Urologic manifestations of hematologic disease

Urol Clin of N Am 30 (2003) 49–61

Urologic manifestations of hematologic disease Sickle cell, leukemia, and thromboembolic disease Joseph A. Molitierno Jr, MD*, Culley C. Carson III, MD Division of Urology, 428 Burnett Womack Building, CB7235, University of North Carolina Medical Center, Chapel Hill, NC 27599, USA

Advances in medicine have allowed patients with sickle cell anemia, leukemia, and other hematologic disorders to live longer than ever before. With better understanding of the pathophysiology and molecular mechanisms of these disorders, medicine holds great promise to further improve the quality and duration of life of these patients. Adding years to these patients’ lives has not come without a price. The patients are developing manifestations of their disease in unrelated organ systems, including the urinary tract and reproductive organs. These new complications may be the result of the disease process itself or a side effect of the treatment. This article discusses the urologic manifestations of sickle cell anemia, leukemia, and thromboembolic disease. Sickle cell anemia The renal manifestations of sickle cell anemia were first noted by Herrick as early as 1910 [1]. Sickle cell anemia and its related hemoglobinopathies can cause a wide spectrum of urologic manifestations. These manifestations range from the benign inability to concentrate urine to an association with a highly malignant form of renal medullary carcinoma. To understand the urologic manifestations of sickle cell anemia, a brief review of the pathophysiology of the disease is needed. Normal adult hemoglobin is a tetramer that is composed of two alpha chains and two beta chains, each conjugated to a heme moiety. The sickle

* Corresponding author. E-mail address: [email protected] (J.A. Molitierno Jr.)

mutation is a single, base-pair substitution in the gene that results in the exchange of the native valine for a glutamic acid at the sixth amino acid position in the beta-globin polypeptide. By replacing an uncharged amino acid with a charged one, the solubility of the resultant hemoglobin is altered. The diminished solubility of the deoxy form of the mutant hemoglobin leads to its polymerization within the red blood cell and to distortion of the cell itself. It is this distortion that gives the sickle red blood cell its characteristic shape and provides an explanation for much of the clinical manifestations of the disease that we will discuss later. Sickle cell follows the classic Mendelian pattern of inheritance; each individual receives one copy of the gene from each parent. Sickle cell disease is comprised of those who are homozygous for the sickle betaglobin gene (genotype¼bS/bS). This homozygous form of the disease affects a predicted 1:650 black Americans and is characterized by the painful sickle crises and a greater number of systemic and urologic complications. Approximately 8% of black Americans carry a single mutant beta-globin gene that encodes the Sickle mutation [2]. These patients are heterozygous for the sickle mutation (genotype¼bA/bS), thus making them carriers of the sickle cell trait and typically characterized by a much milder form of the disease. Additionally, two other heterozygous conditions should also be mentioned under the category of sickle disorders including those who inherit the combination of the sickle b globin gene along with b globin C gene (bC) and sickle b-thalassemia. Hb SC (genotype¼bC/bS) disease affects patients who have inherited a sickle beta-globin gene and a b-globin gene that contains the C mutation (a lysine substituted for a glutamine at the sixth amino acid

0094-0143/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 4 - 0 1 4 3 ( 0 2 ) 0 0 1 1 9 - 2

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position). Patients with sickle b-thalassemia inherit a sickle beta-globin gene and a poorly expressed or unstable mutant beta-globin gene (b globinO), thus making their genotype bO/bS). The amount of normal beta-globin that is produced determines the severity of disease in these latter patients. The sickle cell nephropathies In 1974, Berman [3] identified six sickle cell nephropathies that affect patients with either sickle cell trait or disease. These nephropathies include gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, and pyelonephritis. In 1995, Davis et al [4] added the highly malignant renal medullary carcinoma as the seventh sickle cell nephropathy (Box 1). What follows is a discussion of each of these renal manifestations of sickle cell disease some consideration regarding pathophysiology and treatment options. Hematuria Hematuria is a common manifestation of sickle cell disease and sickle cell trait. The exact etiology of the hematuria is unknown; however, sickling of red blood cells and subsequent microthrombi formation in the peritubular capillaries of the renal medulla are thought to be the initiating event [5,6]. These microthrombi cause small areas of infarction and necrosis within the medulla. In response to the ischemic insult, capillaries become increasingly permeable and allow erythrocytes to leak into the collecting system. This hematuria may be secondary to papillary necrosis or renal medullary carcinoma, which will be discussed later. Patients with sickle cell hematuria may present at any age; those with sickle cell trait often present with painless, gross hematuria as their only symptom. The hematuria may occur from either kidney but when it is unilateral it arises from the left kidney in approximately 80% of cases [7]. The predominance of left-sided hematuria was ascribed to the higher pressure in the left renal vein secondary

Box 1. The sickle cell nephropathies Gross hematuria Papillary necrosis Nephrotic syndrome Renal infarction Hyposthenuria Pyelonephritis Renal medullary carcinoma

to its greater length and position, thus encouraging red cell stasis [8]. The hematuria is often recurrent, but usually benign and self-limiting in nature. Massive hematuria that is refractory to conservative management may occur with the sickle cell disorders. The diagnosis of sickle cell hematuria should only be entertained after all other causes have been excluded. Therefore, the initial workup of sickle cell hematuria should include urinalysis, urine culture, and cytology. Intravenous pyelogram and cystoscopy should be performed to complete the initial workup. Microscopic urinalysis may reveal the presence of sickle erythrocytes; however, the presence of the dysmophic erythrocytes is variable and dependent upon the status of disease and the anatomic point where the cells entered the genitourinary tract [9,10]. Blood work, including hemoglobin electrophoresis in patients who are suspected to have undiagnosed sickle cell trait, a coagulation panel, and a hematocrit, should also be obtained because these patients are already anemic at their baseline secondary to increased red blood cell destruction and a deficiency of erythropoietin. The management of hematuria is usually conservative. Initial treatment should include bed rest, and the maintenance of high urinary flow through oral hydration. Hematuria that lasts longer than 1 to 2 weeks or the need for transfusion necessitates further measures. These patients should be admitted to the hospital and treatment should include a high urinary flow that may be obtained by using a combination of hypotonic fluids and loop diuretics, in addition to urinary alkalinization that may be achieved using sodium bicarbonate and acetazolamide. These therapies are aimed at changing the acidic, hypertonic environment of the renal medulla that favors HbS polymerization. If bleeding persists for 72 hours despite the aforementioned treatment then alternative treatment should be considered. Pariser and Katz [11] successfully used oral urea in three patients with hematuria that was refractory to hydration and urinary alkalinization. Other treatments, including epsilon-amino caproic acid and vasopressin, were used for refractory sickle cell hematuria with inconsistent success. Embolization or nephrectomy should be reserved for prolonged, life-threatening cases of hematuria that require multiple transfusions. Papillary necrosis Papillary necrosis may affect patients with any of the sickle cell disorders and is a frequent cause

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of sickle hematuria. It is thought that papillary necrosis is the cumulative result of recurrent ischemic events caused by sickling within the vasa rectae of the medulla. These ischemic events are often subacute and the papillary necrosis is most often found as an incidental finding in asymptomatic patients [12]. Vaamonde [13] demonstrated that papillary necrosis affected approximately 15% to 36% of patients who were afflicted with a sickle cell hemoglobinopathy [13]. It is most commonly diagnosed in patients with sickle cell trait who are between 30 and 40 years of age [14]. The clinical presentation can be quite variable and range from an incidental finding in an asymptomatic patient to a floridly septic patient with obstruction secondary to sloughed papillae. Papillary necrosis may also present as a single or recurrent episode of gross hematuria with or without renal colic. The workup of papillary necrosis in a sickle cell patient should rule out other common causes including diabetes, analgesic abuse, pyelonephritis, urinary tract obstruction, and tuberculosis. Urinalysis, urine culture, and cytology should be obtained. Microscopic urinalysis may reveal erythrocytes and white blood cells. The urine should also be strained and examined for evidence of sloughed papillae. Although the diagnosis may be made from the presence of sloughed papillae, it is most often made using an intravenous pyelogram. The use of nonionic contrast agents for uroradiography is recommended by most sources to avoid the sickling caused by ionic compounds. The most common finding on IVP is a medullary type of partial papillary necrosis, that appears as cavitation within one or more of the renal papillae [15] with no evidence of cortical thinning (Fig. 1). Additionally, calcification may be seen in old areas of necrosis. The treatment of papillary necrosis caused by a sickle cell hemoglobinopathy does not differ from its treatment if caused by other diseases and is dependent upon the severity of the symptoms. Ureteral obstruction caused by a sloughed papilla and urinary tract infection is a surgical emergency. Prompt relief of the obstruction with a retrograde ureteral stent or placement of a percutaneous nephrostomy tube is essential. Moreover, initial treatment with broad-spectrum antibiotics is also important to treat impending pyelonephritis and avoid the development of sepsis. The necrotic tissue may serve as a nidus for persistent bacterial infections and obviates the need for endoscopic removal Additionally, nonsteroidal anti-inflammatory agents should be avoided in any patients with pap-

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Fig. 1. Intravenous pyelogram that demonstrates bilateral severe renal papillary necrosis caused by sickle cell disease.

illary necrosis so as not to exacerbate the situation. The treatment of hematuria associated with papillary necrosis should be conservative as described in the previous section. Herard et al [15a] described a case of massive hematuria in a 20-year-old male that was associated with papillary necrosis and was successfully tamponaded using a balloon ureteral catheter. Papillary necrosis is a spectrum of disease and some patients may chronically pass small fragments of necrotic tissue and require no treatment. In a study by Powars [16], it was found that renal papillary necrosis was not associated with an increased incidence of renal failure. Proteinuria, nephrotic syndrome, and renal failure Proteinuria has been found in 20% to 30% of patients with sickle cell disease [17]. Although the etiology of sickle cell proteinuria remains undefined, it is thought to be related to increased pressure in the glomerular capillary secondary to microvascular obstruction [18]. Studies on adults and children with sickle cell proteinuria demonstrated a significant reduction in proteinuria using angiotensin-converting enzyme inhibitors. It is thought that ACE inhibitors decrease afferent arteriolar tone which leads to a decrease in the glomerular pressure and subsequent reduction in proteinuria. Other factors that have been implicated in the development of proteinuria include hyperfiltration injury, mesangial phagocytosis of sickled cells, and immune complex glomerulonephritis. Nephrotic syndrome (a complex characterized by proteinuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria, and hypercoagulabilty) is frequently the next step in the progression of the sickle cell glomerulopathy. Unfortunately,

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nephrotic syndrome is a significant predictor of renal failure in patients with sickle cell disease [16]. The development of renal failure in patients with sickle cell and nephrotic syndrome may be inevitable. The rate at which these patients progress to renal failure may be dependent upon genetic associations that have not yet been fully elucidated. Although we cannot determine which patients will progress to renal failure, Powars [16] demonstrated that the manifestations of hypertension, proteinuria, hematuria, increasing anemia, and nephrotic syndrome reliably predict progression to renal failure. Approximately 40% of those who progressed to renal failure developed nephrotic syndrome during the course of their disease. Suprisingly, neither hypocalcemia, urinary tract infection, prior history of acute renal failure, nor renal papillary necrosis were associated with progression to renal failure. It is unclear whether long-term treatment with ACE inhibitors might slow or halt the progression of proteinuria to nephrotic syndrome and subsequent development of renal failure. It is clear that these patients deteriorate very rapidly after the onset of ESRD, with a mean survival of approximately 4 years, despite dialysis. Acute renal failure was reported as a complication in up to 10% of patients who are hospitalized with sickle cell disease [19]. This manifestation is not usually a complication of the sickle cell nephropathy, but is usually a complication of the systemic nature of the disease. Acute renal failure has been associated with hypovolemia, sepsis, hepatorenal syndrome, cardiac failure, renal vein thrombosis and rhabdomyolysis. These patients typically survive and recover their renal function with no increased risk of developing chronic renal failure. Sickle cell disease is not a contraindication to transplantation; renal transplant has become a viable treatment option. Hyposthenuria and other renal tubular abnormalities The inability to maximally concentrate urine (hyposthenuria) in response to water deprivation may be the first finding of sickle cell nephropathy. Hyposthenuria affects patients with sickle cell disease and sickle cell trait; however, the former is affected at an earlier age and more severely. The ability to concentrate urine is dependent upon the counter-current exchange mechanism that exists between the loops of Henle and the medullary blood vessels known as the vasa rectae. In the renal medulla free water leaves the tubules and enters the hypertonic medullary interstitium,

thus concentrating the urine. The environment of the vasa recta (because of its low oxygen tension, acidic pH, and hyperosmolar nature) is conducive to HbS hemoglobin polymerization and subsequent erythrocyte sickling. Hyposthenuria is the cumulative result of recurrent microinfarcts in the vasa recta due to sickling. Microangiographic studies demonstrated a nearly complete loss of the medullary vasa recta which impairs the ability to establish counter-current exchange and concentrate urine [20]. These patients can concentrate urine under normal circumstances because of the relative sparing of the outer medullary nephrons and have no inability to dilute their urine. Under circumstances of water deprivation, however, patients with sickle cell anemia cannot maximally concentrate their urine and may experience hypovolemia and dehydration. Several other abnormalities of renal tubular dysfunction have been found in patients with sickle cell anemia. Under circumstances of mild renal insufficiency these patients may develop an incomplete form of distal renal tubular acidosis. This may manifest itself as hyperchloremic metabolic acidosis [21]. Concomitantly, these patients develop a defect in potassium (Kþ) excretion that is not evident under normal conditions. This manifestation is usually not clinically relevant because these patients do not develop hyperkalemia except in circumstances of renal insufficiency. These patients have supranormal renal hemodynamics that may be responsible for maintaining their glomerular function. Early in life, patients with sickle cell disease have an elevated effective renal plasma flow (EFPF) and glomerular filtration rate. These both gradually decline during the patient’s lifetime and reach subnormal levels sometime after adolescence. It is thought that these supranormal hemodynamics are mediated by prostaglandins. NSAIDs adversely affect EPRF and GFR in patients with sickle cell disease [22]. Patients with sickle cell anemia exhibit an increased proximal tubular secretion of creatinine. Thus, patients may have a significant decline in renal function before it is detected by measuring creatinine clearance. Urinary tract infection and pyelonephritis Patients with sickle cell disease are at a higher risk for urinary tract infections (UTIs) and pyelonephritis than the general population. In a survey of 321 pediatric patients, Tarry et al [23] found that 9% were affected by urinary tract infection, a rate nearly five time higher that that reported

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for the general pediatric population [50]. Of these patients two thirds of the UTIs were febrile, one third were recurrent, and a 10:1 female to male ratio was noted. In a study of the pediatric population by Karayalcin et al [24], a 17% incidence of pyelonephritis was reported; this is three times higher than the incidence rate in the general population [24]. There are little data about the presence of vesicoureteral reflux in these studies, but it is known that vesicoureteric reflux is rare in the black population. Although sickle cell disease and asplenia are associated with a higher incidence of infection with encapsulated organisms, Escherichia coli is the uropathogen in most cases. Septicemia is a rare, but serious, complication of UTIs. Zarkowsky et al [25] found that the mortality rate of bacteremic patients who were younger than 3 years of age was nearly 20%. Urinary tract infection was the most frequent cause of E coli bacteremia across all age groups. The incidence of E coli bacteremia increases with age; it is responsible for 40% of cases of bacteremia in patients older than 20 years. Although UTI is a significant source of bacteremia in the adult population, only 3% of those who present to the emergency room for an acute pain crisis have a positive urinalysis [26]. The workup of UTI in the pediatric patient with sickle cell disease should be complete. Although there are no data to suggest that reflux is associated with UTI in this population, a baseline renal ultrasound should be performed (or IVP for older children). If an abnormality is found, then a voiding cystourethrogram may be indicated to rule out reflux. Persistent urinary tract infections may be secondary to renal papillary necrosis. All urinary tract infections in this patient population should be considered complicated UTIs and should be treated for 10 to 21 days with appropriate antibiotics based on culture results. Acute pyelonephritis is a clinical diagnosis and should be treated for a full 21-day course. Initial treatment should consist of broad-spectrum, parenteral antibiotics followed by oral antibiotics if the patient is afebrile. Renal medullary carcinoma In 1995, Davis et al [4] identified the association between the sickle cell trait and a highly malignant form of renal medullary carcinoma. Thirty-three patients with these tumors were identified and had mean age at presentation of 21 years. These patients most commonly presented with gross hematuria, abdominal and or flank pain, or significant weight loss. At the time of diagnosis more than

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70% had known metastasis. All patients died of the disease, with a mean duration of survival of only 15 weeks after nephrectomy. Lymphatic or vascular invasion was present in all of the surgical specimens. In a recent review by Bruno et al [18], they noted a total of 62 reported cases that further strengthened this association with sickle cell trait and the highly malignant character of the disease. No study has found an association of renal medullary carcinoma with sickle cell disease and only a weak association has been found with sickle C disease. The etiology of renal medullary carcinoma is unknown. The tumors are thought to arise from the proliferating cells of the collecting duct epithelium. Further work is needed to better define these tumors and their lineage. The diagnosis of renal medullary carcinoma must be considered in all patients with sickle cell trait and hematuria. Unfortunately, the presence of gross hematuria is very common in patients with sickle cell trait and even presents in the same age range. Renal medullary carcinoma has a predisposition for the right kidney, whereas unilateral gross hematuria occurs occurs on the left. These associations are not absolute; all cases of hematuria in patients with sickle cell anemia must be evaluated with the proper imaging and urine cytology. There is no successful treatment for this disease. Reports of aggressive chemotherapy and radical surgery have failed to stop the development of metastases or extend life expectancy. Only one patient survived for longer than 1 year [27]. Priapism Sickle cell disorders account for approximately 28% of all cases of priapism [28]. Priapism is a condition that is characterized by unwanted, sustained erection that does not result from sexual desire and is not relieved by sexual activity. Stuttering priapism is a separate entity that is characterized by multiple, brief episodes of sustained, unwanted erection. In a review of reported cases of priapism since 1934, Hamre et al [29] found a bimodal age of initial onset; the first peak occurred between 5 and 13 years and the second peak occurred between 21 and 29 years. Of these cases, 77% occurred during sleep, 17% occurred with sexual activity, 3% occurred with alcohol excess, and 3% occurred spontaneously. The majority of the published cases involved sickle cell disease, however patients with sickle cell trait comprise 14% of the reported cases. Nearly all priapism that occurred in patients with sickle cell anemia was described as ischemic,

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or low-flow, priapism. It is thought that every case of priapism begins with a physiologic erection. The relative stasis of blood within the corpora leads to a decrease in oxygen tension and development of acidosis. These conditions are conducive to HbS polymerization and sickling of erythrocytes within the corporal sinusoids. This sickling causes subsequent venous occlusion and priapism. The higher incidence of priapism during sleep is thought to be caused by physiologic dehydration and the mild acidosis that accompanies hypoventilation. Additionally, the venous channels are compressed during nocturnal detumescence, aiding in their obstruction. High-flow priapism, which is caused by unregulated arterial flow was described in several case reports of sickle cell patients, but will not be discussed here. If there is a doubt whether the priapism is low-flow or high-flow, a blood gas obtained from the corpora should aid in the diagnosis. Priapism is a urologic emergency and future potency depends upon timely diagnosis and detumescence. Physical examination reveals rigid corpora, but flaccid glans and corpus spongiosum. Rigidity of the glans and spongiosum are a poor prognostic indicator. Initially the erection is painless; however, pain develops as the corpora become increasingly ischemic around 4 hours. The goal of treatment is to avoid fibrosis of the corpora and maintain potency. Bertram et al [30] reported a 72% potency rate in patients who received treatment in less than 48 hours, compared with 19% in patients who delayed treatment for 3 days or longer [30]. In a more recent study, Powars and Johnson [31] determined that detumescence within 12 hours was optimal to retain potency. Hamre et al [29] found a 94% potency rate with conservative treatment compared with 58% potency rate in those who required surgical intervention. This may be misleading, however, because only the most severe cases may have required surgery. Taking these data into consideration, initial treatment should be prompt and conservative. Other causes of priapism, such as iatrogenic, traumatic, neoplastic, and neurogenic etiologies, should be ruled out. If the examination is inconclusive and low flow priapism cannot be distinguished high flow priapism, a corporal blood gas or penile duplex Doppler may be obtained. Medical treatment should be directed at reversing the primary cause of priapism. Supplemental oxygen, pain relief, aggressive hydration with hypotonic fluids, and alkalinization should be administered to prevent further sickling. Irrigation and injection with

an alpha-adrenergic agonist should be employed as soon as possible in patients who present less than 36 hours from the onset of priapism. This should be performed after penile anesthesia (dorsal nerve block, circumferential penile block, or subcutaneous, local, penile shaft block) has been established. All pediatric irrigation should be performed under conscious sedation. Alpha-adrenergic agonists were reported not to work after 36 hours after onset of priapism. Hypertransfusion should be reserved for cases that are refractory to the initial, conservative management. The use of hypertransfusion was associated with cerebrovascular accidents in the form of the ASPEN (association of sickle cell disease, priapism, exchange transfusion, and neurologic events) syndrome [32]. There are no existing guidelines about the timing of surgical intervention for refractory priapism. Although the initial reports indicated poor potency rates following shunting procedures, a more recent report by Chakrabarty et al [33] demonstrated excellent potency with early shunting. Based on the available data, shunting should be reserved for patients who fail 24 to 48 hours of medical treatment. Treatments intitiated after 72 hours may have the benefit of relieving the unwanted erection, but will most likely have little effect on preserving potency. Several strategies were used in the treatment of recurrent priapism in sickle cell patients. The selfadministration of alpha-adrenergic agonists, such as etilefrine and phenylephrine, was an effective option [34]. Hydroxyurea was also reported to be effective in at least one case report, however, further studies are needed [35]. Other investigators successfully used chronic transfusion in an effort to prevent priapism. Treatment with antiandrogens, such as diethylstilbesterol or a gonadotropin-releasing hormone agonist, may be useful if sexual function is not a concern. The complications of priapism are primarily related to potency. Thirteen percent of the 169 patients with sickle-related priapism who were reviewed by Hamre et al [29] were impotent. It is currently thought that corporeal ischemia that is caused by erythrocyte sickling induces a local inflammatory response. This inflammatory response leads to the replacement of the corporeal tissue by fibrosis and subsequently results in impotence. Burnett et al [36] demonstrated that the loss of potency was variable among patients with a history of priapism. Patients with a history of multiple episodes of priapism and significant corporeal fibrosis may report fair erections and maintain

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active sex lives. Predictors of impotence seem to include duration of priapism and postpubertal age at initial episode. Testicular infarction Testicular infarction is a very rare complication of sickle cell disease and sickle cell trait. Only three cases have been reported in the literature. It is the result of a vaso-occlusive or thrombotic event secondary to HbS polymerization. Patients with testicaulr infarction presented with nonspecific symptoms of testicular pain and scrotal swelling. Evaluation of the testicular pain should include a thorough workup and be highly dependent upon the physical examination. The work-up should rule out torsion, neoplasm, and infectious etiologies including epididymitis and epididymo-orchitis. Doppler ultrasound with flow might aid in the diagnosis if the examination is unequivocal. Cancer markers should be obtained for any suspected mass. Although all of the reported cases resulted in orchiectomy, theoretically they might have been managed nonoperatively with oxygenation, hydration, exchange transfusion, antibiotics, analgesics, and scrotal support. Suspicion of malignancy and the shortened convalescence make orchiectomy a viable option.

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with the exception of the use of exchange transfusion. The goal should be detumescence within 12 hours to maintain potency. Initial nonsurgical management should be employed. Persistent attempts at corporeal irrigation should be discouraged because of the altered blood counts and platelet dysfunction that are often present in these patients. Oncology consultation may be required for urgent chemotherapy to decrease circulating leukemic cells. Urolithiasis

Leukemia is a disease that is characterized by abnormal development and proliferation of white blood cells and their precursors. In a study performed before the advent of chemotherapy, Watson et al [37] found nearly 57% of leukemic patients had some form of genitourinary involvement at autopsy. Now as leukemic patients live longer, we are seeing the genitourinary manifestations of the disease and its treatment. A review of the urologic manifestation of leukemia and its treatment is presented.

Patients with leukemia are at an increased risk for the development of hyperuricemia and hyperphosphatemia. Uric acid and phosphate are byproducts of cellular degradation. Chemotherapy causes rapid cellular turnover and liberates a large amount of nucleic acids and cellular proteins. The resulting purines are converted to uric acid that is excreted in the urine, resulting in hyperuricosuria. Oversaturation of the urine and an acidic urine pH may lead to subsequent stone formation. Uric acid stones are radiolucent and will be missed with plain radiographs. Examination of the urine may reveal uric acid crystals. Treatment should include alkalinization of the urine to a pH between 6.5 and 7.0, hydration, and the initiation of allopurinol. This drug inhibits the formation of uric acid and treats the hyperuricosuria. Allopurinol and urinary alkalinization are now routinely started with the initiation of chemotherapy. Calcium stones have been reported as a rare complication of the leukemic patient. Pui et al [39] identified only 5 cases in 2,457 patients who were treated for leukemia. This may not represent the true frequency of urolithiasis, however, because only symptomatic patients were screened. Corticosteroids and bed rest are known risk factors for calciuria and might contribute to stone formation in the leukemic patient.

Priapism

Leukemic infiltration and tumor compression

Priapism affects up to 5% of adults with leukemia. It is a very rare occurrence in the pediatric population, but of the reported cases, more that half are associated with chronic granulocytic leukemia [38]. The etiology of priapism in leukemic patients is unknown; it is believed that it may be the result of sludging of leukemic cells within the venous sinusoids of the corpora. Management of priapism in leukemic patients should be similar to that described for sickle cell

Leukemic infiltration or compression may occur at any point along the urinary tract. The kidney is the most frequently involved organ; evidence was found in 63% of autopsies [40]. Infiltration of the kidney is most often asymptomatic; only 13.5% of patients present with flank pain and hematuria [37]. The prostate is the second most commonly affected urologic organ. Terris et al [41] reported that as many as 1.2% of patients who underwent radical prostatectomy were

Leukemia

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subsequently diagnosed with a hematolymphoid malignancy. These patients may present with obstructive voiding symptoms and prostatic enlargement. Testicular infiltration is a common site of extramedullary relapse in children with acute lymphocytic leukemia. In one autopsy study, 70% of pediatric patients with ALL had microscopic evidence of testicular infiltration [42]. Other sites of infiltration include the ureter, bladder, and rarely, the penis. Extrinsic compression of the urinary system that causes obstruction was reported in patients with leukemia. This is most often ureteral obstruction caused by a leukemic infiltration of nodes or adjacent viscera. Persky et al [42a] presented an unusual case of leukemic infiltration of the uterus that caused unilateral ureteral obstruction in a child. The granulocytic sarcoma is another tumor that is involved in urinary tract obstruction in patients with leukemia. It is a myelogenous tumor that is present in up to 8% of patients with granulocytic leukemia. Granulocytic sarcoma may present as a retroperitoneal mass or may be involved with the prostate, bladder, kidney, and spinal cord [43]. Leukemia is a systemic disease and should be treated as such. Any obstruction of the collecting system should be relieved immediately by placement of retrograde or percutaneous stents. Bleeding that is associated with bladder and ureteral infiltration must be controlled. Severe hemorrhage that is refractory to medical management was reported. This uncontrolled hematuria may require radiation or embolization; in some cases, urinary diversion may be necessary. In the stable patient in whom a mass is identified, diagnosis should be confirmed by open or percutaneous biopsy. Initiation of appropriate chemotherapy and use of local radiation should be used to reduce the tumor burden and alleviate symptoms. Urologic complications of chemotherapy and radiation The chemotherapeutic agents that are commonly used in the treatment of leukemia have multiple genitourinary side effects. These effects include urolithiasis, hemorrhagic cystitis, an increased risk of urothelial carcinoma, and testicular dysfunction. Hemorrhagic cystitis is a common side effect of cyclophosphamide, a common alkylating agent that is used to treat leukemia. Acrolein is the active metabolite of cyclophosphamide and is the agent

responsible for necrosis of the urothelium. The resulting hemorrhagic cystitis may be severe and necessitate cystotomy or cystectomy with urinary diversion. Mesna, is often given in conjunction with cyclophosphamide because it has the ability to detoxify acrolein in the urine. Cyclophosphamide was implicated with the development of bladder cancer and its use necessitates routine monitoring with cystoscopy and cytology. Hemorrhagic cystitis might also be caused by other agents, such as ifosfamide, bleomycin, and doxorubicin. Testicular dysfunction that results in infertility has long been recognized as a complication of chemotherapeutic agents. The use of combination drug regimens has made it difficult to determine which agents are cytotoxic to the gonads. The alkylating agents have been implicated in the development of infertility. There are variable opinions about the relationship between age at onset of chemotherapy and fertility. A study by Hensle et al [44] found no correlation with age, but reported that 80% of patients had a significant drop in their fertility index on biopsy across all age groups. Cryogenic sperm banking should be offered to all male patients before the initiation of chemotherapy to circumvent future fertility issues. Histologic changes included interstitial fibrosis and thickening in the basement membrane of the seminiferous tubule. During chemotherapy, levels of follicle stimulating hormone increase as testicular dysfunction develops. Return of FSH to normal usually predicts the recovery of spermatogenesis. It may also be appropriate to advise these patients to avoid conception until their diagnosis is more certain. Radiation exposure may also have adverse effects on the genitourinary system. Retroperitoneal fibrosis is a common complication of radiation exposure. Patients may be asymptomatic, but may present with flank pain. Radiology demonstrates hydronephrosis usually with medial displacement of the affected ureters. Initially, these patients require decompression of their urinary system. The long-term management of these patients is dependent upon their prognosis, performance status, and patient choice. Ureterolysis is not a benign procedure. If prognosis is poor, then management with percutaneous nephrostomy or indwelling ureteral stents are viable options. Corticosteroids have also been demonstrated to be useful in some instances. Ureterolysis should be reserved for those patients with favorable prognosis.

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Thromboembolic disease Thromboembolic disease causes a wide spectrum of complications in the genitourinary tract. These complications range from urinary obstruction secondary to thrombus formation to bilateral renal infarction. They affect all age groups and carry with them a significant morbidity and mortality. In this brief review we present some of the more common causes of thromboembolic disease and its pathophysiology. Antiphospholipid antibody syndrome The antiphosphospholipid antibody syndrome (APS) is the most common hypercoagulable disorder. For the most part it is an acquired disorder that has been associated with a variety of collagen vascular disorders, medications, and infections. APS is the result of antibodies that bind plasma proteins that have an affinity for phospholipid surfaces. The hypercoagulable state develops because these proteins include prothrombin, activated protein C, and activated protein S. Additionally, antiphospholipid antibodies were demonstrated to activate endothelial cells which theoretically leads to production of adhesion molecules and subsequent thrombus formation [45]. APS may be subdivided into two distinct syndromes. The syndromes include the anticardiolipin antibody syndrome, which is the most prevalent, and the lupus anticoagulant syndrome. The incidence of genitourinary complications associated with APS is not clear. APS was associated with arterial and venous thrombosis of the renal vessels and renal artery stenosis. Treatment of APS is beyond the scope of this article, but for an excellent review on the management of thrombosis in APS please refer to Petri [46]. Hereditary hypercoagulable syndromes Over the past several decades, the origin of many of the hypercoagulabilty syndromes was elucidated. These disorders are correctly identified in more than 80% of cases. Many of these disorders are clinically silent and only manifest themselves as the result of an initiating event, such as surgery. Factor V Leiden mutation is the most prevalent hereditary blood coagulation disorder that produces a hypercoagulable state. This mutation causes Factor V to become resistant to inactivation by activated Protein C. It is the cause of renal vein and artery thrombosis. Additionally, a 50-fold increase in venous thrombus formation was found

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in oral-contraceptive users with Factor V Leiden mutation [47]. Activated Protein C and S deficiencies and antithrombin III deficiencies were reported to be associated with renal vein thrombosis. Pregnancy Pregnancy and the initial postpartum period have long been known to be associated with an increased thrombotic tendency. Most commonly this manifests itself in the form of deep vein thrombosis. The DVTs may then shower small emboli into the venous circulation and eventually cause pulmonary embolus and renal vein thrombosis. Mansi [48] reported one case of spontaneous renal infarction caused by renal vein thrombosis in a 36year-old with no evidence of DVT [48]. Additionally, ovarian vein thrombosis occurs at a rate of approximately 1 in 2000 pregnancies. This has a propensity for the right side and often presents as right lower quadrant pain and fever, often mistaken for appendicitis. It is of importance to the urologist because right ureteral obstruction may result from extrinsic compression of this thrombosed vessel. Computed tomography is the study of choice; however, pelvic ultrasonography with duplex Doppler ultrasound might prove helpful in the initial diagnosis [49]. Treatment should include relief of obstruction, antibiotics to prevent the development of septic thrombophlebitis, and anticoagulation. Neoplasm Clinical thrombosis occurs in 15% of all patients with an occult malignancy; as many as 50% of patients with cancer will have evidence of thrombosis at autopsy [50]. A thorough laboratory investigation will uncover an identifiable clotting abnormality in most of these patients. The pathogenesis of the hemostatic disorder is complex and involves the interaction between multiple mechanisms. Tumors were shown to synthesize peptide and polypeptide mediators that promote clotting. Among these mediators are procoagulant molecules, tissue factors, cancer procoagulant, fibrinolytic molecules, and cytokines [51]. Direct cellular interactions that involve the tumor cell surface activate endothelial cells, platelets, and monocyte-macrophages. Additionally, extrinsic compression of venous channels by tumor mass and narrowing of the vessel lumen within the tumor may cause stasis and subsequent thrombus formation. Moreover, stasis that is secondary to immobilization is more of a factor in patients with

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cancer and may further contribute to the increased incidence of thromboembolic disease. The association of thromboembolism and prostate cancer is well-established. Oefelein et al [52] found that 5.7% of men with prostate cancer had an antecedent history of thromboembolism compared with only 1.1% of those who were diagnosed with benign prostatic hyperplasia. Surprisingly, the mean interval between the thromboembolic event and the diagnosis of prostate cancer was more than 10 years. The long interval was attributed to the indolent nature of prostate cancer; a potential of 39 years duration from the initiation of oncogenesis to the development of a palpable tumor was predicted. The exact mechanism that underlies this thromboembolic state is unknown. Nakashima et al [53] demonstrated that tumor necrosis factor might play a pathogenic role in the coagulopathy, at least in the later stages of prostate cancer. Additionally, Henriksson et al [54] showed an increase in factors VII and VIIIc in patients with advanced prostate cancer. The occurrence of an antecedent thromboembolic event was not demonstrated to be a significant prognostic indicator in the progression of prostate cancer [52]. Moreover, the Veteran’s Administration trial demonstrated that the use of prophylactic coumadin in patients with prostate cancer patients was not beneficial [55]. Membranous nephropathy and nephrotic syndrome The nephrotic syndrome has long been linked with the development of renal vein thrombosis. The hypercoagulable state of nephrotic syndrome is thought to result from a loss of antithrombin III in the urine, thrombocytosis with platelet hyperaggregability, decreased fibrinolytic activity, and alterations in other factors in the clotting cascade. A review of the published case reports by Zuchelli [56] found that 42% of all patients with nephrotic syndrome had thromboembolic complications. Moreover, there is an increased risk of renal vein thrombosis if the nephrotic syndrome is the result of membranous nephropathy. Renal vein thrombosis is found in as many as 10% of patients with nephrotic syndrome and membranous nephropathy. The classic presentation of flank pain and gross hematuria is rarely seen. Minimal symptoms should prompt an abdominal ultrasound with Doppler flow study because of the increased risk of renal vein thrombosis in these patients. Other causes of nephrotic syndrome,

including lupus nephritis, amyloidosis, and membranoproliferative glomerulonephritis were also associated with renal vein thrombosis. Neonates Several factors contribute to thromboembolic disease in infants and children. Dehydration, sepsis, maternal insulin use and Factor V Leiden mutation were all associated with renal vein thrombosis. Zigman et al [57] found that the classical presentation of palpable mass, gross hematuria, and thrombocytopenia was present in only 13% of cases. The optimal treatment has yet to be determined. Neonatal polycythemia was also implicated in vascular thrombus formation and testicular infarction [58]. Vascular thrombus is secondary to the hyperviscosity of blood as the hematocrit rises above 60%. Subsequent venous and arterial sludging of the blood results in vessel occlusion and ischemia. Neonatal testicular infarction presents as a painless, ecchymotic mass within the scrotum. These cases are usually attributed to torsion; however, venous hematocrit may reveal polycythemia as the underlying cause. Early postnatal diagnosis and treatment with reduction exchange transfusion may save the contralateral testicle and prevent further vascular thrombus formation. Henoch-Schonlein purpura The involvement of Henoch-Schonlein purpura (HSP) with the genitourinary system warrants its discussion, although it is not strictly a thromboembolic disease. It is a disease of unknown etiology that is characterized by a diffuse vasculitis that involves the skin, joints, intestinal tract, and kidney. Patients typically present with a purpuric rash, arthralgia, abdominal pain, and often, hematuria. The urologic manifestations of this disease include nephritis, orchitis, and ureteritis. HSP nephritis often presents as benign, selflimiting hematuria that usually resolves without sequelae. Severe hemorrhage that required nephrectomy was reported, however [59]. Additionally, a small number of these patients will develop progressive renal failure. The manifestation of HSP as acute orchitis is well-known. The presentation often mimics that of torsion, with sudden onset, testicular swelling, and pain. There are no definitive physical examination findings that differentiate HSP orchitis from torsion. To further complicate clinical decision-making, testicular torsion was described in one patient with HSP and acute scrotal pain [60]. Although some investiga-

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tors advocated the use of imaging studies, such as Doppler ultrasound or nuclear perfusion, torsion is a clinical diagnosis and suspected torsion should be explored. If torsion is not a consideration based upon the examination, then conservative management using corticosteroids and supportive measures are indicated.

Summary Advances in medicine are allowing patients with hematologic disease to live longer and healthier lives than ever before. As these patients age, however, manifestations of their disease processes may develop as complications in other organ systems. We discussed the major genitourinary complications of sickle cell anemia, leukemia, and thromboembolic disease. These range from the benign inability to concentrate urine that is seen in sickle cell disease to renal infarction that results from nephrotic syndrome. Our ability to treat and prevent these complications will improve as our understanding of these disease processes and their pathophysiology grows. Additionally, it is important for urologists to understand the underlying pathophysiology of hematologic disease to best serve the patients. For example, it may be the urologist who makes the diagnosis of ovarian vein thrombosis in a pregnant woman with right lower quadrant pain and fever. This diagnosis, with the proper treatment of antibiotics and anticoagulation, could prevent the potential development of septic thrombophlebitis. Urologists will increasingly be called upon to deal with the manifestations of these complex diseases as these patients are living longer. It is our duty to educate ourselves about these disease processes so that we can make the best clinical decisions for our patients.

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