Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC

Abstract

Background and objectives: Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC.

Design, setting, participants, & measurements: Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007-2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299).

Results: In adults with SCD, eGFR was lower among older individuals: -1.78 ml/min per 1.73 m(2) per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m(2) per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m(2) per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m(2) per year of age (95% CI, -1.39 to -0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function.

Conclusions: In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.

Keywords: acidosis; albuminuria; anemia, sickle cell; blood pressure; chronic kidney disease; glomerular filtration rate; humans; hydroxyurea; hypertension, pulmonary.

Figure 1.

Age distribution, the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial, and the Cooperative Study of Sickle Cell Disease (CSSCD). Shown is the distribution of age at entry by percentage in adult subjects from the Walk-PHaSST Trial (hemoglobin SS [HbSS] and HbSC) and the CSSCD (HbSS).

Figure 2.

Association between age and eGFR in subjects with sickle cell disease (SCD). Shown is the cross-sectional change in eGFR (milliliters per minute per year of linear regression analysis [95% confidence interval (95% CI)]) from people with hemoglobin SS (HbSS) at −1.78 (95% CI, −2.06 to −1.50), −1.72 (95% CI, −2.05 to −1.44), and −1.69 (95% CI, −2.00 to −1.38; the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy [Walk-PHaSST] Trial, the Cooperative Study of Sickle Cell Disease [CSSCD], and the Multicenter Study of Hydroxyurea in Sickle Cell Disease [MSH], respectively), with HbSC at −1.09 (95% CI, −1.39 to −0.79; the Walk-PHaSST Trial) and published non–SCD controls at −0.5 (19).

Figure 3.

Albuminuria in CKD in sickle cell disease. Shown is prevalence in percentages ≤60% by decade of age up to the sixth decade of (A) microalbuminuria and (B) macroalbuminuria in patients with hemoglobin SS (HbSS; black) or HbSC (gray).

Figure 4.

Serum bicarbonate in sickle cell disease (SCD; the Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy Trial). Shown is mean serum bicarbonate (ml/l±SD) in historic nonanemic controls (24.8±2.9 [1]; white bar), subjects with hemoglobin SS (HbSS; 23.8 ±3.4; gray bar; P=0.004 versus HbSC), and subjects with HbSC (24.8±3.3; black bar).