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Published in final edited form as: Br J Haematol. 2018 Nov 21;184(2):246–252. doi: 10.1111/bjh.15651

Effect of Renin-Angiotensin-Aldosterone System Blocking Agents on Progression of Glomerulopathy in Sickle Cell Disease

Ashley Thrower 1, Emily J Ciccone 2, Poulami Maitra 3, Vimal K Derebail 4, Jianwen Cai 3, Kenneth I Ataga 5
PMCID: PMC6326862  NIHMSID: NIHMS992232  PMID: 30460977

Abstract

Although renin-angiotensin-aldosterone system (RAAS) blocking agents decrease albuminuria in short-term studies, there is no evidence confirming their long-term efficacy in sickle cell disease (SCD). In a single-centre, retrospective study, we evaluated the long-term effect of RAAS blocking agents on proteinuria and declining estimated glomerular filtration rates (eGFR). Eighty-six patients on RAAS blocking agents for proteinuria, followed for a median of 2.28 years, were compared with 68 patients with proteinuria followed for 2.24 years who were not receiving such treatment. The log odds of proteinuria decreased over time in patients on RAAS blocking agents (β: −0.23, p = 0.03) and in the non-treatment group (β: −0.54, p < 0.0001), but was not statistically different between both groups (β: 0.31, p = 0.063). The eGFR declined over time in patients on RAAS blocking agents (β: −2.78, p < 0.0001) and in those not on such treatment (β: −4.7, p < 0.0001), and was statistically different between both groups (β: 1.9, p = 0.0002). Baseline eGFR was associated with mortality (Hazard rato: 0.97, p < 0.0001), but RAAS blocking agents had no significant effect on mortality. These data suggest that RAAS blockade may slow the loss of kidney function in SCD.

Keywords: Sickle cell disease, Albuminuria, Estimated Glomerular Filtration Rate, Angiotensin Converting Enzyme Inhibitors, Renin-Angiotensin-Aldosterone Blocking Agents

INTRODUCTION

Glomerulopathy, clinically manifesting as albuminuria and/or decrease in glomerular filtration rate (GFR), is a common complication in patients with sickle cell disease (SCD) (Ataga, et al 2014). It is increasingly recognized that the prevalence of albuminuria is high in children (Dharnidharka, et al 1998; Wigfall, et al 2000; McBurney, et al 2002; McKie, et al 2007; McPherson Yee, et al 2011; Iwalokun, et al 2012; Heimlich, et al 2018) and older patients (Falk, et al 1992; Thompson, et al 2007; Ataga, et al 2010; Guasch, et al 2006; Aleem 2010), with a prevalence of up to 68% in adults. Although the natural history of chronic kidney disease (CKD) in patients with SCD remains inadequately defined, a proportion of patients with albuminuria will progress to end-stage renal disease (Powars, et al 1991). In addition, kidney disease at varying levels of severity has been associated with increased mortality in SCD (Platt 1994; Elmariah, et al 2014).

Despite the high prevalence of albuminuria and its likely association with progressive renal dysfunction and mortality in SCD, the available treatment options remain limited. Although angiotensin converting enzyme (ACE) inhibitors are recommended for the treatment of albuminuria in SCD patients without other apparent cause (Yawn, et al 2014), no controlled studies have been performed to confirm their long-term efficacy in this setting. The amount of proteinuria was observed to fall by over 60% following a brief course of ACE inhibitor therapy (Falk, et al 1992). Other studies suggest that treatment with ACE inhibitors for up to 6 months may be beneficial in patients with albuminuria (Aoki and Saad 1995; Foucan, et al 1998). More recently, following 6 months of treatment with the angiotensin-II-receptor-1 blocker (ARB), losartan, urinary albumin excretion decreased in most SCD patients with albuminuria (Quinn, et al 2017).

In the present study, we evaluated the long-term effect of ACE inhibitors and ARBs on the progression of glomerulopathy (proteinuria and declining estimated GFRs) in patients with SCD. In addition, we evaluated the effect of such therapy on mortality in the same patient population.

METHODS

Study design and participants

We conducted a retrospective study of patients aged at least 18 years old, seen during routine visits to the adult Sickle Cell Clinic at the University of North Carolina at Chapel Hill between January 2004 and December 2013. Clinical and laboratory variables, including assessments of proteinuria and estimated glomerular filtration rate (eGFR), were obtained from medical records. Patients with SCD (HbSS, HbSC, HbSβ0 thalassaemia and HbSβ+ thalassaemia) on treatment with ACE inhibitors or ARBs (subsequently referred to as renin-angiotensin-aldosterone system [RAAS] blocking agents) as prescribed by their medical providers for proteinuria, as well as patients with proteinuria who were not on such therapies, were identified. Patients on RAAS blocking agents who had no history of proteinuria were not included. Patients with proteinuria who were started on RAAS blocking agents during the follow-up period were considered as in the non-treatment group prior to starting treatment, but as in the treatment group following the initiation of treatment. Only patients with at least two assessments of proteinuria or eGFR during the study period were eligible for evaluation. We excluded patients with histories of bone marrow transplantation, systemic lupus erythematosus, human immunodeficiency virus, or hepatitis B or C infection and those who were receiving chronic dialysis or had obtained a kidney transplant at the baseline visit. Mortality status was ascertained using patient medical records and the US Social Security Death Index.

Kidney function was assessed by the eGFR according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey, et al 2009). Hyperfiltration was defined as an eGFR > 130 ml/min per 1.73 m2 for women and > 140 ml/min per 1.73 m2 for men. Progression of CKD was defined as an eGFR decline to less than 90 ml/min per 1.73 m2, combined with ≥ 25% decline in eGFR from baseline. An eGFR < 90 ml/min per 1.73 m2 was used for this definition because serum creatinine-based estimates of eGFR underestimates renal dysfunction in SCD (Thompson, et al 2007; Asnani, et al 2013). Proteinuria was assessed semi-quantitatively by urinalysis and defined as absent if urine dipstick results were 0 to trace and present if 1+ or greater. We recorded routine demographics and relevant treatment data. Laboratory and clinical variables were obtained at study baseline and then as were available during routine follow-up visits. Baseline values for patients not on RAAS blocking agents were obtained at the first available date during the follow-up period, while in the patients receiving these treatments, the baseline values were obtained when the agents were begun during the follow-up period. When RAAS blocking agents were begun prior to the follow-up period, baseline values were obtained as soon as they were available during the follow-up period.

Statistical analyses

For the demographic variables and the follow-up duration, medians and the corresponding interquartile ranges (IQR) were calculated for the continuous variables and proportions were calculated for the discrete variables. Mixed effects models were fit for the longitudinal data for both proteinuria and eGFR to examine the effect of RAAS blocking agents on change in proteinuria risk and eGFR decline over time. A random intercept was included in the model to account for the multiple observations from each patient. The fixed effects were baseline age, sex, baseline eGFR, genotype, baseline haemoglobin (Hb), baseline systolic blood pressure, treatment, time since baseline and a categorized “time since treatment” variable (0 if the patient never received the treatment or received it during the follow-up period, 1 if the treatment was administered within 2 years before the study, and 2 if it was given more than 2 years before the study). We additionally adjusted for hydroxycarbamide use by first testing the 3-way interaction of hydroxycarbamide use, treatment, and time based on Wald test. If the 3-way interaction was not statistically significant, we proceeded to test the 2-way interaction. Interaction terms which were not statistically significant (p > 0.05) were not included in the final model. Selected baseline laboratory variables (white blood cell [WBC] count, Hb, reticulocyte count, fetal haemoglobin [HbF] and lactate dehydrogenase) and baseline clinical variables (systolic blood pressure, diastolic blood pressure and history of diabetes mellitus) were considered to examine whether they modified the treatment effect. We defined a categorical variable based on the eGFR values (whether they declined to < 90 ml/min per 1.73 m2 and the decline was ≥ 25% of the baseline values) to quantify CKD progression and similar mixed effects models were fit to examine the effect of RAAS blocking agents on the change in CKD risk over time. For the mortality analysis, we fit a Cox proportional hazards model to the longitudinal data. We evaluated the effect of baseline proteinuria and eGFR on the risk of mortality, adjusting for baseline age, sex and genotype. We also examined the effect of treatment with RAAS blocking agents on mortality, adjusting for baseline age, sex and genotype.

RESULTS

Demographic and Laboratory Characteristics

The patients in this study were derived from a cohort with SCD (N = 427) followed at an adult SCD clinic between 2004 and 2013. Eighty-six patients on RAAS blocking agents for proteinuria (73 on various ACE inhibitors and 13 on various ARBs), followed for a median of 2.28 years (IQR: 0.79 – 5.73 years) were compared with 68 patients with proteinuria followed for 2.24 years (IQR: 0.72 – 4.1 years) who were not receiving such treatment. Amongst those on treatment with RAAS blocking agents, 58 patients (67.4%) received treatment for more than 1 year, and 66 patients (76.7%) received treatment for more than 6 months. Fifteen patients were already on treatment with RAAS blocking agents prior to the start of the follow-up period. Baseline demographic and laboratory characteristics of both patient groups are shown in Table I. Patients on RAAS blocking agents appeared to be older and more commonly had a history of hypertension than those not receiving such therapy. In addition, patients on RAAS blocking agents appeared to have lower eGFR values at baseline than those not receiving such treatments.

Table I:

Baseline Demographics and Laboratory data

Patients not on RAAS Blocking Agents Patients on RAAS Blocking Agents
Variable n n
Age (years) 68 32 (22 – 43) 86 42.5 (29 – 54)
Sex (female) 68 41 (60) 86 45 (52)
Haemoglobin genotype 68 86 86
 HbSS 57 (83.8) 58 (67.4)
 HbSC 6 (8.8) 22 (25.6)
 HbSβ0 thalassaemia 4 (5.9) 0 (0)
 HbSβ+ thalassaemia 1 (1.5) 6 (7.0)
White blood cell count (x 109/l) 68 12.4 (9.15 – 14.1) 85 9.4 (7.3 – 11.8)
Haemoglobin (g/l) 68 85 (75 – 98.5) 85 91 (76 – 106)
Platelet count (x 109/l) 67 445 (330 – 527) 81 391 (238 – 509)
Fetal haemoglobin (%) 17 5.4 (1.2 – 8.2) 32 4.3 (1.6 – 7.8)
Lactate dehydrogenase (u/l) 40 1028 (868 – 1475.5) 58 842.5 (632 – 1249)
Estimated GFR (ml/min/1.73m2) 61 136.8 (100.6 – 155.6) 86 110.65 (68.7 – 128.1)
Systolic blood pressure (mm Hg) 67 124 (113 – 141) 85 132 (120 – 141)
Diastolic blood pressure (mm Hg) 67 73 (66 – 81) 85 74 (68 – 81)
History of hypertension (Yes) 68 16 (23.5) 84 51 (60.7)
On hydroxycarbamide (Yes) 68 49 (43.8) 86 26 (34.7)
Diabetes mellitus (Yes) 68 3 (4.4) 86 11 (12.8)
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*

Values presented as number (%) or median (interquartile range)

GFR – glomerular filtration rate

RAAS (renin-angiotensin-aldosterone system) blocking agents – angiotensin converting enzyme inhibitors and angiotensin receptor blockers

Effect of Renin-Angiotensin-Aldosterone Blocking Agents on Proteinuria and eGFR

For patients treated with RAAS blocking agents, the log odds of proteinuria decreased over time by 0.23 per year (p = 0.03), adjusting for age, gender, baseline eGFR, SCD genotype, baseline Hb, baseline systolic blood pressure and categorized time since treatment variable. Although the log odds of proteinuria appeared to decrease faster over time in the non-treatment group (β: −0.54, p < 0.0001), the difference in both groups was not statistically different (β: 0.31, p = 0.063). Adjusted for hydroxycarbamide use, treatment with RAAS blocking agents had no significant effect on proteinuria over time (3-way interaction estimate: −0.36, p = 0.30). Patients on RAAS blocking agents had a 2.78 ml/min per 1.73 m2 decline in eGFR per year (p < 0.0001), adjusting for age, gender, baseline eGFR, SCD genotype, baseline Hb, baseline systolic blood pressure and categorized treatment indicator. For patients not on treatment with RAAS blocking agents, the rate of decline in eGFR was 4.70 ml/min per 1.73 m2 per year (p < 0.0001), significantly faster than in those patients on treatment with RAAS blocking agents (β: 1.9, p = 0.0002). Adjusted for hydroxycarbamide use, treatment with RAAS blocking agents was no longer associated with a decline in eGFR over time (β: 1.63, p = 0.11).

When patients with hyperfiltration were excluded from the analyses, the attenuation in eGFR decline following treatment with RAAS blocking agents was consistent with that observed in the overall cohort. Patients on RAAS blocking agents had a 2.87 ml/min per 1.73 m2 decline in eGFR per year (p < 0.0001), adjusting for age, gender, genotype, baseline Hb, baseline systolic blood pressure, baseline eGFR and categorized treatment indicator. For patients not on treatment with RAAS blocking agents, the rate of decline in eGFR was 5.64 ml/min per 1.73 m2 per year (p < 0.0001), significantly faster than in those patients on such treatment (β: 2.77, p < 0.0001).

The risk of CKD increased over time in patients receiving treatment with RAAS blocking agents (β: 0.44, p < 0.0001) as well as those not on such treatment (β: 0.99, p < 0.0001). However, treatment with RAAS blocking agents significantly attenuated the progression of CKD compared to patients not on such treatment (β: −0.57, p value = 0.0026).

We evaluated whether baseline clinical (systolic blood pressure, diastolic blood pressure, history of diabetes mellitus) and laboratory variables (WBC count, Hb, reticulocyte count, HbF and lactate dehydrogenase) modified the effect of RAAS blocking agents on the longitudinal change in eGFR or proteinuria risk. No baseline clinical or laboratory variables significantly modified the effect of RAAS blocking agents on proteinuria risk. The effect of RAAS blocking agents on eGFR was smaller for patients with higher baseline Hb levels (3-way interaction estimate: −1.28, p = 0.0023) (Table II). No other clinical and laboratory variables significantly modified the effect of RAAS agents on eGFR.

Table II:

Association of Baseline Variables with the Effect of RAAS Blocking Agents on Estimated Glomerular Filtration rate

Variable Estimate Standard Error P Value
White blood cell count −0.14 0.19 0.44
Haemoglobin −1.28 0.42 0.0023
Reticulocyte count 0.0022 0.0047 0.65
Fetal haemoglobin −0.74 0.68 0.27
Lactate dehydrogenase 0.00044 0.00069 0.52
Systolic blood pressure −0.013 0.033 0.70
Diastolic blood pressure 0.039 0.047 0.41
History of diabetes −0.94 8.16 0.91
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Effect of Renin-Angiotensin-Aldosterone System Blocking Agents on Mortality

Following adjustment for age, sex and genotype, both baseline proteinuria (hazard ratio [HR]: 2.67, p = 0.012) and baseline eGFR (HR: 0.98, p < 0.0001) were significantly associated with mortality in the overall patient cohort. However, when both variables were included in the model, baseline proteinuria was no longer associated with mortality (HR: 1.03, p = 0.96), but eGFR remained significantly associated with mortality (HR: 0.97, p < 0.0001). In other words, mortality is 3% less likely for every increase in eGFR of 1 ml/min per 1.73 m2 per year at baseline. There was also an association of eGFR with mortality when categorized based on values > 130 ml/min per 1.73m2 vs. 90 – 129 ml/min per 1.73m2 vs. 60 – 89 ml/min per 1.73m2 vs. < 60 ml/min per 1.73m2 (log rank test statistic: 87.96; p < 0.0001) (Figure 1). Treatment with RAAS blocking agents had no significant effect on mortality (HR: 0.92, p = 0.81), adjusted for age, sex and genotype.

Figure 1: Kaplan-Meier survival curves.

Figure 1:

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Kaplan-Meier survival curves for patients with sickle cell disease based on categorized estimated glomerular filtration rate (eGFR; >130 ml/min per 1.73 m2 vs. 90 – 129 ml/min per 1.73 m2 vs. 60 – 89 ml/min per 1.73 m2 vs. < 60 ml/min per 1.73 m2) shows increased mortality for lower eGFR (log rank test statistic: 87.96; p < 0.0001)

Discussion

Sickle cell glomerulopathy appears to occur following repeated sickling events, which contribute to ischaemic injury and increased oxidant stress (Nath, et al 2001; Nath, et al 2005; Juncos, et al 2010). Albuminuria may also occur due to hyperfiltration (Thompson, et al 2007; Haymann, et al 2010; Aygun, et al 2011; King, et al 2011), glomerular hypertension (Falk, et al 1992) and endothelial dysfunction, which is related to increased levels of endothelin-1 (Heimlich, et al 2016; Ataga, et al 2016; Kasztan, et al 2017), soluble fms­like tyrosine kinase-1 (Ataga, et al 2011) and haemolysis (Gurkan, et al 2010; Maier-Redelsperger, et al 2010; Day, et al 2012; Drawz, et al 2016). Adult patients with SCD have accelerated loss of eGFR over time compared with healthy subjects (Asnani, et al 2016; Ciccone, et al 2016; KDIGO [Kidney Disease: Improving Global Outcomes] 2013). The decline in eGFR in patients with SCD appears to be associated with proteinuria (Ciccone, et al 2016; Xu, et al 2016).

Despite multiple studies showing short-term benefits for RAAS blocking agents in the treatment of albuminuria in patients with SCD, there are no published studies of their long-term benefits. In spite of this, RAAS blocking agents are now the standard of care for the treatment of albuminuria in SCD (Yawn, et al 2014). Small studies also suggest that hydroxycarbamide may decrease albuminuria in SCD patients (McKie, et al 2007; Laurin, et al 2014; Fitzhugh, et al 2005; Aygun, et al 2013; Bartolucci, et al 2016), although there are no studies of its long-term benefits. Our data suggests that treatment with RAAS blocking agents beyond 6 months is beneficial in patients with SCD by slowing the rate of decline in eGFR over time as well as the progression of CKD. This finding is consistent with those from studies of ACE inhibitors and ARBs in patients with diabetic nephropathy that show benefit for these agents in decreasing the rate of doubling of serum creatinine and progression to end-stage renal disease (Viberti, et al 1994; Lewis, et al 1993; Lewis, et al 2001; Brenner, et al 2001). Inhibition of angiotensin II (Ang II) leads to improved glomerular haemodynamics with reduced intraglomerular pressure (Taal & Brenner 2000). Further, these drugs may have additional non-haemodynamic effects, as Ang II has been shown to promote mesangial cell proliferation and transforming growth factor beta production, which promotes fibrosis. Ang II also promotes macrophage activation and infiltration, promoting inflammatory changes, and upregulates aldosterone production, which also contributes to glomerular and interstitial fibrosis. The haemodynamic effects of ACE-inhibitors and ARBs are particularly desirable in SCD, in which glomerular hyperfiltration is a notable feature and a likely mechanism of renal injury.

The effect of RAAS blocking agents on eGFR was smaller for patients with higher baseline Hb levels. This may be due to an increased risk of worsening renal function in patients with increased haemolytic rate. Alternatively, as patients with glomerulopathy are more likely to be on treatment with RAAS blocking agents, this relationship may be due to the increased anaemia that accompanies worsening renal function. However, only baseline Hb level was evaluated in this study and the relationship between Hb levels during the follow-up period and response to RAAS blocking agents was not assessed.

Surprisingly, long-term treatment with RAAS blocking agents did not result in a significant decline in the log-odds of proteinuria compared with patients not on such treatment. This finding may be related to the direction of RAAS treatment by clinicians to those perceived to be at higher risk of proteinuria and CKD progression (i.e. a “sicker” population). Furthermore, a substantial number of patients were already on RAAS blocking agents at the start of the retrospective data collection and this may have reduced our ability to detect reductions in proteinuria. Although decreased baseline eGFR was associated with mortality, the use of RAAS blocking agents did not improve survival in this study. However, it is conceivable that improved survival may be observed in larger cohorts and with longer follow-up.

This study is limited by its single-centre, retrospective design. Proteinuria was assessed by dipstick analysis and was only reported in a semi-quantitative fashion. We were unable to ascertain adherence and side effects of the RAAS blocking agents during the follow-up period. It is surprising that so many patients with proteinuria were not on RAAS blocking agents, although this probably reflects a variability in care amongst the medical providers. However, treatment with these agents was discontinued in some patients due to side effects and could not be initiated in others due to contraindications to such therapies. The present study represents the first report of the long-term effects of RAAS blocking agents in SCD patients with glomerulopathy, one that suggests clinical benefit with treatment. As the conduct of placebo-controlled studies evaluating RAAS blocking agents may be challenging in a setting where they are considered standard of care, other cohort studies are required to confirm the long-term benefits of these agents in SCD-related glomerulopathy.

Acknowledgements:

Support: This study was funded by the National Heart, Lung, and Blood Institute, R01HL111659 (KIA, VKD, JC) and U01HL117659 (KIA, JC). We also acknowledge the assistance of the NC Translational and Clinical Sciences (NC TraCS) Institute, supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR001111.

Footnotes

Disclosures: None of the authors have conflicts of interest to declare relevant to the report presented.

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