Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia

Abstract

Summary To evaluate the association between haemoglobinuria and chronic kidney disease (CKD) in sickle cell anaemia (SCA), we analysed 356 adult haemoglobin SS or Sβ° thalassaemia patients from the University of Illinois at Chicago (UIC) and 439 from the multi-centre Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (PHaSST) cohort. CKD was classified according to National Kidney Foundation Kidney Disease Outcomes Quality Initiatives guidelines. Haemoglobinuria, defined as positive haem on urine dipstick with absent red blood cells on microscopy, was confirmed by enzyme-linked immunosorbent assay in a subset of patients. The prevalence of CKD was 58% in the UIC cohort and 54% in the Walk-PHaSST cohort, and haemoglobinuria was observed in 36% and 20% of the patients, respectively. Pathway analysis in both cohorts indicated an independent association of lactate dehydrogenase with haemoglobinuria and, in turn, independent associations of haemoglobinuria and age with CKD (P<0.0001). After a median of 32 months of follow-up in the UIC cohort, haemoglobinuria was associated with progression of CKD (halving of estimated glomerular filtration rate or requirement for dialysis; Hazard ratio [HR] 13.9, 95% confidence interval [CI] 1.7-113.2, P=0.0012) and increasing albuminuria (HR 3.1, 95% CI: 1.3-7.7; logrank P=0.0035). In conclusion haemoglobinuria is common in SCA and is associated with CKD, consistent with a role for intravascular haemolysis in the pathogenesis of renal dysfunction in SCA.

APOL1 , α-thalassemia, and BCL11A variants as a genetic risk profile for progression of chronic kidney disease in sickle cell anemia

“…Age is a significant risk factor for CKD in SCA, 2 and we therefore analyzed the relationship between the genetic variants with ACR and eGFR by age. Inheritance of APOL1 G1/G2, absence of a-thalassemia, and BCL11A wild-type were individually associated with higher urine ACR (Figure 1).…”

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

“…36,37 Urine concentrations of hemoglobin (Bethyl laboratories, Montgomery, TX, USA) and kidney injury molecule-1 (KIM-1) (R&D Systems, Minneapolis, MN, USA) were measured using enzyme-linked immunosorbent assays (ELISA). Urine albumin and creatinine values were determined by the UIC Clinical Pathology Laboratories using methods approved by Clinical Laboratory Improvement Amendments.…”

“…Given our recent report of the association of hemoglobinuria with albuminuria and CKD in SCD patients, 36 we also tested the association of APOL1 G1/G2 variants with hemoglobinuria and found this to be the strongest association (OR 2.5, P=4.3x10 -6 ) (Figure 1). Associations of the APOL1 G1/G2 variants with urine albumin concentration (β 1.4, P=0.0001) and CKD stage (OR 3.8, P=0.005) were strengthened when using the average urine albumin concentration over three consecutive visits in 170 patients.…”

“…19 Markers of hemolysis have been associated with kidney disease in some [26][27][28][29][30] but not all [31][32][33] SCD cohorts. Hemoglobinuria, determined by urine dipstick analysis, has been observed in 15-42% of adults with SCD, [34][35][36] and is associated with elevated markers of hemolysis and risk of CKD progression. 36 Not all patients with SCD develop hemoglobinuria and not all patients with SCD and hemoglobinuria develop progressive CKD, suggesting that inherent susceptibilities to hemoglobinuria and CKD may differ.…”

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

“…However, the clinical picture is incomplete. Reports of CKD in SCD have focused primarily on patients with HbSS (8,14,15). Furthermore, the life expectancy of adults with SCD has lengthened, and more recent multicentered studies are likely to be more informative about the current status of renal disease in this population.…”