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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by 99mTc-DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long-term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty-three children with SCA (median age 7.5 years, range, 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3–30.6 mg/kg/day). After 3 years of treatment, GFR measured by 99mTc-DTPA decreased significantly from 167 ± 46 mL/min/1.73 m2 to 145 ± 27 mL/min/1.73 m2 (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. Am. J. Hematol., 88:116–119, 2013. © 2012 Wiley Periodicals, Inc.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The clinical manifestations of renal involvement in sickle cell anemia (SCA) include urinary concentrating defects, incomplete urinary acidification, glomerular hyperfiltration, microalbuminuria/proteinuria, hematuria, and renal failure [1, 2]. The pathogenesis of sickle nephropathy is not well defined. One explanation is that sickling of the red blood cells in the hypertonic, hypoxic, and acidic environment of the renal medulla leads to vaso-occlusion, ischemia, and infarction of the vasa recta. As a result, the levels of vasodilating agents such as prostaglandins and nitric oxide increase and augment the blood flow to the glomerulus resulting in hyperfiltration [3, 4]. Over time, hyperfiltration may lead to microalbuminuria, proteinuria and, in a small percentage of patients, renal failure. In addition, intra-renal renin-angiotensin system, relative hypertension, possibly renal iron deposition may play a role in sickle nephropathy.

Glomerular hyperfiltration may play an important role in the pathogenesis of sickle nephropathy and if treated, may prevent development of proteinuria and eventually renal failure. Hyperfiltration has been described in both children and adults with SCA. It starts as early as 9–19 months of age as described in the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) study [5]. The GFR usually increases as the children get older and may eventually decrease in young adults [6, 7]. However, hyperfiltration can persist into adulthood [8, 9]. There are only a few studies describing the effects of hydroxyurea and chronic transfusion therapy on sickle nephropathy [10-15]. In this prospective study, we aimed to analyze the effects of hydroxyurea treatment on GFR, microalbuminuria and cystatin C levels in children with SCA.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Study overview

The hydroxyurea study of long-term effects is a prospective observational study (HUSTLE, NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Enrollment in this study is offered to all children with SCA who fulfill clinical or laboratory criteria for treatment with hydroxyurea as follows: recurrent vaso-occlusive pain events (three or more events per year requiring missed school/work, emergency room visit or hospitalization), acute chest syndrome, chronic hypoxemia, low hemoglobin level (less than 7.0 g/dL), low %HbF (less than 8% after 24 months of age), elevated white blood cell (WBC) count (more than 20.0 × 109/L), elevated lactate dehydrogenase (LDH) (more than twice the upper limit of normal) [16]. For this analysis, only children in the New Cohort (i.e., children not previously treated with hydroxyurea) were included.

Hydroxyurea treatment

Prior to treatment initiation, vital signs and growth parameters such as weight and height were recorded. Blood pressure (BP) measurements were performed with the child sitting down using an oscillometric device, with an appropriate cuff size based on the size of the child. Hydroxyurea was started at a dose of 20 mg/kg/day and the dose was escalated in 5 mg/kg increments every 8 weeks to maximum tolerated dose (MTD) which was defined by an absolute neutrophil count of 2.0–4.0 × 109/L or other hematologic toxicity [17]. All of the clinical and laboratory studies were repeated after 3 years of treatment with hydroxyurea.

Laboratory evaluations

Laboratory evaluations included complete blood count with WBC differential, reticulocyte count, hemoglobin identification (using high performance liquid chromatography), serum chemistries, LDH, serum cystatin C, quantitative urine albumin and direct GFR measurement by 99mTc-DTPA plasma clearance. With peripheral intravenous access, 2mCi/m2 (total dose: 2-4mCi) of 99mTc-DTPA were administered intravenously. Plasma samples were collected at 1, 2, and 4 hr after injection using the same IV site, after discarding 3 mL blood to prevent contamination. After these specimens were analyzed, a plasma DTPA clearance curve was calculated and the quantitative GFR value was derived [18]. Hyperfiltration was defined as GFR >1SD above the normal mean for age [19].

Serum creatinine was determined by a 4-step enzymatic method (Roche Diagnostics, Indianapolis, IN) using creatininase, creatinase, sarcosine oxidase, and peroxidase to form a colored quinone imine which is measured spectrophotometrically. Serum cystatin C was quantified by a turbidimetric method (Roche Diagnostics, Indianapolis, IN) using latex particles which are coated with anti-cystatin C. Urine albumin and creatinine measurements were performed from a random single sample using a turbidimetric method at Quest Diagnostics Laboratories (San Juan Capistrano, CA). Microalbuminuria was defined as >30 μg albumin/g creatinine. More than 300 μg albumin/gm creatinine was considered proteinuria.

Statistical analyses

Changes in values from Baseline to Year 3 for HUSTLE subjects were evaluated using the Wilcoxon Signed Rank test. Patients with increased GFR were compared with those with decreased GFR using the Wilcoxon Mann Whitney test. Associations between continuous variables were evaluated using Spearman correlation coefficient. P-values less than 0.05 were considered statistically significant and all analyses were conducted using SAS Version 9.2 (Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Baseline data

Twenty-three children with SCA (15 males) with paired renal studies started hydroxyurea treatment at a mean age of 7.4 ± 3.5 years (range, 2.5–14.0 years). Their clinical and laboratory characteristics are presented in Table 1. All 23 had SCA (20 with HbSS and 3 with HbS/β0-thalassemia). None of the children was on chronic transfusion therapy or receiving antihypertensive treatment. All children were normotensive based on published ranges for children with SCA [20], with mean systolic and diastolic blood pressure measurements of 105 ± 11 and 60 ± 10 mmHg, respectively. Mean serum creatinine was low at 0.29 ± 0.04 mg/dL (range, 0.2–0.4 mg/dL) and serum cystatin C was 0.72 ± 0.09 mg/L (range, 0.59–0.93 mg/L; normal range: 0.55–1.15 mg/L). Mean 99mTc-DTPA GFR values were elevated at 167 ± 46 mL/min/1.73 m2 (median, 159; range, 100–308 mL/min/1.73 m2) and 87% of the children had measured GFR >1SD above the normal mean for age (normal for age 104 ± 20 mL/min/1.73 m2) [19]. Four children (17.4%) had microalbuminuria. None of the children had proteinuria.

Table 1. Clinical and Laboratory Characteristics of 23 Children at Enrollment and After 3 Years of Hydroxyurea Treatment
 At enrollmentAfter 3 years of hydroxyurea treatmentChange over 3 yearsP value
  1. Values shown are mean ± SD; Median (IQR).

Age (years)7.4 ± 3.5 7.4 (4.6, 10.0)10.6 ± 3.5 10.6 (7.5, 13.5)3.2 (0.3) 3.2 (3.1, 3.5)<0.0001
Height (cm)122.4 ± 21.5 125.4 (101.2, 135.1)141.4 ± 21.0 139.9 (123.1, 155.3)19.0 ± 5.3 18.6 (14.4, 22.1)<0.0001
Weight (kg)24.0 (8.9) 23.4 (16.1, 27.5)35.8 ± 13.0 36.0 (25.1, 43.7)11.8 ± 6.3 9.6 (7.5, 15.6)<0.0001
Systolic BP (mmHg)105 ± 11 105 (96, 113)111 ± 8 112 (107, 116)6 ± 14 8 (−5, 16)0.06
Diastolic BP (mmHg)60 ± 10 61 (55, 69)60 ± 7 58 (54, 68)0 ± 10 1 (−9, 6)1.0
Hb (g/dL)8.1 ± 1.3 8.0 (7.1, 9.1)9.1 ± 1.3 9.1 (8.2, 9.9)0.9 ± 1.1 1.1 (0.4, 1.4)0.0006
MCV (fL)85.2 ± 6.7 85.6 (82.9, 89.1)102.5 ± 11.4 104.1 (97.4, 110.1)17.3 ± 7.7 18.2 (12.4, 23.3)<0.0001
HbF/F+S (%)10.9 ± 7.5 10.0 (4.3, 12.7)20.3 ± 8.8 17.2 (13.3, 28.4)9.5 ± 7.0 10.6 (5.4, 13.3)<0.0001
WBC (x109/L)11.4 ± 4.3 10.6 (9.1, 13.3)8.2 ± 2.3 7.8 (6.5, 10.1)−3.2 ± 3.2 −3.2 (−5.1, −0.4)<0.0001
ANC (x106/L)4,895 ± 2,417 4,872 (2,881, 6,360)4,301 ± 1,643 4,312 (3,024, 5,151)−594 ± 2565 −655 (−1543, 1458)0.65
LDH (units/L)680 ± 257 656 (458, 814)523 ± 180 478 (423, 576)−161 ± 290 −80 (−285, −2)0.0244
Total bilirubin (mg/dL)3.0 ± 2.4 2.2 (1.7, 3.7)1.7 ± 1.6 1.4 (0.9, 1.8)−1.2 ± 1.5 −0.6 (−1.5, −0.3)0.0001
Serum creatinine (mg/dL)0.29 ± 0.04 0.3 (0.3, 0.3)0.38 ± 0.07 0.4 (0.3, 0.4)0.09 ± 0.06 0.10 (0.10, 0.10)<0.0001
GFR (mL/min/1.73 m2)167 ± 46 159 (137, 184)145 ± 27 141 (126, 164)−21.5 ± 43.0 −15.0 (−42.0, −2.0)0.0159
Urine microalbumin (μg protein/mg creatinine)23.2 ± 28.8 13.0 (8.0, 23.0)20.9 ± 39.5 6.0 (5.0, 17.0)−4.5 ± 37.3 −5.0 (−14.0, 7.0)0.25
Cystatin C (mg/L)0.72 ± 0.09 0.71 (0.65, 0.77)0.74 ± 0.13 0.74 (0.67, 0.80)0.02 ± 0.12 0.03 (−0.03, 0.09)0.46

After 3 years of treatment with hydroxyurea at MTD

The average age of the patients at the time of repeat studies was 10.6 ± 4.0 years. All of them remained normotensive with mean systolic and diastolic blood pressure measurements of 111 ± 8 and 60 ± 7 mmHg, respectively. Serum creatinine was slightly but significantly increased to 0.38 ± 0.07 mg/dL. Cystatin C was basically unchanged at 0.74 ± 0.13 mg/L.

Although the mean GFR after 3 years of therapy was still elevated at 145 ± 27 mL/min/1.73 m2 (median, 141; range, 94–197 mL/min/1.73 m2), there was a significant decrease when compared with the value obtained 3 years prior, before the start of hydroxyurea (median decrease: 15, P = 0.016). After 3 years of treatment with hydroxyurea at MTD, the GFR decreased in 18 patients (78%, Fig. 1). In addition, we performed a post-hoc analysis of the change in GFR according to age at enrollment. Despite the small sample size, we divided subjects into four different age groups: 1–3 years, 4–7 years, 8–11 years, and >12 years. There was a significant decrease in GFR in the subjects who started hydroxyurea at 4–7 years of age (median decrease 29.7; P = 0.03); but in other age groups, the changes were not significant.

image

Figure 1. Glomerular filtration rate at baseline and then after 3 years of treatment with hydroxyurea at maximum tolerated dose.

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This decrease in GFR had a significant association with the change in %HbF (r = −0.42, P = 0.042) and LDH (r = 0.46, P = 0.035). None of the other clinical or laboratory parameters had a significant association with this decrease in GFR. In addition, when children who had a decrease in their GFR were compared with the ones who had an increase, there were statistically significant differences in the changes observed in MCV, MCH, %HbF, and LDH levels in 3 years (Table 2).

Table 2. Changes in laboratory parameters of subjects whose GFR decreased after 3 years of hydroxyurea therapy vs. those whose GFRincreased
Change in laboratory parameterGFR decreased (n = 18)GFR increased (n = 5)P value
  1. Values shown are mean ± SD; Median (IQR).

Hb (gm/dL)± 1.0 1.2 (0.8, 1.4)0.4 ± 1.3 0.9 (−0.6, 1.1)0.32
MCV (fL)19.7 ± 6.3 19.3 (13.9, 26.2)8.4 ± 5.6 8.5 (5.4, 12.4)0.0024
MCH (pg)6.5 ± 2.6 6.4 (5.1, 7.7)3.4 ± 2.2 3.3 (1.9, 4.9)0.0481
HbF (%)11.2 ± 6.2 11.5 (5.9, 14.2)2.7 ± 3.8 1.1 (0.5, 6.4)0.0151
ARC (x106/L)−62.4 ± 146.5 −76.1 (−107.8, 28.2)16.8 ± 102.9 12.7 (−42.7, 23.8)0.29
WBC (x 106/L)−3.0 ± 3.2 −2.8 (−5.1, −0.4)−3.7 ± 3.3 −3.5 (−4.6, −1.4)0.73
ANC (x106/L)−614 ± 2,687 −516 (−1,543, 1,458)−522 ± 2,345 −655 (−1,276, 1,368)0.97
LDH (units/L)−226 ± 303 −137 (−382, −61)46 ± 83 60 (−34, 80)0.0147

Twenty-one children had repeat urine microalbumin measurements: in two children, microalbuminuria resolved; two had persistence and two had newly developed microalbuminuria. None of the children had proteinuria. In the two patients whose microalbuminuria resolved, the GFR decreased from 308 to 160 and from 137 to 132 mL/min/1.73 m2, respectively. In the patients who developed new onset microalbuminuria, the GFR also decreased (from 248 to 187 and from 188 to 166 mL/min/1.73 m2, respectively).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

There have been very few prospective studies analyzing the effect of disease modifying treatments on renal complications in SCA. No renal measurements (other than serum creatinine) were reported in the Phase I/II hydroxyurea trial in adults [21], the Phase I/II trial for school-aged children [22], and the Phase I/II infant trial [23]. The Phase III Multicenter Study of Hydroxyurea (MSH) also did not report renal effects of hydroxyurea treatment [24]. The small prospective Toddler HUG study did measure GFR by DTPA clearance, and reported that hydroxyurea treatment prevented the expected GFR increase with age [11]. In 11 children enrolled in this study who were treated with hydroxyurea at MTD for 25 months, the difference between entry and exit GFR was 5.1 ± 14.1 mL/min/1.73 m2 (P = 0.26), a reduction of 13% from baseline. The average age of children in this study was 35 months, an age when we would expect an increase in GFR in children with SCA, so maintaining GFR at the same level while on hydroxyurea might be considered a beneficial effect.

Several retrospective studies, however, have suggested a salutary effect of hydroxyurea and transfusions on renal function in SCA. In one retrospective study, only 13% of children with SCA treated with hydroxyurea developed microalbuminuria, compared with 24% of children not receiving any treatment and 26% of children on chronic transfusions [12]. In a case report of 3 children with SCA and nephrotic syndrome who had persistent albuminuria while on enalapril, addition of hydroxyurea at MTD normalized the urine protein/creatinine ratio [13]. In another retrospective study, 4 out 9 children who were treated with hydroxyurea for other SCA-related indications had normalization of their proteinuria [14]. Transfusion therapy has also been shown to have effects on renal function. In one retrospective review of 23 children on chronic transfusions, age at onset of chronic transfusions was significantly associated with the development of microalbuminuria [15]. Those without microalbuminuria (19/23) started transfusions at an earlier age (mean age 7.8 ± 3.7 years) than those with microalbuminuria (mean age 12.2 ± 1.9 years, P = 0.03).

The BABY HUG study compared renal function before and after 24 months of treatment with hydroxyurea vs. placebo in infants 9–18 months of age [10]. Glomerular hyperfiltration was evaluated by 99mTc-DTPA clearance in 176 infants at entry and 142 infants at exit. The mean GFR at entry was significantly elevated when compared to published norms. At exit, there was no difference in mean GFR between the hydroxyurea and placebo groups (146 ± 44 mL/min/1.73 m2 and 146 ± 48 mL/min/1.73 m2, respectively). The age at initiation of treatment, Hb and HbF levels did not have any effects on DTPA-GFR measurements.

Our prospective data indicate that hydroxyurea at MTD was associated with a significant decrease in GFR (Fig. 1), and the effect was most significantly associated with increased HbF and decreased LDH (Table 2). Similar to BABY HUG study, our results did not show a significant change in GFR in children who started hydroxyurea at 1–3 years of age. Although there was a significant decrease in GFR in children who started hydroxyurea between 4 and 7 years of age, this information should be interpreted with caution as this was detected in a post-hoc secondary analysis and the patient numbers were too small to have adequate power. There are several possible explanations for the discrepancy between BABY HUG results and our report. In BABY HUG, hydroxyurea dose was not escalated to more than 20 mg/kg/day and the DTPA-GFR measurements were obtained locally in 14 centers, several of which did not routinely perform this test [5]. Finally, although 24 months of study treatment in BABY HUG did not have significant effects on GFR, hydroxyurea was associated with better urine concentrating ability and less renal enlargement [25].

There are several potential mechanisms by which hydroxyurea might prevent renal damage in SCA such as increasing hemoglobin and HbF levels, lowering WBC and reducing hemolysis. In a study evaluating adults with SCA, glomerular hyperfiltration was significantly associated with a young age, absence of alpha thalassemia, a lower Hb level and lower %HbF [9]. In our study, the decrease in GFR was significantly associated with increasing %HbF levels and decreasing LDH confirming the beneficial effects of hydroxyurea. In view of our data along with the BABY HUG data showing better urine concentrating ability in the hydroxyurea treated group, one may speculate that hydroxyurea works by reducing sickling in the renal medulla. In addition, hydroxyurea increases Hb and decreases LDH, which would lead to improved oxygenation, decreased cardiac output, reduced renal blood flow and in response, decreased hyperfiltration.

Our study has several limitations. This was not a randomized study, so we do not have results on simultaneously untreated children with SCA. However, the natural history of glomerular hyperfiltration during childhood is well described and shows continued elevation of GFR until late teenage years, so we would expect the GFR to increase among our patients without hydroxyurea treatment [6, 7]. In our treated cohort, the repeat GFR after 3 years of hydroxyurea therapy was lower than pretreatment levels (Fig. 1), but also lower than published results for children with untreated SCA at 7–12 years (170 mL/min/1.73 m2) and at 8–11 years (159 ± 34 mL/min/1.73 m2) [6, 7]. Another possible limitation is that measuring GFR by the 99mTc-DTPA has not been validated in patient populations with hyperfiltration. We did not perform inulin clearance, which is considered the gold standard for GFR calculation, but this technique is difficult to perform and rarely used even in research settings.

In summary, this is the first prospective study showing a beneficial effect of hydroxyurea on glomerular hyperfiltration in SCA. If one of the underlying pathologies of renal dysfunction in SCA is hyperfiltration, this result may have future implications for progression of renal disease in children and adults with SCA. Future studies are necessary to confirm these findings in larger cohorts of children with SCA.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The authors would like to thank all the patients and families who participated in the HUSTLE study, Amy C. Kimble FNP for her help with the study, and Terri Davis for assistance with text formatting.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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