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. 2023 Aug 4;8(8):CD012380.
doi: 10.1002/14651858.CD012380.pub3.

Interventions for chronic kidney disease in people with sickle cell disease

Noemi Ba Roy  1 , Abigail Carpenter  2 , Isabella Dale-Harris  3 , Carolyn Dorée  4 , Lise J Estcourt  5
Affiliations

Interventions for chronic kidney disease in people with sickle cell disease

Noemi Ba Roy et al. Cochrane Database Syst Rev. .

Abstract

Background: Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017.

Objectives: To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination.

Search methods: We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers.

Selection criteria: Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status.

Data collection and analysis: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE).

Main results: We included three RCTs with 385 participants. We rated the certainty of the evidence as low to very low across different outcomes according to GRADE methodology, downgrading for risk of bias concerns, indirectness, and imprecision. Hydroxyurea versus placebo One RCT published in 2011 compared hydroxyurea to placebo in 193 children aged nine to 18 months. We are unsure if hydroxyurea compared to placebo reduces or prevents progression of kidney disease assessed by change in glomerular filtration rate (mean difference (MD) 0.58 mL/min /1.73 m2, 95% confidence interval (CI) -14.60 to 15.76; 142 participants; very low certainty). Hydroxyurea compared to placebo may improve the ability to concentrate urine (MD 42.23 mOsm/kg, 95% CI 12.14 to 72.32; 178 participants; low certainty), and may make little or no difference to SCD-related serious adverse events, including acute chest syndrome (risk ratio (RR) 0.39, 99% CI 0.13 to 1.16; 193 participants; low certainty), painful crisis (RR 0.68, 99% CI 0.45 to 1.02; 193 participants; low certainty); and hospitalisations (RR 0.83, 99% CI 0.68 to 1.01; 193 participants; low certainty). No deaths occurred in either trial arm and the RCT did not report quality of life. Angiotensin-converting enzyme inhibitors versus placebo One RCT published in 1998 compared an ACEI (captopril) to placebo in 22 adults with normal blood pressure and microalbuminuria. We are unsure if captopril compared to placebo reduces proteinuria (MD -49.00 mg/day, 95% CI -124.10 to 26.10; 22 participants; very low certainty). We are unsure if captopril reduces or prevents kidney disease as measured by creatinine clearance; the trial authors stated that creatinine clearance remained constant over six months in both groups, but provided no comparative data (very low certainty). The RCT did not report serious adverse events, all-cause mortality, or quality of life. Angiotensin-converting enzyme inhibitors versus vitamin C One RCT published in 2020 compared an ACEI (lisinopril) with vitamin C in 170 children aged one to 18 years with normal blood pressure and microalbuminuria. It reported no data we could analyse. We are unsure if lisinopril compared to vitamin C reduces proteinuria in this population: the large drop in microalbuminuria in both arms of the trial after only one month on treatment may have been due to an overestimation of microalbuminuria at baseline rather than a true effect. The RCT did not report serious adverse events, all-cause mortality, or quality of life.

Authors' conclusions: We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.

PubMed Disclaimer

Conflict of interest statement

NR: none known AC: none known IDH: none known CD: none known LE: declares employment by NHS Blood and Transplant.

Figures

1
1
Sickle cell nephropathy pathophysiology in sickle cell disease: Adapted from Okafor 2013 and Nath 2015. RBC: red blood cell; FSGS: focal segmental glomerulosclerosis; ESRD: end‐stage renal disease
2
2
Structure of the kidney. From: Wikispaces. Human Physiology. 12. Urology.humanphysiology2011.wikispaces.com/12.+Urology
3
3
4
4
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
5
5
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 1: GFR (mL/min/1.73 m2)
1.2
1.2. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 2: Ability to concentrate urine (mOsm/kg)
1.3
1.3. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 3: Acute chest syndrome
1.4
1.4. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 4: Painful crisis
1.5
1.5. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 5: Hospitalisations
1.6
1.6. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 6: Stroke
1.7
1.7. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 7: Neutropenia
1.8
1.8. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 8: Thrombocytopenia
1.9
1.9. Analysis
Comparison 1: Hydroxyurea versus placebo, Outcome 9: Number of participants transfused
2.1
2.1. Analysis
Comparison 2: ACEI (captopril) versus placebo, Outcome 1: Proteinuria (mg/day)
2.2
2.2. Analysis
Comparison 2: ACEI (captopril) versus placebo, Outcome 2: Other drug‐related adverse events (dry cough)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Aliu 2020 {published data only}
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BABY HUG 2011 {published data only}
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    1. Alvarez O, Miller ST, Wang WC, Luo Z, McCarville MB, Schwartz GJ, et al. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatric Blood & Cancer 2012;59(4):668-74. [CENTRAL: 848700] [CFGD REGISTER: SC180gg] [PMID: ] - PMC - PubMed
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Foucan 1998 {published data only}
    1. Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL. A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. American Journal of Medicine 1998;104(4):339-42. [CFGD REGISTER: SC34] - PubMed

References to studies excluded from this review

Ataga 2019 (ENDO) {published data only}
    1. Ataga KI, Wichlan D, Elsherif L, Derebail VK, Wogu AF, Maitra P, et al. A pilot study of the effect of atorvastatin on endothelial function and albuminuria in sickle cell disease. American Journal of Hematology 2019;94(11):E299-301. [CENTRAL: CN-02005431] [CFGD REGISTER: SC390] [EMBASE: 2002542331] [PMID: ] - PubMed
    1. NCT01732718. Effect of Atorvastatin on Endothelial Dysfunction and Albuminuria in Sickle Cell Disease (ENDO). clinicaltrials.gov/ct2/show/NCT01732718 (first received 9 November 2012).
Ataga 2021 (HIBISCUS) {published data only}
    1. Ataga K, Wood K, Geib J, Wu E, Berlin J, Webster I, et al. Hibiscus, an adaptive, randomized, placebo-controlled, double-blind, multicenter study of oral ft-4202, a pyruvate kinase activator in patients with sickle cell disease. HemaSphere 2021;5(Suppl 2):831.
    1. NCT04624659. A study of etavopivat in adults and adolescents with sickle cell disease (HIBISCUS). clinicaltrials.gov/ct2/show/NCT04624659 (first received 5 November 2020).
    1. Wood K, Geib J, Wu E, Berlin J, Webster I, Ataga K, et al. Hibiscus, an adaptive, randomized, placebo-controlled, double-blind, multi-centre study of oral FT-4202, a pyruvate kinase activator in patients with sickle cell disease. British Journal of Haematology 2021;193(Suppl 1):31-2.
Choi 2016 {published data only}
    1. Choi J, Singh N, Han J, Gowhari M, Hassan J, Jain S, et al. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on kidney function in patients with sickle cell disease. Blood 2016;128(22):3666. [DOI: 10.1182/blood.V128.22.3666.3666] - DOI
Estcourt 2016 {published data only}
    1. Estcourt LJ, Fortin PM, Hopewell S, Trivella M. Red blood cell transfusion to treat or prevent complications in sickle cell disease: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No: CD012082. [DOI: 10.1002/14651858.CD012082] - DOI - PMC - PubMed
George 2020 {published data only}
    1. George A, Aygun B, Mortier N, Sparreboom A, Ware R. A randomized controlled trial of a dose-prediction equation to determine maximum tolerated dose of hydroxyurea in children with sickle cell anemia. Pediatric Blood & Cancer 2013;60(Suppl):S32. [CFGD REGISTER: SC283b]
    1. George A, Dinu B, Estrada N, Minard C, Hurwitz RL, Mahoney D, et al. NDEPTH: a randomized controlled trial of a novel dose-prediction equation to determine maximum tolerated dose for hydroxyurea therapy in pediatric patients with sickle cell anemia. Blood 2019;134:2267. [CFGD REGISTER: SC283c] - PubMed
    1. George A, Dinu B, Estrada N, Minard CG, Hurwitz R, Mahoney DH, et al. Novel dose escalation to predict treatment with hydroxyurea (NDEPTH): a randomized controlled trial of a dose-prediction equation to determine maximum tolerated dose of hydroxyurea in pediatric sickle cell disease. American Journal of Hematology 2020;95(9):E242-4. [CFGD REGISTER: SC283d] [DOI: 10.1002/ajh.25883] [PMID: ] - DOI - PubMed
    1. George A, Dinu BR, Ware RE. Ndepth: novel dose escalation to predict treatment with hydroxyurea. Blood 2015;126(23):3419. [CFGD REGISTER: SC283a]
    1. NCT02042222. Novel dose escalation to predict treatment with hydroxyurea. clinicaltrials.gov/ct2/show/NCT02042222 (first posted 20 January 2014).
Jain 2012 {published data only}
    1. Jain D. Low dose hydroxyurea in children severely affected with sickle cell disease: hospital based randomized controlled study. American Journal of Hematology 2010;85(8):E42. [CFGD REGISTER: SC211a]
    1. Jain D. Low dose hydroxyurea in children severely affected with sickle cell disease: hospital based randomized controlled study. In: 4th Annual Sickle Cell Disease Research and Educational Symposium & Grant Writing Institute AND Annual Sickle Cell Disease Scientific Meeting; 2010 Feb 14-19; Hollywood, Florida. 2010:52, Abstract no: 076. [CFGD REGISTER: SC211b]
    1. Jain DL, Sarathi V, Desai S, Bhatnagar M, Lodha A. Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease. Hemoglobin 2012;36(4):323-32. [FGD REGISTER: SC211c] - PubMed
Laurin 2014 {published data only}
    1. Laurin LP, Nachman PH, Desai PC, Ataga KI, Derebail VK. Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease. Nephrology Dialysis Transplantation 2014;29(6):1211-8. - PMC - PubMed
NCT01096121 (MADREPIEC) {published data only}
    1. NCT01096121. Angiotensin-converting enzyme Inhibitors and early sickle cell renal disease in children (MADREPIEC). clinicaltrials.gov/ct2/show/record/NCT01096121 (first posted 29 March 2010). [CFGD REGISTER: SC427]
NCT01195818 (RAND) {unpublished data only}
    1. NCT01195818. Albuminuria reduction with renin angiotensin system inhibitors in SCA patients (RAND). clinicaltrials.gov/ct2/show/NCT01195818 (first posted 3 September 2010).
NCT01891292 {published data only}
    1. NCT01891292. Efficacy of antioxidant therapy compared with enalapril in sickle nephropathy. clinicaltrials.gov/ct2/show/NCT01891292 (first posted 22 January 2013). [CFGD REGISTER: SC428]
NCT01989078 (SCD‐Losaratan) {published data only}
    1. NCT01989078. Losartan for sickle cell kidney disease (SCD-Losartan). clinicaltrials.gov/ct2/show/NCT01989078 (first received 26 February 2013).
NCT02286154 (TREAT) {published data only}
    1. NCT02286154. Therapeutic response evaluation and adherence trial (TREAT). clinicaltrials.gov/ct2/show/NCT02286154 (first posted 1 October 2014).
NCT02373241 {published data only}
    1. NCT02373241. Preventing sickle cell kidney disease [Chronobiology and chronopharmacology to prevent sickle cell kidney disease]. clinicaltrials.gov/ct2/show/NCT02373241 (first posted 5 February 2015). [CFGD REGISTER: SC463]
NCT02522104 (DARH) {published data only}
    1. NCT02522104. Evaluation of the impact of renal function on the pharmacokinetics of SIKLOS ® (DARH). clinicaltrials.gov/ct2/show/NCT02522104 (first posted 4 August 2015).
Quinn 2017 {published data only}
    1. NCT01479439. Losartan to reverse sickle nephropathy. clinicaltrials.gov/ct2/show/NCT01479439 (first received 16 November 2011).
    1. Quinn C, Saraf S, Gordeuk V, Fitzhugh C, Creary S, Bodas P, et al. A multi-center, phase-2 trial of losartan for the nephropathy of sickle cell anemia. Pediatric Blood & Cancer 2016;63:S13.
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Silva Junior 2014 {published data only}
    1. Silva Junior GB, Vieira AP, Couto Bem AX, Alves MP, Meneses GC, Martins AM, et al. Proteinuria in adults with sickle-cell disease: the role of hydroxycarbamide (hydroxyurea) as a protective agent. International Journal of Clinical Pharmacy 2014;36(4):766-70. - PubMed
Steinberg 2003 {published data only}
    1. Steinberg MH, Barton F, Castro, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of hydroxyurea on mortality and Morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003;289(13):1645-51. - PubMed
Wood 2020 (PRAISE) {published data only}
    1. Wood KW, Geib J, Wu E, Berlin J, Webster I, Ataga KI, Howard J, et al. An adaptive, randomized, placebo-controlled, double-blind, multi-center study of oral FT-4202, a pyruvate kinase activator in patients with sickle cell disease (PRAISE). Blood 2020;136(Suppl 1):19-20.
Zahr 2019 {published data only}
    1. Zahr RS, Hankins JS, Kang G, Li C, Wang WC, Lebensburger J, et al. Hydroxyurea prevents onset and progression of albuminuria in children with sickle cell anemia. American Journal of Hematology 2019;94(1):E27-9. - PMC - PubMed

References to studies awaiting assessment

NCT05392894 (REDRESS) {published data only}
    1. NCT05392894. Related haplo-donor haematopoietic stem cell transplantation for adults with severe sickle cell disease (REDRESS). clinicaltrials.gov/ct2/show/NCT05392894 (first received 23 May 2022).

References to ongoing studies

Ataga 2019 (STEADFAST) {published data only}
    1. Ataga KI, Saraf SL, Derebail VK, Sharpe CC, Inati A, Lebensburger JD, et al. The effect of crizanlizumab plus standard of care (SoC) versus soc alone on renal function in patients with sickle cell disease and chronic kidney disease: a randomized, multicenter, open-label, phase II study (STEADFAST). Blood 2019;134(Suppl 1):1018. [CENTRAL: CN-02050662] [CFGD REGISTER: SC391a] [DOI: 10.1182/blood-2019-124823] [EMBASE: 630319168] - DOI
    1. Bartolucci P, Saraf SL, Derebail VK, Sharpe CC, Inati A, Lebensburger JD, et al. STEADFAST: a phase II study investigating the effect of crizanlizumab and standard of care (SOC) vs SOC alone on renal function in patients with chronic kidney disease due to sickle cell nephropathy. HemaSphere 2020;4(Suppl 1):1055. [CFGD REGISTER: SC391c]
    1. EUCTR2018-003608-38-GR. Study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease [A Phase II, multicenter, randomized, open label two arm study comparing the effect of crizanlizumab + standard of care to standard of care alone on renal function in sickle cell disease patients = 16 years with chronic kidney disease due to sickle cell nephropathy (STEADFAST)]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2018-003608-38-GR 2019. [CENTRAL: CN-02068279] [CFGD REGISTER: SC391b]
    1. LBCTR2020094586. A phase II, multicenter, randomized, open label two arm study comparing the effect of crizanlizumab + standard of care to standard of care alone on renal function in sickle cell disease patients = 16 years with chronic kidney disease due to sickle cell nephropathy. trialsearch.who.int/Trial2.aspx?TrialID=LBCTR2020094586 (first received 24 May 2021).
    1. NCT04053764. Study exploring the effect of crizanlizumab on kidney function in patients with chronic kidney disease caused by sickle cell disease (STEADFAST). clinicaltrials.gov/ct2/show/NCT04053764 (first posted 9 August 2019). [CFGD REGISTER: SC391e]
EUCTR2019‐004471‐39‐GB {published data only}
    1. EUCTR2019-004471-39. A phase 2b study to evaluate the safety and efficacy of IMR-687 in subjects with sickle cell disease. www.clinicaltrialsregister.eu/ctr-search/trial/2019-004471-39/results (first received 23 July 2022).
Kutlar 2019 {published data only}
    1. Kutlar A, Pollock J, Meiler SE, Harris R, Hongyan X, Wells L, et al. Phase-I study of ETA receptor antagonist ambrisentan in sickle cell disease. Blood 2019;134(Suppl 1):617.
    1. NCT02712346. The role of endothelin-1 in sickle cell disease. clinicaltrials.gov/ct2/show/results/NCT02712346 (first received 2 October 2015).
NCT03806452 (SIKAMIC) {unpublished data only}
    1. NCT03806452. SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial) (SIKAMIC). clinicaltrials.gov/ct2/show/NCT03806452 (first posted 9 January 2019). [CFGD REGISTER: SC433]
    1. PACTR202103526168929. Multicentre randomized double-blind placebo-controlled study to evaluate the effect on albuminuria of 6 months treatment with hydroxycarbamide (Siklos®) or a placebo in adults with sickle cell disease:SIKAMIC (SIklos on Kidney function and AlbuMInuria Clinical trial). trialsearch.who.int/Trial2.aspx?TrialID=PACTR202103526168929 (first received 28 January 2021).
NCT03814746 (STAND) {published data only}
    1. EUCTR 2017-001746-10. A phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab versus placebo, with or without hydroxyurea/hydroxycarbamide therapy, in adolescent and adult sickle cell disease patients with vaso-occlusive crises (STAND). clinicaltrialsregister.eu/ctr-search/trial/2017-001746-10/NL (first posted 23 April 2019).
    1. NCT03814746. Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle cell disease patients (STAND). clinicaltrials.gov/ct2/show/NCT03814746 (first posted 21 January 2019). [CFGD REGISTER: SC392]
NCT04084080 (SCD‐CARRE) {published data only}
    1. NCT04084080. Sickle cell disease and cardiovascular risk – red cell exchange trial (SCD-CARRE). clinicaltrials.gov/ct2/show/NCT04084080 (first posted 26 August 2019).
NCT04335721 {published data only}
    1. NCT04335721. A voxelotor for sickle cell anemia patients at highest risk for progression of chronic kidney disease. clinicaltrials.gov/ct2/show/NCT04335721 (first received 2 April 2020).

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References to other published versions of this review

Roy 2016
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