Abstract
Sickle cell anemia is caused by the homozygous inheritance of the sickle β-globin gene and affects multiple organ systems. Because of its unique physiology, the kidney is particularly susceptible to injury in sickle cell disease (SCD). Individuals with SCD exhibit glomerular hyperfiltration and also present with urinary concentrating defects, hematuria, and overt papillary necrosis. As patients age, they are prone to developing sickle cell glomerulopathy and subsequent albuminuria and overt proteinuria. Low-level albuminuria may be present in up to 60% of sickle cell patients over the age of 35. Determination of chronic kidney disease (CKD) is somewhat impaired when using creatinine-based measures of the estimated glomerular filtration rate due to the hyperfiltration noted in these individuals. As CKD and end-stage kidney disease develop, sickle cell anemia poses some unique management challenges, including that of anemia management and kidney transplantation. The use of angiotensin-converting enzyme inhibitors may reduce proteinuria in SCD, but their long-term benefit remains unknown. Similarly, hydroxyurea has suggested, but unproven, benefit. Sickle cell trait (SCT), and less commonly SCD, is associated with renal medullary carcinoma, a rare and aggressive malignancy. Recent data have suggested that SCT, the heterozygous inheritance of the sickle β-globin gene, may be associated with CKD.
Keywords
sickle cell, albuminuria, glomerulopathy, renal medullary carcinoma, papillary necrosis
Sickle cell anemia is caused by the homozygous inheritance of the sickle β-globin gene (HbSS), produced by a single point mutation in chromosome 11. The resultant β chain of the hemoglobin molecule possesses a substitution of valine for glutamic acid at position 6, leading to an unstable form of hemoglobin (hemoglobin S). Under conditions of low oxygen tension, acidity, extreme temperatures, and other stressors, the altered hemoglobin undergoes polymerization, leading to the “sickling” of red blood cells ( Fig. 39.1 ). These red cells are rigid, leading to both microvascular obstruction and the activation of inflammation and coagulation. Sickle cell disease (SCD) is also seen in the double heterozygous inheritance of hemoglobin mutations HbS gene and another mutation, such as hemoglobin SCD and sickle β-thalassemia.
The prevalence of sickle cell trait (SCT; HbAS) in the United States is between 6% and 9% among African-Americans, with sickle cell anemia occurring in approximately 1 of 500 African-American live births. In the global population, the prevalence of the hemoglobin S mutation varies greatly and is often highest in areas where malaria is endemic because of the protection it affords against malarial infection. In 2010, an estimated 312,000 neonates were born worldwide with sickle cell anemia.
Although SCD affects multiple systems throughout the body and is characterized by acute pain crises and progressive multiorgan damage, the kidney is a particularly susceptible organ. The renal medulla, with its lower oxygen tension, high osmolarity, lower pH, and relatively sluggish blood flow, is an ideal environment for “sickling” and microvascular obstruction. As a result, kidney manifestations are common in SCD ( Table 39.1 ).
| Kidney Abnormality | Clinical Consequence |
|---|---|
| Glomerular | |
| Hyperfiltration | Increased GFR (early), albuminuria/proteinuria, sickle glomerulopathy, CKD (late) |
| Proximal Tubule | |
| Enhanced proximal tubule activity | Increased creatinine secretion, increased phosphate resorption (hyperphosphatemia) |
| Depressed renin | Hyporeninemic hypoaldosteronism (hyperkalemia) |
| Distal Tubule/Cortical Collection Duct | |
| Impaired hydrogen ion secretion | Metabolic acidosis (type 4 RTA) |
| Impaired potassium secretion | Hyperkalemia |
| Impaired urinary concentration | Hyposthenuria |
| Interstitial | |
| Chronic “sickling” in vasa recta | Hematuria, renal papillary necrosis (due to ischemia), renal medullary carcinoma, CKD |
Pathophysiology
Although the classic understanding of SCD is based on microvascular obstruction, its pathophysiology is better understood in the context of recurrent vasoocclusion with ischemia-reperfusion injury and hemolytic anemia. In addition to triggering hemoglobin polymerization, inflammation and other stressors also initiate erythrocyte adhesion to endothelium and leukocytes, beginning the process of microvascular obstruction. These processes are dynamic, resulting in ischemia followed by the restoration of blood flow and the subsequent reperfusion injury, with resultant oxidative stress and inflammatory cytokine production. Intravascular hemolysis is another contributor to disease burden, with the release of free hemoglobin into the plasma generating reactive oxygen species and depleting nitric oxide. These processes produce endothelial dysfunction and activate the coagulation system.
Disease severity in SCD appears to be modulated by the relative concentration of sickle hemoglobin (HbS). The presence of fetal hemoglobin (HbF), which can be increased with hydroxyurea therapy, reduces the relative content of hemoglobin S; accordingly, haplotypes of the mutation that correlate with lower HbF production, most notably the Central African Republic haplotype, typically have the most severe disease manifestations. Similarly, coinheritance of α-thalassemia mutations reduces intracellular HbS concentration and leads to reduced hemolysis and fewer complications.
Within the kidney, these pathologic mechanisms lead to changes in kidney hemodynamics, tubulointerstitial damage, and, in some patients, glomerular disease.
Kidney Hemodynamics
Glomerular hyperfiltration is extraordinarily common among patients with SCD and can be detected at as early as 13 months of age. Glomerulomegaly is evident even in patients without clinical disease and may contribute to hyperfiltration. Glomerular hyperfiltration is likely driven by vasodilatation of the afferent arteriole, which may occur as a compensatory response to chronic tissue hypoxia in the renal medulla. The exact mechanisms behind this response are not fully known, but it may be mediated by up-regulation of prostaglandins and the nitric oxide systems. Indomethacin and other prostaglandin inhibitors, administered at doses that would not affect the glomerular filtration rate (GFR) in normal individuals, can reduce GFR to more normal values in patients with SCD. Hemolysis and production of free heme may also play a role in the process. Sickle cell animal models have demonstrated that hemolysis induces up-regulation of heme-oxygenase-1 (HO-1) with subsequent production of carbon monoxide (CO), a local vasodilator.
Tubulointerstitial Disease
Impaired Urinary Concentration
The most commonly reported kidney manifestation in patients with SCD is the loss of complete urinary concentrating ability. Typically, the generation of concentrated urine requires an intact collecting duct and a medullary concentration gradient. The juxtamedullary nephrons, which extend deepest into the medulla and are most capable of producing a high concentration gradient, are also those most likely to be affected by sickling in the medullary vasa recta. Microangiographic studies demonstrate the obliteration of the vasa recta in these patients, with subsequent fibrosis and shortening of the renal papilla. The functional result of these anatomic changes ultimately manifests as an inability to achieve a urinary osmolarity above 400 mOsm/kg. Early in life, this defect is partially reversible following blood transfusions that rapidly increase normal hemoglobin A (HbA) and reduce sickling in the vasa recta. However, impaired urinary concentration becomes fixed later in life (as early as age 15) and no longer improves with transfusion. As a result, depending on water and solute intake, patients with SCD may have obligatory water losses of up to 2.0 L/day, predisposing them to higher serum osmolality and thereby potentially exacerbating sickle crises. The ability to produce a maximally dilute urine and to excrete free water remains intact.
Hematuria
Hematuria can be one of the most dramatic kidney presentations in patients with SCD and may range from microscopic hematuria to gross hematuria. Gross hematuria may occur in patients of any age, including young children. Although the etiology of hematuria remains unclear, vasoocclusion occurring in the acidic, hyperosmolar, low oxygen tension environment of the medulla is thought to play a central role. Studies of kidneys removed from sickle cell patients with severe hematuria demonstrate severe stasis of peritubular capillaries, particularly those in the medulla, as well as erythrocytes extravasated into the collecting tubules. In addition to the aforementioned vascular occlusion–mediated ischemia and oxidative/reperfusion injury, sickling in these vessels may also lead to vessel wall injury and necrosis, which could cause the structural changes leading to hematuria.
Typically, hematuria is unilateral and occurs nearly 4 times more often from the left kidney. The longer course and higher venous pressures of the left renal vein as it traverses between the aorta and superior mesenteric artery likely lead to this phenomenon.
Although bleeding is typically benign and self-limited, massive hemorrhage can occur and can be potentially life threatening. Treatment consists of conservative management, including bed-rest and the maintenance of high urine output to prevent clots. Alkalinization of the urine may help by raising medullary pH, thereby reducing sickling; however, no studies have shown a proven benefit of this intervention. Intravenous fluids may be used to ensure high urine flow but must be used with caution in patients at risk for congestive heart failure or acute chest syndrome. Diuretics can also be used to increase urine flow rates, but care must be taken to avoid volume depletion.
For those patients with massive and persistent hematuria despite conservative therapy, ε-aminocaproic acid (EACA) can be beneficial. This agent inhibits fibrinolysis and can induce clotting to halt hematuria. Reports have demonstrated improvement with EACA, although no standard dose regimen or length of therapy has been defined. However, EACA can be prothrombotic; accordingly, it must be used with caution in SCD patients who are already at risk for thrombotic events. Currently, EACA use is recommended only for a limited period and at the lowest dose necessary to achieve inhibition of urinary fibrinolytic activity. In addition to EACA, intravenous vasopressin to limit hematuria has been successful in case reports.
In patients who are refractory to medical therapy, invasive intervention may be necessary. If a source of bleeding can be localized via imaging, percutaneous embolization can be attempted. In rare cases, unilateral nephrectomy of the affected kidney may be required. In all patients presenting with hematuria, and particularly in those with persistent or massive hematuria, alternative causes should be considered, including acquired or hereditary bleeding disorders or abnormalities, such as nephrolithiasis, polycystic kidney disease, or renal medullary carcinoma (RMC; see next sections).
Renal Papillary Necrosis
Renal papillary necrosis (RPN) is fairly common in SCD, occurring in more than 60% of patients in some series. Although often accompanied by hematuria, a similar proportion of patients may be asymptomatic. With severe sickling in the vasa recta, the renal papillae that depend on these vessels can undergo focal, repetitive infarcts leading to necrosis ( Fig. 39.2 ). If hematuria is present, as described earlier, patients should undergo an evaluation for other potential causes, including kidney masses or nephrolithiasis. This imaging can be performed with ultrasonography, although a helical computed tomography (CT) scan may detect RPN earlier. In many patients, RPN ultimately results in calcification around the renal pelvis. Treatment, as with hematuria, is generally supportive, using similar measures. If significant sloughing occurs, necrotic and thrombotic material may lead to ureteral obstruction, which can be diagnosed by urography and relieved by stenting.
