Angiotensin receptor signaling in sickle cell anemia has a reno‐protective effect on urine concentrating ability but results in sickle glomerulopathy

Roy, Swarnava; Rai, Parul; Mpollo, Marthe Sandrine Eiymo Mwa; Chang, Kyung Hee; Rizvi, Tilat A.; Shanmukhappa, Shiva Kumar; VandenHeuvel, Katherine; Aronow, Bruce J.; Inagami, Tadashi; Cancelas, José A.

doi:10.1002/ajh.25118

Cited by 16 publications

(11 citation statements)

References 16 publications

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“…6,13,14 Recently, we showed that the renin-angiotensin system is activated in SCA in the absence of hypertension, and increased angiotensin receptor-1 signaling significantly contributes to the glomerulopathy of SCA. 15,16 Despite a high prevalence of albuminuria in SCA, ranging from 15% to 50%, 6 the natural progression of albuminuria and sickle cell nephropathy is poorly defined, because most data are extrapolated from cross-sectional studies. Albuminuria is defined by excretion of .30 mg albumin per gram of creatinine 17 ; however, measurements of urine albumin/creatinine ratio (ACR) are inherently variable, and not all ACR changes are indicative of changing kidney function.…”

Section: Introductionmentioning

confidence: 99%

Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study

et al. 2020

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Sickle cell nephropathy results in chronic kidney disease (CKD), which is associated with significant morbidity and mortality in sickle cell anemia (SCA). Albuminuria is an early manifestation of sickle nephropathy; however, little is known about progression of albuminuria or its correlation with glomerular filtration rate (GFR) decline or CKD. We studied nephropathy progression in 303 SCA participants in a prospective, multicenter, longitudinal study. We collected steady-state urine and serum samples yearly and assessed albumin/creatinine ratio (ACR), estimated GFR (eGFR), and SCA and nephropathy biomarkers. Participants with albuminuria (ACR ≥30 mg/g) for ≥2 annual measurements were classified as having persistent albuminuria (PA). At baseline (mean age, 21 years; range, 2-64 years), 32% had albuminuria. In longitudinal multivariate analysis, ACR was associated with sex, anemia, older age, and higher bilirubin and kidney injury molecule-1 levels. Albuminuria increased with age by 3.5 mg/g per year (P < .0001). Of 175 participants with ≥3 annual samples, 81% with baseline albuminuria ≥100 mg/g developed PA. Decreased eGFR and adult CKD were associated with PA (P = .002 and P = .02, respectively), but not with baseline albuminuria. Rate of eGFR decline was steeper among adults (but not children) with albuminuria, compared with those without (P = .02). Participants with PA were more likely to have rapid eGFR decline compared with those without (P = .03). In this longitudinal study, albuminuria progressed with age, and adults with albuminuria had worse eGFR decline than those without. Albuminuria ≥100 mg/g predicted PA, which was associated with rapid eGFR decline and CKD development in adults with SCA. This trial was registered at www.clinicaltrials.gov as #NCT02239016.

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Section: Introductionmentioning

confidence: 99%

Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study

et al. 2020

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Section: Introductionmentioning

confidence: 99%

“…The changes in the levels of enzymes and peptides from RAAS using SCD animal models were described by Roy et al (2018). Their findings suggest that blockade of AT1 receptor, together with agonism of AT2R signaling, prevents sickle glomerulopathy 14 . Several authors have described a statistically significant increase of ACE 1 activity in patients with chronic renal disease 15,16 , type 1 diabetes, and systemic inflammatory disease involving kidney impairment before starting enzymatic treatments, as described by our working group 17 .…”

Section: Introductionmentioning

confidence: 99%

Levels of angiotensin-converting enzyme 1 and 2 in serum and urine of children with Sickle Cell Disease

et al. 2021

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Introduction: Sickle cell nephropathy begins in childhood and presents early increases in glomerular filtration, which, over the long term, can lead to chronic renal failure. Several diseases have increased circulating and urinary angiotensin-converting enzyme (ACE) activity, but there is little information about changes in ACEs activity in children with sickle cell disease (SCD). Objective: We examined circulating and urinary ACE 1 activity in children with SCD. Methods: This cross-sectional study compared children who were carriers of SCD with children who comprised a control group (CG). Serum and urinary activities of ACE were evaluated, as were biochemical factors, urinary album/creatinine rates, and estimated glomerular filtration rate. Results: Urinary ACE activity was significantly higher in patients with SCD than in healthy children (median 0.01; range 0.00-0.07 vs median 0.00; range 0.00-0.01 mU/mL·creatinine, p < 0.001. No significant difference in serum ACE activities between the SCD and CG groups was observed (median 32.25; range 16.2-59.3 vs median 40.9; range 18.0-53.4) mU/m`L·creatinine, p < 0.05. Conclusion: Our data revealed a high urinary ACE 1 activity, different than plasmatic level, in SCD patients suggesting a dissociation between the intrarenal and systemic RAAS. The increase of urinary ACE 1 activity in SCD patients suggests higher levels of Ang II with a predominance of classical RAAS axis, that can induce kidney damage.

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“…Intense ligation and affinity of Ang II to AT 1 receptors would reduce urinary levels of Ang II, as previously reported in plasma Ang II of sickle cell mice (dos Santos et al , ). Excessive renal AT1 receptor stimulation would contribute to vasoconstriction in the vasa recta, mesangial proliferation and glomerular hypertrophy (Nath & Hebbel, ; Roy et al , ). Ang II may also contribute to renal inflammation and fibrosis (Xu et al , ).…”

Section: Clinical and Laboratory Features Of Patients With Sickle Celmentioning

confidence: 99%

“…No studies have evaluated renin‐angiotensin system (RAS) components in patients with SCA, and whether RAS activity plays a role in albuminuria. Animal models of sickle cell disease (SCD) have demonstrated changes in the levels of RAS components (dos Santos et al , ; Roy et al , ). However, there is currently no data available regarding RAS molecules in humans with SCD, which is crucial to understand the role of RAS components in sickle cell nephropathy, and to identify therapeutic targets.…”

Section: Clinical and Laboratory Features Of Patients With Sickle Celmentioning

confidence: 99%

Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

et al. 2018

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Angiotensin receptor signaling in sickle cell anemia has a reno‐protective effect on urine concentrating ability but results in sickle glomerulopathy

Cited by 16 publications

References 16 publications

Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study

Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study

Levels of angiotensin-converting enzyme 1 and 2 in serum and urine of children with Sickle Cell Disease

Low urinary levels of angiotensin‐converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia

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