Rapid decline in estimated glomerular filtration rate in sickle cell anemia: Results of a multicenter pooled analysis

Chronic kidney disease (CKD), typically defined as kidney damage or decreased kidney function for 3 or more months, is common in sickle cell disease (SCD). Increasing evidence suggests that the glomerulopathy of SCD is progressive. CKD is associated with increased mortality in SCD. Based on single center studies, we previously reported on the high prevalence of rapid decline in kidney function, defined as estimated glomerular filtration rate (eGFR) loss >3.0 mL/min/1.73 m2per year, in SCD. In the present study, we further examine rapid eGFR decline in sickle cell anemia, using a pooled analysis of patients to better characterize factors associated with such decline and its association with mortality

Longitudinal study of glomerular hyperfiltration in adults with sickle cell anemia: a multicenter pooled analysis

Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI–2009, 506 patients had baseline estimated GFR (eGFR) $90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR$140 and $130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI–2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P, .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P 5 .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P 5 .001). Using CKD-EPI–2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P, .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P, .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P 5 .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI–2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P 5 .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P 5 .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P 5 .05). Using CKD-EPI–2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P, .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure

Differences in the clinical and genotypic presentation of sickle cell disease around the world.

Sickle cell disease (SCD), caused by a mutation in the β-globin gene HBB, is widely distributed in malaria endemic regions. Cardiopulmonary complications are major causes of morbidity and mortality. Hemoglobin SS (Hb SS) represents a large proportion of SCD in the Americas, United Kingdom, and certain regions of Africa while higher proportions of hemoglobin SC are observed in Burkina Faso and hemoglobin Sβ-thalassemia in Greece and India. Coinheritance of α-thalassemia and persistence of hemoglobin F production are observed in highest frequency in certain regions of India and the Middle East. As confirmed in the PUSH and Walk-PHaSST studies, Hb SS, absence of co-inheriting alpha-thalassemia, and low hemoglobin F levels tend to be associated with more hemolysis, lower hemoglobin oxygen saturations, greater proportions of elevated tricuspid regurgitant jet velocity and brain natriuretic peptide, and increased left ventricular mass index. Identification of additional genetic modifiers will improve prediction of cardiopulmonary complications in SCD

Hyperfiltration is Associated with the Development of Microalbuminuria in Patients 1 with Sickle Cell Anemia

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Hemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anemia.

To evaluate the association between haemoglobinuria and chronic kidney disease (CKD) in sickle cell anaemia (SCA), we analysed 356 adult haemoglobin SS or Sβ(o) 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 (Walk-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

Comparison of Patients from Nigeria and U.S.A. Highlights Modifiable Risk Factors for Sickle Cell Complications

To identify factors that affect manifestations of sickle cell anemia (SCA), we compared patients 11-30 years of age from University of Ibadan, Nigeria (n=214) and University of Illinois at Chicago, U.S.A. (n=209). Paralleling findings in the general populations of the two countries, Chicago patients were more often overweight or obese defined by CDC Guidelines (Age<18: 6% vs. 3%, P=0.02; Age≥18: 25% vs. 3%, P<0.0001) and more often had elevated blood pressure defined by NHLBI Guidelines (Age<18: 16% vs. 3%, P=0.02; Age≥18: 47% vs. 17%, P<0.0001). Ibadan patients less often had received pneumococcal vaccination (Age<18: 0% vs. 88%, P<0.0001; Age≥18: 1% vs. 91%, P<0.0001) or hydroxyurea therapy (Age<18: 7% vs. 44%, P<0.0001; Age≥18: 3% vs. 46%, P<0.0001). Consistent with lower rates of elevated blood pressure and increased body mass index (BMI), stroke history was less frequent in Ibadan patients ≥ 18 years old (2% vs. 24%, P<0.0001). Furthermore, in combined analyses, systolic and diastolic blood pressure directly correlated with BMI, and elevated weight status independently associated with history of stroke (OR 2.7, P=0.019). In conclusion, our findings are consistent with the possibility that higher values for BMI and blood pressure in Chicago SCA patients may contribute to an increased risk of stroke and highlights the need for measures to reduce these risk factors. On the other hand, in Ibadan patients, lower pneumococcal vaccination and hydroxyurea therapy rates highlight the need for more improved vaccination coverage and for studies to define the role of hydroxyurea therapy in Africa