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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 148Urologic Complications

, MD and , MD.

The appropriate anticipation and management of urologic complications of cancer and its therapy may significantly improve the opportunity for the treatment of patients with metastatic disease. The management of obstructive uropathy, the criteria for detection of drug-induced renal toxicity, and the management of such toxicity without excessive dose reduction are important ingredients that contribute to the successful treatment of cancer patients. Adjustment of the dose of different chemotherapeutic agents on the basis of renal function and interaction with other agents that may be delivered concomitantly is an essential component of oncologic practice. This brief chapter will review the most frequent urologic complications of cancers and therapy.

Complications Resulting from Primary Cancer Progression

Urinary Tract Obstruction

Obstruction of the urinary tract may occur at multiple levels (ureter, bladder, and urethra). Large retroperitoneal tumors may result in ureteral obstruction, whereas urethral and outlet obstruction occurs from cancers involving the bladder, distal urethra, or prostate. Such involvement can be by direct extension, encasement, or invasion of these structures. Obstruction can also occur from metastatic deposits involving these same sites. The course and management of obstructive uropathy are determined by the primary tumor causing the obstruction. Factors which influence the treatment of obstructive uropathy include the anticipated benefit from therapy and the curability of the patient, sensitivity of the neoplasm to cytotoxic therapy, rapidity of response to therapy, and anatomic access to the obstruction. The development of newer imaging techniques that allow early discovery and therapy has reduced the need for extensive surgery to palliate distal ureteral obstruction.

Ureteral Obstruction

Ureteral obstruction most commonly occurs because of large periaortic nodal metastases in the retroperitoneal space adjacent to the ureters. Such obstructive uropathy is most frequently the result of either primary nodal diseases (lymphomas) or of urologic neoplasms metastasizing to the periaortic nodes, particularly prostate cancer and germ cell tumors. Advanced retroperitoneal germ cell tumors and lymphomas are a unique subset of chemotherapy-sensitive tumors that frequently result in obstructive uropathy. These cancers best illustrate the different approaches that can be used to treat a particular urologic complication produced by different tumors. When the cancer has the typical pathologic and serologic markers of a seminoma, obstructive uropathy is frequently observed with regionally advanced disease, in the absence of distant metastases. Radiation therapy or chemotherapy can relieve obstruction rapidly without requiring percutaneous nephrostomies. An equally curable germ cell tumor, teratoma, is less likely to exhibit a rapid, gratifying reduction in size. Percutaneous nephrostomy is needed to ensure adequate renal function during cisplatin-based chemotherapy. Surgical resection of the teratoma can then follow. In both instances, high cure rates can be achieved.1,2 The rapidity of the anticipated response and the degree of compromise in renal functional often govern whether percutaneous nephrostomy is necessary or whether a reasonable expectation exists that relief of obstruction can be achieved with cytotoxic chemotherapy. Similar approaches can be used for the treatment of lymphomas in which one can anticipate a rapid response to therapy. For curable cancers that require cisplatin-based therapies, particular attention to the prompt reversal of obstructive uropathy is important to permit renal excretion of the drug. Although a unilateral percutaneous nephrostomy may preserve adequate renal function, patients whose long-term disease-free survival is dependent on cisplatin-based therapy require maximal preservation of renal function. Bilateral percutaneous nephrostomy is often required in these settings.

In most patients with acute urinary tract obstruction treated with urinary diversion, retrograde stent placement is attempted initially. Large prostate or bladder tumors, multiple sites of ureteric obstruction, long occlusions, or a tortuous ureter may be indications to directly proceed with percutaneous nephrostomy.3 During nephrostomy tube placement, the intrarenal collecting system must be properly imaged to select a site of renal entry. Unless the patient is azotemic or allergic to contrast material, the site of entry can be best determined fluoroscopically after intravenous urographic contrast. In experienced hands, an appropriate nephrostomy tract can be established in 98% of cases, with major complications occurring in about 4%.4 Major complications include renal hemorrhage requiring transfusion (1–3%), vascular injury (0.5–1.0%), sepsis (1–2.5%), bowel injury (0.1%), lung injury (0.5–1.0%), and mortality (0.046–0.3%).3 After the intrarenal collecting system and dilated ureter are allowed to decompress, an internal double “J” stent is placed, if cystocopic management of the stent is anticipated. This is performed in an antegrade fashion using the nephrostomy. When cystoscopic management of the stent is inadequate or the stent fails rapidly after placement, permanent percutaneous nephrostomy with external drainage or an internal–external stent is preferred. Complications from such procedures may include infections, tube obstruction, and dislodgement.

Ureteral obstruction due to retroperitoneal metastases from cervical or breast cancer, or from retroperitoneal radiation fibrosis, is often treated by stenting. The decision to stent the ureters is influenced by other considerations, including the potential response of the disease to available treatment and the presence of pain. The neoplasm causing the retroperitoneal ureteral obstruction often invades the lumbar or sacral nerve roots, leading to excruciating pain. The wisdom of substituting a prolonged painful death for an earlier relatively painless uremic death must be considered before stenting procedures are undertaken.

Bladder Outlet Obstruction

Bladder outlet obstruction as a result of a large prostatic carcinoma can be rapidly palliated by hormonal therapy or radiation therapy. In a patient with prostate cancer who exhibits androgen-independent growth or progression after radiation therapy, or in patients with primary urethral cancer, effective palliation is a much greater challenge. The symptoms resulting from small bladder capacity, bladder irritability, or outlet obstruction can substantially reduce the quality of life for such patients. If a decision has been made to attempt palliation with cytotoxic therapy, the judicious use of a percutaneous nephrostomy can be considered. If the cytotoxic agents used are not nephrotoxic or primarily dependent on renal metabolism for excretion, a unilateral nephrostomy is usually required to preserve sufficient renal function. If agents considered for use are either nephrotoxic or metabolized in the kidney, bilateral nephrostomy may be considered.

The decision to place percutaneous nephrostomies is simple for patients who have reversible and highly curable lesions obstructing the kidneys (lymphomas, seminomas, embryonal carcinomas, and other germ cell tumors). In addition, nephrostomies are logical choices for patients in whom excellent and sustained palliation can be achieved (breast carcinoma and urothelial malignancies).5 In those patients with refractory tumors with limited therapeutic options, the implication of percutaneous nephrostomy placement without control of the primary tumor should be discussed before placement. Although obstructive uropathy can be relieved, control of symptoms related to the continued growth of the cancer can be difficult.

Pathologically, acute urinary tract obstruction results in increased central renal pressure and dilation of the ureter. This is reflected in the increased size and weight of the kidney. With persistent and progressive obstructive uropathy, irreversible injury finally manifests itself with renal cortical atrophy. The selection of a patient for percutaneous nephrostomy should be based, in part, on the cortical thickness. In the absence of significant atrophy, the obstructed kidney most likely will regain significant function, and percutaneous nephrostomy should be considered. Small atrophic kidneys due to longstanding obstructive uropathy frequently do not benefit from percutaneous drainage. Placement of a percutaneous nephrostomy in a markedly atrophic kidney results in significant morbidity without benefit.

Following relief of obstructive uropathy, metabolic problems may occur. Difficulties in maximum concentration of urine and other tubular defects can result in a brisk postobstructive diuresis. This occurs most often after high-grade acute obstruction. Replacement of fluid and electrolytes is important until normal renal function returns.6

Lower Urinary Tract Obstruction

Distal outlet obstructions by locally advancing tumors that invade the urethra, or primary urethral, prostatic, or bladder tumors are frequently drained unsatisfactorily by placement of Foley catheters or suprapubic tubes. In general, a suprapubic tube is contraindicated in patients with urothelial malignancies, when there is curative intent, because it violates the normal anatomic barriers and increases the probability of regional spread of the disease. Urothelial malignancies that diffusely involve the bladder have a propensity to recur in surgical wounds. The inability to place a Foley catheter is sometimes a complication of primary urethral or prostatic tumors. In such instances, suprapubic catheter drainage can be used to relieve symptoms of acute obstruction. In patients with urinary frequency due to bladder invasion or with bladder irritability due to treatment, Foley catheter placement to relieve symptoms can be attempted but has limited success.

Poorly controlled primary cancers of the bladder, prostate, or urethra frequently result in a debilitating dysuria, frequency, and nocturia that compromise the quality of life. The palliation of severe urinary tract symptoms infrequently requires permanent urinary diversion. Urethral and suprapubic catheters are sometimes associated with urethral discomfort, however. Under such circumstances, urinary diversion to reduce these symptoms is helpful. Because of the limited overall benefit patients can expect to achieve, when they require diversion for advanced cancer, the method of diversion with the least morbidity is chosen. Thus, percutaneous nephrostomies are used more frequently than surgically constructed urinary diversion.

Diagnostic Studies

The first indication of obstructive uropathy is frequently a rising serum creatinine level. Urinalysis may reveal isosthenuria, and, in addition, the blood urea nitrogen (BUN) level may rise. Proteinuria is not uncommon in obstructive uropathy.7 Difficulties sometimes exist in detecting small degrees of low-grade obstructive uropathy with equivocal radiographic abnormalities. In such rare circumstances, radionuclide scans with the use of diuretics may help distinguish between a vascular and an obstructive lesion. The mainstays for the study of obstructive uropathy are ultrasonography and computed tomography (CT). When ultrasonography cannot be effectively performed because of gaseous distension, CT scans can be helpful. The superiority of ultrasonography in such patients lies in its value for marking the area for percutaneous drainage of the kidney and in the absence of contrast material, which could be injurious to renal function. More recently, endoureteral ultrasonography is used to define the anatomy of the obstruction.

Hemorrhagic Cystitis

Hematuria is frequently a striking and frightening event in the course of cancer and its treatment. Hematuria can be a result of bleeding anywhere along the entire urinary tract. Gross hematuria frequently requires palliation. The characteristics of the hematuria often permit physicians to suspect the origin of the bleeding. Long, vermiform clots typically indicate upper tract bleeding and are a result of a ureteral cast (broader clots are occasionally difficult to evacuate and cause ureteral colic or are indicative of lower tract bleeding). Bright red blood without a clot that clears partially during urination usually indicates a lower tract bleed. Hemorrhage can be due to drug- or radiation-induced effects or due to progressive cancer.

Drug-Induced Hematuria

Cyclophosphamide and ifosfamide are the most commonly used oxazaphosphorines. Both agents are metabolized to acrolein, the main urothelial toxic metabolite.8,9 In addition to acrolein, thrombocytopenia tends to exacerbate the bleeding. Sterile hemorrhagic cystitis has been reported in up to 20% of patients receiving high doses of cyclophosphamide and in about 8% of patients receiving ifosfamide.10 With conventional doses of cyclophosphamide, cystitis can be prevented by encouraging aggressive oral hydration at the time of chemotherapy. In the case of ifosfamide, this complication can be reduced with intravenous hyperhydration and the use of uroprotective mesna. Mesna is given as an intravenous bolus equal to 20% of the ifosfamide dose 15 minutes before ifosfamide administration, as well as 4 and 8 hours later (total dose of mesna should be equivalent to 60% of the ifosfamide dose).11 Mesna can also be given as a continuous infusion at a dose 100% equal to the ifosfamide dose. Continuous infusion of mesna should be maintained for 4 to 8 hours after completion of the ifosfamide infusion. In the case of cyclophosphamide, mesna is given mainly with high-dose chemotherapy in bone marrow transplantation. The dose of mesna used is about 60 to 160% of the cyclophosphamide dose, and it is given intravenously in 3 to 5 divided doses or by continuous infusion.10 Other agents that can produce gross hematuria include intravesical treatment with doxorubicin, mitomycin, and bacillus Calmette-Guérin (BCG).11

With the use of high-dose chemotherapy, hemorrhagic cystitis occurs in about 2% of conditioning regimen without cyclophosphamide. This bleeding is most commonly associated with thrombocytopenia.12 When cyclophosphamide is used, up to 20% of patients may develop macrohematuria.13 Moreover, the use of busulfan in addition to cyclophosphamide in high-dose chemotherapy tends to increase the risk of bleeding.14 Hemorrhagic cystitis in bone marrow transplantation can also be associated with infection from adenovirus15 or BK human polyomavirus.16

Radiation-Induced Hematuria

From about 5.7 to 11.5% of patients treated with pelvic irradiation (TD50 of 80 Gray) can develop bladder complications.17 Although less common, hemorrhagic cystitis can be seen in the treatment of pelvic neoplasms with both external beam radiation and brachytherapy. Up to 9% of these patients can develop hematuria,18 and about 10% will have bleeding more than 6 months after treatment.19 Total body irradiation for bone marrow transplantation has been associated with hemorrhagic cystitis in 10 to 17% of patients.14,20 Symptoms include recurrent hemorrhage, urinary urgency, and pain. The patients at highest risk are those with previous operations and those receiving cyclophosphamide. It is important to note that about 85% of the patients who develop macrohematuria after radiation actually have a recurrence of their tumor.19 The pathophysiology of radiation induced cystitis involves damage to the vascular endothelium and endarteritis causing progressive ischemia, inflammation, and fibrosis, with the end result being tissue necrosis. This is also complicated by infections that prevent proper healing.

Recurrence of Tumor

Another important cause of gross hematuria is related to recurrence of bladder tumors or invasion by other pelvic neoplasms. Most of these patients have advanced disease. In many, the treatments are palliative and directed to the underlying malignancy and symptoms.

Treatment

Clot retention is a painful complication of lower urinary tract bleeding. Intermittent bladder injections or constant two-channel bladder irrigation with antibiotic-containing saline or water usually can dissolve or dissociate clots. Cystoscopic evacuation of clots is sometimes required for palliation. In patients who have not been treated with radiation therapy for their bleeding tumors, radiation is a useful approach. Cyclophosphamide-, ifosfamide-, or radiation-induced cystitis and bleeding are far more challenging problems. Embolization of bladder vessels or instillation of steroids has occasionally palliated such patients; but treatment is frequently unsatisfactory. Diluted formaldehyde may denature and fix superficial tissue layers. Emergency cystectomy has been undertaken to avoid exsanguination. Other treatments include hyperhydration, bladder irrigation, intravesical alum,20 and intravesical prostaglandins.21 Experimental approaches include amifostine,22 hyperbaric oxygenation,23 conjugated estrogens,24 and glucose–mannose binding plant lectins.25

Radiation Nephritis

Radiation is frequently delivered to control nodal metastasis from radiation-sensitive tumors (e.g., lymphomas and seminomas). The dose of radiation delivered to the kidneys can sometimes result in significant renal compromise from radiation-induced nephritis. The kidney is an important dose-limiting organ in radiation therapy. When both kidneys are radiated, the dose tolerance (TD5/5) is 20 Gy in adults, and about 17% of the patients will develop symptomatic renal disease. When only one kidney is irradiated, the tolerance decreases. Glomerular function starts to decrease at 15 Gy, and function is completely lost at 25 to 30 Gy. Radiosensitizers, such as cisplatin, carmustine (BCNU), and actinomycin D, tend to lower normal tissue radiation tolerance. Symptoms are rarely seen acutely within 6 months of treatment. Subacute symptoms, such as anemia, hypertension, edema, albuminuria, active urinary sediment, and increase in BUN and creatinine, are seen 6 to 12 months after radiation. In the chronic phase (> 12 months), benign or malignant hypertension is the most common finding. Eventually, the patient may develop hyper-reninemic hypertension related to renal scarring, atrophy of cortical tubules, and glomerulosclerosis. Management involves decreasing the renal workload with salt and fluid restriction and a low protein diet. Some patients may develop progressive deterioration of renal function requiring hemodialysis or renal transplantation.26 Avoiding the debilitating complications of radiation injury to genitourinary tissue is an essential aspect to the good practice of oncology. Use of modern radiation techniques and an understanding of genitourinary tissue tolerance furnish the practicing physician with clear guidelines for the safe use of radiation therapy.

Long-term renal toxicity related to total body irradiation in bone marrow transplantation is associated with hypertension, anemia, decreased glomerular filtration rate, hematuria, and proteinuria. These findings are caused by subendothelial widening of basement membrane, endothelial cell dropout, glomerular arteriolar intimal thickening, and tubular atrophy. These effects are dose dependent. In a review of bone marrow transplantation patients receiving total body irradiation with 14 Gray, it was noted that the incidence of nephropathy decreased with increased shielding of the kidneys. Of the patients without shielding of the kidneys, 30% develop nephropathy. When the kidneys were partially shielded reducing dosage by 15%, the fraction of patients developing nephropathy decreased to 15%. When the shielding was increased and the dosage was reduced by 30%, none of the patients developed nephropathy.27 These patients are more susceptible to radiation-induced renal injury secondary to the use of higher doses of chemotherapy, aminoglycosides, and antifungal medications, as well as infections and the development of graft-versus-host disease.

Diagnosis, Treatment, and Prevention of Nephrotoxicity of Cancer Therapeutic Agents

With the advent of effective cytotoxic chemotherapy, attention has turned to the side effects of these widely used agents (Table 148.1). These side effects include tumor lysis syndrome, paraneoplastic glomerulonephritis, obstructive uropathy, and nephrotoxicity with renal failure and electrolyte disturbances. These are more common in the geriatric population secondary to polypharmacy/drug interactions and comorbid conditions. Also, nephrotoxicity with these agents is more common in bone marrow transplantation, secondary to high-dose chemotherapy, polypharmacy, and total body irradiation. Below, we describe commonly used agents that cause serious renal toxicity. Table 148.2 lists other agents that less commonly cause renal side effects. Table 148.3 lists the mechanism of renal injury for some of the drugs. Another important aspect related to prevention of nephrotoxicity involves the interaction among drugs. Drug interactions, by decreasing liver metabolism or renal clearance, can increase the serum concentration of antineoplastic agents. This increase can cause unexpected nephrotoxicity, even though the correct doses have been prescribed. A careful review of the patient’s medications is essential in the prevention of renal toxicity. Some of these drug interactions are described in Table 148.4. Also important is a baseline evaluation of the patient’s renal function, since several drugs may need a dose adjustment in the presence of renal insufficiency (Table 148.5).

Table 148.1. Therapy Agents Associated with Nephrotoxicity.

Table 148.1

Therapy Agents Associated with Nephrotoxicity.

Table 148.2. Clinical and Pathologic Features of Chemotherapy-Associated Nephrotoxicity.

Table 148.2

Clinical and Pathologic Features of Chemotherapy-Associated Nephrotoxicity.

Table 148.3. Types of Renal Injury Caused by Cancer Chemotherapeutic Agents.

Table 148.3

Types of Renal Injury Caused by Cancer Chemotherapeutic Agents.

Table 148.4. Drug Interactions that can Increase Serum Levels of Antineoplastic Agents or Add Renal Toxicity.

Table 148.4

Drug Interactions that can Increase Serum Levels of Antineoplastic Agents or Add Renal Toxicity.

Table 148.5. Adjustment of Antineoplastic Agents Based on Renal Insufficiency.

Table 148.5

Adjustment of Antineoplastic Agents Based on Renal Insufficiency.

Cisplatin

The introduction of cisplatin to the clinic highlighted the hazards that follow failure to understand the renal complications of cytotoxic agents.28 Effectively overcoming this principal toxicity of cisplatin has allowed significant benefit to patients with many types of cancer. Development of platinum analogues has, in part, been motivated by the renal toxicity associated with cisplatin. However, cisplatin continues to be widely used as a major cancer drug because of its differential antitumor activity when compared with the available analogues. The study of cisplatin, the modification of its delivery, and the anticipation of and screening for nephrotoxicity provide a paradigm for the study of nephrotoxic agents in general.

The principal excretion route of cisplatin is renal. However, only a small portion of the total cisplatin dose can be recovered in the urine in the first few days after therapy.29 Much of the drug is irreversibly bound to protein, but active metabolites, the aquated diammino derivative, as well as the parent dichlorodiamminoplatinum, are found in the ultrafiltrable plasma fraction. This plasma clearance is triphasic with nearly all the drug gone in 4 hours, but it has a terminal half-life of over 24 hours. The primary lesion of cisplatin toxicity is necrosis of the proximal convoluted tubules. The severity of the nephrotoxicity can be modified by hydration. The strong emetic effects of cisplatin can, however, produce dehydration. These dual side effects—severe nausea and vomiting and primary nephrotoxicity exaggerated by dehydration—have been largely overcome with hydration schedules and the aggressive use of new antiemetics.30,31

Reduction in glomerular filtration rate (GFR) is the primary cisplatin-induced injury that is measured clinically. Other complications include hypomagnesemia and modest amounts of proteinuria. The proteinuria associated with cisplatin nephrotoxicity is attributed to a tubular defect.32 Hemolytic uremic syndrome has also been described, especially when cisplatin is combined with bleomycin.33 Sequential measurement of the GFR is essential for monitoring of cisplatin toxicity. An accurate urine collection for inulin clearance is superior to 24-hour urine collection for creatinine clearance, but we have used the serum creatinine concentration and calculation of the creatinine clearance. Assay of electrolytes, including calcium, magnesium, and phosphorus, has also been routinely made. For patients treated at the University of Texas M.D. Anderson Cancer Center (UTMDACC) in the Department of Genitourinary Medical Oncology, electrolytes, BUN, and creatinine are monitored prior to each dose of therapy. There is a minimum interval of 7 days between cisplatin doses. This interval is important because maximal nephrotoxicity frequently does not manifest itself in less than 7 days. A significant decline in the creatinine clearance, as measured by the Cockroft formula, should result in a delay of therapy (Table 148.6).

Table 148.6. Cockroft Formula.

Table 148.6

Cockroft Formula.

Prevention of toxicity is important in patient care. Empirical observations, both in the laboratory and the clinic, have demonstrated that hydration with the use of mannitol or hypertonic saline has significantly reduced the cisplatin-induced decline in renal function.30,31 Although hypertonic saline is not commonly used, normal saline is important to provide abundant chloride ions. This diminishes the formation of the aquated species by mass action, thereby lessening the impact on renal function. Minimum urine flow should be sustained at 100 mL/h before cisplatin administration. Multiple clinical trials have demonstrated the effectiveness of using mannitol in different schedules. Conflicting reports exist regarding use of furosemide (Lasix) and its ability to affect cisplatin’s nephrotoxicity. Its use has generally been avoided at the UTMDACC.34,35 More recently, amifostine (phosphorylated aminothiol pro-drug) has been used in the prevention of nephrotoxicity by cisplatin. Amifostine is metabolized to WR-1065 and WR-33278, which reduce formation of DNA–DNA cross-links,36 reverse platinum–DNA adducts,37 and bind to oxygen free radicals. Several studies have shown that amifostine decreases the number of patients with a greater than 40% reduction in creatinine clearance or glomerular filtration secondary to cisplatin nephrotoxicity from 30 to 40% to about 10%.38-40 It has been noted that amifostine does not affect the response to chemotherapy. Certain chemotherapeutic agents and other nephrotoxic drugs can impact significantly on nephrotoxicity. Cisplatin is used frequently in combination with other agents, such as ifosfamide and methotrexate. The side effects seem to be greatly diminished by adequate hydration. Paclitaxel in combination with cisplatin has been associated with elevation of serum creatinine in the treament of gynecologic cancers.41 Concurrent aminoglycoside antibiotics have been reported to result in a significantly greater reduction of renal function.42 Meticulous attention to detail, adequate hydration, and avoidance of these interactions is important.

Methotrexate

Methotrexate (MTX), an agent dependent on renal glomerular filtration as its principal excretory route, can also induced renal toxicity.43,44 Renal toxicity can be particularly devastating because prolonged exposure to MTX at elevated levels substantially increases toxicity in the bone marrow and the oral cavity of the alimentary canal. The renal toxicity of MTX is a dose-dependent phenomenon. Renal failure has often been implicated in deaths associated with the use of this agent.

The nephrotoxicity of MTX is manifested primarily in the renal tubule, where extensive necrosis of the convoluted tubules occurs. The lesion has been termed crystalline hydronephrosis and has been attributed to deposition of the agent. The precipitation of MTX and its less soluble principal metabolite, 7-hydroxy MTX, in the renal tubule results in changes in preglomerular vascular pressure and a direct decrease in glomerular filtration.

Avoidance of MTX nephrotoxicity can be accomplished by selecting patients with normal renal function, ensuring adequate hydration, and alkalinizing the urine to pH 7 or higher. Prior to administration of MTX at doses of 100 mg/m2 or greater (and some doses are 100–200 times this amount) adequate renal function should be ensured by normal serum creatinine and minimum urinary flow of 100 mL/h. Urine should have a pH of 7 or higher, and leucovorin can be administered after MTX. Methotrexate is highly protein bound, and it is not readily removed by dialysis.33 Specific attention to interaction with other agents is important when administering MTX. Weak organic acids, such as salicylates or sulfisoxazole, increase MTX levels by displacing the drug from binding sites on plasma proteins. In addition, renal tubular transport is diminished by probenecid and by salicylates. Specific avoidance of these agents reduces the risk of inducing nephrotoxicity or increasing other side effects.

Nitrosoureas

Each of the nitrosoureas (CCNU, methyl-CCNU, BCNU) was predicted to have significant nephrotoxicity.45,46 Initial small phase I and phase II trials failed to reveal evidence of renal compromise, but with their use in large phase III trials, drug-induced nephrotoxicity was encountered.47–49 Unlike the nephrotoxicity associated with MTX and cisplatin, these agents cause interstitial nephritis. The specific mechanism by which this occurs is unclear. At present, limiting the total cumulative dose of the agents is the only way of preventing this; hydration does not appear to alter it. Monitoring such patients with serial urinalysis and serum creatinine concentrations appears to be the most reliable way to screen for nephrotoxicity.

Mitomycin C

Mitomycin C is an antibiotic isolated from Streptomyces caespitosus. Although this agent has significant activity against a variety of tumors, it has received rather limited use because of prolonged thrombocytopenia and unpredictable side effects, which are dose limiting.

The unique clinical nephrotoxicity of mitomycin C is a striking hemolytic–uremic syndrome (HUS). This is sometimes manifested by early elevation of serum creatinine or anemia, with a rise in serum lactate dehydrogenase (LDH), indicating hemolysis. Patients receiving mitomycin C should be carefully monitored for HUS. Total cumulative doses of less than 30 mg/m2 of body surface area are rarely, if ever, associated with HUS. The most difficult problem in managing the HUS of patients treated with mitomycin C is that it is sometimes difficult to anticipate because the onset can be delayed after the time of delivery of the agent.

Mitomycin C–induced nephrotoxicity can be prevented by limiting the cumulative dose to less than 30 mg/m2 of body surface area. The use of steroids, which are believed to reduce the pulmonary toxicity of this agent, has not clearly demonstrated a role in reducing nephrotoxicity. Plasmapheresis appears to provide therapeutic benefit in selected patients, although only limited studies have been performed.50,51 Small numbers of studies have been performed, but they seem to indicate that therapeutic benefit can be achieved in selected patients.

Immunologic Agents

Interleukin-2 (IL-2) causes renal insufficiency by direct toxic effect on the kidneys and by prerenal azotemia from capillary leak syndrome. This renal toxicity is commonly reversible after discontinuation of the drug, intravenous saline, albumin, pressors, and renal dose dopamine.33

Cyclosporine produces renal vasoconstriction primarily at the afferent arteriole, causing arterial hypertension, fluid retention, and ultimately renal dysfunction.52 The acute nephrotoxicity is reversible with dose modification. In contrast, chronic administration may cause a slowly irreversible renal failure secondary to renal tubular fibrosis and afferent arteriopathy with proteinaceous material.53

Tacrolimus causes renal injury in a fashion similar to cyclosporine. In contrast to cyclosporine, however, it is less likely to cause arterial hypertension. Tacrolimus stimulates transforming growth factor (TGF)-β1 expression and inhibits matrix protein degradation.54

Other Agents

On the basis of preclinical studies, the anthracyclines daunorubicin and doxorubicin were predicted to cause renal toxicity.55–57 Anthracycline-induced nephrotoxicity has not, however, been convincingly reported in clinical trials. Ifosfamide can cause proximal tubular dysfunction, distal renal tubular acidosis, nephrogenic diabetes insipidus, and a syndrome of inappropriate antidiuretic hormone release. Multiple new agents have been associated with kidney toxicity, but data are limited. Fludarabine has been reported to cause urologic complications related to urinary tract infections in 12 to 22% of patients.10,58,59 Abnormal renal function is observed in less than 5% of patients treated with fludarabine,10,59–61 and it is related to tumor lysis syndrome. Paclitaxel has been associated with elevation of serum creatinine in about 18% of HIV patients treated for Kaposi’s sarcoma.10,62,63 Gemcitabine is linked to sporadic renal failure associated with thrombotic microangiopathy.64

Monitoring for Drug-Induced Nephrotoxicity

The principle that should guide clinicians in the use of potentially nephrotoxic agents in the treatment of cancer is close monitoring for the development of renal toxicity, its early detection, and management. The wide range of renal insults induced by cytotoxic drugs complicates the selection of the appropriate study to monitor potential nephrotoxicity.65 Clinicians apply similar screening studies to detect a wide range of renal insults from cytotoxic agents. The use of specific studies that focus on the nature of the cytotoxic injury induced by the specific agent is more likely to detect early injury. For example, tubular defects resulting from cisplatin nephrotoxicity are not directly correlated with reduction in the GFR, while hypermagnesiuria and hypomagnesemia are characteristic. Monitoring patients for nephrotoxicity for agents that can cause interstitial nephritis (nitrosoureas) or glomerular injury (mitomycin C) requires routine and frequent urinalyses. The appearance of microhematuria should lead physicians to further exclude drug-induced renal injury.

The most common renal functional abnormality as a result of cytotoxic therapy is a decline in GFR. The most frequently used measure of GFR is creatinine clearance. Creatinine clearance is less accurate than other measures of GFR but, for practical reasons, has been widely applied clinically.66 A serial decline in creatinine clearance is a reliable index of worsening renal function. Significant limitations are encountered in estimating a creatinine clearance from serum creatinine alone, using predictive formulas (Cockroft; see Table 148.6). Use of such formulae has, however, been widely applied in clinical oncology, in view of the difficulties in collecting reliable 24-hour urine specimens. The 24-hour collection for creatinine clearance has been supplanted by the use of the Cockroft formula at UTMDACC in the Department of Genitourinary Medical Oncology. No increase in the frequency of renal compromise associated with cisplatin administration has been noted since this procedure was adopted. A practical approach has been to follow only the serum creatine concentrations. In the absence of any change in the serum creatine concentration or calculated clearance (Cockroft), no further study is required. In patients whose serum creatine concentration increases more than 0.4 mg/dL, further investigation of renal function is undertaken. Adjustment in dose or change in therapy may then be ordered as required. Particular attention should be paid to the correct calculation of the renal function by adjusting for weight. The creatinine clearance calculated by the Cockroft formula is sufficient in patients of average body habitus but may result in erroneous predictions in patients who are emaciated or in those with a large muscle mass. The wide fluctuations in weight that occur in patients undergoing cancer therapy require that the patients be weighed before each dose of chemotherapy and that doses be adjusted for changes in weight.

References

1.
Logothetis C J, Samuels M L, Ogden S L. et al. Cyclophosphamide and sequential cisplatin for advanced seminoma: long-term follow-up in 52 patients. J Urol. 1987;138:789–794. [PubMed: 3656535]
2.
Logothetis C J, Samuels M L, Selig D E. et al. Cyclic chemotherapy with cyclophosphamide, doxorubicin, and cisplatin plus vinblastine and bleomycin in advanced germinal tumors: results with 100 patients. Am J Med. 1986;81:219–228. [PubMed: 2426944]
3.
Dyer R B, Assimos D G, Regan S D. Update on interventional uroradiology. Urol Clin North Am. 1997;24:623–652. [PubMed: 9275982]
4.
Stables D P. Percutaneous nephrostomy: techniques, indications and results. Urol Clin North Am. 1982;9:15–29. [PubMed: 7080284]
5.
Carrasco CH, Charnsangavej C, Richli WR, Wallace S. Percutaneous drainage. In: Hickey RC, editor. Current problems in cancer. Vol X, No 12. Chicago: Year Book; 1986. p. 599–600.
6.
Gillenwater JY. The pathophysiology of urinary obstructions. In: Harrison JH, editor. Campbell’s Urology, 4th ed. Philadelphia: WB Saunders; 1979. p. 377.
7.
Gutmann FD, Boxer RJ. Pathophysiology and management of urinary tract obstruction. In: Rieselbach RE, Garnick MB, editors. Cancer and the kidney. Philadelphia: Lea & Febiger; 1982. p. 594–624.
8.
Cox P J. Cyclophosphamide cystitis—identification of acrolein as the causative agent. Biochem Pharmcol. 1979;28:2045–2049. [PubMed: 475846]
9.
Brade W P, Herdrich K, Varani M. Ifosfamide—pharmacology, safety and therapeutic potential. Cancer Treat Rep. 1985;12:1–47. [PubMed: 3896483]
10.
McEvoy GK. Drug information. Bethesda, MD: American Society of Health System Pharmacists; 1999. p. 832–837, 873–877, 891–897, 969–980.
11.
Drake M J, Nixon P M, Crew J. Drug-induced bladder and urinary disorders. Incidence, prevention and management. Drug Saf. 1998;19:45–55. [PubMed: 9673857]
12.
Brugieres L, Hartmann O, Travagli J P. et al. Hemorrhagic cystitis following high dose chemotherapy and bone marrow transplantation in children with malignancies: incidence, clinical course and outcome. J Clin Oncol. 1989;7:194–199. [PubMed: 2644398]
13.
Klingemann J D, Shepherd J D, Reece D E. et al. Regimen-related acute toxicities: pathophysiology, risk factors, clinical evaluation and preventive strategies. Bone Marrow Transplant. 1994;14 Suppl 4:S14–S18. [PubMed: 7728119]
14.
Ringden Q, Remberger M, Ruutu T. et al. Increased risk of chronic graft versus host disease, obstructive bronchiolitis and alopecia with busulfan versus total body irradiation. Blood. 1999;93:2196–2201. [PubMed: 10090927]
15.
Mufsen M A, Belshe R B. A review of adenoviruses in the etiology of acute hemorrhagic cystitis. J Urol. 1976;115:191–194. [PubMed: 175174]
16.
Bedi A, Miller, CB, Hanson, JL et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol. 1995;13:1103–1109. [PubMed: 7738616]
17.
Burman C, Kutcher G J, Goitein M. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys. 1991;21:123–135. [PubMed: 2032883]
18.
DeVries C R, Freiha, FS Hemorrhagic cystitis: a review. J Urol. 1990;143:1–9. [PubMed: 2403595]
19.
Dean R J, Bernard L. Urologic complications of pelvic radiation. J Urol. 1978;119:64–67. [PubMed: 621818]
20.
Kohno A, Takeyama K, Narabajashi M. et al. Hemorrhagic cystitis associated with allogeneic and autologous bone marrow transplantation for malignant neoplasm in adults. Jpn J Clin Oncol. 1993;23:46–52. [PubMed: 8459641]
21.
Miller L J, Chandler S W, Ippolit C M. Tretament of cyclophosphamide-induced hemorrhagic cystitis with prostaglandins. Ann Pharmacother. 1994;28:590–594. [PubMed: 8068996]
22.
Srivastava A, Nair S C, Srivastava V M. et al. Evaluation of uroprotective efficacy of amifostine against cyclophosphamide induced hemorrhagic cystitis. Bone Marrow Transplant. 1999;23:463–467. [PubMed: 10100560]
23.
Yazawa H, Nakada T, Sasawaga I. et al. Hyperbaric oxygenation therapy for cyclophosphamide induced hemorrhagic cystitis. Int Urol Nephrol. 1995;27:381–385. [PubMed: 8586509]
24.
Liu Y K, Harty J I, Steinbok G S. et al. Tretament of radiation or cyclophosphamide induced cystitis using conjugated estrogens. J Urol. 1990;144:41–43. [PubMed: 2162975]
25.
Assreuy A M, Martins G J, Moreira M E. Prevention of cyclophosphamide-induced hemorrhagic cystitis by glucose-mannose binding plant lectins. J Urol. 1999;161:1988–1993. [PubMed: 10332487]
26.
Perez C, Brady L. Principles and practice of radiation oncology. 3rd ed. Philadelphia (PA): Lippincott-Raven; 1998. p. 185–189.
27.
Lawton C A, Cohen E P, Murray K J. et al. Long term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant. 1997;20:1069–1074. [PubMed: 9466280]
28.
Walker E M, Gale G R. Methods of reduction of cisplatin nephrotoxicity. Ann Clin Lab Sci. 1981;11:397–410. [PubMed: 6277229]
29.
Speer R J, Ridgway H, Hall L M. Coordination complexes of platinum as antitumor agents. Cancer Chemother Rep. 1979;59:629–641. [PubMed: 1203887]
30.
Ozols R F, Cordon B J, Jacobs J. et al. High-dose cisplatin in hypertonic saline. Ann Intern Med. 1984;100:19–24. [PubMed: 6197916]
31.
Gonzales-Vitale J C, Hayes D M, Cvitkovic E, Sternberg S S. The renal pathology in clinical trial of cis-platinum (II) diamminodichloride. Cancer. 1977;39:1362–1371. [PubMed: 851939]
32.
Buamah P K, Howell A, Whitby H. et al. Assessment of renal function during high-dose cisplatin therapy in patients with ovarian carcinoma. Cancer Chemother Pharmacol. 1982;8:281–284. [PubMed: 6127169]
33.
Berns J, Ford P. Renal toxicities of antineoplastic drugs and bone marrow transplantation. Semin Nephrol. 1997;17:54–66. [PubMed: 9000550]
34.
Pera M F, Harder H C. Effects of furosemide- and mannitol-induced diuresis on the nephrotoxicity and physiologic disposition of cis-dichlorodiamminoplatinum in rats. Proc Am Assoc Cancer Res. 1978;19:100.
35.
Pera M F Jr, Zook B C, Harder H C. Effects of mannitol or furosemide diuresis on the nephrotoxicity and physiological disposition of cis-diammineplatinum (II) in rats. Cancer Res. 1979;39:1269–1278. [PubMed: 421210]
36.
De Neve W J, Everett C K, Suminski J E. et al. Influence of WR-2721 on DNA’s cross-linking by nitrogen mustard in normal mouse bone marrow and leukemia cells in vivo. Cancer Res. 1988;48:6002–6005. [PubMed: 2844397]
37.
Treskes M, Nijtmans L G, Fichtinger-Schepman A M. et al. Effects of the modulating agent WR 2721 and its main metabolites of the formation and stability of cisplatin DNA adducts in vitro in comparison to the effects of thiosulphate and diethylthiocarbamate. Biochem Pharmacol. 1992;43:1013–1019. [PubMed: 1313234]
38.
Kemp G, Rose P, Lurain J. et al. Amifostine pretreatment for protection against cyclophosphamide and cisplatin induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996;14:2101–2112. [PubMed: 8683243]
39.
Alberts D S, Green S, Hannigan E V. et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stage IV ovarian cancer. J Clin Oncol. 1992;10:706–717. [PubMed: 1569443]
40.
Schiller J H, Berry W, Storer B. et al. Phase II trial of amifostine, cisplatin and vinblastine for metastatic non small cell lung cancer. Proc Am Soc Clin Oncol. 1995;14:356.
41.
Merouani A, Davidson S A, Schrier R W. Increased nephrotoxicity of combination taxol and cisplatin chemotherapy in gynecolgic cancers as compared to cisplatin alone. Am J Nephrol. 1997;17:53–58. [PubMed: 9057954]
42.
Gonzales-Vitale J C, Hayes D M, Cvitkovic E, Sternberg S S. Acute renal failure after cis-dichlorodiammineplatinum (II) and gentamicin-cephalothin therapies. Cancer Treat Rep. 1978;62:693–698. [PubMed: 657154]
43.
Evans B D, Rajn K S, Calvert A H. et al. Phase II study of JM-8, a new platinum analog, in advanced ovarian carcinoma. Cancer Treat Rep. 1983;67:997–1000. [PubMed: 6315233]
44.
Frei E. Methotrexate revisited. Med Pediatr Oncol. 1976;2:227–241. [PubMed: 790144]
45.
Denine E P, Harrison S D, Pechkam J C. Qualitative and quantitative toxicity of sublethal doses of methyl-CCNU in BDF1 mice. Cancer Treat Rep. 1977;61:409–417. [PubMed: 872140]
46.
Carter S K, Broder L, Friedman M. Streptozotocin and metastatic insulinoma. Ann Intern Med. 1971;74:445–446. [PubMed: 4324025]
47.
Harmon W E, Cohen H J, Schneeberger E E, Grupe W E. Chronic renal failure in children treated with methyl CCNU. N Engl J Med. 1979;300:1200–1203. [PubMed: 431647]
48.
Berglund J. Progredierande njurinsufficiens efter CCNU-behandling. Lakartidningen. 1980;77:1760. [PubMed: 7382694]
49.
Ellis M E, Weiss R B, Kuperminc M. Nephrotoxicity of lomustine. Cancer Chemother Pharmacol. 1985;15:174–175. [PubMed: 4017166]
50.
Cantrell J E, Philips T M, Schein P S. Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy. J Clin Oncol. 1985;3:723–734. [PubMed: 3923162]
51.
Lempert K D. Haemolysis and renal impairment syndrome in patients on 5-fluorouracil and mitomycin-C. Lancet. 1980;2:369–370. [PubMed: 6105503]
52.
Elzinga L, Kelley V E, Houghton D C, Bennett W M. Fish oil vehicle for cyclosporine lowers renal thromboxanes and reduces experimental nephrotoxicity. Transplant Proc. 1987;19:1403–1406. [PubMed: 3824502]
53.
Bennet W M, de Mattos A, Meyer M M. et al. Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int. 1996;50:1089–1100. [PubMed: 8887265]
54.
Bennet W M. The nephrotoxicity of new and old immunosuppressive drugs. Ren Fail. 1998;20:687–690. [PubMed: 9768435]
55.
Sternberg S S. Cross-striated fibrils and other ultra-structural alterations in glomeruli of rats with daunomycin nephrosis. Lab Invest. 1970;23:39–51. [PubMed: 5431221]
56.
Buss H, Lamberts B. The kidney glomerulus of the rat during experimental daunomycin nephrosis. A comparative transmission-scanning electron microscopic study. Beitr Pathol. 1973;148:360–387. [PubMed: 4717736]
57.
Serpick A A, Henderson E S. Observations on toxicity and clinical trials with daunomycin. Pathol Biol. 1967;15:909–912. [PubMed: 4967536]
58.
Keating M J, Kantarjian H, Talpaz M. et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989;74:19–25. [PubMed: 2473795]
59.
Puccio C A, Mittleman A, Lichtman S M. et al. A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia. J Clin Oncol. 1991;9:1562–1569. [PubMed: 1714949]
60.
Chun H G, Leylan-Jones B, Cheson B D. Fludarabine phosphate: a synthetic purine metabolite with significant activity against lymphoid malignancies. J Clin Oncol. 1991;9:175–188. [PubMed: 1702143]
61.
List A F, Kummett T D, Adams J D. et al. Tumor lysis syndrome complicating chronic lymphocytic leukemia with fludarabine phosphate. Am J Med. 1990;89:383–390. [PubMed: 1697447]
62.
Welles L, Saville M W, Lietzau J. et al. Phase II trial with dose titration of paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi’s sarcoma. J Clin Oncol. 1998;16:1112–1121. [PubMed: 9508198]
63.
Saville M W, Lietzau J, Pluda J M. et al. Treatment of HIV-associated Kaposi’s sarcoma. Lancet. 1995;346:26–28. [PubMed: 7603142]
64.
Flombaum C D, Mouradian J A, Casper E S. et al. Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine. Am J Kidney Dis. 1999;33:552–562. [PubMed: 10070921]
65.
Daugaard G, Abildgaard U. Evaluation of nephrotoxicity secondary to cytostatic agents. Crit Rev Oncol Hematol. 1992;13:215–240. [PubMed: 1476654]
66.
Kassirer JP, Harrington JT. Laboratory evaluation of renal function. In: Schrier RW, Gottschalk CW, editors. Diseases of the kidney. Vol 1. Boston (MA): Little, Brown; 1988. p. 393–441.
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Bookshelf ID: NBK20838

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