Abstract
Background: The prolonged survival in patients with beta thalassemia major and other transfusion dependent disorders has exposed the multi-organ effects of multiple transfusions and chelation therapy. Renal deficits were described with the focus on tubular and glomerular function. Nephrolithiasis has not been systematically explored in these patients. Contributing factors to stone formation may include hypercalcuria, abnormal vitamin D homeostasis, and proximal tubulopathy.
Objective: We analyzed hematologic and nephrologic parameters of 22 transfusion- dependent pediatric patients to investigate contributors to nephrolithiasis.
Methods: The study included patients with beta thalassemia major (TM) (13), transfusion-dependent beta thalassemia intermedia (TDTI) (4), Diamond-Blackfan anemia (DBA) (3), other transfusion-dependent hemoglobinopathies (2). Patients' ages were from 4-20 years (overall median -11 years, TM/TDTI median - 11.5, DBA median - 7.5 years). At the time of analysis 11 received iron chelation with deferasirox, 8 with combined desferoxamine & deferiprone, 2 with combined desferoxamine & deferasirox and one patient received desferoxamine alone. All patients had previously been treated with deferasirox alone and due to either significant adverse events or failure to control iron overload were switched to an alternate regimen. Seven patients were treated with vitamin D supplements for a median of 3 years (range: 0.2-4.3), 6 patients received vitamin D+calcium for a median of 4.5 years (range: 4.3-10). Venous blood samples, 24-hour urine collections and spot urine samples were collected to assess urine chemistry, vitamin D metabolism, electrolytes and renal function. Renal sonography and directed computerized tomography were used to diagnose nephrolithiasis/nephrocalcinosis.
Results: Three patients, all with TM/TDTI, had symptomatic and radiographically identified renal stones, an additional TM patient had symptomatic nephrocalcinosis (Table 1). Among the entire cohort hypercalcuria was identified in 75% with increased Ca/Cr in 68%. 25(OH)D3 was abnormal in 81% of patients, mostly in the "insufficient" range (25-75 mmol/L). No significant relationship between presence of nephrolithiasis and chelation regimen, Ca mg/kg/d, Ca/Cr, renal fractional excretion (Fe) of phosphate (FePhos(, FeNa, FeUA, oxalate, cystein, citrate, 25(OH)D3, or treatment with vitamin D± calcium was identified, possibly in part due to the small sample size.
Conclusions: The incidence rate of nephrolithiasis in our pediatric transfusion-dependent population was 1000x that published in various pediatric populations. Hypercalcuria and relatively low vitamin D levels were found in the majority of our patients, notably in all with nephrolithiasis. All 4 patients with nephrolithiasis/calcinosis were ≥ 13 years old, receiving vitamin D±calcium supplements and had received deferasirox chelation. Of note none of the patients not receiving vitamin D±calcium therapy presented with renal stones or calcinosis. The pathophysiology of nephrolithiasis/calcinosis is unclear among these adolescents; however the role of vitamin D±calcium supplemental therapy and the contribution of deferasirox must be further studied to find the proper formulation needed to maintain bone health without increasing the risk for renal stones.
Abstract 4895. Table 1- Characteristics of patients with nephrolithiasis/nephrocalcinosis Patient Diagnoses Age at onset (years) Chelation (at onset) Duration of vitamin D+Ca supplement (years) Low vitamin D levels (mmol/L) Urine calcium (mg/kg/d) 1 TM/NL 16 DFX 2.3 + 7.6 2 TM/NL 16 DFX 5 - 6.9 3 TDTI/NL 13 DFO&DFP (prior DFX) 0.25 (vitamin D only) + 4.4 4 TM/NC 18 DFX 4 + 2.7
TM-thalassemia major, TDTI-transfusion-dependent thalassemia intermedia, NL-nephrolithiasis, NC-nephrocalcinosis, DFX-deferasirox, DFO-desferoxamine, DFP-deferiprone, Ca-calcium,
normal values: vitamin D>75mmol/L, urine calcium<4mg/kg/d
Disclosures
No relevant conflicts of interest to declare.
Efficacy and safety of ruxolitinib in ineffective erythropoiesis suppression as a pretransplantation treatment for pediatric patients with beta‐thalassemia major
