We reviewed the evidence on the effect of drugs that aim to prevent people with sickle cell disease losing protein or albumin (a protein made in the liver) in their urine.
Sickle cell disease is a group of inherited conditions that often lead to kidney damage. High protein or albumin levels in urine is a strong predictor of future kidney failure. Angiotensin-converting enzyme (ACE) inhibitors are often given to reduce the level of protein or albumin in urine and to protect the kidneys from damage. However, we do not know very much about how effective and safe these are in people with sickle cell disease.
The evidence is current to: 22 August 2021.
We only included and analysed one study (with 22 adults with sickle cell disease) in the review. The participants had high levels of protein (proteinuria) or albumin (microalbuminuria) in their urine and were randomly selected to be treated for six months with either captopril (an angiotensin-converting enzyme inhibitor) or placebo (dummy drug with no active medication).
The results from this small and very low-quality study were not convincing. We downgraded our judgements on the certainty of the evidence because of at least an unclear or a high risk of bias in almost all areas we assessed, as well as imprecision (results showed a wide range of possible effects) and indirectness (the study did not include any children and only a small number of adults with normal blood pressure and microalbuminuria). This study did not show that ACE inhibitors could reduce the level of protein or albumin in the urine. The levels of creatinine (a chemical compound left over from energy-producing processes in muscles; a high level can indicate kidney failure) and potassium in the blood were reported as constant throughout the study. No serious adverse events were noted, although the potential for causing low blood pressure should be highlighted. More long-term studies involving multiple centers and larger numbers of participants are needed.
Certainty of the evidence
Overall certainty of the evidence was very low, since we thought there was either a high or unclear risk of bias from all aspects that may contribute to biasing the results (e.g. randomisation, the way treatment allocations were concealed, whether all participants recruited were analysed, whether all planned outcomes were reported, as well as blinding of participants, research personnel and outcome assessment). We also noted that the study did not include children, which limits the evidence for this treatment in children. Our statistical calculations on the effect found a high degree of imprecision. There may be selective reporting on sodium levels, but other electrolyte levels were reported. Nevertheless, the amount of data with detailed descriptions has allowed only limited analysis in this review.
Overall, we judged the certainty of the evidence to be very low. The included study selectively reported its results, was not powered to detect a group difference, should it exist, and otherwise did not offer enough information to allow us to judge the bias inherent in the study. Indirectness (in relation to the limited age and type of population included) and imprecision (wide confidence intervals around the effect estimate) were observed. More long-term studies involving multiple centers and larger cohorts using a randomized-controlled design are warranted, especially among the pediatric age group. Detailed reporting of each outcome measure is necessary to allow a clear cut interpretation in a systematic review. One of the difficulties encountered in this review was the lack of detailed data reported in the included study.
Overall, we judged the certainty of this evidence to be very low.
Sickle cell disease is a group of disorders characterized by deformation of erythrocytes. Renal damage is a frequent complication in sickle cell disease as a result of long-standing anemia and disturbed circulation through the renal medullary capillaries. Due to the improvement in life expectancy of people with sickle cell disease, there has been a corresponding significant increase in the incidence of renal complications. Microalbuminuria and proteinuria are noted to be a strong predictor of subsequent renal failure. There is extensive experience and evidence with angiotensin-converting enzyme (ACE) inhibitors over many years in a variety of clinical situations for patients who do not have sickle cell disease, but their effect in people with this disease is unknown. It is common practice to administer ACE inhibitors for sickle nephropathy due to their renoprotective properties; however, little is known about their effectiveness and safety in this setting. This is an update of a Cochrane Review first published in 2013 and 2015.
To determine the effectiveness of ACE inhibitor administration in people with sickle cell disease for decreasing intraglomerular pressure, microalbuminuria and proteinuria and to to assess the safety of ACE inhibitors as pertains to their adverse effects.
The authors searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Hameoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of the most recent search: 18 October 2021.
We also searched clinical trial registries. Date of the most recent search: 22 August 2021.
Randomized or quasi-randomized controlled trials of ACE inhibitors designed to reduce microalbuminuria and proteinuria in people with sickle cell disease compared to either placebo or standard treatment regimen.
Three authors independently applied the inclusion criteria in order to select studies for inclusion in the review. Two authors assessed the risk of bias of studies and extracted data and the third author verified these assessments.
Seven studies were identified through the searches. Six studies were excluded. The included study randomized 22 participants (7 males and 15 females) having proteinuria or microalbuminuria with sickle cell disease and treated the participants for six months (median length of follow up of three months) with captopril or placebo. Overall, the certainty of the evidence provided in this review was very low, since most risk of bias domains were judged to have either an unclear or a high risk of bias. Because of this, we are uncertain whether captopril makes any difference, in total urinary albumin excretion (at six months) as compared to the placebo group, although it yielded a mean difference of -49.00 (95% confidence interval (CI) -124.10 to 26.10) or in the absolute change score, although it yielded a mean difference of -63.00 (95% CI -93.78 to -32.22). At six months albumin excretion in the captopril group was noted to decrease from baseline by a mean (standard deviation) of 45 (23) mg/day and the placebo group was noted to increase by 18 (45) mg/day. Serum creatinine and potassium levels were reported constant throughout the study (very low-certainty evidence). The potential for inducing hypotension should be highlighted; the study reported a decrease of 8 mmHg in systolic pressure and 5 mmHg in diastolic and mean blood pressure (very low-certainty evidence).