Long Term Treatment with Hydroxyurea Does Not Prevent Development of Renal Dysfunction and Osteodystrophy in Patients with Sickle Cell Disease.

Hydroxyurea (HU) is presently considered as the main treatment for the reduction of sickle-cell crises; however, information regarding the potential of HU to inhibit progressive organ failure is scarce. The gradually failing renal function and renal osteodystrophy are well known complications of sickle cell disease (SCD). The pending question is whether administration of hydroxyurea over very long period of time may delay or prevent the appearance of these abnormalities. To this effect we evaluated the renal function and bone metabolism in 57 patients with HbS/β-thal (31M/26F; median age 32 years, range: 19–67 years) receiving hydroxyurea (usually 1 g/daily) continuously for 1 to 14 years (median 10.2 years). In addition to conventional renal biochemistry we measured the levels of serum and urinary β₂-microglobulin (β₂M), serum cystatin C (specific and sensitive index of glomerular filtration rate), and urine N-acetyl-b-D-glucosaminidase (NAG; reflecting the distal tubular cells function). The extent of renal osteodystrophy was evaluated by DEXA scans assessing bone mineral density (BMD), and by assaying various markers of (a) osteoclast function [soluble receptor activator of nuclear factor κB ligand (sRANKL), osteoprotegerin (OPG), and tartrate resistant acid phosphatase isoform 5b (TRACP-5b)], (b) bone resorption [C-telopeptide of collagen type I (CTX)], and (c) bone formation [bone-alkaline phosphatase (bALP) and osteocalcin (OC)]. The above parameters were also evaluated in 16 age- and gender-matched controls. Three patients (5.2%) had increased serum creatinine levels; 16 patients (28%) had more than 300 mg/day protein excretion in the urine, and 13 patients (22.8%) had microalbuminuria. Moreover, serum cystatin C was elevated in 16 patients (28%), NAG in 21 (36.8%), serum β₂M in 34 (59.6%) and urinary β₂M in one patient. In addition, 17 patients (29.8%) had osteoporosis/osteopenia in DEXA scans (comparable to HbS/β-thal patients who did not receive HU). Furthermore, all patients displayed significantly elevated levels of OPG (p=.001), sRANKL (p<.01), sRANKL/OPG ratio (p=.022), and CTX (p=.02), while significant correlations were found between serum cystatin C vs. both serum OPG and β₂M levels as well as between cystatin C and the sRANKL/OPG ratio. Not only do these results suggest that HU does not prevent renal dysfunction in this cohort of patients but also highlight the role of RANKL/OPG pathway in the renal-induced bone disease of sickle cell syndromes. Furthermore, NAG, cystatin C and OPG may be useful as early biochemical markers for the assessment of renal impairment in SCD patients.