Dapagliflozin for treatment of sickle cell nephropathy: A multi-centre experience Free

Background

Chronic kidney disease (CKD) is a common complication in sickle cell disease and current guidelines recommend pro-active management of proteinuria and hypertension to reduce risk of progression to end stage kidney failure. Sodium-glucose-co-transporter-2 inhibitors (SGLT2i) are now first-line treatment of CKD in adults, as an adjunct, or alternative to angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-2 receptor antagonists (ARB). However, data on SGLT2i use in patients with sickle cell nephropathy are limited. We conducted a retrospective audit and case-series review across two hospitals with large sickle cell cohorts in the United Kingdom to assess clinical effect and tolerability of dapagliflozin (an SGLT2i) in this population.

Methods

All patients with sickle cell disease who attended joint renal-haemoglobinopathy clinics and who were prescribed dapagliflozin for routine indications were included. Records were reviewed for baseline characteristics, indication for treatment, comorbidities and adverse events. Laboratory microbiology and primary care records were examined for evidence of confirmed urinary tract infections. Changes in estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (uACR) after commencing dapagliflozin were evaluated using paired t-tests for eGFR (normally distributed data) and Wilcoxon-signed rank tests for uACR (non-parametric distribution).

Results

Thirty-nine patients with sickle cell disease who were prescribed dapagliflozin were included. Most patients (90%) were HbSS or HbSβ⁰ genotype, the remainder were HbSC or HbSβ⁺genotype. The median age was 54 years (range 24-75 years). Renal indications for starting dapagliflozin, aligned with National Institute of Health and Care Excellence (NICE) recommendations, included: 1) eGFR<45ml/min/1.73m² (N=13) or 2) eGFR 45-90 ml/min/1.73m² and uACR >= 22.6mg/mmol (N=19). Other indications for treatment with SGLT2i included cardiac failure (N=8) and type 2 diabetes (N=6). Some patients had multiple indications for treatment. Thirty-one patients (79%) were co-prescribed an ACEi/ARB; in 2 other patients this therapy had been discontinued due to persistent hyperkalaemia. Thirty-five patients (90%) were receiving disease-modifying therapy for sickle cell disease (23 patients taking hydroxyurea and 12 patients on a regular transfusion programme). Six patients were also prescribed anti-hypertensive therapy (amlodipine, doxazosin or indapamide) and 6 patients were prescribed erythropoietin stimulating agents (ESA).

Mean eGFR prior to starting dapagliflozin was 50ml/min/1.73m²(standard deviation 14ml/min/1.73m²). There was a small reduction in eGFR shortly after commencing dapagliflozin treatment: mean decrease of 5ml/min/1.73m²(95% confidence interval 2-7ml/min/1.73m², P<0.001), evaluated in 36 patients with eGFR measured at least one month (median 4.5months) after starting dapagliflozin. Median uACR prior to starting dapagliflozin was 109mg/mmol(interquartile range 55-247mg/mmol) and was significantly reduced after commencing dapagliflozin: median decrease 29mg/mmol (95% confidence interval 17-88mg/mmol, P<0.001), evaluated in 25 patients with paired uACR measurements. Two patients received antibiotics for a confirmed urinary tract infection after starting dapagliflozin; these patients subsequently continued with dapagliflozin treatment. Two patients had dapagliflozin temporarily interrupted due to a reduction in eGFR but later restarted therapy. There were no other dapagliflozin-related complications reported.

Conclusion

In our cohort of patients with sickle cell disease, dapagliflozin is being used either alone or in combination with ACEi/ARB treatment and/or anti-hypertensive medications for management of CKD. There was a significant improvement in albuminuria after commencing dapagliflozin. Dapagliflozin appeared generally well tolerated, with a few patients experiencing a recognised complication of urinary tract infections. A small rise in creatinine is expected during initial treatment due to a reduction in intraglomerular pressure caused by dapagliflozin's protective mechanism of action.