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

ABSTRACT: 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.

SUBMITTER: Niss O

PROVIDER: S-EPMC7160281 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Niss Omar O Lane Adam A Asnani Monika R MR Yee Marianne E ME Raj Ashok A Creary Susan S Fitzhugh Courtney C Bodas Prasad P Saraf Santosh L SL Sarnaik Sharada S Devarajan Prasad P Malik Punam P

Blood advances 20200401 7

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 s ...[more]

PMID: 32289161

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Project description:BackgroundSickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial.MethodsHOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea.DiscussionHOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response.Trial registrationClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.

Dataset Information

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

Publications

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

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