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Polymerization of deoxygenated sickle hemoglobin (HbS), resulting in fragile red blood cells (RBCs) and anemia, is the first step in a pathophysiologic cascade that involves the kidney. Damage arises from the cumulative impact of abnormal red cells, hemolysis, and microvascular occlusion. These insults include hyperfiltration in response to anemia, cellular toxicity from plasma and urine cell-free hemoglobin, oxidative stress, inflammation, and potentiation of erythrocyte sickling in the hypoxic and acidotic milieu of the renal medulla. Genetic modifiers of renal disease in sickle cell disease (SCD) include sickle genotype, mutations that modulate HbS polymerization such as α thalassemia and hereditary persistence of fetal hemoglobin (HbF), and haplotypes such as APOL1 G1 and G2 that increase the risk of kidney disease in the background population.

The effects of kidney disease on the person with SCD include relative hypertension, rapid decrements in glomerular filtration over the life span, depressed erythropoiesis, impaired bone health, altered acid-base homeostasis, and an inability to concentrate urine, which can lead to dehydration. The decreased ability to concentrate urine is present in HbAS trait individuals, in whom it may contribute to an increase in the risk of exercise-related heat stroke. Overall, renal disease is more pronounced in people with homozygous HbSS than HbSC or HbS-β+ thalassemia. Most people with SCD living in resource-replete settings, whether homozygous or compound heterozygous, are now surviving into adulthood, and some impairment in kidney function and perturbation in the cardiorenal axis (summarized in Table 16-1)1-12 is nearly universal with increasing age. Evolution of the clinical phenotype over the life span is affected by recent advances in standard care for SCD. Consideration of these factors is necessary for proper interpretation of historical studies of renal function in SCD.

TABLE 16-1Cardiorenal physiology: an overview

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