Visual Abstract
Keywords: clinical trial, hyperfiltration, microalbuminuria, pediatric nephrology
Abstract
Key Points
Sickle cell nephropathy regression.
Hydroxyurea action on sickle cell nephropathy.
Background
Renal complications of sickle cell disease are becoming very common, and patients generally do not respond to conventional nephroprotective treatments. Among the drugs used, hydroxyurea (HU) seems to have produced good results according to some studies. This molecule has not yet been evaluated in the Democratic Republic of Congo to evaluate albuminuria and GFR after 9 months of HU treatment in a population of children with incipient sickle cell nephropathy (SCN).
Methods
This was an open clinical trial involving sickle cell syndrome children younger than 18 years followed by incipient SCN (glomerular hyperfiltration [GHF] and/or microalbuminuria). A mean HU dose of 20 mg/kg per day was administered to each child, with quarterly clinical and biologic controls. GHF (new Schwartz formula) was defined as a rate >130 ml/min per 1.73 m2 for girls and >140 ml/min per 1.73 m2 for boys; albuminuria was defined as the albuminuria/creatinuria ratio in mg/g. The Wilcoxon and McNemar tests were used to compare the results at admission and at the ninth month of treatment.
Results
In total, 30 children (mean age 8.9±4.1 years; 40% boys) whose mean fetal hemoglobin level increased from 10%±7.4% to 18.8%±4.9% (P < 0.001), mean number of blood transfusions ranged from 7.4±6.7 to 0.1±0.3 bags/mo (P < 0.001), and number of vaso-occlusive crises ranged from 1.8±1.1 to 0.2±0.4/mo (P < 0.03) were included. The frequency of GHF decreased from 30% to 3.3% (P < 0.001). The mean albuminuria decreased from 122.5±16.3 to 30±2.4 mg/g.
Conclusions
HU improved the course of SCN. The mechanism of action behind this result seems to be an improvement in blood rheology.
Introduction
Renal complications of sickle cell disease are becoming very common and constitute a major risk factor for early mortality in these patients. Previous studies have reported that renal complications occur in 5%–18% of children and adolescents with sickle cell disease, and over 9% of deaths in young adult sickle cell syndrome patients are attributable to complications related to renal damage.1,2 Kidney damage is a major complication of sickle cell disease because of recurrent renal vaso-occlusive crises (VOCs), postischemic reperfusion lesions leading to nephron reduction, reduced urinary concentrating capacity, renal tubular acidosis, and glomerular ischemia, which are ultimately responsible for CKD.3,4 Nevertheless, over the years, it has become clear that the pathophysiology of sickle cell nephropathy (SCN) is more complex than that of a pure vascular perfusion anomaly. Indeed, evolving evidence suggests that kidney damage mediated by hemolysis through heme, free hemoglobin, and oxidative stress also plays a crucial role.5
SCN is a well-described renal entity with specific risk factors and clinical manifestations.6,7 Glomerular damage, one of the most important renal manifestations observed in these patients, is characterized by an early increase in the GFR associated with microalbuminuria or macroalbuminuria, leading to a progressive decrease in the GFR and chronic renal failure.4,8,9
SCN begins in childhood and can progress to overt renal failure.4 In childhood, it is dominated by urinary concentration disorders, glomerular hyperfiltration (GHF), and, occasionally, microalbuminuria, whereas in adulthood, microalbuminuria is more common (36%–40%) and can progress to macroalbuminuria associated with a progressive decrease in GFR, which can lead to ESKD.3
SCN has been linked to focal and segmental glomerusclerosis, often the perihilar variant, which is found in glomerulopathies and involves adaptive changes to hyperfiltration.5,10
Manifestations of CKD in children are high, with approximately 10%–30% of pediatric patients with the severe form of sickle cell disease (comprising homozygous sickle cell disease [homozygous hemoglobin S disease] and sickle β0 thalassemia [HbSβ0]) developing albuminuria. Many patients transitioning from hyperfiltration to a normal filtration rate in kidney function during adolescence.11
Early diagnosis and management of this disease are essential to avoid progression to advanced renal failure. Glomerular changes begin as early as the first decade of life in otherwise asymptomatic renal patients.4 Common clinical markers of renal function, such as serum creatinine, are not reliable indicators of early-stage glomerulopathy in nephropathy because of the increased GFR, decreased muscle mass, and increased tubular creatinine secretion in sickle cell disease patients.
Microalbuminuria, which occurs in the subclinical phase of SCN and precedes the onset of severe, persistent proteinuria, has been identified as an early marker of glomerular dysfunction.2,4
Optimal therapeutic management of SCN remains difficult, and few options are available.
The usual renoprotective measures, including inhibitors of the renin-angiotensin system (angiotensin-converting enzyme inhibitor [ACEI] and angiotensin II receptor blocker), are likely to slow the progression of kidney disease in sickle patients, which is observed in proteinuric diabetic patients or patients with no diabetic nephropathy. However, to date, no prospective randomized clinical trial has clearly demonstrated this hypothesis.
Falk et al. first reported that, in ten patients, 2 weeks of enalapril treatment was associated with a 57% reduction in proteinuria, which rebounded after treatment withdrawal.10 These preliminary results were confirmed by a 6-month controlled study of 22 patients and suggested that the use of an ACEI might be appropriate for reducing proteinuria.12 However, in SCN, the long-term inhibitory effect of angiotensin-converting enzyme and its tolerability remains unknown.
Hydroxyurea (HU) is one of the cornerstones of therapeutic management for sickle cell disease.13,14 In addition, hydroxycarbamide is a potent inhibitor of ribonucleotide reductase, decreasing sickle hemoglobin synthesis and increasing fetal hemoglobin (HbF) concentrations. It is the only US Food and Drug Administration–approved drug effective in the management of sickle cell disease in adults.15 HU has previously been shown to reduce the frequency of VOCs, acute chest syndrome, and the need for red blood cell transfusions and, ultimately, to improve patient survival, as it increases HbF, alters the expression of adhesion molecules, decreases the number of reticulocytes and neutrophils, and improves local nitric oxide generation, thereby reducing mortality in patients with severe sickle cell syndrome.15–17
Hence, interest in the use of HU for SCN has increased, as such treatment reduces renal hypertrophy, improves urinary concentrating capacity in infants, reduces GHF in children, and is associated with less albuminuria in adults.16
Intravascular hemolysis causes vasculopathy linked to chronic depletion of nitric oxide and an increase in endothelin-1,18 which is a marker of endothelial dysfunction, because it induces the production of free radicals and directly damages podocytes by binding to specific receptors.19
Free heme released during hemolysis associated with erythrocyte injury promotes inflammation by activating the innate toll-like receptor 4.19 This receptor is present on endothelial and mesangial epithelial cells, tubular cells, and podocytes.16 Heme also activates the generation of erythrocyte damage-associated molecular patterns at the origin of the synthesis of inflammatory cytokines, which, in turn, aggravate cell adhesion and vaso-occlusion. All these mechanisms contribute to the worsening of kidney damage.
There are multiple potential mechanisms by which HU affects proteinuria. Indeed, HU increases HbF, modifies the expression of adhesion molecules, decreases the number of reticulocytes and neutrophils, and improves the local generation of nitric oxide.20–22 Nitric oxide release may also abrogate endothelial dysfunction, which has been suggested to play a role in albuminuria.23 In podocytes, HU prevents red blood cell sickling and hemolysis,24 which are the main causes of kidney damage in sickle cell disease. Thus, increasing the HbF level and the bioavailability of nitric oxide protect the kidneys against the harmful effects of hemolysis and free heme.
A previous study conducted by Aygun et al. reported that HU treatment reduces GHF in children with sickle cell disease.25 Given that hyperfiltration always precedes microalbuminuria in children with sickle cell disease, the use of HU with the aim of preventing the progression of CKD in sickle cell disease patients could be further justified.26
Zahr et al. reported that disease-modifying agents such as HU are effective at reducing sickle cell hemoglobin concentrations and decreasing albuminuria in children and adults with sickle cell disease and could be continued after transplantation.11
In the Democratic Republic of Congo (DRC), the second most sickle cell–affected country in Africa with a recent incidence estimated at between 40,000 and 50,000 newborns per year,27 information on SCN is extremely limited.20 Aloni et al. recently reported that among the pediatric sickle cell population, 30% had GHF, 2% had dipstick-tested proteinuria, and 18% had microalbuminuria.2,20 However, no clear therapeutic strategy has been adopted for the management of SCN in this country, and HU has not yet been evaluated for this indication.
In this cohort study, we sought to determine the potential effects of HU on albuminuria and the GFR after 9 months of treatment in a population of children who were followed up for incipient SCN in the DRC.
Methods
This is an open clinical trial conducted at Saint-Luc of Kisantu Hospital in a rural area 120 km west of the capital Kinshasa. Saint-Luc of Kisantu Hospital is the main referral hospital in the region, treating approximately 250 adult and pediatric sickle cell patients (Figures 1 and 2).
Figure 1.
Changes in the number of transfusions 9 months after treatment with HU. HU, hydroxyurea.
Figure 2.
Changes in the number of VOCs 9 months after treatment with HU. VOC, vaso-occlusive crisis.
Over a 9-month period, from October 2018 to June 2019, we included patients aged 2 to younger than 18 years who met the following inclusion criteria: sickle cell disease confirmed by capillary hemoglobin electrophoresis and DNA testing and the presence of early markers of renal impairment (pathologic albuminuria, GHF). Patients were also required to be in a state of equilibrium, defined by the absence of painful attacks and infections in the last 4 weeks and the absence of blood transfusion in the last 4 months. Parents or legal guardians were asked to provide signed consent forms. Children meeting the inclusion criteria underwent an initial clinical examination, including history-taking and physical examination. An ad hoc questionnaire was used to collect the following anamnestic data: sociodemographic data, age, sex, medical history (number of hospitalizations in days, transfusions, and VOCs in the previous year), and complete physical examination data, including anthropometric parameters and BP. Patients on ACEI and HU therapy were excluded.
Biochemical analyses included analyses of lactate dehydrogenase (LDH), bilirubin (Bili), and serum creatinine levels. Hemoglobin electrophoresis was performed using a Minicap automaton (Sebia, Phoresis Rel 8.6.3.). DNA was extracted through the salting-out method, and mutation analysis for the sickle cell anemia mutation (E7 V) was performed at the University of Kinshasa Human Genetics Laboratory. Serum creatinine was measured in all participants through an enzymatic method with a COBAS C111 instrument (Roche Instrument Center, Rotkreuz, Switzerland).
The estimated GFR was calculated using the Schwartz formula. Reduced renal function was defined as an eGFR <60 ml/min per 1.73 m2. GHF (new Schwartz formula) was defined as >130 ml/min per 1.73 m2 for girls and >140 ml/min per 1.73 m2 for boys; albuminuria was defined as the albuminuria/creatinuria ratio (ACR) in mg/g. The first sample of fasting fresh morning urine was collected from each participant. The ACR was assessed through the immunoturbidimetric method with a Vintage DCA analyzer (Siemens Healthineers Global, Erlangen, Germany). Pathologic albuminuria was defined as at least a urinary albumin-creatinine ratio ≥30 mg/g.
Pathologic albuminuria and hyperfiltration, which are early markers of renal impairment, are the main indications for HU treatment. The average dose was 20 mg/kg per day (15–30 mg/kg per day). The duration of treatment was 9 months. This mean HU dose of 20 mg/kg per day was administered to each child with quarterly clinical and biologic controls.
Given that this is an open-label clinical trial in the DRC, we referred to a previous single-arm clinical trial in homozygous sickle cell disease (SS) patients conducted by Pablo Bartolucci, who used HU for 6 months with pathologic albuminuria. We therefore opted for 9 months of treatment, allowing the evaluation of the presence or absence of persistent albuminuria. Our primary end point was albuminuria and hyperfiltration.
All aspects of the study were approved by our Institutional Review Board in accordance with the Declaration of Helsinki.
Statistical Analysis
We collected the data on an Excel sheet in Microsoft Windows 2010 and imported and analyzed them with IBM SPSS Statistics 25.0 software. Continuous variables with a normal distribution are expressed as the means±SDs and were compared using Student t tests. Nonparametric variables are expressed as medians (interquartile ranges) and were compared using the Mann‒Whitney U test or the Kruskal-Wallis test. The chi-square test or Fisher exact test was used to compare all categorical variables with the presence of albuminuria, microalbuminuria, and macroalbuminuria, as well as HU use. The Wilcoxon and McNemar tests were used to compare the results at admission and at the ninth month of treatment. A value of P < 0.05 indicated statistical significance. The confidence intervals included 95% of the expected values.
Results
A total of 30 homozygous sickle cell syndrome children (SS children) with SCN were identified: 12 boys and 18 girls (sex ratio M/F 0.66). The ages ranged from 2 years to younger than 18 years, with a mean age (±SD) of 8.9±4.1 years (males 8.1±4.1). The mean age of the boys and girls was 9.6±4.2 years (P = 0.316). Seven children (23.3%) were preschool aged (2–5 years), 9 (30%) were school aged (6–10 years), and 14 (46.6%) were adolescents (11 to younger than 18 years; Table 1). The mean numbers of VOCs and blood transfusions were 1.8±1.1 and 7.4±6.7, respectively (P = 0.125).
Table 1.
Sociodemographic and clinical characteristics of the study population
| Variables | Whole Group (N=30) | Sex | P Value | |
|---|---|---|---|---|
| Male (N=12) | Female (N=18) | |||
| Age: X±ET | 8.9±4.1 | 8.1±4.1 | 9.6±4.2 | 0.316 |
| 2–5 yr | 7 (23.3) | 3 (25) | 4 (22.2) | |
| 6–10 yr | 9 (30) | 5 (41.7) | 4 (22.2) | |
| 11–15 yr old | 13 (43.3) | 4 (33.3) | 9 (50) | |
| >15 to <18 yr | 1 (3.3) | 0 | 1 (5.6) | |
| Transfusion: X±ET | 7.4±6.7 | 7.1±6.2 | 8.2±6.9 | 0.125 |
| N (%) | 0.535 | |||
| 1–8 | 15 (50) | 6 (50) | 9 (50) | |
| 9–16 | 10 (33.3) | 3 (25) | 7 (38.9) | |
| ≥16 | 5 (16.7) | 3 (25) | 2 (11.1) | 0.215 |
| VOC: X±ET | 1.8±1.1 | 1.6±1.1 | 2.1±1.2 | 0.125 |
| N (%) | 0.836 | |||
| None | 6 (20) | 3 (25) | 3 (16.7) | |
| 1–2 | 10 (33.3) | 4 (33.3) | 6 (33.3) | |
| ≥3 | 14 (46.7) | 5 (41.7) | 9 (50) | 0.567 |
| SBP, mm Hg | 102.9±17.3 | 100.8±21.6 | 104.5±13.6 | 0.582 |
| DBP, mm Hg | 67.8±9.4 | 66.6±10.3 | 68.6±8.9 | 0.127 |
| Weight, kg | 21.3±7.1 | 19.1±6.7 | 23.1±7.1 | 0.214 |
| Size, m | 1.1±0.2 | 1.0±0.0 | 1.1±0.3 | 0.686 |
| BMI, kg/m2 | 15.8±4.3 | 15.4±3.3 | 16.1±5.1 | |
| HU utilization (%) | 30 (100) | 12 (40) | 18 (60) | 0.03 |
The data are expressed as the means±SDs and absolute (n) and relative (%) frequencies. BMI, body mass index; DBP, diastolic BP; HU, hydroxyurea; SBP, systolic BP; VOC, vaso-occlusive crisis; X±ET, means ± SD.
When comparing female and male children, female children were, on average, older (9.6±4.2 versus 8.1±4.1 years; P = 0.316) than male children were, but the difference did not reach statistical significance. Differences in other variables of interest between the sexes were not statistically significant (Table 1). HU was used for 9 months in all our patients. The indications for starting HU were GHF and pathologic albuminuria (Table 2).
Table 2.
Biologic characteristics of homozygous sickle cell syndrome patients according to sex
| Variables | Whole Group (N=30) | Sex | P Value | |
|---|---|---|---|---|
| Male (N=12) | Female (N=18) | |||
| ACR, mg/g | 122.5±16.3 | 116.3±44.4 | 130.3±91.7 | 0.000 |
| X±ET, mg/l | 40.7 (31–145.1) | 41.9 (30–110.3) | 37 (30–124.7) | |
| Albuminuria, mg/g | 40.7 (16.5–130.4) | 51.6 (40–138.7) | 37.6 (30.1–87.9) | 0.825 |
| Creatininuria, mg/g | 63.9 (41.6–93.3) | 71.5 (15.2–83.1) | 56.4 (15–60.5) | 0.828 |
| eGFR, ml/min per 1.73 m 2 | 128.9±69.1 | 145.3±91.7 | 116.3±44.4 | 0.871 |
| <60 | 2 (6.7) | 1 (8.3) | 1 (5.6) | <0.000 |
| 60–134.9 | 16 (53.3) | 4 (33.3) | 12 (66.7) | 0.340 |
| ≥135 | 12 (40) | 7 (58.3) | 5 (27.8) | 0.922 |
| GHF, n (%) | 9 (30) | 5 (41.6) | 4 (22.2) | 0.995 |
| HbF. % | 10±7.4 | 7.64±4.91 | 11.73±7.69 | 0.043 |
| LDH, mg/dl | 1726.2±752.7 | 1717.4±198.9 | 1750.6±194.2 | 0.383 |
| BI, mg/dl | 2.8±1.5 | 3.1±1.6 | 2.6±1.4 | 0.662 |
| BT, mg/dl | 3.41±2.68 | 3.03±2.21 | 2.67±1.60 | 0.217 |
The data are expressed as the means±SDs, absolute frequencies (n), and relative frequencies (%). ACR, albuminuria/creatinuria ratio; BI, indirect bilirubin; BT, total bilirubin; GHF, glomerular hyperfiltration; HbF, fetal hemoglobin; LDH, lactate dehydrogenase; X ± ET, means ± SDs.
Biologic Parameters before Treatment with HU
The mean ACR and eGFR of the entire group were 122.5±16.3 mg/g and 128.9±69.1 ml/min per 1.73 m2, respectively; these values were significantly different between girls and boys, with higher rates in girls. Thirty percent of our patients had GHF. The mean LDH and indirect bilirubin levels, which are markers of hemolysis, were 1726.2±752.7 IU/L and 2.8±1.5 mg/dl, respectively. The mean HbF level was 10±7.4 and was significantly greater in girls (11.73%±7.69%) than in boys (7.64%±4.91%; P = 0.043; Table 2).
When comparing female and male children, the differences observed in the other variables of interest between the two sexes were not statistically significant.
The use of HU had potential effects on clinical and biologic parameters; the mean number of blood transfusions and VOC decreased from 7.4±6.7 to 0.1±0.3/mo (P < 0.001), and the number of VOCs decreased from 1.8±1.1 to 0.2±0.4/mo (P < 0.03). Our results revealed that 9 months of HU treatment significantly reduced the number of VOCs and transfusions, and this reduction in attacks was observed as early as the third month of treatment, when the body mass index increased significantly over the 9 months of observation (P = 0.02), whereas the systolic and diastolic BPs remained unchanged. The mean HbF increased from 10%±7.4% to 18.8%±4.9% (P < 0.001; Table 3). The values of the biologic hemolysis parameters significantly improved, as indicated by decreases in the mean LDH and indirect bilirubin levels, from 1726.2±752.7 to 503.5±113.4 (P = 0.003) and from 2.8±1.5 to 0.7±0.2 (P = 0.023), respectively.
Table 3.
Changes in clinical and biologic parameters after treatment with hydroxyurea
| Settings | Starting Values | Evolution over Time | P Value | ||
|---|---|---|---|---|---|
| 3 mo Later | 6 mo Later | 9 mo Later | |||
| No. of transfusion | 7.4±6.7 | 1.8±1.4 | 0.4±0.5 | 0.1±0.3 | <0.001 |
| No. of VOC | 1.8±1.1 | 1.1±0.8 | 0.5±0.5 | 0.2±0.4 | 0.03 |
| BMI, kg/m2 | 15.8±4.3 | 16.1±5.1 | 17.2±3.2 | 18.3±3.1 | 0.02 |
| ACR | 122.5±16.3 | 59.1±28.8 | 31.5±2.6 | 30±2.4 | 0.002 |
| Cr | 0.4±0.4 | 0.3±0.4 | 0.4±0.4 | 0.6±0.4 | 0.053 |
| eGFR, ml/min per 1.73 m2 | 128.9±69.1 | 112.2±21.1 | 108±11.1 | 92.86±4.8 | 0.02 |
| GHF, n (%) | 9 (30) | 6 (20) | 4 (13.3) | 1 (3.3) | <0.001 |
| LDH, mg/dl | 1726.2±752.7 | 1225.1±353.7 | 817.3±151.2 | 503.5±113.4 | 0.003 |
| BI, mg/dl | 2.8±1.5 | 1.8±1.2 | 1.3±1.1 | 0.7±0.2 | 0.023 |
| HbF, % | 10±7.4 | 12.1±5.8 | 14.4±5.1 | 18.8±4.9 | <0.001 |
ACR, albuminuria/creatinuria ratio; BI, indirect bilirubin; BMI, body mass index; Cr, creatinine; GHF, glomerular hyperfiltration ≥135 ml/min per 1.73 m2 SC; HbF, fetal hemoglobin; LDH, lactate dehydrogenase; VOC, vaso-occlusive crisis.
Early markers of renal impairment (GHF and ACR), the main indications for HU in this study, were significantly reduced after 9 months of treatment (Figures 3–5). The frequency of GHF decreased from 30% to 3.3% (P < 0.001), and the mean albuminuria decreased from 122.5±16.3 to 30±2.4 mg/g (P = 0.002; Table 3). The mean eGFR decreased from 128.9±69.1 to 92.86±4.8 ml/min per 1.73 m2 (P = 0.02; Table 3).
Figure 3.
Progression of ACR 9 months after treatment with HU. ACR, albuminuria/creatinuria ratio.
Figure 5.
Evolution of GHF 9 months after treatment with HU. GHF, glomerular hyperfiltration.
Figure 4.
Changes in microalbuminuria at 9 months after treatment with HU.
Discussion
The two main observations of this study are related to the significant improvement in the clinical and biologic parameters of patients under HU. Clinically, the frequency of VOCs has decreased, as has that of transfusions. Biologically, there was a reduction in albuminuria, GHF, and hemolysis markers (LDH, indirect bilirubin) and an increase in HbF (P < 0.05) (Table 3).
The results of this clinical trial are similar to those reported by Bartolucci and Galactéros, Charache et al., in a single-center cohort study11,13–17 and in a retrospective study by Lebenburger et al.26
By contrast, Aygun et al. did not find a significant change in microalbuminuria in 23 children taking HU for 3 years.25
The exact mechanism involved in the decline in albuminuria during HU remains unclear. This drop in albumin could result from a reduction in the glomerular filtered albumin load (linked to reduced GFR) or from the fact that it increases HbF, thus preventing the sickling involved in the vasophenon. Occlusive and hemolytic effects play key roles in the genesis of SCN.17 Zahr et al. reported that HU can prevent the development of albuminuria and improve the ACR in children with existing albuminuria.28
In a case report of three children with acute coronary syndrome and nephrotic syndrome who had persistent albuminuria on enalapril, the addition of HU to the maximum total dose normalized the urinary protein/creatinine ratio.29 In another retrospective study, four of nine children treated with HU for other sickle cell anemia-related indications experienced normalization of proteinuria.30
Many markers of hemolysis have been associated with increased urinary albumin excretion.31 In our own cohort, a significant decline in LDH and bilirubin levels was observed (Table 3), suggesting less hemolysis under HU treatment in these children. Whether decreased hemolysis is the primary mechanism by which HU affects albuminuria remains unclear. Our study revealed a clear direct association between hemolysis markers and HU use, suggesting that HU may play a role in hemolysis. This could be partly explained by the reduction in free heme (Figures 6 and 7).
Figure 6.
Changes in HbF at 9 months after treatment with HU. HbF, fetal hemoglobin.
Figure 7.
Creatinine evolution 9 months after HU treatment.
Our results demonstrated a decrease in the frequency of albuminuria in children with early SCN on HU. After controlling for relevant clinical and biologic variables quarterly, in addition to albuminuria, the frequency of GHF was significantly lower in children taking HU. We also noted a significant decrease in the mean GFR after 9 months of treatment, but it remained within normal limits (Figure 8 and Table 3). This finding corroborates the results of HU study of long-term effects, which is a prospective clinical trial not controlled by placebo in subjects with sickle cell disease who started treatment with HU,25 which demonstrated that at 3 years, this treatment was associated with a reduction in GHF in children with sickle cell disease. Although the GFR remained above normal, there was a significant decrease in the GFR (median level of 29.7 ml/min per 1.73 m2). A decrease in the GFR has also been associated with increased HbF and decreased LDH levels, similar to the BABY HUG trial.32
Figure 8.
Changes in the eGFR 9 months after treatment with HU.
In one trial, children treated with HU had better kidney function, as assessed by the ability to concentrate urine, than those treated with placebo did.33 In a nonrandomized study of children with sickle cell disease requiring HU for standard indications, treatment for 3 years resulted in a mean decrease in the GFR of 167 (SD 46) ml/min per 1.73 m2 at 145 (SD 27) ml/min per 1.73 m2,25 indicating improvement in hyperfiltration.24
Alternatively, treatment with HU was evaluated for its association with albuminuria in adult patients with SCN. In real-world observational studies, patients receiving HU had a significantly lower incidence of albuminuria than did those receiving no treatment (34.7% versus 55.4%).17 Although the mechanism of the reduction in albuminuria remains unclear, it has been suggested that HU causes a reduction in hemolysis and sickling of red blood cells, which in turn leads to a reduction in ischemic kidney injury.31
In a single-arm trial in homozygous SS patients, long-term treatment with HU for 6 months was associated with a significant reduction in the urinary albumin/creatinine ratio of approximately 1.7–3.0 mg/mmol.21 When further subgroup analyses were performed, the benefit of HU was shown to be due primarily to a reduction in patients who had microalbuminuria at baseline. By contrast, patients without baseline microalbuminuria had no significant benefit from HU. Interestingly, the trial also demonstrated a close association between a reduced albumin/creatinine ratio and elevated baseline hemolysis markers.21 Following these positive results, the duration of HU treatment was then retrospectively reevaluated compared with that of patients with SCN not receiving HU. In the HU group, albuminuria normalized in 37.5% of patients at 1 year compared with only 15% in the nonhydroxyurea group.33
Finally, when reconciling the results of these trials, it seems that patients with initial albuminuria, and perhaps initial hemolysis, may be the target population of interest to enrich in future studies that include HU, and differences in outcomes may be seen when HU is administered for prolonged durations of up to 6 months to 3 years of treatment.21,25,32
Despite these clearly beneficial effects, the potential effects of HU on renal function parameters are still controversial.25,32
On the basis of our results and those of previous case series, HU may be beneficial for the prevention of SCN or for delaying its progression, as seen with ACEI/angiotensin receptor blocker two in diabetic nephropathy. This hypothesis can be better tested by a prospective randomized controlled clinical trial in a sickle cell population with kidney disease. HU is promising, particularly because of its ready availability and affordability, and our results provide at least additional incentives for physicians to prescribe HU in children with SCN and to adhere to it. Patients should adhere to HU when prescribed. Our results suggest that HU may reduce the frequency of early markers of kidney damage in patients with sickle cell disease. Further investigations are needed to determine whether it can prevent overt progression of SCN to ESKD.
In conclusion, our results strongly suggest that 9 months of HU significantly attenuated the microalbuminuria and GHF observed during the early stages of SCN. A close relationship between the reduction in hemolysis markers and HU treatment has been established. We found that HU can prevent the development of albuminuria and improve the ACR in children with existing albuminuria.28
The results of this clinical trial revealed a beneficial effect of HU in the short term (9 months) on ACR and GHF in children with SCN, suggesting that in the future, its use in sickle cell syndrome may include an indication of renal protection. This finding underlines the need to initiate renal protection therapy at the subclinical stage of glomerular damage (microalbuminuria and GHF) to reduce the risk of progressive deterioration in renal function. Observations from previous nonprospective studies have suggested that the combination of HU and ACEI/angiotensin receptor blocker two could be considered for patients with persistent significant proteinuria.21
We found that HU can reduce erythrocyte sickling and hemolysis, which are directly responsible for kidney damage.17
HU at a mean dose of 20 mg improved the course of SCN. The mechanism of action behind this result seems to be an improvement in blood rheology, a reduction in VOCs and vasculopathy linked to hemolysis.
We are considering a placebo-controlled study with a more representative sample of SS homozygous sickle cell patients in the DRC.
Disclosures
Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B19.
Funding
None.
Author Contributions
Conceptualization: Dieumerci Betukumesu Kabasele, Jean-Lambert Gini Ehungu, Prosper Lukusa, Arriel Makembi Bunkete, Jean-Robert Makulo Rissassi, Gloire Mbayabo, Tite Mikobi, Ernest Sumaili.
Data curation: Dieumerci Betukumesu Kabasele, Ernest Sumaili.
Formal analysis: Dieumerci Betukumesu Kabasele, Gloire Mbayabo.
Investigation: Michel Aloni, Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, Orly Kazadi, Prosper Lukusa, Odio Matondo.
Methodology: Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, François Kajingulu, Prosper Lukusa, Jean-Robert Makulo Rissassi, Gloire Mbayabo, Tite Mikobi, Ernest Sumaili.
Project administration: Dieumerci Betukumesu Kabasele, Jean-Lambert Gini Ehungu.
Resources: Dieumerci Betukumesu Kabasele.
Software: Dieumerci Betukumesu Kabasele, Ernest Sumaili.
Supervision: Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, Orly Kazadi, Prosper Lukusa, Arriel Makembi Bunkete, Jean-Robert Makulo Rissassi, Gloire Mbayabo, Tite Mikobi, Ernest Sumaili.
Validation: Michel Aloni, Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, François Kajingulu, Orly Kazadi, Prosper Lukusa, Arriel Makembi Bunkete, Jean-Robert Makulo Rissassi, Odio Matondo, Gloire Mbayabo, Tite Mikobi, Ernest Sumaili.
Visualization: Michel Aloni, Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, François Kajingulu, Prosper Lukusa, Arriel Makembi Bunkete, Jean-Robert Makulo Rissassi, Odio Matondo, Gloire Mbayabo, Ernest Sumaili.
Writing – original draft: Dieumerci Betukumesu Kabasele, Arriel Makembi Bunkete.
Writing – review & editing: Michel Aloni, Dieumerci Betukumesu Kabasele, Joseph Bodi Mabiala, Jean-Lambert Gini Ehungu, François Kajingulu, Orly Kazadi, Prosper Lukusa, Paul Lumbala, Arriel Makembi Bunkete, Jean-Robert Makulo Rissassi, Odio Matondo, Tite Mikobi, Ernest Sumaili.
Data Sharing Statement
Partial restrictions to the data and/or materials apply. Data is available upon reasonable request to the corresponding author.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Partial restrictions to the data and/or materials apply. Data is available upon reasonable request to the corresponding author.