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:

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  Increased glomerular growth

  
  
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  Heme-induced injury to mesangial cells with chronic hemolysis

  
  
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  Repetitive vascular congestion and vasoocclusion-induced endothelial injury

  
  
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  Capillary rarefaction (reduced capillary density)

  
  
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  Ischemia-reperfusion-induced proinflammatory and profibrogenic responses

Contributing factors to kidney vascular congestion and dysfunction include:

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

  
  
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  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

  
  
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  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?

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  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.

  
  
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  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?

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  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.

  
  
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  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.

  
  
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  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?

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  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.

  
  
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  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.

6. How does SCD affect blood pressure?

Patients with SCD generally have lower blood pressure compared with their healthy unaffected counterparts due to presumed reduced vascular reactivity, compensatory systemic vasodilatation associated with microvascular disturbances from the sickling of red blood cells and thrombotic complications, elevated levels of prostaglandins and nitric oxide, and possibly kidney sodium and water wasting associated with suboptimal medullary concentrating activity. Blood pressures in the “normal” range defined for the general population may thus represent hypertension in patients with SCD. Whether the lower blood pressure reduces long-term cardiovascular disease risks is not known as the median survival for patients with SCD is only 40 years.

7. How do SCD and sickle cell trait (SCT) differ with respect to common kidney manifestations?

Kidney manifestations are generally more common and severe in SCD compared with those seen in sickle cell trait. However, one notable exception is the increased frequency of aggressive renal medullary carcinoma seen among patients with sickle cell trait. Renal medullary carcinoma occurs almost exclusively in patients with sickle cell trait (not SCD). Renal medullary carcinoma typically presents in young patients (20 to 30 years old) as an aggressive metastatic disease at the time of diagnosis. Median survival is 3 months following diagnosis. Affected individuals may present with hematuria, flank pain, and/or abdominal mass.

8. What are the underlying pathogenesis of chronic kidney disease (CKD) and risk factors associated with CKD progression in patients with SCN?

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  Pathogenesis of CKD: Although glomerular filtration is increased in younger patients with SCD, it progressively declines after the age of 30. The development of CKD is thought to be due to early glomerular hypertrophy and hyperfiltration; tubular hyperfunctioning; endothelial injury with repeated sickling and vasoocclusive episodes; hemolysis and iron-induced proinflammatory and profibrotic changes in endothelial cells; and glomerular mesangium and tubulointerstitium.

  
  
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  Risk factors for CKD progression: underlying hypertension, nephrotic range proteinuria, severe anemia, vasoocclusive crisis, acute chest syndrome, stroke, β ^S -gene haplotype, genetic variants of MYH9 and APOL1 , pulmonary hypertension, and infection with parvovirus B19. Of note, although studies have provided statistical evidence implicating APOL1 variation in nondiabetic nephropathies, MYH9 risk variants are still associated with CKD in non–African American populations and in SCD nephropathy. It has been hypothesized that MYH9 and APOL1 may be coregulated and interact under anemic stress to induce nephropathy risk.

  
  
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  Protective factors: coinheritance with α-thalassemia, higher fetal hemoglobin.