Angiotensin Blockage with Losartan Is Associated with Decreased Albuminuria and Stable Renal Function in Adults and Children with HbSS on Hydroxyurea

Introduction: Sickle cell nephropathy (SCN) is a progressive complication of sickle cell disease (SCD) that begins in childhood and may result in renal failure and early mortality; yet the potential for prevention and reversal of SCN is not known. Urinary albumin/creatinine ratio (ACR) is a biomarker of glomerular damage but may not correlate with renal hemodynamic abnormalities that are indicative of early renal failure, e.g. glomerular filtration rate (GFR), renal plasma flow (RPF), and glomerular membrane permeability.  We hypothesized that the angiotensin receptor blocker losartan will improve GFR and decrease excretion of high molecular weight (HMW) proteins that are restricted at the glomerulus, while not affecting abnormalities in markers of tubular injury and ischemia.

Methods:  Adults and children ≥10 years with HbSS who were on hydroxyurea (HU) for ≥6 months but had persistent microalbuminuria (MiA; ACR ≥30 mg/g) or macroalbuminuria (MA; ACR ≥300 mg/g) on ≥2 consecutive occasions were eligible.  Target enrollment was 30 subjects (half with MA), with interim analysis after 15 enrolled. Losartan therapy was given for 12 months, titrated to 100 mg daily.  At baseline and 2 time points after starting losartan (≥1 month, ≥12 months), GFR and RPF were measured by urinary clearance of intravenous iohexol and para-hippuric acid (PAH). Excretion rates of HWM proteins (albumin and immunoglobulin G (IgG)) were measured. Urinary levels of tubular proteins α1-microglobulin (α1M), β2-microglobulin (β2M), kidney injury marker-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) were measured by ELISA and expressed as the ratio of urinary protein/ creatinine to account for urine concentration.

Results: At interim analysis, 12 subjects (9 male) have completed baseline and 1-month studies, and 5 have also completed 12-month studies; 3 subjects completed baseline only and are excluded from analysis. Mean age was 27.6 years (range 10.2 – 42.9). Median time on losartan was 44 days (27 – 210 days) at the first (≥1 month) renal function study and 426 days (393 – 519 days) at the last (≥12 month) study. Baseline GFR was 105 ml/min/1.73 m² (range 71 – 147); 3 (25%) subjects had GFR <90 ml/min/1.73 m² (stage 2 chronic kidney disease, CKD), and 6 (50%) had MA.  At ≥1 month on losartan, the mean reduction in ACR was 51.0% (range 27.3% - 81.7%; p=0.006); the % reduction was similar for those with MA (60.1%) vs MiA (41.8%), p=0.32. Five of 6 with MA improved to MiA. Two of 3 with stage 2 CKD had improvement in GFR to >90 ml/min/1.73 m² (stage 1 CKD).  At ≥12 months on losartan, mean reduction in ACR was 34.5% from baseline (range -5.3% - 69.2%). The Table shows renal hemodynamics and urinary biomarkers at baseline and changes at 1 and 12 months. Excretion of albumin and IgG were significantly lower at ≥1 month. GFR and tubular biomarkers had no significant changes at either time point. There was no significant correlation of ACR with urinary biomarker ratios at baseline, nor any correlation of ΔACR with change in biomarkers at 1 month. No episodes of hyperkalemia or other adverse event occurred while on losartan therapy.

Conclusions: In adults and children with HbSS and albuminuria (stage >=1 CKD) despite HU, losartan significantly reduced excretion of large proteins that are restricted at the glomerulus, with no changes in measured GFR. Markers of tubular injury and ischemic damage were unchanged by losartan, suggesting that losartan improves glomerular permability defects without significantly affecting the distal nephron. These findings warrant a larger, randomized controlled study of losartan with HU to determine if losartan prevents or slows progression to renal failure in SCD.

	Baseline (n=12)		Change at ≥1 month (n=12)			Change at ≥12 months (n=5)
	median	range	median	95% CI	p	median	95% CI	p
MAP (mm Hg)	86	68 - 109	-5.0	-15.3, 1.3	0.15	-1.3	-22.3, 6	1.0
Albumin excretion (mcg/min)	293.2	38.8 – 812.8	-134.2	-326.9, -66.8	0.006	-196.2	-493.5, 19.3	0.38
IgG excretion (mcg/min)	10.3	0.7 – 36.1	-2.2	-3.5, -1.6	0.006	2.1	-7.2, 3.2	1.0
GFR (ml/min/1.73 m2)	112	71 - 147	7.5	-13, 20	0.39	1.0	-23, 15	1.0
RPF (ml/min/1.73 m2)	881	369 - 1217	173	-60, 451	0.39	-61	-182, 91	0.38
α1M (mg/g Cr)	15.7	4.5 – 130.8	-2.2	-17.8, 1.5	0.15	-17.1	-23.0, -1.8	0.06
β2M (mg/g Cr)	20.0	11.3 – 45.4	-6.2	-17.6, 7.3	0.77	2.2	-17.1, 28.8	1.0
KIM-1 (pg/g Cr)	383.0	71.9 – 1223	81.6	-160, 214	0.39	192.8	-181, 4521	1.0
NGAL (ng/g Cr)	5.2	1.9 – 29.0	0.2	-4.6, 1.2	1.0	-0.9	-3.2, 1.7	0.38