A Retrospective Study Of The Anti-Proteinuric Effects Of Hydroxyurea and Angiotensin-Converting Enzyme Inhibitors Or Angiotensin II Receptor Blockers In Adults With Sickle Cell Disease

Glomerulopathy, associated with initial glomerular hyperfiltration followed by the development of microalbuminuria/proteinuria, is a well recognised complication of Sickle Cell Disease. There is evidence for the efficacy of Angiotensin-Converting Enzyme Inhibitors (ACE-I) or Angiotensin II Receptor Blockers (ARB) in reducing microalbuminuria in this population, and in common with other proteinuric kidney diseases the use of these agents is increasingly commonplace. In children the additional benefit of Hydroxyurea (HU) with microalbuminuria/proteinuria has previously been shown. The effect of HU on kidney function and proteinuria in adult Sickle Cell patients, alone or in combination with ACE-I/ARB, has not been fully explored.

The aim of this study was to review the impact in real clinical practice of HU alone or in concurrent use with ACE-I/ARB on estimated Glomerular Filtration Rate (eGFR) and Urinary Protein-Creatinine Ratio (uPCR).

A retrospective analysis of data from 59 adult Sickle Cell Disease patients taking HU was undertaken and patients were classified as haematological responders to HU if HbF > 8%. Patients with no haematological response were excluded from further analysis as the majority of them had intermittent adherence to HU therapy. Creatinine (Cr), uPCR, Haemoglobin (Hb), Haemoglobin F (HbF) and Lactate Dehydrogenase (LDH) data were extracted on a monthly basis over the preceding 11 years. eGFR was calculated using the MDRD formulation. Commencement dates of HU / ACE-I/ARB were confirmed by note review. Patients were not further divided according to sex, age or other co-morbidities.

44/59 were deemed haematological responders to HU and of these 17 (39%) were also taking an ACE-I/ARB. 42/44 had HbSS, 1 patient HbSC and 1 HbSB^oThal. Mean age was 36.7 years (range 18-76).

The sample population was divided into three groups. Group A (27 patients) were taking HU alone, Group B (9 patients) were initially treated with HU and subsequently commenced ACE-I/ARB treatment, and Group C (7 patients) were initially treated with ACE-I/ARB and subsequently HU was added. 1 patient initiated the two therapies simultaneously.

Group A (mean age 33 years, range 19 – 53), had been on HU for a mean of 7 years. 22 patients had been treated for >10 years or had moved from another hospital already on HU. None of these patients showed any progression of proteinuria or eGFR during the time studied. In 5/27 patients uPCR results before and 1 year after commencing HU were analysed and there was no difference in uPCR or eGFR results.

Group B, (mean age 46 years, range 26-76), showed no response or worsening of uPCR on HU alone and were commenced on ACE-I/ARB. They had been taking HU for a mean of 10 years and ACE-I or ARB for a mean of 5 years. Following the addition of ACE-I/ARB 7/9 patients showed a reduction in proteinuria. All patients had stable eGFR.

Group C (mean age 41 years, range 23-59), were commenced on HU for non-renal factors. They had been taking HU for a mean of 3 years and ACE-I/ARB for a mean of 7 years. Addition of HU to ACE-I/ARB showed no consistent effect; in 2 patients uPCR was increasing prior to addition of HU; it subsequently stabilised in 1 patient and reduced in the other. The remaining patient's uPCR were stable (3/7 patients) or increased (2/7). eGFR was stable in all patients.

The patient commenced on HU and ACE-I concurrently was aged 59 years and had been on both therapies for 12 years. Both her uPCR and eGFR were stable.

HU and ACE-I/ARBs are often used together in adult patients with SCD. From our retrospectve data it seems possible that the combination of HU with ACE-I/ARB may offer benefit in adult patients with SCD who have persistent proteinuria. HU could be considered as part of the treatment options in this group of patients. The potential use of this combination treatment needs further study, ideally in a controlled trial.