Sickle cell nephropathy is an important cause of morbidity and mortality in patients with sickle cell disease, an autosomal recessive genetic disorder of impaired hemoglobin synthesis. Nephropathy stems from progressive obstruction of renal vessels, subsequent hypoxia, and ischemia of the renal parenchyma, eventually causing fibrosis, glomerulosclerosis, and renal failure. Hematuria, proteinuria, and hypertension are main symptoms. Clinical findings and laboratory studies are necessary components of the workup, but advanced genetic and molecular methods must confirm sickle cell disease as the underlying cause.
Sickle cell disease (SCD), globally regarded as one of the most prevalent hereditary diseases of the hematologic system, stems from mutations of genes (inherited through an autosomal recessive pattern) responsible for the formation of hemoglobin, specifically the β-globin chain [1] [2]. Depending on the phenotype, the medical entity may have a very poor prognosis in homozygous forms, whereas compound heterozygotes, as well as the heterozygotes, carry a slightly better life expectancy with less severe clinical manifestations [1]. The pathogenesis of SCD is centered around the defective hemoglobin molecules, which bind together in the circulation causing obstruction of the blood flow, sludging, and increased blood viscosity [3] [4]. As a result, ischemia and hypoxia of many tissues may arise. Renal failure, occurring on the grounds of microvascular obstruction, medullary fibrosis, focal segmental glomerulosclerosis (FSGS), and papillary necrosis, is known as sickle cell nephropathy (SCN), affecting up to 18% of all SCD cases [3] [4] [5]. Signs of SCN can start as early as infancy, when the capacity for urine concentration is diminished, resulting in polyuria and dehydration [3] [5] [6] [7]. In addition, microalbuminuria and proteinuria, as well as hematuria, anemia, and hypertension are main symptoms of SCN [3] [5] [6] [7]. In virtually all patients, progressive deterioration of glomerular filtration rate (GFR) increases the risk of acute kidney injury (AKI), chronic kidney disease (CKD, seen in up to 39% of SCD cases), and end-stage renal disease (ESRD) [1] [3] [5] [6] [8].
The diagnosis of sickle cell nephropathy can be made through a comprehensive clinical approach and subsequent laboratory testing. After collection of anamnestic data, during which findings such as hematuria and polyuria (and weakness due to dehydration and anemia) are noticed, urinalysis and additional imaging studies need to be performed. Urine dipstick testing is a useful initial tool to detect proteinuria and more detailed exams that assess the extent of protein loss are mandatory [3]. Further urinalysis reveals hematuria, in which case ultrasonography of the kidneys and the urinary bladder, cystoscopy, or urography, might be necessary to exclude other diagnoses (eg. the presence of stones or other lesions ) [2] [6]. Hyperechogenic renal pyramids and clubbing of the renal calyces are highly suggestive of SCN on ultrasonography and urography, respectively [5]. Serum creatinine and blood urea nitrogen (BUN) are important components of the workup, mainly in order to calculate the GFR and establish the severity of kidney disease. Erythropoietin (EPO) levels are markedly reduced in patients with sickle cell nephropathy, particularly in severe stages of renal failure [6]. To identify SCD as the underlying etiology of nephropathy, the aberrant hemoglobin (HbS) must be recognized through procedures such as isoelectric focusing (IEF), genetic studies, or high-performance liquid chromatography [2].