Urologic complications

Rachel A. Sanford, MD Ala Abudayyeh, MD Christopher J. Logothetis, MD Nizar M. Tannir, MD, FACP

Overview

The management of patients with cancer requires anticipation and timely intervention for urologic complications including urinary tract obstruction, cystitis, nephritis, and nephrotoxicity from chemotherapeutic agents. In patients with limited-stage disease receiving therapy with curative intent, skilled management of urologic complications is crucial for delivering adequate doses of chemotherapy and avoiding dose reductions that may compromise the likelihood of cure. In the metastatic setting, skillful management of urologic complications including urinary obstruction can provide significant palliation of symptoms. This chapter reviews the diagnosis and management of urinary tract obstruction occurring at the level of the ureters, the bladder, and the urethra. Mechanisms of chemotherapy- and radiation-induced cystitis and nephritis and their management are reviewed. Finally, an overview of the most commonly used potentially nephrotoxic therapeutic agents is provided, with an emphasis on diagnosis, treatment, and prevention. In addition to cytotoxic chemotherapy, the nephrotoxicity caused by targeted therapies is discussed, and emerging insights into immune-related adverse events (irAE) that may affect the kidney are reviewed.

Introduction

Anticipation and timely intervention for urologic complications of cancer and its therapy may facilitate treatment of patients with localized disease and expand opportunities for the treatment of patients with metastatic disease. Management of obstructive uropathy, prompt detection of drug-induced renal toxicity, and the management of such toxicity without excessive dose reduction are critical to the successful treatment of cancer patients. Renally based dose adjustment and the monitoring of multiple agents with nephrotoxic potential are nuanced yet essential components of oncologic practice, and management of urologic complications often requires coordinated multidisciplinary care. This chapter reviews the most frequent urologic complications of cancer and its therapy.

Urinary tract obstruction

Obstruction of the urinary tract may occur at multiple levels (ureter, bladder, or urethra) due to direct extension, encasement, or invasion of these structures by cancer. The natural history and management of obstructive uropathy are determined by the obstruction’s location, time course (acute versus chronic), and the anticipated responsiveness to therapy of the malignancy implicated in the obstruction. For curable cancers whose therapies contain essential components that are nephrotoxic [cisplatin, ifosfamide, and methotrexate (MTX)], prompt reversal of obstructive uropathy is important to permit adequate chemotherapy dosing. In patients with advanced cancers of the GU tract resulting in obstruction and debilitating urinary symptoms that compromise quality of life, urinary diversion is an important palliative procedure aimed at relieving suffering and prolonging survival. In both scenarios, a range of less invasive interventions including stenting and external drainage of the urinary tract, which are performed by an urologist or an interventional radiologist, may allow early intervention and reduce the need for extensive surgical procedures.

The first suggestion of the presence of an obstructive uropathy may be a rising serum creatinine level, particularly in ureteral obstructions, which are often painless. Bladder outlet or urethral obstruction resulting in a distended bladder may be palpable on physical exam. Acute unilateral hydronephrosis may cause hypertension, due to activation of the renin-angiotensin system;¹ this hypertension is reversible with relief of the obstruction. Urinalysis may be bland, or may reveal significant hematuria.² The cornerstones of diagnostic imaging are ultrasound and CT with contrast, with the former often pursued first to avoid the potential nephrotoxicity of IV contrast and exposure to radiation. Detailed anatomic imaging may be obtained by MRI, but the use of this modality is limited in patients with GFR < 30 due to concerns about nephrogenic systemic fibrosis (NSF).

Regardless of the location of the urinary obstruction, with time, the inability to pass urine leads to increased pressure on the renal pelvis, hydronephrosis, and renal tubule atrophy. If allowed to continue, irreversible injury may occur.³ Urinary obstruction may also provide a nidus for infection. The radiographic appearance of the kidney under conditions of acute and chronic obstruction is distinct, with the former appearing as an enlarged kidney with a normal-to-thickened renal cortex, and the latter appearing smaller than average with a thinned cortex. Relief of the obstruction is unlikely to result in significant improvement in renal function with chronic obstruction, and the visualization of a small kidney with thinned cortex on ultrasound should usually halt a planned intervention.

Following relief of an acute obstruction, return of renal function is anticipated in 7–10 days, although longer periods of recovery may be observed.⁴ In the period immediately following relief of the obstruction, the renal tubule’s concentrating capacity is abnormal, which may cause a period of postobstructive diuresis. This is most commonly observed with acute high-grade obstructions.

Ureteral obstruction

The ureters are located in the retroperitoneum, making them particularly vulnerable to mechanical obstruction by pathologic retroperitoneal lymphadenopathy or retroperitoneal fibrosis. Such obstructive uropathy is most frequently the result of either primary nodal diseases (lymphomas) or periaortic lymph node metastases of urologic neoplasms, particularly prostate cancer and germ cell tumors. In the case of retroperitoneal adenopathy due to highly chemotherapy-responsive malignancies, particularly some germ cell tumors or aggressive lymphomas, the expected prompt response to therapy may allow the clinician to avoid acute intervention to relieve the obstruction, particularly in the case of unilateral or partial obstruction. The need to administer nephrotoxic curative-intent chemotherapy (for example, cisplatin) may require intervention to bypass the obstruction even in chemoresponsive disease. The rate and degree of anticipated response to therapy and the degree of compromise in renal function together indicate whether placement of a percutaneous nephrostomy is necessary or whether a reasonable expectation exists that relief of obstruction can be achieved with cytotoxic chemotherapy alone.

When mechanical bypass of a ureteral obstruction is required, a ureteral stent or percutaneous nephrostomy may be employed. Multiple sites of ureteric obstruction, long occlusions, or a tortuous ureter may be indications to proceed directly with percutaneous nephrostomy.⁵ While a unilateral percutaneous nephrostomy may preserve adequate renal function for palliative therapy, patients whose long-term disease-free survival is dependent on nephrotoxic therapy require maximal preservation of renal function and bilateral percutaneous nephrostomy is often required in this setting. Although they may be key to the delivery of therapy, percutaneous nephrostomies are not without risk and are a potential source of infection that may complicate, delay, or even require modification of treatment plans.^{6, 7} Attention to detail in the placement and care of nephrostomies is required. This includes the optimal placement of catheters to reduce pain, frequent changes of the catheter, and care of the insertion site.

During nephrostomy tube placement, the intrarenal collecting system is imaged with ultrasound and/or fluoroscopy to select a site of renal entry. In experienced hands, an appropriate nephrostomy tract can be established in 98% of cases, with major complications occurring in approximately 4%.⁵ Major complications may include hematoma formation, hemorrhage, vascular injury, sepsis, bowel or lung injury, or death. Following relief of the obstruction and the resultant intrarenal pressure by nephrostomy tube placement, an internal double-J stent may be placed. This is performed in an antegrade manner using the nephrostomy as an entry point. While intervention with percutaneous nephrostomy or stenting may allow for delivery of curative-intent treatment in a patient who might not otherwise be able to receive therapy, the risk-benefit analysis may be markedly different in a patient with advanced incurable disease. Recent studies show that intervention for urinary obstruction results in patients with metastatic cancer spending a significant percentage of their remaining life hospitalized,^{7, 8} and it has long been recognized that progressive uremia due to renal failure may provide a peaceful death for highly symptomatic patients suffering from terminal disease. A patient with severe pain (unrelated to obstruction) and very short life expectancy may be best served by no intervention, but rather implementation of comfort measures. This difficult decision requires careful communication between physician, patient, and the patient’s family members.

Bladder outlet and urethral obstruction

Malignant bladder outlet and urethral obstructions are most commonly caused by prostate or bladder cancers, and may also be seen with ovarian, cervical, and uterine cancers. While ureteral obstruction is frequently asymptomatic, patients with bladder outlet and urethral obstruction often present with troublesome symptoms resulting from bladder irritation and distension. These may have a significant impact on a patient’s perceived quality of life.^{9, 10} Prostate cancers that arise from the portion of the prostate immediately adjacent to the intraprostatic urethra need not be large to cause marked symptoms. Urine output may fluctuate, with periods of both relative oliguria and increased urinary output because of overflow incontinence.

The management of obstructions due to prostate cancer is guided by the stage of the prostate cancer. Newly diagnosed prostate cancer is likely to be exquisitely sensitive to hormonal manipulation, and prompt androgen deprivation therapy (ADT) with temporary foley catheter placement may result in relief of the obstruction with fairly prompt removal of the indwelling foley. In contrast, castrate-resistant prostate cancer, which nearly invariably develops after a period of response to ADT, will not exhibit this prompt response to therapy and will likely require more permanent relief of obstruction, either by nephrostomy or suprapubic catheter. In addition, very large prostate or bladder tumors, regardless of their anticipated response to therapy, may be indications to proceed directly with placement of percutaneous nephrostomy tubes.³ Bladder outlet or urethral obstruction may be managed by the placement of a suprapubic urinary catheter. Generally, this technique provides palliation of symptoms and should not be pursued in patients being treated with curative intent as it violates normal anatomic barriers of the GU tract.

For patients with urethral obstruction, symptoms are often difficult to relieve. Although percutaneous nephrostomies and suprapubic catheters can divert urinary flow, they do not fully relieve symptoms related to urgency, hematuria, dysuria, and frequency. Transurethral resection of the prostate may be considered for palliation of symptoms in advanced disease, and definitive prostate surgery may provide significant relief in prostate cancers treated with curative intent. The management of these symptoms remains a therapeutic challenge for clinicians.

Cystitis and nephritis

Hematuria can be a frightening event for the cancer patient. Hematuria may result from bleeding anywhere along the urinary tract, and gross hematuria may require palliation to prevent excessive blood loss. The location of bleeding may be suggested by the appearance of the hematuria: long, vermiform clots typically indicate upper tract bleeding, while bright red blood without clots that partially clears with urination usually indicates a lower tract bleed. Recurrence of hematuria after treatment of malignancy may herald relapse within the GU tract.

Management of hematuria focuses on controlling blood loss and preventing retention of blood clots which may cause urinary obstruction and renal damage. The most common initial management of lower urinary tract bleeding is continuous bladder irrigation with normal saline. Cystoscopic evacuation of clots may be required for palliation. In selected patients, a bleeding tumor may be brought under control with radiation.¹¹ The management of cyclophosphamide-, ifosfamide-, or radiation-induced cystitis and bleeding is a challenging clinical problem. 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,¹² bladder irrigation, oral or intravesical aminocaproic acid (for lower urinary tract bleeding only),¹³ intravesical alum,¹⁴ and intravesical prostaglandins.^{15, 16} Experimental approaches include argon laser coagulation,¹⁷ amifostine,¹⁸ hyperbaric oxygenation,¹⁹ and conjugated estrogens.²⁰

Chemotherapy-induced cystitis

Cyclophosphamide and ifosfamide are the most commonly used oxazaphosphorines. Other therapeutic agents that can produce gross hematuria include intravesical treatment with doxorubicin, mitomycin, and bacillus Calmette-Guérin.²¹ Both cyclophosphamide and ifosfamide are metabolized to acrolein, an urothelium-toxic metabolite.²² Chemotherapy-induced thrombocytopenia may exacerbate bleeding. Sterile hemorrhagic cystitis has been reported in up to 20% of patients receiving high doses of cyclophosphamide and in approximately 8% of patients receiving ifosfamide.²³ With conventional doses of cyclophosphamide, cystitis can be prevented by encouraging abundant oral hydration at the time of chemotherapy. With 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 min before ifosfamide administration, as well as 4 and 8 h later (the total dose of mesna should be equivalent to 60% of the ifosfamide dose). Mesna may also be given as a continuous infusion at a dose equivalent to the ifosfamide dose. Continuous infusion of mesna should be maintained for 4–8 h after completion of ifosfamide infusion. When given with cyclophosphamide, mesna is predominantly used with high-dose chemotherapy in bone marrow transplantation. The dose of mesna used is approximately 60–160% of the cyclophosphamide dose and is given intravenously in 3–5 divided doses or by continuous infusion.^{21, 24}

Hemorrhagic cystitis may occur with chemotherapy regimens that do not contain cyclophosphamide due to chemotherapy-associated thrombocytopenia, and the presence of a GU malignancy may serve as a nidus for bleeding. Hemorrhagic cystitis in bone marrow transplantation due to chemotherapeutic regimens must be differentiated from infectious hematuria as a result of adenovirus²⁵ or BK human polyomavirus²⁶ infection.

Radiation-induced cystitis

Although relatively uncommon, hemorrhagic cystitis may develop following the treatment of pelvic neoplasms with either external beam radiation or brachytherapy. The pathophysiology of radiation-induced cystitis involves damage to vascular endothelium and endarteritis leading to progressive ischemia, inflammation, fibrosis, and ultimately tissue necrosis.²⁷ It may appear from 6 months to several decades following completion of radiation, and in one study, affected 6.5% of patients receiving pelvic radiation.²⁸ Total-body irradiation for bone marrow transplantation is associated with hemorrhagic cystitis in 10–17% of patients.^{14, 29} Patients at highest risk are those receiving concurrent cyclophosphamide or who have undergone urologic interventions. Radiation cystitis may develop decades after the completion of radiation therapy, but as this scenario may also represent disease recurrence, thorough investigation must be undertaken before ascribing new hematuria to radiation cystitis.

Radiation nephritis

Radiation is often delivered near the kidneys to control nodal metastasis from radiation-sensitive tumors (e.g., lymphomas and seminomas). Radiation-induced nephritis may develop as a result of irradiation of the kidneys, and is related to both the total dose of radiation and the volume treated.³⁰ However, modern shielding techniques have dramatically decreased the incidence of this complication. Renal dose tolerance (TD5/5) is estimated to be 20 Gy in adults, with glomerular function declining at 15 Gy and function nearly completely lost at 25–30 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). Six to twelve months after radiation, signs and symptoms including hypertension, edema, albuminuria, active urinary sediment, and rise in BUN and serum creatinine may be noted. In the chronic phase (>12 months), hypertension is the most common finding. Eventually, patients may develop hyperreninemic hypertension related to renal scarring, atrophy of cortical tubules, and glomerulosclerosis. Rarely, patients may develop progressive deterioration of renal function requiring hemodialysis or renal transplantation.³¹ Avoiding these debilitating complications is an essential aspect of sophisticated modern radiation techniques.

Total-body irradiation in bone marrow transplantation has been associated with dose-dependent long-term renal toxicities including hypertension, anemia, decreased glomerular filtration rate (GFR), hematuria, and proteinuria. Pathologic findings include necrosis of vascular structures and disruption of both endothelial and epithelial cells of the basement membrane.³² In a review of bone marrow transplant patients receiving total-body irradiation with 14 Gy, the incidence of nephropathy decreased with increased renal shielding: 30% of patients treated without shielding developed nephropathy, 15% of patients treated with partial shielding developed nephropathy, and no patients developed nephropathy with 30% shielding.³³

Diagnosis, treatment, and prevention of nephrotoxicity of cancer therapeutic agents

Many widely used chemotherapy agents have the potential for renal toxicity (Table 1). Adverse effects include tumor lysis syndrome, paraneoplastic glomerulonephritis, obstructive uropathy, and direct nephrotoxicity resulting in renal failure and electrolyte disturbances. These are more common in the geriatric population secondary to polypharmacy and comorbid conditions. The nephrotoxic effects of these agents are more commonly observed in bone marrow transplantation due to high-dose chemotherapy, polypharmacy, and total-body irradiation. In the following sections, we describe commonly used agents that cause serious renal toxicity. Table 2 lists additional agents that may cause nephrotoxicity. Table 3 lists the mechanism of renal injury for several drugs. Drug–drug interaction is another crucial consideration in the administration of potentially nephrotoxic agents; Table 4 highlights some of these drug interactions. These tables are not comprehensive, and careful review of all prescription and over-the-counter medications is essential to the prevention of renal toxicity in the cancer patient. Dose adjustment for several essential chemotherapy agents is summarized in Table 5.