{"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, 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","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> < 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> < 0001). (Table 2). At last follow-up, eGFR remained > 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, 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\",\"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> < 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> < 0001). (Table 2). At last follow-up, eGFR remained > 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}
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.
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.