Review question
Are there any safe and effective interventions that prevent or reduce kidney complications in people with sickle cell disease (SCD)?
Background
SCD is a serious inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally. Normal red blood cells are flexible and disc-shaped, but sickled cells are rigid and crescent-shaped, and stickier than normal red blood cells. This can lead to blockage of blood vessels, resulting in tissue and organ damage and episodes of severe pain. The abnormal cells are fragile and break apart easily, which leads to a decreased number of red blood cells, known as anaemia.
Kidney complications can start at an early age in children with SCD and are common in adults with the condition. Kidney complications leading to kidney protein leak and chronic kidney disease can be severe, with serious effects on health. Severe complications include the need for dialysis (a procedure to remove waste products and excess fluid from the blood when the kidneys stop working properly) or a kidney transplant. Identifying therapies that can prevent or slow down the decline in kidney function in people with SCD is critical for improving health outcomes.
Search date
The evidence is current to 22 September 2022.
Study characteristics
We found three randomised controlled trials, which enroled a total of 385 people. One trial, published in 2011, compared the drug hydroxyurea (which helps to maintain the shape and flexibility of red blood cells), to placebo (dummy treatment) in 193 children aged nine to 18 months. The second trial, published in 1998, compared captopril (a drug used to treat high blood pressure) to placebo in 22 adults with normal blood pressure and microalbuminuria (high levels of protein in the urine). The third trial, published in 2020, compared lisinopril (a drug used to treat high blood pressure) to vitamin C in 170 children aged one to 18 years.
Two trials received government funding; it was unclear how the third trial was funded.
Key results
In children aged nine to 18 months, hydroxyurea may increase the ability to produce normal urine, but we are unsure if it has any effect on the glomerular filtration rate (network of filters in the kidney that filter waste from the blood). Hydroxyurea may make little or no difference to the occurrence of serious complications including acute chest syndrome (pain, cough, fever, low oxygen levels, and abnormal substances in the lungs), painful crises, and hospitalisations.
We are unsure if giving captopril to adults with SCD who have normal blood pressure and early signs of kidney damage (microalbuminuria) reduces progression of kidney damage.
We are unsure if giving lisinopril to children aged one to 18 years with SCD who have normal blood pressure and early signs of kidney damage (microalbuminuria) reduces progression of kidney damage.
No trials reported quality of life.
Limitations of the evidence
We have little or very little confidence in the evidence because we only found three trials, and they had specific populations (only children or only adults), few participants, and wide variations in results.
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.
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.
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.
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.
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.
Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE).
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.