Sickle cell nephropathy

1. What is the pathophysiology of sickle cell disease (SCD)?

Hemolysis, vasoocclusion, and ischemia reperfusion are the clinical hallmarks of SCD. The substitution of glutamate for valine at position 6 of the hemoglobin β-chain is the mutation defining hemoglobin S (HbS). HbS polymerizes when the concentration of its deoxygenated form exceeds a critical threshold. Conditions that promote HbS polymerization and red blood cell sickling include low local oxygen tension, acidemia (reduces HbS affinity for oxygen), and hyperosmolality (dehydrates red blood cells and increases HbS concentration).

Extensive HbS polymerization, red blood cell sickling, cell membrane injury, and associated cell membrane adhesive interactions with the endothelium contribute to vasoocclusion leading to multiorgan damage.

2. What is the pathophysiology of sickle cell nephropathy (SCN)?

Increased blood viscosity and red blood cell sickling promoted by the renal medullary milieu of low oxygen tension, low pH, and high osmolality lead to vasoocclusion and hypoperfusion in the medullary microcirculatory beds, and result in local ischemia and infarction. Severe medullary hypoperfusion can lead to papillary necrosis, sloughing, and obstructive uropathy.

In contrast to medullary hypoperfusion, glomerular ischemia appears to promote compensatory increase in kidney blood flow and the glomerular filtration rate (GFR). Glomerular hyperfiltration is mediated by glomerular hypertrophy and increased activity of vasodilatory factors including prostaglandins, kallikrein, carbon monoxide, and possibly nitric oxide (NO).

Proximal tubular secretory and absorptive hyperfunctioning are characteristic of SCD. Tubular hyperfunctioning is thought to reflect glomerulotubular balance in the face of glomerular hyperfiltration, and is evidenced by increased proximal tubular secretion of uric acid and creatinine and increased tubular reabsorption of low-molecular-weight protein (β2-microglobulins) and phosphate. Hypersecretion of creatinine causes an overestimation of the true GFR when using serum creatinine-based estimated GFR equations.

Chronic hemolysis and hemoglobinuria involving HbS can induce oxidant-mediated tubular injury, proliferation of mesangial cells, and upregulation of proinflammatory and profibrogenic responses to promote glomerulosclerosis and tubulointerstitial fibrosis.

Progressive kidney failure occurs due to:

• Increased glomerular growth

• Heme-induced injury to mesangial cells with chronic hemolysis

• Repetitive vascular congestion and vasoocclusion-induced endothelial injury

• Capillary rarefaction (reduced capillary density)

• Ischemia-reperfusion-induced proinflammatory and profibrogenic responses

Contributing factors to kidney vascular congestion and dysfunction include:

• Endothelin-1: increases kidney vascular congestion, inflammation, and vasoconstriction induced by hypoxia

• Thrombospondin: induces shedding of microparticles from red blood cells that can lead to oxidant-mediated endothelial injury, red blood cell adhesion to the endothelium, and worsening of kidney vasoocclusive disease

• Adenosine: promotes red blood cell sickling by increasing levels of 2,3-diphosphoglycerate in red blood cells.

3. In addition to proximal tubular hyperfunctioning, what other tubular abnormalities may be seen in patients with SCD?

• Diminished concentrating ability: Red blood cell sickling and congestion in the vasa recta leads to ischemia and associated impairment of solute reabsorption by the ascending limb of Henle loop and the vasa recta function as countercurrent exchangers. The suboptimal maintenance of the high interstitial osmolality in the inner medulla reduces effective water reabsorption across the collecting ducts, hence the reduced kidney concentrating ability. A diminished concentrating ability leads to hypo- or isosthenuria where urine osmolality typically does not exceed 450 mosm/Kg. Affected adults present with polyuria, nocturia, and volume depletion and children with enuresis. Blood transfusions of HbA-containing red blood cells can improve concentrating ability in children younger than age 15, but not thereafter due to permanent injury.

• Renal tubular acidosis: Patients may develop incomplete distal renal tubular acidosis via reduced H+-ATPase activity due to hypoxemia, selective aldosterone deficiency, distal nephron resistance to aldosterone, reduced ammonium availability, or, in rare cases, hyporenin hypoaldosteronism.

4. What are the common abnormal urinary findings in SCD?

• Hematuria: Both microscopic and macroscopic hematuria may be observed. The left kidney is affected four times greater than the right due to the increased venous pressure within the longer left vein that is compressed between the aorta and the superior mesenteric artery. This is known as the “nutcracker phenomenon.” The increased venous pressure leads to increased relative hypoxia in the renal medulla, hence sickling. In 10% of cases, hematuria occurs bilaterally. Hematuria may also indicate the presence of papillary necrosis and, in rare cases, renal medullary carcinoma. The latter is predominantly observed in sickle cell trait rather than SCD.

• Proteinuria: The prevalence of albuminuria and proteinuria is 30% within the first three decades of life and increases up to 70% in older patients. Proteinuria may be associated with defects in glomerular permselectivity, tubular injury, and/or specific single nucleotide polymorphisms in the APOL1 genes.

• Bacteriuria: Patients with SCD may be at increased risk for urinary tract infections from encapsulated organisms due to autosplenectomy, abnormally dilute and alkaline urine (more favorable for bacterial growth compared with hypertonic and acidic urine), and papillary necrosis. However, significant bacteriuria generally occurs in less than 10% of sickle cell patients, half of whom are asymptomatic.

5. What are the common causes of acute kidney injury (AKI) in patients with SCD?

• AKI may occur more frequently among patients with acute chest syndrome than those with a painful crisis. Predisposing factors leading to AKI include volume depletion due to concentrating defects, sickling process, and hemolysis. Patients may present with acute tubular necrosis from volume depletion or sepsis, tubular injury from ischemia-induced rhabdomyolysis, hemosiderin accumulation, or chronic use of nonsteroidal antiinflamatory drugs, kidney vein thrombosis, or, in rare cases, hepatorenal syndrome due to liver failure associated with the sickling process per se or transfusion-associated complications.

• Kidney infarction and papillary necrosis: Severe ischemia can lead to kidney infarction and papillary necrosis. Papillary necrosis typically presents as painless gross hematuria, but may be complicated by obstructive uropathy and urinary tract infections. Current data suggest that hematuria and papillary necrosis do not portend greater risk for kidney failure. Acute segmental or total kidney infarction may present with flank or abdominal pain, nausea, vomiting, fevers, and presumably renin-mediated hypertension.