We wanted to determine if there were any safe and effective interventions that prevent or reduce kidney complications in people with sickle cell disease (SCD).
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 in SCD they can become rigid and crescent shaped. Sickled cells are not only less flexible than healthy red blood cells, they are also stickier. This can lead to blockage of blood vessels, resulting in tissue and organ damage and episodes of severe pain. The abnormal blood cells are more fragile and break apart, 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 (such as the need for dialysis or a kidney transplant). Identifying therapies, which can prevent or slow down the decline in kidney function in people with SCD, will be critical in improving health outcomes.
The evidence is current to: 13 April 2017.
We found two randomised controlled trials which enrolled a total of 215 participants. One trial, published in 2011, was conducted in 193 infants aged 9 months to 18 months and compared the drug hydroxyurea to placebo. The second trial, published in 1998, was conducted in 22 adults with normal blood pressure and microalbuminuria (an increase of protein in the urine) and compared captopril (a drug used to treat high blood pressure) to placebo.
Both trials received government funding.
In infants aged 9 months to 18 months, hydroxyurea may increase the ability to produce normal urine, but we are very uncertain 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 on the incidence of SCD-related serious complications (including acute chest syndrome, painful crises and hospitalisations).
We are very uncertain if giving captopril to adults with SCD who have normal blood pressure and early signs of kidney damage (microalbuminuria) reduces progression of kidney damage.
Quality of life was not reported in either trial.
Quality of the evidence
The evidence for all outcomes was rated as low- to very low-quality due to trials being at high risk of bias and because there were a small number of trials and a small number of participants included in the trials.
In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children's ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations.
We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications.
This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications.
Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD.
We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD.
Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to 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 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, and increases in 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.
To assess the effectiveness of any intervention in preventing or reducing kidney complications or chronic kidney disease in people with SCD (including red blood cell transfusions, hydroxyurea and angiotensin-converting enzyme inhibitor (ACEI)), either alone or in combination with each other.
We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 05 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 13 April 2017.
Randomised controlled trials comparing interventions to prevent or reduce kidney complications or chronic kidney disease in people with SCD. There were no restrictions by outcomes examined, language or publication status.
Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias.
We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo.
We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm.
Hydroxyurea versus placebo
We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m²)) (one study; 142 participants; very low-quality evidence).
In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence).
Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence).
No deaths occurred in the trial. Quality of life was not reported.
ACEI versus placebo
We are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD -49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence).
All-cause mortality, serious adverse events and quality of life were not reported.