Reversible kidney iron accumulation in a patient with sickle cell disease treated with hydroxyurea.

Abstract

In patients with homozygous sickle cell disease (SCD), albuminuria and hyperfiltration are associated with intensity of hemolysis 1, 2, suggesting that a chronic hemolysis-induced vasculopathy may play a role in the development of sickle cell nephropathy (SCN) 1. Magnetic resonance imaging (MRI) has revealed accumulation of iron in the kidney parenchyma 3, 4 and renal biopsy data have demonstrated abundant hemosiderin deposits in proximal tubular epithelial cells in patients with SCD 1. The optimal therapeutic management of SCN remains unclear, but we recently showed that hydroxyurea (HU), the cornerstone of SCD treatment, may decrease albuminuria by reducing hemolysis 5. We report here the case of a 32-year-old man with SCD, who displayed a total disappearance of MRI-proven kidney iron overload and a significant decrease in albuminuria after a 16-month course of HU treatment. A 32-year-old African man was referred to our center, for the evaluation of homozygous SCD disease. His medical history included bouts of malaria, and resolved hepatitis B virus infection. In the preceding two years, he reported two vaso-occlusive crisis (VOC) episodes and two acute chest syndromes (ACS) requiring hospitalization. He had not previously been included in a blood exchange transfusion protocol and he was not taking any iron-chelating agent or antihypertensive therapy. On admission, his clinical examination was unremarkable and his blood pressure was 115/75 mmHg. The laboratory findings are summarized in Supporting Information Table 1. Marked anemia was associated with a high rate of hemolysis, as highlighted by elevated lactate dehydrogenase (LDH) (1144 U/L), total bilirubin (140 µmol/L), and aspartate aminotransferase (AST) (85 IU/L). Haptoglobin was undetectable. The percentage of dense red blood cells (DRBC), defined as the percentage of RBCs with a density >1.11, was high, at 22% 5. Urine albumin-to-creatinine ratio (ACR) was high, at 58 mg/mmol, and urinary sediment analysis showed hematuria (5 × 104/mm3) without leukocyturia. In the two months immediately before referral, the patient had experienced two episodes of abdominal pain associated with macroscopic hematuria, but the findings of a kidney Doppler ultrasound scan were unremarkable. Renal MRI was performed but did not reveal findings typical of papillary necrosis or medullary carcinoma. However, the T2* gradient images showed the signal intensity to be much lower in the cortex than in the medulla, due to renal cortex iron overload (Image 1A). The liver signal was in the normal range and was not suggestive of significant iron overload. We decided to initiate HU treatment, at a dose of 1 g per day, because of the history of ACS and because we have recently shown that HU treatment was associated with a decrease in ACR 5. Sixteen months later, the patient had suffered no further VOC episodes and displayed a significant improvement in the levels of hemolysis markers (Supporting Information Table 1). The patient did not require red blood cell transfusion or the introduction of iron-chelating agents over this period. A new episode of acute left low back pain led to a second kidney MRI scan being performed. The cortical signal was found to be normal on T2* gradient images (acquired with the same parameters as for the first MRI) (Image 1B), suggesting that renal iron overload had either completely disappeared or, at least, markedly decreased on HU treatment. We also observed concomitant decrease in urine ACR (4.1 mg/mmol). Origin and consequences of iron deposits within the kidney, a common finding in SCD patients, are not well understood. Cortical iron kidney deposits may result from severe intravascular hemolysis rather than post-transfusional iron loading 3, 4. Consistent with this hypothesis, our patient had not been transfused and the first MRI showed iron accumulation in the renal cortex, but not in the liver. This case provides the first demonstration, to our knowledge, that HU therapy can eliminate iron deposits detected on MRI from the renal cortex in SCD patients. Moreover this treatment may modulate albuminuria by decreasing iron deposition in tubular cells. Further studies are required to confirm that HU can prevent the tubular deposition of iron in the renal cortex, and to improve our understanding of its clinical significance, particularly in terms of the role of tubular iron deposits in the occurrence of albuminuria in SCD patients. Coronal T2*-weighted MRI of the kidneys, with a weak cortical signal on the first MRI scan (A) suggestive of iron deposition. The cortical signal is normal on the second examination (B) probably due to the clearance of iron deposits from the cortex. The medullary signal was similar on the two MRI examinations. Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.