Investigation of Sickle Cell Nephropathy

Abstract

Sickle cell nephropathy is a complication of sickle cell anemia (SCD), a genetically inherited blood disease. It is a genetic disorder characterized by the presence of HbS modified due to amino acid mutation. The mutation causes hemoglobin to assume a sickle shape under certain conditions, leading to various complications such as decreased elasticity, increased hemolysis, and vascular occlusion. Polymerization of HbS in an oxygen-free environment causes organ dysfunction by contributing to vascular occlusion and tissue hypoxia. These sickle-shaped cells can cause blockages in the circulatory system and tissue hypoxia, leading to damage to various organs. Nephropathy is known as one of the common complications of sickle cell disease. Sickle cell nephropathy is generally characterized by impaired renal function, proteinuria, hematuria, hyposthenuria, and sometimes renal failure. Treatment of sickle cell nephropathy focuses on symptomatic supportive treatments, and in advanced cases such as renal failure, kidney transplantation may be required. In summary, sickle cell nephropathy is a condition that causes damage to the kidneys as a result of sickle cell anemia and can lead to serious complications. For these reasons, it becomes important to conduct further research to support the literature.

1. Introduction

In 1910, Herrick JB first described sickle cell nephropathy in a black student. He described anemia with elongated sickle-shaped red blood cells, increased urine volume, and decreased urine density [1]. Sickle cell disease (SCD) is a genetically inherited disease that affects many systems and is a clinical condition that occurs when red blood cells contain modified HbS. The main features of the disease are recurrent painful attacks, chronic hemolytic anemia, and acute and chronic organ dysfunction [2]. HbS is formed by the replacement of glutamine at position 6 at the amino (-NH₂) end of the beta-globin chain with the amino acid valine. It is formed when GTG (Guanine-Tymine-Guanine) replaces GAG (Guanine-Adenine-Guanine) at the base level. As a result of this mutation, the oxygen-free HbS polymerizes, and the solid precipitates into crystals. Erythrocytes take from a biconcave disc shape to a crescent-like sickle shape (Figure 1) [3]. The deformed cells are destroyed early in the spleen, and it also reduces blood flow and causes congestion, especially in small vessels.

Figure 1.

Normal and abnormal erythrocyte cell image [3].

Hemoglobin distributes oxygen to the tissues and its high density inside the erythrocytes provides the ability of the erythrocyte to maintain and change shape. Normal human hemoglobin has 4 polypeptide chains and 4 heme groups. Polypeptide chains consist of 2 alpha and 2 beta chains. The main hemoglobin found in adults is HbA and the amount of HbA2 is very small. The HbF level is high throughout fetal life and its proportion in erythrocytes decreases after birth. Hemoglobinopathies result from changes that result in abnormal hemoglobin synthesis [4].

Hemoglobinopathies are examined in 5 basic groups and the most common ones are sickle cell syndromes (structural hemoglobinopathies) and thalassemias (globin chain synthesis disorder). Structural hemoglobinopathies, including sickle cell anemia, occur due to a mutation that changes the amino acid sequence of a globin chain, which changes the physiological properties of hemoglobin and creates the typical clinical symptoms of the disease (Figure 2) [5].

Figure 2.

Gene mutation of sickle cell disease.

With a single point mutation, the replacement of glutamic acid in the 6th position of the β globin chain with valine, that is, the replacement of adenine in deoxyribonucleic acid (DNA) with thymine (GAG-GTG) results in the HbS molecule. A small genetic change significantly affects the molecular balance [6].

2. Overview of sickle cell nephropathy

The most common hemoglobinopathy in the world is SCD. Clinical findings in SCD are quite variable. While some patients are asymptomatic and detected in community screenings, some patients may apply to a doctor with a severe crisis. Most of the patients live completely asymptomatic except during these crisis periods [7]. Atherosclerosis seen in patients with sickle cell anemia is an important cause of morbidity and mortality due to organ damage and disease [8]. One of the patients’ most frequently affected organs is the kidneys. Atherosclerosis develops as a result of the sickling of erythrocytes and the adhesion of sickle cells to the endothelium. This causes structural and functional disorders in the kidneys. Changes are seen throughout the nephron from the glomeruli to the papillary end. Side effects such as hyposthenuria, renal acidification potassium (K) secretion disorders, hypertension, hematuria, proteinuria, nephrotic syndrome, renal papillary necrosis (RPN), renal medullary carcinoma, acute, and chronic renal failure may occur [9, 10].

After the erythrocytes take the shape of a sickle, they slow down the blood flow by reducing the fluidity in the circulation, and this causes congestion and an oxygen-free environment in the small vessels. Generally, sickle erythrocytes regain their former shape with re-oxygenation, while some of them cannot return to their normal shape due to permanent damage to the cell membranes. These cells cause vascular occlusion, creating hypoxia in the tissues, cause the painful crises, organ necrosis, and ultimately acute and chronic tissue destruction [11]. The mechanisms of irreversible sickling of cells are not fully understood. The number of irreversibly sickled cells for each patient is usually constant and is mainly related to the degree of anemia. This cell number is not associated with the patient’s crises, nor is it a determinant of conditions such as pain attacks. Recent studies on the pathogenesis of SCD have focused on the pathological conditions that occur during avascular occlusion by polymerization of HbS in an oxygen-free environment [12]. Structural and functional disorders are found in the kidneys in sickle cell anemia patients. Sickling of erythrocytes as a result of HbS polymerization, resulting in vascular occlusion and hypoxia, causes dysfunction in the renal medulla. Inhibition of sickling is the most important mechanism to prevent renal involvement of SCD. Symptoms progressing to chronic kidney disease and end-stage renal disease can be seen in SCD [13, 14]. In tubular dysfunctions, the most common renal side effect in sickle cell patients is hyposthenuria, which is defined as the inability to achieve the maximum concentration of urine. This situation manifests itself with increased frequency of urination and enuresis in early childhood in homozygous SCD patients, and often with nocturia in later periods [15]. Dehydration occurs more quickly in hot weather, due to the inability to achieve the maximum concentration ability of urine. Since vasopressin production is normal, the concentration defect in SCD does not respond to vasopressin. The degree of hyposthenuria is different in sickle cell anemia carriers. Impairment in the ability to concentrate urine may be temporarily corrected by blood transfusions in the early stages of the disease. However, medullary fibrosis and permanent damage to the collecting ducts render the concentration defect irreversible [16]. It is recommended that hypostenuric patients take more fluids orally or intravenously to compensate for fluid loss. Urine dilution is dependent on solute reabsorption in the ascending limb of the loop of Henle in the cortical nephron. Since there is no involvement in these regions in SCD, patients can dilute the urine normally. Proximal tubular functions are higher than normal in sickle cell patients. As a result of increased sodium (Na) reabsorption from the proximal tubule in patients, less Na is transferred to the distal region, resulting in a poorer response to diuretics [17]. It has been suggested that these changes are a balancing mechanism against medullary damage for Na and water retention [18]. Phosphorus (P) reabsorption and uric acid secretion are also increased in patients with SCD. Therefore, patients may develop hyperphosphatemia and hyperuricemia as a result of hemolysis. In sickle cell patients, serum potassium and uric acid levels were high, and tubular phosphate reabsorption and potassium excretion were low. Although the renin-aldosterone axis functions normally in sickle cell patients, there may be an increase in plasma renin and aldosterone levels due to medullary fibrosis [8]. The tubular secretion of creatinine is increased in patients. Therefore, creatinine clearance (Cr/Kl) is found to be higher than the value estimated as glomerular filtration rate (GFR). Serum creatinine level is low in SCD. Decreased CrKl in SCD suggests decreased functional ability of renal tubules [19]. The pathogenesis of hematuria is explained by sickled erythrocytes causing vascular occlusion in the medulla and then extravasation of blood cells. Painless macroscopic hematuria is the most dramatic clinical picture in SCD [20]. Bleeding is unilateral in 80–90% of cases and mostly originates from the left kidney. This is due to the higher venous pressure in the left kidney. Occlusion in the renal vessels causes damage to the vasa recta and small infarctions, resulting in the development of renal papillary necrosis (RPN). The most important finding of patients with RPN is hematuria. RPN occurs in more than 40% of homozygous patients. In RPN due to SCD, unlike papillary necrosis due to the use of analgesics, the vasa recta are empty and the peritubular capillaries are primarily involved [21, 22].

Acute renal failure is one of the common side effects in sickle cell patients, and it is especially seen in hospitalized patients. Acute renal failure is most commonly seen due to infections and rhabdomyolysis. Fluid loss is the most important trigger for acute renal failure. The use of anti-inflammatory drugs is also accepted as a factor that increases this deficiency [23].

Another sign of kidney involvement in sickle cell anemia is proteinuria, and it is among the most common findings in kidney disease related to SCD. Proteinuria is detected in 17–33% of patients with SCD with the dipstick method. Its incidence is age-related, and it is less common in children and more common in older ages. Proteinuria is seen at a higher rate in homozygous SCD than in heterozygous sickle cell carriers [24]. Proteinuria was associated with the severity of the disease. Microalbuminuria and the presence of immunoglobulin G (IgG) in the urine are accepted as early predictors of glomerular damage [25]. The association of significant proteinuria with hematuria in sickle cell anemia is well known. Sickle cell glomerulopathy is defined as proteinuria at the nephrotic border. SCD glomerulopathy has a faster course than other causes of nephrotic syndrome. Glomerulopathy, proteinuria, and nephrotic syndrome may progress in sickle cell patients [26]. While hypertension alone is not observed in patients with SCD, hypertension can be detected if nephrotic syndrome is present with SCD. Sickled cells block glomerular capillaries, causing direct endothelial damage, endothelial hyperplasia, and glomerular fibrosis. The development of focal segmental glomerulosclerosis in SCD is believed to be due to hyperfiltration. In SCD nephropathy, enlargement of the glomeruli, perihilar focal segmental glomerulosclerosis, and hemosiderosis are seen in the early period, while membranoproliferative glomerulonephritis develops in advanced cases [13, 27].