy are consistent with those of the BABY-HUG trial, in which GFR was high for age at baseline but a fixed dose of HU (20 mg/kg/day) had no effect on glomerular hyperfiltration. By contrast, two small studies using the maximum tolerated dose (MTD) of HU suggested some efficacy. One of these studies showed that GFR was stabilized according to DTPA clearance or Schwartz estimates after 2 years of HU treatment in 14 preschool-aged children [<span>5</span>]. The other reported a significant decrease in measured DTPA GFR after 3 years of HU treatment in 23 children. This decrease was significantly associated with an increase in %HbF [<span>6</span>]. HU dose was not recorded in our database, but laboratory tests following the introduction of HU treatment showed significant increases in %HbF along with significant decreases in reticulocyte and ANC.</p><p>For chronic transfusion programs, after a mean of 4 years of TP maintaining Hb levels over 9 g/dL (mean 9.3 ± 1.2 g/dL) and HbS levels under 40% (mean 34.6% ± 14.6%), we observed no significant change in eGFR. Our data are consistent with the only other study to date investigating eGFR in transfused children (4–15 years) with SCA. Mean eGFR in these children did not differ significantly from the mean eGFR in age-matched children not receiving TP or HU [<span>7</span>].</p><p>In our cohort, 66 children underwent HSCT at a median age of 7 years (range 3–17 years), mostly from a genoidentical sibling (63/66) and with the same myeloablative conditioning regimen based on busulfan and cyclophosphamide chemotherapy combined with rabbit anti-thymocyte globulin (62/66). In the post-transplantation period, the main immunosuppressive treatment was cyclosporine, with or without methotrexate. Cyclosporine dose was generally gradually reduced between 6 and 9 months after transplantation. The characteristics of the children undergoing HSCT are summarized in Table 1. Following HSCT, all 66 patients displayed successful engraftment, with donor-type hemoglobin (median HbS 31.7%, IQR [0%–37.8%]). As expected, Hb levels (median 12.5 g/dL, IQR [11.5–13.2] g/dL) and reticulocyte counts (median 48 × 10<sup>9</sup>/L, IQR [35–67] × 10<sup>9</sup>/L) normalized after transplantation and were stable at last check-up (median 55 × 10<sup>9</sup>/L, IQR [46–80 × 10<sup>9</sup>/L]). All patients underwent a pre-transplantation TP, and most had received HU before HSCT. The pre-transplantation eGFRs were therefore collected in patients on HU or TP. The mean duration between transplantation and last eGFR assessment was 7.3 ± 2.9 years. We observed a significant decrease in eGFR between the value obtained immediately before HSCT (median 127.2, IQR [105.8–141.1] mL/min/1.73 m<sup>2</sup>) and 1 year after HSCT (median 114.9, IQR [97.9–134.3] mL/min/1.73 m<sup>2</sup>). This decrease was maintained at the last check-up (median 104.0, IQR [91.0–116.8] mL/min/1.73 m<sup>2</sup>) (<i>p</i> &lt; 0001). (Table 2). At last follow-up, eGFR remained &gt; 75 mL/min/1.73 m<sup>2</sup> in all children. Interestingly, a previous study reported stable renal function, with less hyperfiltration at last follow-up, in 18 children and adolescents with SCA who underwent non-myeloablative HSCT [<span>8</span>]. In our cohort, only one boy developed post-transplantation macro-albuminuria (albuminuria-to-creatininuria ratio ≥ 300 mg/g), while under sirolimus therapy, which persisted after discontinuation. HSCT was performed at 17 years of age using a non-myeloablative regimen.</p><p>Finally, we compared post-transplantation eGFR levels with those of age-matched children with HbSC disease, from the ages of 6 to 16 years. After transplantation, eGFR decreased to levels similar to those observed in HbSC disease for children of all ages, suggesting that glomerular hyperfiltration was reversed following HSCT (Table 3).</p><p>In conclusion, we report the largest prospective longitudinal study of eGFR in a cohort of children with SCD. Our study has limitations that should be noted. First, this study relied on surrogate markers of renal function (i.e., no measured GFR). Second, we did not systematically collect serum creatinine values within the first 100 days post-HSCT. As a result, we may have missed early episodes of acute kidney injury during the immediate post-transplantation period.</p><p>Our results confirm that, in the absence of intensification, eGFR is significantly higher in the SCA (HbSS/Sβ<sup>0</sup> thalassemia) subgroup than in the subgroup with milder disease (HbSC/Sβ<sup>+</sup> thalassemia). The basis of the early increase in eGFR in the SCA cohort remains a matter for speculation, but the earlier and higher viscosity vaso-occlusion and hemolysis–endothelial dysfunction associated with the SCA phenotype may account for the differences in the course of glomerular filtration in these populations.</p><p>Anemia improved after HU and TP, but neither of these treatment intensifications had any effect on eGFR. The absence of HU dose information is another limitation in our study. In our center, an escalation of HU treatment to the MTD was recommended from 2015, but was rarely implemented before, as reflected by the moderate myelosuppression observed under HU (mean ANC 2.8 ± 1.1 × 10<sup>9</sup>/L on HU at last check-up; Table S1B). Further investigations are required to determine whether earlier HU initiation and escalation to the MTD can help prevent the development of glomerular hyperfiltration. By contrast, eGFR decreased rapidly within 1 year of successful HSCT and was lower at the last follow-up visit (mean post-transplantation FU of 7 years). These changes were associated with a normalization of hemoglobin levels and reticulocyte counts, and improvements in inflammation markers, with a significant decrease in ANC. Hyperfiltration during early childhood precedes albuminuria. The reversal of hyperfiltration after HSCT may, therefore, prevent long-term renal morbidity in the population of SCA patients. Long-term studies are, however, warranted to better understand the impact of HSCT-related toxicities (conditioning regimen, immunosuppressive medications, infections, graft-vs.-host disease) versus reversal of the SCD phenotype on kidney function. In addition, kidney function after transplantation may differ significantly between pediatric and adult populations. We believe that our results provide a rationale for the early performance of genoidentical myeloablative HSCT in this population.</p><p>S.H. and C.P. cared for patients, designed the study, collected and interpreted the data, wrote the article, and took final responsibility for the decision to submit for publication. A.K. cared for patients, collected and interpreted data. C.A. cared for patients and collected data. V.B. collected and interpreted data. E.B. collected data. S.B. carried out the statistical analysis. A.D. and B.K. provided biological data. K.Y., N.D., C.Pa., I.H., C.F., and C.D. cared for the patients. All the authors reviewed the paper and approved the final manuscript.</p><p>The authors confirm that the PI for this paper is Corinne Pondarré and that the PI had direct clinical responsibility for patients.</p><p>C.P. reports honoraria and expert consultancy for Theravia and Pfizer. The other authors declare no conflicts of interest.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 10","pages":"1886-1890"},"PeriodicalIF":9.9000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70004","citationCount":"0","resultStr":"{\"title\":\"Reversal of Glomerular Hyperfiltration Following Hematopoietic Stem Cell Transplantation in Children With Sickle-Cell Anemia\",\"authors\":\"Stella Huet,&nbsp;Annie Kamdem,&nbsp;Valentine Beaufront,&nbsp;Karima Yakouben,&nbsp;Nathalie Dhedin,&nbsp;Catherine Paillard,&nbsp;Isabelle Hau,&nbsp;Claire Falguière,&nbsp;Aoufa Dahmani,&nbsp;Bassem Khazem,&nbsp;Ekaterina Belozertsteva,&nbsp;Céline Delestrain,&nbsp;Stéphane Bechet,&nbsp;Cécile Arnaud,&nbsp;Corinne Pondarré\",\"doi\":\"10.1002/ajh.70004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Glomerular hyperfiltration is one of the earliest manifestations of sickle nephropathy, preceding the development of albuminuria and, ultimately, renal failure [<span>1</span>]. Among sickle genotypes, the sickle cell anemia (SCA) subgroup (HbSS and HbSβ<sup>0</sup> thalassemia) is associated with a higher estimated glomerular filtration rate (eGFR) [<span>2</span>], that may begin in infancy, as described in the BABY-HUG trial [<span>3</span>]. The pathogenesis of glomerular hyperfiltration in SCA remains unclear, but it involves chronic hemolysis and anemia resulting in a high renal plasma flow, with sickling of the red blood cells in the hypertonic, hypoxic, and acidic environment of the renal medulla leading to vaso-occlusion (VO), ischemia, and infarction of the vasa recta.</p><p>In our recently published regional newborn sickle cell disease (SCD) cohort study, we described substantial persistent morbidity due to acute complications and chronic organ damage in the SCA subgroup, providing a rationale for the earlier introduction of disease-modifying therapies (DMTs) [<span>4</span>]. However, there have been few investigations of the ability of DMTs to normalize eGFR in children with SCA [<span>3, 5</span>].</p><p>Our main objective was to study the impact of therapeutic intensification, such as hydroxyurea (HU), chronic transfusion program (TP) and hematopoietic stem cell transplantation (HSCT), on eGFR, using prospectively collected longitudinal data from our sickle cell disease (SCD) cohort.</p><p>This study was approved by our institutional ethics committee (no. 2021-07-09). We included only children diagnosed with SCD by newborn screening. Serum creatinine concentration and height data were collected prospectively during complete annual check-ups as part of standard patient management and were recorded in our database, allowing longitudinal GFR estimation. We used the pediatric under-25 formula, a method derived from the CKiD Schwartz formula for use in children and young adults up to 25 years old, to provide an estimate of kidney function adjusted for age and sex. In addition, patient and treatment characteristics such as age, DMT, routine blood count, hemoglobin (Hb), HbF, and HbS levels and hemolytic parameters were also monitored, making it possible to assess eGFR changes following DMT.</p><p>In accordance with national guidelines, at our regional center, HU is introduced after the recurrence of VO complications and/or low Hb levels, and TP, mainly for stroke prevention. Our center also specifically offers HSCT to patients with cerebral vasculopathy or frequent VO complications with a human leukocyte antigen-identical sibling [<span>4</span>].</p><p>Statistical analysis was conducted with STATA v17. The eGFR values (mL/min/1.73 m<sup>2</sup>) were described with mean, standard deviation (SD), median, interquartile range (IQR) and comparisons between sickle genotype groups were performed with non-parametric Wilcoxon–Mann–Whitney tests. For comparisons of eGFR and other biological parameters before therapeutic intensification with those obtained after DMT, we restricted the analysis to patients with both pre- and post-DMT eGFR values. Time-based groups were compared in non-parametric Kruskal–Wallis tests. Values of <i>p</i> &lt; 0.05 in two-tailed tests were considered statistically significant.</p><p>From 1993 to 2021, 606 children aged two to 18 years—474 with severe SCA genotypes and 132 with milder genotypes (HbSC and HbSβ<sup>+</sup> thalassemia)—had at least one complete clinical and biological check-up. In total, 3795 (mean 6.4 ± 3.8 per child) eGFR values were collected and analyzed.</p><p>We first investigated the natural course of eGFR values in patients with SCD, by restricting our analysis to data collected before any therapeutic intensification. The differences between the SCA and milder subgroups are shown in Figure S1. All the comparisons were statistically significant, indicating that eGFR was higher in the SCA subgroup for children of all age groups considered. Significantly higher eGFR values for this subgroup became apparent very early, in children as young as 2 years of age, consistent with the BABY-HUG results showing early hyperfiltration according to measured DTPA GFR [<span>3</span>]. Interestingly, estimation with the U25 formula, which is more accurate for young patients than adult-based equations, revealed that eGFR remained significantly higher in this subgroup until the age of 18 years.</p><p>To evaluate the impact of therapeutic intensification on eGFR, we limited our analysis to children with SCA. We compared eGFR values obtained close to the date of treatment modification: the last value obtained before and the first value obtained after treatment intensification. We also evaluated eGFR at the last check-up. To evaluate the impact of HU and TP on eGFR, only data for children for whom these treatments were the first therapeutic intensification were analyzed. To assess changes in renal function associated with HSCT, given that most children received some DMT before undergoing HSCT, post-transplant eGFRs were compared to pre-transplant levels, regardless of whether the patients were on HU or TP before transplantation.</p><p>We investigated the mechanisms contributing to changes in eGFR after therapeutic intensification by analyzing Hb, HbF, and HbS levels; reticulocyte, absolute leukocyte, and neutrophil counts (ANC); total bilirubin levels; and lactate dehydrogenase (LDH) activity immediately before and after therapeutic intensification.</p><p>No modification of eGFR was observed following the introduction of either HU (106 children, median 123.8 [IQR 110.1–145.6] after vs. 120.7 [IQR 102.9–138.9] mL/min/1.73 m<sup>2</sup> before HU), or a TP (74 children, 128.5 [IQR 107.4–148.1] after vs. 121.1 [IQR 104.3–142.5] mL/min/1.73 m<sup>2</sup> before TP). Conversely, both these treatments significantly improved Hb levels and decreased hemolysis (Table S1A,B). After a mean duration between HU initiation and last eGFR assessment of 5.8 ± 2.1 years, we observed no significant change in eGFR. Our data for HU therapy are consistent with those of the BABY-HUG trial, in which GFR was high for age at baseline but a fixed dose of HU (20 mg/kg/day) had no effect on glomerular hyperfiltration. By contrast, two small studies using the maximum tolerated dose (MTD) of HU suggested some efficacy. One of these studies showed that GFR was stabilized according to DTPA clearance or Schwartz estimates after 2 years of HU treatment in 14 preschool-aged children [<span>5</span>]. The other reported a significant decrease in measured DTPA GFR after 3 years of HU treatment in 23 children. This decrease was significantly associated with an increase in %HbF [<span>6</span>]. HU dose was not recorded in our database, but laboratory tests following the introduction of HU treatment showed significant increases in %HbF along with significant decreases in reticulocyte and ANC.</p><p>For chronic transfusion programs, after a mean of 4 years of TP maintaining Hb levels over 9 g/dL (mean 9.3 ± 1.2 g/dL) and HbS levels under 40% (mean 34.6% ± 14.6%), we observed no significant change in eGFR. Our data are consistent with the only other study to date investigating eGFR in transfused children (4–15 years) with SCA. Mean eGFR in these children did not differ significantly from the mean eGFR in age-matched children not receiving TP or HU [<span>7</span>].</p><p>In our cohort, 66 children underwent HSCT at a median age of 7 years (range 3–17 years), mostly from a genoidentical sibling (63/66) and with the same myeloablative conditioning regimen based on busulfan and cyclophosphamide chemotherapy combined with rabbit anti-thymocyte globulin (62/66). In the post-transplantation period, the main immunosuppressive treatment was cyclosporine, with or without methotrexate. Cyclosporine dose was generally gradually reduced between 6 and 9 months after transplantation. The characteristics of the children undergoing HSCT are summarized in Table 1. Following HSCT, all 66 patients displayed successful engraftment, with donor-type hemoglobin (median HbS 31.7%, IQR [0%–37.8%]). As expected, Hb levels (median 12.5 g/dL, IQR [11.5–13.2] g/dL) and reticulocyte counts (median 48 × 10<sup>9</sup>/L, IQR [35–67] × 10<sup>9</sup>/L) normalized after transplantation and were stable at last check-up (median 55 × 10<sup>9</sup>/L, IQR [46–80 × 10<sup>9</sup>/L]). All patients underwent a pre-transplantation TP, and most had received HU before HSCT. The pre-transplantation eGFRs were therefore collected in patients on HU or TP. The mean duration between transplantation and last eGFR assessment was 7.3 ± 2.9 years. We observed a significant decrease in eGFR between the value obtained immediately before HSCT (median 127.2, IQR [105.8–141.1] mL/min/1.73 m<sup>2</sup>) and 1 year after HSCT (median 114.9, IQR [97.9–134.3] mL/min/1.73 m<sup>2</sup>). This decrease was maintained at the last check-up (median 104.0, IQR [91.0–116.8] mL/min/1.73 m<sup>2</sup>) (<i>p</i> &lt; 0001). (Table 2). At last follow-up, eGFR remained &gt; 75 mL/min/1.73 m<sup>2</sup> in all children. Interestingly, a previous study reported stable renal function, with less hyperfiltration at last follow-up, in 18 children and adolescents with SCA who underwent non-myeloablative HSCT [<span>8</span>]. In our cohort, only one boy developed post-transplantation macro-albuminuria (albuminuria-to-creatininuria ratio ≥ 300 mg/g), while under sirolimus therapy, which persisted after discontinuation. HSCT was performed at 17 years of age using a non-myeloablative regimen.</p><p>Finally, we compared post-transplantation eGFR levels with those of age-matched children with HbSC disease, from the ages of 6 to 16 years. After transplantation, eGFR decreased to levels similar to those observed in HbSC disease for children of all ages, suggesting that glomerular hyperfiltration was reversed following HSCT (Table 3).</p><p>In conclusion, we report the largest prospective longitudinal study of eGFR in a cohort of children with SCD. Our study has limitations that should be noted. First, this study relied on surrogate markers of renal function (i.e., no measured GFR). Second, we did not systematically collect serum creatinine values within the first 100 days post-HSCT. As a result, we may have missed early episodes of acute kidney injury during the immediate post-transplantation period.</p><p>Our results confirm that, in the absence of intensification, eGFR is significantly higher in the SCA (HbSS/Sβ<sup>0</sup> thalassemia) subgroup than in the subgroup with milder disease (HbSC/Sβ<sup>+</sup> thalassemia). The basis of the early increase in eGFR in the SCA cohort remains a matter for speculation, but the earlier and higher viscosity vaso-occlusion and hemolysis–endothelial dysfunction associated with the SCA phenotype may account for the differences in the course of glomerular filtration in these populations.</p><p>Anemia improved after HU and TP, but neither of these treatment intensifications had any effect on eGFR. The absence of HU dose information is another limitation in our study. In our center, an escalation of HU treatment to the MTD was recommended from 2015, but was rarely implemented before, as reflected by the moderate myelosuppression observed under HU (mean ANC 2.8 ± 1.1 × 10<sup>9</sup>/L on HU at last check-up; Table S1B). Further investigations are required to determine whether earlier HU initiation and escalation to the MTD can help prevent the development of glomerular hyperfiltration. By contrast, eGFR decreased rapidly within 1 year of successful HSCT and was lower at the last follow-up visit (mean post-transplantation FU of 7 years). These changes were associated with a normalization of hemoglobin levels and reticulocyte counts, and improvements in inflammation markers, with a significant decrease in ANC. Hyperfiltration during early childhood precedes albuminuria. The reversal of hyperfiltration after HSCT may, therefore, prevent long-term renal morbidity in the population of SCA patients. Long-term studies are, however, warranted to better understand the impact of HSCT-related toxicities (conditioning regimen, immunosuppressive medications, infections, graft-vs.-host disease) versus reversal of the SCD phenotype on kidney function. In addition, kidney function after transplantation may differ significantly between pediatric and adult populations. We believe that our results provide a rationale for the early performance of genoidentical myeloablative HSCT in this population.</p><p>S.H. and C.P. cared for patients, designed the study, collected and interpreted the data, wrote the article, and took final responsibility for the decision to submit for publication. A.K. cared for patients, collected and interpreted data. C.A. cared for patients and collected data. V.B. collected and interpreted data. E.B. collected data. S.B. carried out the statistical analysis. A.D. and B.K. provided biological data. K.Y., N.D., C.Pa., I.H., C.F., and C.D. cared for the patients. All the authors reviewed the paper and approved the final manuscript.</p><p>The authors confirm that the PI for this paper is Corinne Pondarré and that the PI had direct clinical responsibility for patients.</p><p>C.P. reports honoraria and expert consultancy for Theravia and Pfizer. The other authors declare no conflicts of interest.</p>\",\"PeriodicalId\":7724,\"journal\":{\"name\":\"American Journal of Hematology\",\"volume\":\"100 10\",\"pages\":\"1886-1890\"},\"PeriodicalIF\":9.9000,\"publicationDate\":\"2025-07-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70004\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Hematology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ajh.70004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Hematology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ajh.70004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肾小球高滤过是镰状肾病的早期表现之一,早于蛋白尿的发展,最终导致肾功能衰竭。在镰状细胞性贫血基因型中,镰状细胞性贫血(SCA)亚组(HbSS和HbSβ0地中海贫血)与较高的肾小球滤过率(eGFR)[2]相关,这可能始于婴儿期,如婴儿拥抱试验[3]所述。SCA患者肾小球高滤过的发病机制尚不清楚,但它涉及慢性溶血和贫血,导致肾血浆流量高,肾髓质高渗、缺氧和酸性环境中的红细胞镰状坏死,导致血管闭塞(VO)、缺血和直血管梗死。在我们最近发表的区域性新生儿镰状细胞病(SCD)队列研究中,我们描述了SCA亚组中由于急性并发症和慢性器官损伤而导致的大量持续发病率,为早期引入疾病修饰疗法(DMTs)提供了理论依据。然而,很少有关于dmt使SCA患儿eGFR正常化能力的研究[3,5]。我们的主要目的是研究强化治疗,如羟基脲(HU)、慢性输血计划(TP)和造血干细胞移植(HSCT)对eGFR的影响,使用镰状细胞病(SCD)队列前瞻性收集的纵向数据。本研究已获我院伦理委员会批准(编号:no。2021-07-09)。我们只纳入通过新生儿筛查诊断为SCD的儿童。作为标准患者管理的一部分,在完整的年度检查期间前瞻性地收集血清肌酐浓度和身高数据,并记录在我们的数据库中,以便纵向估计GFR。我们使用了25岁以下的儿童公式,这是一种源自CKiD Schwartz公式的方法,用于25岁以下的儿童和年轻人,以提供根据年龄和性别调整的肾功能估计。此外,还监测了患者和治疗特征,如年龄、DMT、常规血细胞计数、血红蛋白(Hb)、HbF和HbS水平以及溶血参数,从而可以评估DMT后eGFR的变化。根据国家指南,在我们的区域中心,在VO并发症复发和/或低Hb水平后引入HU,而TP主要用于预防脑卒中。我们的中心还专门为患有脑血管病或经常伴有人类白细胞抗原相同的兄弟姐妹[4]的VO并发症的患者提供HSCT。采用STATA v17软件进行统计分析。eGFR值(mL/min/1.73 m2)用均数、标准差(SD)、中位数、四分位间距(IQR)描述,镰状基因型组间比较采用非参数Wilcoxon-Mann-Whitney检验。为了比较强化治疗前与DMT后获得的eGFR和其他生物学参数,我们将分析限制在DMT前和DMT后的eGFR值患者。在非参数Kruskal-Wallis检验中比较基于时间的组。双侧检验p &lt; 0.05的值被认为具有统计学意义。从1993年到2021年,606名2至18岁的儿童(474名患有重度SCA基因型,132名患有轻度基因型(HbSC和HbSβ+地中海贫血))至少进行了一次完整的临床和生物学检查。共收集和分析了3795个(平均每名儿童6.4±3.8个)eGFR值。我们首先研究了SCD患者eGFR值的自然过程,将我们的分析限制在任何强化治疗前收集的数据。SCA和较温和的子组之间的差异如图S1所示。所有的比较都具有统计学意义,表明所有年龄组的SCA亚组儿童的eGFR较高。该亚组的eGFR值明显升高,在2岁的儿童中就很早就显现出来,与BABY-HUG结果一致,根据测量的DTPA GFR[3]显示早期超滤。有趣的是,使用U25公式(对年轻患者的估计比基于成人的公式更准确)的估计显示,直到18岁,该亚组的eGFR仍然显着较高。为了评估强化治疗对eGFR的影响,我们将分析局限于SCA患儿。我们比较了接近治疗修改日期获得的eGFR值:治疗强化前获得的最后一个值和治疗强化后获得的第一个值。我们还在最后一次检查中评估了eGFR。为了评估HU和TP对eGFR的影响,只分析了这些治疗是第一次强化治疗的儿童的数据。 为了评估与HSCT相关的肾功能变化,考虑到大多数儿童在接受HSCT之前接受了一些DMT,移植后的egfr与移植前的水平进行了比较,无论患者在移植前是使用HU还是TP。我们通过分析Hb、HbF和HbS水平来研究强化治疗后eGFR变化的机制;网织细胞、绝对白细胞和中性粒细胞计数(ANC);总胆红素水平;乳酸脱氢酶(LDH)活性。引入HU(106名儿童,HU前中位数为123.8 [IQR 110.1-145.6], HU前中位数为120.7 [IQR 102.9-138.9] mL/min/1.73 m2)或TP(74名儿童,TP后中位数为128.5 [IQR 107.4-148.1], TP前中位数为121.1 [IQR 104.3-142.5] mL/min/1.73 m2)均未观察到eGFR的改变。相反,这两种治疗都显著改善了Hb水平,降低了溶血(表S1A,B)。从HU开始到最后一次eGFR评估的平均持续时间为5.8±2.1年,我们观察到eGFR没有显著变化。我们关于HU治疗的数据与BABY-HUG试验的数据一致,在该试验中,GFR在基线时高于年龄,但固定剂量的HU (20mg /kg/天)对肾小球高滤过没有影响。相比之下,两项使用HU最大耐受剂量(MTD)的小型研究显示有一定疗效。其中一项研究显示,14名学龄前儿童接受2年胡治疗后,GFR根据DTPA清除率或Schwartz估计值趋于稳定。另一项研究报告了23名儿童在HU治疗3年后DTPA GFR测量值的显著下降。这种下降与% hbf[6]的增加显著相关。我们的数据库中没有记录HU的剂量,但引入HU治疗后的实验室检查显示HbF显著增加,网织红细胞和ANC显著降低。对于慢性输血项目,平均4年后,TP维持Hb水平超过9 g/dL(平均9.3±1.2 g/dL)和HbS水平低于40%(平均34.6%±14.6%),我们观察到eGFR没有显著变化。我们的数据与迄今为止唯一一项调查输血儿童(4-15岁)SCA患者eGFR的研究一致。这些儿童的平均eGFR与未接受TP或HU治疗的同龄儿童的平均eGFR无显著差异。在我们的队列中,66名儿童在中位年龄为7岁(范围3-17岁)时接受了HSCT,其中大多数来自基因相同的兄弟姐妹(63/66),并且采用相同的骨髓清除调节方案,基于布苏凡和环磷酰胺化疗联合兔抗胸腺细胞球蛋白(62/66)。在移植后,主要的免疫抑制治疗是环孢素,联合或不联合甲氨蝶呤。环孢素剂量一般在移植后6 ~ 9个月逐渐减少。表1总结了接受HSCT的儿童的特征。HSCT后,所有66例患者均成功移植,具有供体型血红蛋白(HbS中位数为31.7%,IQR[0%-37.8%])。正如预期的那样,Hb水平(中位数12.5 g/dL, IQR [11.5-13.2] g/dL)和网织红细胞计数(中位数48 × 109/L, IQR [35-67] × 109/L)在移植后恢复正常,最后一次检查时稳定(中位数55 × 109/L, IQR [46-80 × 109/L])。所有患者在移植前都接受了TP,大多数患者在移植前接受了HU。因此,在HU或TP患者中收集移植前egfr。移植至最后一次eGFR评估的平均时间为7.3±2.9年。我们观察到,在HSCT前(中位数127.2,IQR [105.8-141.1] mL/min/1.73 m2)和HSCT后1年(中位数114.9,IQR [97.9-134.3] mL/min/1.73 m2)获得的eGFR值显著下降。这种下降在最后一次检查时保持不变(中位数104.0,IQR [91.0-116.8] mL/min/1.73 m2) (p &lt; 0001)。(表2)。最后一次随访中,所有儿童的eGFR维持在75 mL/min/1.73 m2。有趣的是,先前的一项研究报告了18名患有SCA的儿童和青少年接受非清髓性造血干细胞移植后,肾功能稳定,最后随访时高滤过较少。在我们的队列中,只有一名男孩在接受西罗莫司治疗后出现移植后大量蛋白尿(蛋白尿与肌酐尿比值≥300mg /g),停药后持续存在。HSCT于17岁时采用非清髓方案进行。最后,我们比较了移植后的eGFR水平与年龄匹配的6至16岁HbSC疾病儿童的eGFR水平。移植后,所有年龄段儿童的eGFR下降到与HbSC疾病相似的水平,表明HSCT后肾小球高滤过被逆转(表3)。总之,我们报告了SCD儿童队列中最大的eGFR前瞻性纵向研究。我们的研究有局限性,值得注意。 首先,本研究依赖于肾功能的替代标志物(即未测量GFR)。其次,我们没有系统地收集造血干细胞移植后前100天内的血清肌酐值。因此,我们可能会在移植后立即错过急性肾损伤的早期发作。我们的研究结果证实,在没有强化的情况下,SCA (HbSS/ s - β0地中海贫血)亚组的eGFR明显高于病情较轻的亚组(HbSC/ s - β+地中海贫血)。SCA队列中eGFR早期升高的基础仍有待推测,但SCA表型相关的更早和更高粘度的血管闭塞和溶血内皮功能障碍可能解释了这些人群肾小球滤过过程的差异。HU和TP治疗后贫血有所改善,但这两种强化治疗对eGFR均无影响。缺乏HU剂量信息是我们研究的另一个限制。在我们中心,从2015年开始推荐将HU治疗升级到MTD,但之前很少实施,这反映在HU治疗下观察到中度骨髓抑制(最后一次检查时HU的平均ANC为2.8±1.1 × 109/L;表S1B)。需要进一步的研究来确定早期HU的发生和升级到MTD是否有助于预防肾小球高滤过的发展。相比之下,eGFR在移植成功后1年内迅速下降,在最后一次随访时更低(移植后平均FU为7年)。这些变化与血红蛋白水平和网织红细胞计数的正常化、炎症标志物的改善以及ANC的显著降低有关。儿童早期的高滤过先于蛋白尿。因此,造血干细胞移植后高滤过的逆转可以预防SCA患者群体的长期肾脏发病率。然而,为了更好地了解hsct相关毒性(调节方案、免疫抑制药物、感染、移植物vs.移植)的影响,需要进行长期研究。-宿主病)与逆转SCD表型对肾功能的影响。此外,移植后的肾功能在儿童和成人人群中可能存在显著差异。我们相信,我们的结果为基因相同的清髓性造血干细胞移植在这一人群中的早期表现提供了理论依据。cp照顾病人,设计研究,收集和解释数据,撰写文章,并对提交发表的决定承担最终责任。A.K.照顾病人,收集和解释数据。ca照顾病人并收集数据。V.B.收集并解释数据。E.B.收集数据。S.B.进行了统计分析。ad和B.K.提供了生物学数据。纽约州,北达科他州,宾夕法尼亚州。, i.h., c.f.和C.D.负责照顾病人。所有的作者都审阅了论文并批准了最终的手稿。作者确认本文的PI是Corinne pondarr<e:1>,并且PI对患者的cp有直接的临床责任。报告酬金和专家咨询Theravia和辉瑞。其他作者声明没有利益冲突。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reversal of Glomerular Hyperfiltration Following Hematopoietic Stem Cell Transplantation in Children With Sickle-Cell Anemia

Glomerular hyperfiltration is one of the earliest manifestations of sickle nephropathy, preceding the development of albuminuria and, ultimately, renal failure [1]. Among sickle genotypes, the sickle cell anemia (SCA) subgroup (HbSS and HbSβ0 thalassemia) is associated with a higher estimated glomerular filtration rate (eGFR) [2], that may begin in infancy, as described in the BABY-HUG trial [3]. The pathogenesis of glomerular hyperfiltration in SCA remains unclear, but it involves chronic hemolysis and anemia resulting in a high renal plasma flow, with sickling of the red blood cells in the hypertonic, hypoxic, and acidic environment of the renal medulla leading to vaso-occlusion (VO), ischemia, and infarction of the vasa recta.

In our recently published regional newborn sickle cell disease (SCD) cohort study, we described substantial persistent morbidity due to acute complications and chronic organ damage in the SCA subgroup, providing a rationale for the earlier introduction of disease-modifying therapies (DMTs) [4]. However, there have been few investigations of the ability of DMTs to normalize eGFR in children with SCA [3, 5].

Our main objective was to study the impact of therapeutic intensification, such as hydroxyurea (HU), chronic transfusion program (TP) and hematopoietic stem cell transplantation (HSCT), on eGFR, using prospectively collected longitudinal data from our sickle cell disease (SCD) cohort.

This study was approved by our institutional ethics committee (no. 2021-07-09). We included only children diagnosed with SCD by newborn screening. Serum creatinine concentration and height data were collected prospectively during complete annual check-ups as part of standard patient management and were recorded in our database, allowing longitudinal GFR estimation. We used the pediatric under-25 formula, a method derived from the CKiD Schwartz formula for use in children and young adults up to 25 years old, to provide an estimate of kidney function adjusted for age and sex. In addition, patient and treatment characteristics such as age, DMT, routine blood count, hemoglobin (Hb), HbF, and HbS levels and hemolytic parameters were also monitored, making it possible to assess eGFR changes following DMT.

In accordance with national guidelines, at our regional center, HU is introduced after the recurrence of VO complications and/or low Hb levels, and TP, mainly for stroke prevention. Our center also specifically offers HSCT to patients with cerebral vasculopathy or frequent VO complications with a human leukocyte antigen-identical sibling [4].

Statistical analysis was conducted with STATA v17. The eGFR values (mL/min/1.73 m2) were described with mean, standard deviation (SD), median, interquartile range (IQR) and comparisons between sickle genotype groups were performed with non-parametric Wilcoxon–Mann–Whitney tests. For comparisons of eGFR and other biological parameters before therapeutic intensification with those obtained after DMT, we restricted the analysis to patients with both pre- and post-DMT eGFR values. Time-based groups were compared in non-parametric Kruskal–Wallis tests. Values of p < 0.05 in two-tailed tests were considered statistically significant.

From 1993 to 2021, 606 children aged two to 18 years—474 with severe SCA genotypes and 132 with milder genotypes (HbSC and HbSβ+ thalassemia)—had at least one complete clinical and biological check-up. In total, 3795 (mean 6.4 ± 3.8 per child) eGFR values were collected and analyzed.

We first investigated the natural course of eGFR values in patients with SCD, by restricting our analysis to data collected before any therapeutic intensification. The differences between the SCA and milder subgroups are shown in Figure S1. All the comparisons were statistically significant, indicating that eGFR was higher in the SCA subgroup for children of all age groups considered. Significantly higher eGFR values for this subgroup became apparent very early, in children as young as 2 years of age, consistent with the BABY-HUG results showing early hyperfiltration according to measured DTPA GFR [3]. Interestingly, estimation with the U25 formula, which is more accurate for young patients than adult-based equations, revealed that eGFR remained significantly higher in this subgroup until the age of 18 years.

To evaluate the impact of therapeutic intensification on eGFR, we limited our analysis to children with SCA. We compared eGFR values obtained close to the date of treatment modification: the last value obtained before and the first value obtained after treatment intensification. We also evaluated eGFR at the last check-up. To evaluate the impact of HU and TP on eGFR, only data for children for whom these treatments were the first therapeutic intensification were analyzed. To assess changes in renal function associated with HSCT, given that most children received some DMT before undergoing HSCT, post-transplant eGFRs were compared to pre-transplant levels, regardless of whether the patients were on HU or TP before transplantation.

We investigated the mechanisms contributing to changes in eGFR after therapeutic intensification by analyzing Hb, HbF, and HbS levels; reticulocyte, absolute leukocyte, and neutrophil counts (ANC); total bilirubin levels; and lactate dehydrogenase (LDH) activity immediately before and after therapeutic intensification.

No modification of eGFR was observed following the introduction of either HU (106 children, median 123.8 [IQR 110.1–145.6] after vs. 120.7 [IQR 102.9–138.9] mL/min/1.73 m2 before HU), or a TP (74 children, 128.5 [IQR 107.4–148.1] after vs. 121.1 [IQR 104.3–142.5] mL/min/1.73 m2 before TP). Conversely, both these treatments significantly improved Hb levels and decreased hemolysis (Table S1A,B). After a mean duration between HU initiation and last eGFR assessment of 5.8 ± 2.1 years, we observed no significant change in eGFR. Our data for HU therapy are consistent with those of the BABY-HUG trial, in which GFR was high for age at baseline but a fixed dose of HU (20 mg/kg/day) had no effect on glomerular hyperfiltration. By contrast, two small studies using the maximum tolerated dose (MTD) of HU suggested some efficacy. One of these studies showed that GFR was stabilized according to DTPA clearance or Schwartz estimates after 2 years of HU treatment in 14 preschool-aged children [5]. The other reported a significant decrease in measured DTPA GFR after 3 years of HU treatment in 23 children. This decrease was significantly associated with an increase in %HbF [6]. HU dose was not recorded in our database, but laboratory tests following the introduction of HU treatment showed significant increases in %HbF along with significant decreases in reticulocyte and ANC.

For chronic transfusion programs, after a mean of 4 years of TP maintaining Hb levels over 9 g/dL (mean 9.3 ± 1.2 g/dL) and HbS levels under 40% (mean 34.6% ± 14.6%), we observed no significant change in eGFR. Our data are consistent with the only other study to date investigating eGFR in transfused children (4–15 years) with SCA. Mean eGFR in these children did not differ significantly from the mean eGFR in age-matched children not receiving TP or HU [7].

In our cohort, 66 children underwent HSCT at a median age of 7 years (range 3–17 years), mostly from a genoidentical sibling (63/66) and with the same myeloablative conditioning regimen based on busulfan and cyclophosphamide chemotherapy combined with rabbit anti-thymocyte globulin (62/66). In the post-transplantation period, the main immunosuppressive treatment was cyclosporine, with or without methotrexate. Cyclosporine dose was generally gradually reduced between 6 and 9 months after transplantation. The characteristics of the children undergoing HSCT are summarized in Table 1. Following HSCT, all 66 patients displayed successful engraftment, with donor-type hemoglobin (median HbS 31.7%, IQR [0%–37.8%]). As expected, Hb levels (median 12.5 g/dL, IQR [11.5–13.2] g/dL) and reticulocyte counts (median 48 × 109/L, IQR [35–67] × 109/L) normalized after transplantation and were stable at last check-up (median 55 × 109/L, IQR [46–80 × 109/L]). All patients underwent a pre-transplantation TP, and most had received HU before HSCT. The pre-transplantation eGFRs were therefore collected in patients on HU or TP. The mean duration between transplantation and last eGFR assessment was 7.3 ± 2.9 years. We observed a significant decrease in eGFR between the value obtained immediately before HSCT (median 127.2, IQR [105.8–141.1] mL/min/1.73 m2) and 1 year after HSCT (median 114.9, IQR [97.9–134.3] mL/min/1.73 m2). This decrease was maintained at the last check-up (median 104.0, IQR [91.0–116.8] mL/min/1.73 m2) (p < 0001). (Table 2). At last follow-up, eGFR remained > 75 mL/min/1.73 m2 in all children. Interestingly, a previous study reported stable renal function, with less hyperfiltration at last follow-up, in 18 children and adolescents with SCA who underwent non-myeloablative HSCT [8]. In our cohort, only one boy developed post-transplantation macro-albuminuria (albuminuria-to-creatininuria ratio ≥ 300 mg/g), while under sirolimus therapy, which persisted after discontinuation. HSCT was performed at 17 years of age using a non-myeloablative regimen.

Finally, we compared post-transplantation eGFR levels with those of age-matched children with HbSC disease, from the ages of 6 to 16 years. After transplantation, eGFR decreased to levels similar to those observed in HbSC disease for children of all ages, suggesting that glomerular hyperfiltration was reversed following HSCT (Table 3).

In conclusion, we report the largest prospective longitudinal study of eGFR in a cohort of children with SCD. Our study has limitations that should be noted. First, this study relied on surrogate markers of renal function (i.e., no measured GFR). Second, we did not systematically collect serum creatinine values within the first 100 days post-HSCT. As a result, we may have missed early episodes of acute kidney injury during the immediate post-transplantation period.

Our results confirm that, in the absence of intensification, eGFR is significantly higher in the SCA (HbSS/Sβ0 thalassemia) subgroup than in the subgroup with milder disease (HbSC/Sβ+ thalassemia). The basis of the early increase in eGFR in the SCA cohort remains a matter for speculation, but the earlier and higher viscosity vaso-occlusion and hemolysis–endothelial dysfunction associated with the SCA phenotype may account for the differences in the course of glomerular filtration in these populations.

Anemia improved after HU and TP, but neither of these treatment intensifications had any effect on eGFR. The absence of HU dose information is another limitation in our study. In our center, an escalation of HU treatment to the MTD was recommended from 2015, but was rarely implemented before, as reflected by the moderate myelosuppression observed under HU (mean ANC 2.8 ± 1.1 × 109/L on HU at last check-up; Table S1B). Further investigations are required to determine whether earlier HU initiation and escalation to the MTD can help prevent the development of glomerular hyperfiltration. By contrast, eGFR decreased rapidly within 1 year of successful HSCT and was lower at the last follow-up visit (mean post-transplantation FU of 7 years). These changes were associated with a normalization of hemoglobin levels and reticulocyte counts, and improvements in inflammation markers, with a significant decrease in ANC. Hyperfiltration during early childhood precedes albuminuria. The reversal of hyperfiltration after HSCT may, therefore, prevent long-term renal morbidity in the population of SCA patients. Long-term studies are, however, warranted to better understand the impact of HSCT-related toxicities (conditioning regimen, immunosuppressive medications, infections, graft-vs.-host disease) versus reversal of the SCD phenotype on kidney function. In addition, kidney function after transplantation may differ significantly between pediatric and adult populations. We believe that our results provide a rationale for the early performance of genoidentical myeloablative HSCT in this population.

S.H. and C.P. cared for patients, designed the study, collected and interpreted the data, wrote the article, and took final responsibility for the decision to submit for publication. A.K. cared for patients, collected and interpreted data. C.A. cared for patients and collected data. V.B. collected and interpreted data. E.B. collected data. S.B. carried out the statistical analysis. A.D. and B.K. provided biological data. K.Y., N.D., C.Pa., I.H., C.F., and C.D. cared for the patients. All the authors reviewed the paper and approved the final manuscript.

The authors confirm that the PI for this paper is Corinne Pondarré and that the PI had direct clinical responsibility for patients.

C.P. reports honoraria and expert consultancy for Theravia and Pfizer. The other authors declare no conflicts of interest.

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来源期刊
CiteScore
15.70
自引率
3.90%
发文量
363
审稿时长
3-6 weeks
期刊介绍: The American Journal of Hematology offers extensive coverage of experimental and clinical aspects of blood diseases in humans and animal models. The journal publishes original contributions in both non-malignant and malignant hematological diseases, encompassing clinical and basic studies in areas such as hemostasis, thrombosis, immunology, blood banking, and stem cell biology. Clinical translational reports highlighting innovative therapeutic approaches for the diagnosis and treatment of hematological diseases are actively encouraged.The American Journal of Hematology features regular original laboratory and clinical research articles, brief research reports, critical reviews, images in hematology, as well as letters and correspondence.
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