Addressing Disparities in Health Care

Genitourinary manifestations of sickle cell disease

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ABSTRACTSickle cell disease is a common genetic disorder characterized by sickling of red blood cells under conditions of reduced oxygen tension. In turn, sickling leads to intravascular hemolysis and vaso-occlusive events with subsequent tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system. Our review of the genitourinary manifestations of sickle cell disease focuses on sickle cell nephropathy, priapism, and other genitourinary complications such as papillary necrosis and renal medullary carcinoma.

KEY POINTS

  • Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
  • Ischemic priapism is a medical emergency. Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease.
  • In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis.


 

References

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.1 The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,2 causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.10

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.14 From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.15

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m2, and 16.7% had elevated blood pressure (prehypertension and hypertension).16

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.9 In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.9

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.15

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.22

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

  • Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
  • Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
  • ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
  • Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
  • Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

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