Genitourinary manifestations of sickle cell disease
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.
PRIAPISM IN SICKLE CELL DISEASE
Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.
Ischemic priapism
Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),23 glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.24
Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.25
Men with a subtype of ischemic priapism called “stuttering” priapism26 suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.
Nonischemic priapism
In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.
Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.
Treatment guidelines
Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.27
Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.27
Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.25
As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.
Prevalence in sickle cell trait vs sickle cell disease
Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.28 In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.29
Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.31
Take-home messages
- Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
- 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 (hydration, oxygen, exchange transfusions).
OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE
Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.
Special considerations
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. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.
Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.
Renal medullary carcinoma
Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.32
When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.
On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.
Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.
