Philip J. Dorsey, Jr., MD, MPH
Benjamin R. Lee, MD, FACS
BASICS
DESCRIPTION
• Sickle cell (SC) disease is a chronic hemoglobinopathy transmitted genetically and marked by severe chronic hemolytic anemia and periodic acute painful episodes.
• The heterozygote is termed SC trait and usually has no symptoms.
• Major GU complications can include priapism and a spectrum of renal disorders from hematuria and decreased renal concentrating ability through renal medullary carcinoma and renal failure.
EPIDEMIOLOGY
Incidence
• 1:500 African American births
• 1:1,000 Hispanic American births
• 2 million Americans, or 1 in 12 African Americans, carry the SC trait.
• ∼4,000–5,000 pregnancies are at risk of SC disease.
• Life expectancy: Men, 42 yr; women, 48 yr
Prevalence
• Prevalence estimated at 8% of African Americans
• 8–10% of African Americans have SC trait
• 25–30% of Western Africans have SC trait
RISK FACTORS
Family history of disease
Genetics
• Autosomal codominant inheritance pattern
• Allele is on chromosome 11
• Several haplotypes; allelic with β-thalassemia
• SC disease: Inheritance of 2 alleles, all RBCs contain hemoglobin (Hb)S
• SC trait: From 1 allele, 40% of Hb is HbS
PATHOPHYSIOLOGY
• Sickling of RBCs caused by HbS in ischemic state leading to vaso-occlusive state and causing most complications of SC disease:
– Substitution of valine for glutamate at 6th amino acid position
• HbS tetramer: The deoxygenated state polymerizes into double-stranded filaments and bundles
• Chronic anemia is the hallmark of the disease; RBC mean lifespan: 17 days
• SC trait (heterozygote) usually asymptomatic
• Decreased renal concentrating ability is common and results in polyuria and nocturia
• Hematuria is due to chronic papillary infarctions:
• Predominantly left-sided
• Renal infarction due to ischemia; may present with nausea, vomiting, abdominal and flank pain, and HTN
• Renal papillary necrosis due to ischemia; may cause secondary infection or obstruction
• Progressive renal failure and proteinuria due to glomerular injury; renal failure in ∼10%
• Renal medullary carcinoma:
– An aggressive malignancy
– Almost exclusively found in young African American patients with SC trait, or SC disease
ASSOCIATED CONDITIONS
• Acute papillary necrosis
• Anemia
• Hepatitis C and HIV (increased risk for these and other transfusion-associated infections)
• Priapism
• Renal medullary carcinoma
• Hyposthenuria (Urine with low specific gravity)
• Urinary tract infections
GENERAL PREVENTION
Avoid situations that precipitate sickling episodes (dehydration, hypoxia, cold, infections, fever, acidosis).
DIAGNOSIS
HISTORY
• Prior episodes of SC complications and outcomes
• Timing of sexual maturation (delayed puberty)
• Determine time length of any priapism episodes
• Painful crisis brought on by cold or dehydration
• Nocturnal enuresis
PHYSICAL EXAM
• HTN is unusual.
• Look for staging of sexual maturation.
• Palpate testes in men to check for atrophy.
• In cases of priapism, examine the glans to determine bi- or tricorporal involvement.
• Splenic sequestration causes painful enlargement of the spleen.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Complete blood count (CBC): Note degree of anemia
• Peripheral blood smear: Presence of sickled or deformed RBCs with high reticulocyte count
• Hb electrophoresis: Types and percentages of Hb present
• SC prep: Rapid determination of SC disease vs. trait vs. normal. Check fet al Hb level
• Urine analysis: Hematuria, proteinuria, or infection
• Urine culture: Infection if indicated by urine analysis or symptoms
• Serum creatinine
• Monitor for renal insufficiency, and calculate GFR as needed. The creatinine clearance may overestimate the GFR.
• Hyperphosphatemia may be present
• Blood Gas (BG) measurement on corporal blood aspirates in priapism setting to assess high- vs. low-flow state:
– pH <7.10 (acidotic) suggests a low-flow state.
Imaging
• CT urogram using low osmolar contrast, as indicated for hematuria:
– May not be useful in progressive renal insufficiency (poor concentrating ability limits visualization)
– Papillary necrosis may be present
• Renal medullary carcinoma may present as a centrally located infiltrative lesion invading the renal sinus with peripheral caliectasis
• US: Noninvasive; look for renal source of hematuria if renal insufficiency precludes contrast use
• MRI when indicated
Diagnostic Procedures/Surgery
• Cystoscopy: As needed for hematuria
• Retrograde pyelograms: Upper-tract sources of bleeding if IVP limited or suspect papillary necrosis
• Ureteroscopy: For hematuria as indicated
• Renal biopsy: As needed for specific glomerulopathies
• Impotence evaluation with duplex blood flow studies. (Preferred over nocturnal penile tumesence (NPT) monitoring).
Pathologic Findings
• Peripheral blood smear: Presence of sickled or deformed RBCs
• Penile corporal fibrosis seen in patients with stuttering or recurrent priapism
• Hb electrophoresis: Types and percentage of Hb present
• Renal biopsy:
– Early: Glomerular hypertrophy, hemosiderin deposits, focal areas of hemorrhage or necrosis
– Late: Interstitial inflammation, edema, fibrosis, tubular atrophy, and papillary infarcts
DIFFERENTIAL DIAGNOSIS
• Other SC diseases: SC trait, sickle-β thalassemia, etc.
• Hematuria (see Section I topic)
• Papillary necrosis (see Section I topic)
• Priapism (see Section I topic)
TREATMENT
GENERAL MEASURES
• For acute SC crisis:
– Oxygenation, nasal canula
– Aggressive hydration: Counters dehydration, increases perfusion, and improves blood rheology
– Metabolic alkalinization limits further sickling
– Pain control
– Narcotics for pain: Risk of addiction is negligible in the acute setting
Patient controlled analgesia (PCA) for inpatients
MEDICATION
First Line
• Simple transfusion:
– Transfusion performed to increase proportion of RBCs with normal Hb to decrease sludging
– Blood transfusion performed less liberally than in past because of risks of exposure to antigens
– Indications for transfusion:
Acutely: Persistent, recurrent priapism after failure of corporal irrigation, injection of vasoactive medications and other measures before shunting procedure or if life-threatening hemorrhage
Preoperative transfusion if significant anemia or if indicated by procedure
• Exchange transfusion:
– Used when needed to remove RBCs and replace with transfused blood products if simple transfusion fails
– Risk of cerebrovascular accidents with increased hematocrit, causing a relative hyperviscosity (ASPEN syndrome)
• Antibiotics: As needed for infections
• Hematuria:
– Diuresis with IV hydration is standard
– Alkalization decreases sickling and hematuria
– Aminocaproic acid is used to induce thrombosis and control persistent and threatening hematuria, but can cause clot formation in the urinary tract
– Persistent or life-threatening hematuria may rarely necessitate nephrectomy
– High-dose urea in selected cases
• Priapism (see Section I “Priapism”):
– Prompt corporal irrigation to induce detumescence and remove old clotted blood
– Use α-adrenergic agents for corporal injection to decrease inflow to corpora for detumescence
– Impotence due to fibrosis can be managed with penile prosthesis after 6 mo
• Delayed sexual maturation:
– Cautious supplementation of testosterone
Second Line
NA
SURGERY/OTHER PROCEDURES
May be needed in the acute setting for priapism or urinary tract obstruction due to sloughed papilla
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Follow-up and monitoring by hematologist
• Hydroxyurea
• α-Adrenergic medication (ie, pseudoephedrine) and low-dose PDE-5 inhibitors used for prevention of stuttering priapism
• Folic acid and penicillin in pediatrics
• Genetic counseling
Complementary & Alternative Therapies
NA
ONGOING CARE
PROGNOSIS
Several factors aside from genetic inheritance determine prognosis, including frequency, severity, and nature of specific complications.
COMPLICATIONS
• Nephropathy:
– Renal insufficiency
– Vaso-occlusion in renal medulla secondary to hypertonicity, inducing HbS sickling
– Progressive cortical infarction leads to CRF; average age of onset is 23 yr
– Hyposthenuria: Inability to maximally concentrate urine in the face of dehydration or vasopressin
– Usually associated with renal insufficiency; able to dilute urine
– Associated impairment of K excretion
Renal biopsy: Focal and segmental glomerulosclerosis, membranous glomerulopathy, or MPGN
Proteinuria can progress to full-blown nephrotic syndrome
• Hematuria:
– Microscopic or gross hematuria; mechanism unknown. Source rarely identified; possibly due to papillary necrosis
– Usually unilateral (left-sided)
– Male > female
– Usually remits with conservative measures (eg, bedrest, hydration) with 50% recurrence
• Papillary necrosis:
– Due to medullary ischemia from sickling in vasa recta (see in 40% of patients with SCD)
– Radiologic diagnosis can be difficult due to poor concentrating ability of kidneys
– Can cause hematuria
– Can obstruct, if sloughed papillae blocks the UPJ or ureter
• Priapism:
– Affects ∼66% of SC disease patients
– 2 age peaks; onset usually after puberty
– 5–13 yr, then at 21–29 yr
– Initiating factors: Nocturnal penile tumescence and sexual arousal
– Typically, bicorporal involvement
– Pathophysiology: Engorgement and sludging of the corpora, with no outflow and low flow
– Major risk is fibrosis and subsequent impotence; children have greater chance of recovery and subsequent erectile function
• Impotence:
– Fibrosis from recurrent episodes of priapism
• Delayed sexual maturation:
– Primary hypogonadism, due to testicular ischemia or infarction, hypopituitarism, or hypothalamic insufficiency
– Correlates with severity of sickle disease
• Infertility:
– Complication of hypogonadism and direct testicular insult by ischemia and infarction
• UTI:
– Usually Escherichia coli, or other gram-negative bacteria
– Can lead to more serious infections or bacteremia
• RTA:
– Incomplete distal RTA (type IV) from progressive medullary infarction
– Inability to lower urine pH to <5
– Can develop hyperchloremic metabolic acidosis in SC disease and renal insufficiency
– Not associated with nephrolithiasis
• Acute urinary retention:
– Related to acute, painful SC; transient, resolves with resolution of the acute episode
• Renal medullary carcinoma:
– Median age 13 yr
– High mortality
FOLLOW-UP
Patient Monitoring
• Renal function over time
• Regular follow-up
Patient Resources
• http://www.cdc.gov/ncbddd/sicklecell/freematerials.html
REFERENCES
1. Morrison BF, Burnett AL. Urological complications of sickle cell disease. AUA Update Series. 2012;31(29):289–296.
2. Panepinto JA, Bonner M. Health-related quality of life in sickle cell disease: Past, present, and future. Pediatric Blood Cancer. 2012;59(2):377–385.
3. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018–2031.
ADDITIONAL READING
• Levey HR, Kutlu O, Bivalacqua TJ. Medical management of ischemic stuttering priapism: A contemporary review of the literature. Asian J Androl. 2012;14(1):156–163.
• Brawley OW, Cornelius LJ, Edwards LR. National Institutes of Health Consensus Development Conference statement: Hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008;148(12):932–938.
See Also (Topic, Algorithm, Media)
• Papillary Necrosis, Renal
• Priapism
• Priapism, stuttering (intermittent priapism)
• Renal Medullary Carcinoma (Renomedullary Interstitial Cell Tumor)
CODES
ICD9
• 282.60 Sickle-cell disease, unspecified
• 599.70 Hematuria, unspecified
• 607.3 Priapism
ICD10
• D57.1 Sickle-cell disease without crisis
• N48.30 Priapism, unspecified
• R31.9 Hematuria, unspecified
CLINICAL/SURGICAL PEARLS
Urologic complications are common in SC disease.